If you need to fidget whereas working, this can be a harmful illness .. In such an individual, contemplating it as weak spot of the physique, ignores it. Many instances it occurs that whereas performing some work, abruptly the individual's hand begins to tremble or typically whereas holding one thing mild, the individual's arms begin trembling. In such a scenario, the individual considers it a weak spot of the physique and ignores it. If your arms additionally tremble like this whereas working or whereas holding one thing, dont make the error of ignoring it even after forgetting it. That is as a result of it isnt due to weak spot in your physique however it may be one thing else.

For your data, inform me that the rationale for trembling arms and ft cant be the one weak spot.

->So today we are going to let you know about some such particular causes for trembling arms and ft, realizing about which youll be shocked. So, allow us to now clarify these causes intimately.

1. Significantly, trembling of arms could be a symptom of diabetes. For your data, inform me that when the quantity of sugar within the physique begins lowering, then the stress of the human physique will increase. Due to which the individual's arms tremble. So if potential, hold management of your sugar.

2. Apart from this, many instances an individual doesnt eat nutritious meals in his life. Yes, an individual doesnt eat such meals in his life, in order that the dearth of blood in his physique will be fulfilled. Due to which theres a scarcity of blood within the individual's physique. Significantly, as a consequence of anemia on this scenario, arms begin trembling.

3. Significantly, one of many predominant causes for shaking arms will be that your blood stress is just not regular. Yes, to your data, inform me that when BP abruptly will increase or decreases, even in such a scenario the arms of an individual begin trembling. Now its apparent that when your blood stress is just not underneath management, then trembling arms is certain to occur.

4. It is vital to notice that because of the improve of the hormone cartisol current within the physique, the stress of an individual will increase considerably. Now its apparent that when an individual is underneath stress in thoughts and physique, then its essential to have vibrations in his arms and legs. Please inform that as a consequence of this, the individual's arms begin to tremble.

However, in case your arms begin to tremble on a regular basis as an alternative of trembling, then you must instantly go to the physician, as a result of to disregard such a scenario means to play with your personal physique. That is why we are going to say that in case you ever see such a symptom in your self, then dont delay in going to the physician in any respect, as a result of later you might have to bear the implications.

Born to a PIO businessman, Parmesh loves travelling and writing about everything related to technology, entertainment, sports and business. He is from Istanbul and loves his Falafels and Hummus. Parmesh also has an expensive taste in wine and writes for various food magazines in Europe.

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If you need to fidget whereas working, this harmful illness can occur - OBN

Recommendation and review posted by Bethany Smith

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

Controlling the Doses of Gene Therapy

Gene therapy is relatively new, with only a few approved therapies. The techniques typically involve taking a normal gene, inserting it into a hollowed-out virus, and injecting it into the patient, where the gene produces normal proteins that are otherwise abnormal. Researchers at The Scripps Research Institute developed a molecular switch that could potentially be embedded into gene therapies that would control dosing. They published their research in the journal Nature Biotechnology.

I think that our approach offers the only practical way at present to regulate the dose of a gene therapy in an animal or a human, said Michael Farzan, principal investigator of the research.

The researchers demonstrated the work by incorporating the switch into a gene therapy for anemia that produces the hormone erythropoietin. The switch suppressed expression of the gene to very low levels but could then increase the genes expression using injected control molecules called morpholinos. Morpholinos are already approved by the FDA as safe for other applications.

Machine Learning to Interpret Gene Regulation

Although big data is helpful in biological systems, the data sets are so complicated that interpreting the data is still difficult and complex. Researchers at Cold Spring Harbor Laboratory designed advanced machine learning algorithms that cut through the complexity, making the data from gene regulation more easy to understand for biologists. The algorithms are a form of artificial neural network (ANN) that appears to bridge the gap between computational tools and how biologists think.

Deep Learning Predicts Disease-Associated Mutations

Researchers at the University of Hong Kong developed a deep learning method to predict disease-associated mutations of the metal-binding sites in a protein. It is the first time a deep learning approach has been used to predict disease-associated metal-relevant site mutations of metalloproteins. Metal ions play important roles structurally or functionally in the pathophysiology of many human biological systems, such as zinc, iron and copper. Deficiencies in these can cause severe diseases. They utilized omics data to develop a training dataset, finding that a mutation in zinc-binding sites played a major role in breast, liver, kidney, immune system and prostate diseases, while calcium- and magnesium-binding sites are linked to muscular and immune system diseases, respectively. Iron-binding site mutations are associated with metabolic diseases.

The Science Behind Intermittent Fasting

There are, generally speaking, two types of intermittent fasting. One is daily time-restricted feeding, narrowing eating times to 6-8 hours per day, and 5:2 intermittent fasting, where individuals limit themselves to one moderate-sized meal two days a week. Research suggests that the reason this works is that they trigger metabolic switching, an evolutionary adaptation to periods of food scarcity. When people eat three meals a day plus snacks, the switching does not occur. The research study also found that intermittent fasting decreased blood pressure, blood lipid levels and resting heart rates. Additional studies also suggest it can improve brain health, such as learning and memory.

Many Younger Patients with Stomach Cancer Appear to Have Distinct Disease

Mayo Clinic researchers found that many people who developed stomach cancer under the age of 60 had genetically and clinically distinct disease from stomach cancer patients who were older. The new, early onset type of stomach cancer appears to grow and metastasize more quickly and has a worse prognosis. It is also more resistant to traditional chemotherapy. The investigators evaluated more than 75,225 cases from several databases to review stomach cancer statistics from 1973 to 2015. The average age of stomach cancer diagnosis is 68, but there appears to be growing occurrence in individuals in their 30s, 40s and 50s.

Dementia Vaccine Successful in Animal Trials

Investigators successfully tested an experimental vaccine to remove brain plaque and tau protein aggregates linked to Alzheimers disease in laboratory mice. The researchers from the Institute for Molecular Medicine and University of California, Irvine and Flinders University in South Australia, believe it supports clinical trials in humans, potentially in the next two years. The vaccine was a combination of two MultiTEP epitope vaccines, AV-1959R and AV-1980R, that target amyloid-beta and tau, respectively. It is formulated in AdvaxCpG, a polysaccharide adjuvant.

RNA-Targeting Approach Successfully Blocks Driver of Parkinsons Disease

Researchers at Scripps Research in Florida developed a compound that prevents production of an underlying cause of Parkinsons disease, an abnormal protein called alpha-synuclein. Dubbed Synucleozid, the protein halts the ribosome from detecting the messenger RNA (mRNA) template, preventing the translation of the disordered alpha-synuclein protein. This proof-of-concept study hints that the compound could become a potential Parkinsons drug candidate.

Original post:
Research Roundup: Controlling Gene Therapy and More - BioSpace

Recommendation and review posted by Bethany Smith

If you, or someone you know, has received a breast cancer diagnosis, it's likely you feel incredibly overwhelmed and have lots of questions about what happens next.

Its important to remember the resources which are available to support you through your breast cancer diagnosis and cancer treatment, including your doctors, cancer support groups and charities.

Weve worked with Breast Cancer Now to put together a guide explaining what to expect after your breast cancer diagnosis and what breast cancer treatment options you have.

No one knows your body better than you, so its important to regularly look and feel for any unusual breast changes and report anything different or new, such as a lump or a change to the skin, like puckering or dimpling, to your doctor as soon as possible.

If you suspect your have breast cancer symptomsarrange an appointment with your GP. At your appointment, your GP will examine your breast and may refer you to a specialist breast clinic for tests.

The Breast Cancer Nowwebsite says, Being referred to a breast clinic doesnt necessarily mean that you have breast cancer. It just means that more tests are needed to find out whats going on.

Once referred to a breast clinic you will have an examination and various tests of your breasts that may take several hours to complete. You can take a family member or friend to your appointment for support if you are worried. Though, some people prefer to attend their appointment on their own.

At the appointment the doctor or nurse may ask you questions about your family history to find if anyone in your family has had breast health problems previously. They will also ask questions about any other health problems you may have, and whether you are currently taking any medications.

What to expect after a breast cancer diagnosis | Credit: Getty

According to Breast Cancer Now, you will usually have a breast examination, followed by one or more of the following further tests and procedures.

During the initial examination the doctor will feel your breast when you are sitting down and lying down. They will also check the armpit area, as breast cancer can sometimes spread to your lymph nodes.

A mammogram is a breast x ray. During your appointment, a mammographer (an expert in taking breast x-rays) will ask you to undress to the waist and stand in front of the mammogram machine. Your breasts will be placed one at a time on the x-ray machine. The breast will be pressed down firmly on the surface by a clear plate.

An ultrasound scan uses sound waves to produce an image of the breast tissue. The scan is painless and generallydone in a few minutes, but can take longer.

Youll be asked to undress to the waist and lie on a couch with your arm above your head. To help gain a clear image, some gel will be spread over the area of the breast first. The person doing the scan will move a handheld scanning probe over the breast to look at the underlying breast tissue. The area under your arm may also be scanned.

A core biopsy will be carried outwhen your mammogram or ultrasound picks up something in your breast that needs analysing more closely. A corebiopsy involves taking a small part of your breast tissue through a small cut in your skin. You will have an injection to numb the area beforehand.The doctor will send the sample tissue to the laboratory for testing.

Fine needle aspiration will be carried outif your mammogram or ultrasound picks up something in your breast that needs analysing more closely. Fine needle aspiration is a process of taking a sample of cells from your breast using a syringe with a fine needle. This might feel a little uncomfortable, but the procedure doesnt last very long. The doctor will send the sample tissue to the laboratory for testing.

Once your doctor diagnoses your breast cancer, they will work out the extent of your cancer and determine what cancer stage you are in.

Carolyn Rogers, clinical nurse specialist at Breast Cancer Now said, Your cancer stage will be determined by the size of the cancer and how far it has spread. The grade is how different the cancer cells are to normalbreastcells and how quickly they are growing.

Your cancers stage and grade helps determine your prognosis and the best treatment options. There are different ways to stage breast cancer. Most hospitals use two main types of cancer staging systems including the TNM Staging System. and the number system.

You can read more about these on Breast Cancer Nows website.

TNM stands for Tumour, Node, Metastasis. This system describes the size of the initial cancer whether the cancer has spread to the lymph nodes, and a different part of the body.

T refers to the size of the cancer it can be 1, 2, 3 or 4, with 1 being the smallest

N refers to whether the cancer has spread to the lymph nodes it can be between 0 and 3 with 0 meaning no lymph nodes

M refers to whether the cancer has spread to another part of the body it can either be 0 meaning the cancer hasnt spread or 1 it has a spread

According to Cancer UK, here is a summary of the difference cancer stages graded by the number system.

Stage 1 means that a cancer is relatively small and contained within the organ it started in.

Stage 2means that the tumour is larger than in stage 1, but the cancer has not started to spread into the surrounding tissues.

Stage 3 means the cancer is larger. It may have started to spread into surrounding tissues and there are cancer cells in the lymph nodes in the area.

Stage 4 means the cancer has spread from where it started to another area in the body or organ.

Doctor showing a woman cancer test results on an wireless tablet / Credit: Getty

Carolyn Rogers explains, After all the necessary tests if you are diagnosed with breast cancer, the next step will be for a Multidisciplinary team (MDT), including surgeons, oncologists, breast care nurses and radiologists, to have a meeting to discuss and agree on a treatment plan for you.

This treatment plan and possible side effects of treatment will then be discussed with you. Treatment plans will vary depending on the features of your breast cancer.

The type of cancer you have and the features of the cancer Position of the cancer in the breast Other treatment youve had in the past or planning Your general health and fitness

Surgery is often the first treatment for women with breast cancer.

Carolyn Rogers further explains, Treatment will depend on the features of the breast cancer and may include surgery, chemotherapy, radiotherapy, hormone therapy and targeted therapy. You may be offered the option to take part in a clinical trial and your treatment team will explain this to you.

There are two types of breast cancer surgery:

Breast-conserving surgery:The cancer is removed along with a border of healthy breast tissue.

Mastectomy:All breast tissue is removed including the skin and nipple area.

Chemotherapy can be given before and after breast cancer surgery. Chemotherapy may be given before surgery to slow the growth of rapidly growing breast cancer or to shrink a larger breast cancer (this may mean breast-conserving surgery is an option, rather than a mastectomy).

Chemotherapy can also be given aftersurgeryforprimary breast cancerto reduce the risk of cancer coming back in the future.

Chemotherapy is a treatment that uses anti-cancer drugs to destroy cancer cells. It works by interfering with the cancer cells ability to divide and grow. Differentchemotherapy drugswork in different ways and a combination of drugs is often used. Chemotherapy affects cells throughout the body and can causeside effects such as hair loss, nausea and fatigue.

Radiotherapy uses high-energy x-rays to destroy cancer cells.Radiotherapy uses ionising radiation (high energy) to destroy any cancer cells that may have been left in the breast and surrounding area aftersurgery.

Radiotherapy is given after your breast cancer surgery to reduce the risk of breast cancer coming back in the future. If youre breast cancer treatment also involves chemotherapy, radiotherapy is usually given after the chemotherapy treatment.

Some breast cancers are stimulated by the hormone oestrogen. This means that oestrogen in the body helps the cancer to grow. This type of breast cancer is called oestrogen receptor positive (ER+).

If your breast cancer is oestrogen receptor positive, hormone therapy drugs such as tamoxifen, anastrozole and letrozole may be used to block the effect of oestrogen on the cancer cells.

All breast cancers are tested for oestrogen receptors using tissue from a biopsy or after surgery.If hormone receptors are not found, then hormone therapy will not be of any benefit.

As cancer researchers learn more about the cause of cancer, theyve developed new types of drugs that specifically target cancer cell changes.For some cancer types, targeted cancer drugs my work better compared to other treatments such as chemotherapy or radiotherapy.

This is a group of drugs that block the growth and spread of cancer. They target and interfere with processes in the cells that help cancer to grow. Targeted therapies can cause side effects such as flu like symptoms. The most common targeted therapies used for primary breast cancer are trastuzumab and pertuzumab. Whether you are offered this type of treatment will depend on the features of your breast cancer.

Breast cancer Now nurse offering advice on telephone / Credit: Breast Cancer Now

Carolyn Rogers said, Hearing the news you have breast cancer can be life-changing and telling your loved ones can be incredibly difficult. Who you tell and how you tell them is up to you. While you may find it difficult to talk openly about your cancer, especially at first, the support of those around you can be really helpful when you are going through breast cancer treatment.

If you have children, deciding what and how to tell them can be challenging. Its usually best to be honest. Breast Cancer Now offers some information about how to talk to children.

If you have questions about your breast cancer diagnosis, or you are worried about your breast health, you can call the Breast Cancer Now helpline for free on 0808 800 6000.

Macmillan Cancer Support also have advisers who you can contact online or on the phone if you have any questions about your breast cancer diagnosis, financial issues, or just want someone to talk to.

If youre worried about your breast cancer diagnosis,Breast Cancer Now offers a variety of free face-to-face support that provides the opportunity to meet others diagnosed, share experiences or concerns and hear from expert speakers providing a wealth of information, including Younger Women Together events for women diagnosed with breast cancer under 45 years old and Moving Forward courses, run in partnership with NHS hospitals, at the end of hospital treatment.

Read more here:
What to expect after a breast cancer diagnosis, including breast cancer stages and treatments - goodtoknow

Recommendation and review posted by Bethany Smith

The Fulton County Health Department has scheduled the following health clinics and services.

CANTON The Fulton County Health Department has scheduled the following health clinics and services. Please call the number listed with each service for an appointment or more information.

Maternal child health: Health screenings, WIC nutrition education and supplemental food coupons for women, infants and children. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria clinic appointments call 329-2922.

Canton - Clinic - Monday, Jan 6 - 8-4 - Appt needed

Canton - WIC Nutrition Education - Tuesday, Jan 7 - 8-4 - Appt needed

Canton - Clinic/Immunizations - Tuesday, Jan 7 - 4-7 - Appt needed

Astoria - Clinic, WIC Nutrition Educ. - Wednesday, Jan 8 - 9-3 - Appt needed

Canton - Clinic - Thursday, Jan 9 - 8-4 - Appt needed

Adult Health Immunizations: Various vaccines are available. There is a fee for immunization administration. Medicaid cards are accepted. To make an appointment or for more information call 647-1134 (ext. 254).

Canton - Immunizations - Tuesday, Jan 7 - 8-4 Appt needed

Other times available by special arrangement at Canton, Cuba and Astoria.

Blood Lead Screening: Blood lead screenings are available for children ages one to six years. A fee is based on income. To make an appointment or for more information call 647-1134 (ext. 254). For Astoria appointments call 329-2922.

Family Planning: Confidential family planning services are available by appointment at the Canton office for families and males of child-bearing age. Services provided include physical exams, pap smears, sexually transmitted disease testing, contraceptive methods, pregnancy testing, education and counseling. Services are available to individuals of all income levels. Fees are based on a sliding fee scale with services provided at no charge to many clients. Medicaid and many insurances are accepted. After hours appointments are available. To make an appointment or for more information call the 647-1134 (ext. 244). *Program funding includes a grant from the US DHHS Title X.

Pregnancy testing: Confidential urine pregnancy testing is available at the Canton and Astoria offices. This service is available to females of all income levels. A nominal fee is charged. No appointment is needed. A first morning urine specimen should be collected for optimal testing and brought to the health department. Services are provided on a walk-in basis on the following days each week:

Canton: Every Wednesday & Thursday, 8-3:30 (for more information call 647-1134 ext. 244)

Astoria: Every Wednesday, 9-2:30 (for more information call 329-2922)

Womens Health: A womens clinic for pap tests, clinical breast examinations and vaginal examinations is available by appointment. There is a nominal fee for this service. Medicaid cards are accepted. Financial assistance is available for a mammogram. Cardiovascular screenings may be available to age and income eligible women. To make an appointment or for more information call 647-1134 (ext. 244).

Mammograms: Age and income eligible women may receive mammograms at no charge. Speakers are available to provide information to clubs and organizations. For more information or to apply for financial assistance, call 647-1134 (ext. 254).

Mens Health: Prostate specific antigen (PSA) blood tests are available for men for a fee. To make an appointment or for more information call 647-1134 (ext. 224).

Sexually Transmitted Disease (STD) Clinic: Confidential STD and HIV testing services are available by appointment to males and females at the Canton office. Services include physical exams to identify STDs, a variety of STD testing, HIV testing, education, counseling, medications and condoms. There is a nominal fee for services. Services are available to individuals of all income levels. Medicaid cards are accepted. To make an appointment or for more information call 746-1134 (ext. 224).

HIV Testing and Counseling: Confidential HIV testing and counseling services are available by appointment through the sexually transmitted disease (STD) clinic at the Canton office. To make an appointment or for more information call 647-1134 (ext. 224).

Tuberculosis (TB) Testing: TB skin tests are available at no charge by appointment. To make an appointment or for more information call 647-1134 (ext. 254).

Blood Pressure Screenings: The Fulton County Health Department provides blood pressure screenings at no charge on a walk-in basis during the following times:

Astoria - Screening - Wednesday, Jan 8 - 9-12 - Walk in

Health Watch Wellness Program: The Health Watch Program provides low cost lab services. Through this program adults can obtain venous blood draws for a variety of blood tests. Blood tests offered without a doctors order Comprehensive Metabolic Panel (CMP), Complete Blood Count (CBC), Lipid Panel, Prostate Specific Antigen (PSA) test, Hepatitis C test, and Thyroid Stimulating Hormone (TSH). A wide variety of blood tests are also available with a doctors order. There is a charge at the time of service. To make an appointment or for more information call 647-1134 (ext. 254).

Dental Services: The Dental Center offers a variety of basic dental services to children and adults. An appointment is needed. Medicaid and Kid Care cards are accepted. To make an appointment or for more information call 647-1134 (ext. 292).

Read more:
Health Department announces services for the week of Jan 6 - Canton Daily Ledger

Recommendation and review posted by Bethany Smith

If your heart feels like its doing something out of the ordinary, you might find yourself frantically Googling to figure out whats going on. Chances are, youre experiencing whats commonly known as heart palpitations, which is a catchall term for feeling like your heart is acting weird. Seriously.

Your heart beats because it has the very important job of sending oxygen-rich blood and nutrients to every part of your body. It also sends the carbon dioxide your body produces as a waste product to your lungs so you can expel it. When theres a glitch in this system, you might experience a palpitation. Heart palpitations may feel like your heart is beating too quickly, beating irregularly, fluttering in a strange way, or thumping hard in your chest, according to the Mayo Clinic.

Generally when we talk about palpitations, it means youre aware of your heart beating, and it feels like its not normal, Shephal Doshi, M.D., director of cardiac electrophysiology at Providence Saint Johns Health Center in Santa Monica, Calif., tells SELF.

If you ask four people with heart palpitations to describe them, you might get four varying answers. When people say, I have heart palpitations, they can mean so many different things that you have to tease out some details as to what exactly they feel, Sanjiv Patel, M.D., cardiologist at MemorialCare Heart & Vascular Institute at Orange Coast Medical Center in Fountain Valley, Calif., tells SELF. Which is all to say that the symptoms of heart palpitations arent cut and dry.

When to worry about heart palpitations depends on a few factors. In reality, heart palpitations usually arent a sign your hearts decided to give up the ghostbut in some cases, they can be a cause for concern. Heres how to tell the difference.

Most of the time when people feel palpitations, their heart is not doing anything bad, Dr. Doshi says. There are tons of reasons your heart can go a little wonky, and most of them are nothing to worry about.

Typically, your heart knows when to squeeze based on electrical impulses from a group of cells known as your sinoatrial (SA) node, according to the National Heart, Lung, and Blood Institute (NHLBI). These cells are housed in your hearts right chamber, also known as its right atrium. If your SA node starts sending wonky electrical impulses, you might experience heart palpitations.

Anything that increases the adrenaline in your body can affect these electrical impulses, Dr. Doshi says. That includes stress, panic attacks, caffeine, having a cold or flu, being sleep-deprived, and taking medications that contain stimulants. Your heart has receptors that pick up on heightened adrenaline, so any surges of this hormone can cause it to act differently.

Things that make your heart work harder can also cause palpitations, Dr. Doshi says. Thats why experiencing palpitations during or after a tough workout isnt immediately a reason to worry. Same goes for having them during pregnancy, when your blood volume goes up and your heart has to pump out that extra fluid.

Getty Shot of a unrecognisable young man holding his chest in discomfort with his hands due to pain in that areaTheres also a chance you might think you have heart palpitations, but actually dont. Some people are very attuned to their bodies, feel their hearts beating faster and think its a palpitation, but its still beating at a normal speed of up to 100 beats a minute, Dr. Patel says.

For example, these impulses go offbeat due to arrhythmias, which are basically short circuits in your hearts electrical system. Arrhythmias can make your heart beat irregularly and feel strange, along with weakness, dizziness, feeling light-headed, fainting, shortness of breath, and chest pain, among others.

While arrhythmias often arent dangerous and can be treated in many ways, sometimes they can be life-threatening. Only a doctor can tell you for sure, but any symptoms besides the strange heart sensations are typically a clue that your arrhythmia may be more serious, says the NHLBI. If you think youre experiencing any strange symptoms along with your heart palpitations, seek medical attention immediately.

Other times, heart palpitations can be a sign that somethings up with a different organ, like your thyroid gland. Your thyroid produces hormones like thyroxine and triiodothyronine, which influence many of your bodys systems, according to the Mayo Clinic. If your thyroid is on overdrive (aka, you have hyperthyroidism), it will generate too much thyroxine, which kicks up your bodys metabolism. This can lead to a rapid or irregular heartbeat, along with symptoms like an increased appetite and sudden weight loss.

You may also experience heart palpitations if you have a physical abnormality like a weaker or larger heart than usual, which you typically wouldnt know about unless it showed up during some kind of medical exam.

You may be wondering when to worry about heart palpitations, especially when most of the time, theyre NBD. One-off heart palpitations that just last a few seconds are a normal part of having a heart. That said, experiencing them regularly is not. If heart palpitations happen every time you do [a certain activity], like walk half a mile or lift something, thats not a random event and you should be evaluated, Dr. Patel says.

If your heart palpitations come along with any symptoms like dizziness, feeling unsteady, fainting, or chest discomfort or pain, thats a sign your hearts functioning may be compromised. That warrants further investigating to make sure its nothing dangerous, Dr. Doshi says.

Your medical history also comes into play, especially if you have a history of health conditions involving your heart. A healthy 30-year-old has less reason for concern than a 60-year-old with heart disease, Dr. Doshi says.

With that said, if your heart palpitations are random, dont come with other symptoms, and youre in great health, they might still feel too weird to ignore. Theres no law against seeing your doctor just to be on the safe side. They can test your heart to make sure its working as it should so you can skip worrying about your health the next time your heart skips a beat.

Video: Exactly how often you really need to see different kinds of doctors (Provided by Self) Provided by Conde Nast Entertainment LLC

Read the rest here:
This Is When You Should Actually Worry About Heart Palpitations - msnNOW

Recommendation and review posted by Bethany Smith

ROCHESTER, Minn. A litany of high-impact health stories stood out in 2019, nearly all of them with endings that remain to be written.

These included record-breaking opioid settlements, a new treatment for cystic fibrosis, the promise and peril of large IT brands like Google and Apple moving into the healthcare space, and a devastating outbreak of serious lung disease in healthy young persons from vaping illicit THC.

But in terms of the health story with the greatest potential for taming sickness and the ballooning cost of healthcare, a case can be made for the recognition by health officials in 2019 of the ketogenic diet as a first line-treatment for type 2 diabetes.

The ketogenic diet, as many by now know, is a low-carb diet on steroids, a calorically-unrestricted eating pattern in which just 10-20% of daily calories (or less than 50 grams) come from carbohydrates, with dietary fat making up the majority of remaining energy (roughly 70% of daily calories).

Type 2 diabetes, on the other hand, is an acquired metabolic disorder affecting 340,000 Minnesotans and 30 million Americans, one that currently extracts $250 billion in direct costs each year in the US, and which can lead to heart disease, hypertension, Alzheimers, amputation, blindness and cancer.

Because it is often accompanied by obesity, type 2 diabetes is routinely attributed to overeating and lack of exercise, but a more precise description of its mechanism comes down to an elevation of the bodys emergency hormone insulin. Given that the body only releases insulin in response to dietary carbohydrates, type 2 diabetes is arguably a food-borne illness, with the food in question being carbohydrates. That is the rationale, in any event, for treating the predominant illness of our time with a ketogenic diet.

We need to recognize that conventional diets have not worked well, and reduce the scientific barriers to studying novel approaches, like the ketogenic diet, says Dr. David Ludwig, an endocrinologist at Boston Childrens Hospital and professor of pediatrics at Harvard Medical School, in an email to Forum News Service. These long-term studies will provide the definitive data to understand effectiveness for various chronic conditions, and potential side-effects.

Ludwig recently authored a paper in the Journal of Nutrition compiling the evidence for ketogenic diets, past and present, a paper complete with a section heading noting there is no human requirement for dietary fiber or carbohydrate. A century ago, he reminds readers, the ketogenic diet was a standard of care in diabetes, used to prolong the life of children with type 1 diabetes and to control the symptoms of type 2 diabetes in adult.

It was only following the discovery of insulin in the 1920s, Ludwig writes, that high carbohydrate diets gave us our present day medication protocols for type 2 diabetes, treatments anchored by the use of pricey commercial insulin analogs and daily ingestion of glucose-control medications.

Ludwig says he wrote the article to counter a spate of negative articles (that) have been rewritten about the ketogenic diet by nutrition experts, articles focusing on rare side-effects.

Viable approach

The case for keto in 2019 kicked off in May, when the American Diabetes Association released a Consensus Report calling low carbohydrate or very low carbohydrate diets a a viable approach for certain patients with T2D, including those hoping to reduce medications.

Describing the diets as among the most studied eating patterns for type 2 diabetes, the nations diabetes authorities added the caveat that ketogenic therapy for diabetes generally requries medical oversight to prevent hypoglycemia. In other words, keto can work so effectively in diabetics that should patients fail to carefully taper medications with medical guidance as their condition improves, they can become dangerously overmedicated.

June of 2019 saw the release of still more arguments for keto, in the form of second-year trial results by researchers from Indiana University Health and Verta Health. Their non-randomized clinical trial of the diet produced data showing that more than half of 262 patients studied had reversed their illness on a remote-monitored ketogenic diet, with many having discontinued the need for all medications except for Metformin.

While noting that the Verta Health results should be interpreted with caution, Ludwig says these exceptional outcomes at two years, with many participants coming off diabetes medications and improving blood glucose control, highlights the exciting possibility that diabetes can be reversed without bariatric surgery.

The arrival of keto for type 2 diabetes comes along at a time when the standard of care is increasingly coming up short. The year saw widespread shortages and price hikes for insulin, leading politicians to threaten price control legislation and stirring insurers to issue competing press releases touting their full- or highly discounted insulin coverage packages.

As endocrinology researchers from Mayo Clinic recently wrote in the journal BMJ, the body of evidence shows no meaningful benefit for intensive glucose-lowering regimens when it comes to the health outcomes that matter most to patients. And as researchers from Norway confirmed in 2018, telling high-risk individuals the advice to eat more fiber and polyunsaturated fat, plus the familiar five servings of fruit and vegetables with plentiful intake of beans, wholegrain and low-fat dairy, produced no improvement either.

For its part, the device industry is taking steps to build a ketogenic diabetes care product line, offering portable ketone breath meters and continuous glucose monitors allowing patients to see the effects on their blood sugar of carbohydrate rich foods in real time.

Still to be determined is whether dietary officials will heed the call by groups like the Low-Carb Action Network to include a true low-carbohydrate diet in the next installment of the dietary guidelines. Under the current USDA definition, diets up to 45% carbohydrates, are deemed low-carbohydrate, a too-high allowance for carbohydrates potentially washing out the ability of researchers to accurately test the intervention for disease reversal and prevention.

Its new research on an old method. As Ludwig notes, before insulin was discovered, a very-low-carbohydrate diet was considered the standard of care for diabetes. From this perspective, modern nutrition science may be in the process of rediscovering the wheel, so to speak.

Read more:
Health story of the 2019: Keto can help with Type 2 Diabetes - Southernminn.com

Recommendation and review posted by Bethany Smith

Although the general story of ghostwriting in trials of psychiatric drugs is now pretty well known, the details of the corruption in specific trials are still emerging into the public record, often a decade or more after the original sin of fraudulent publication. The latest study to finally see the full light of day is GlaxoSmithKlines study 352.

Perhaps the most infamous ghostwritten study is GSKs study 329, which, in a 2001 report published in the American Journal of Psychiatry, falsely touted paroxetine (Paxil) as an effective treatment for adolescent depression. The company paid over $3 billion in penalties for fraud.

That same year, study 352 made its first appearance in the research literature. That was when Charles Nemeroff, who in the years ahead would become the public face of research misconduct, authored an article on the efficacy of paroxetine for bipolar disorder. It has taken 18 years for the full story of that corruption to become known, the final chapter recently emerging when a large cache of study 352 documentsemails, memos, and other internal correspondence between the key playerswas made public.

The documents reveal a web of corruption that went beyond the fraud of ghostwriting into the spinning of negative results into positive conclusions, and the abetting of that corruption by an editor of the scientific journal that published the article. The documents also reveal a whitewashing of the corruption by the University of Pennsylvania.

However, it was the publication of these documents that provided Jay Amsterdam, an investigator in the trial who turned whistleblower after he smelled a rat, with a chance to say case closed. Amsterdam and Leemon McHenry have now published two articles that provide a step-by-step deconstruction of the studythe ghostwriting, the spinning of results, the betrayal of public trust.

Here is the story of that whistleblowing.

Starting in the late 1970s, Amsterdam became a go-to guy for studying pharmaceutical interventions, especially antidepressants. By the time he got involved with study 352, he was running a prestigious bipolar disorder clinic at the University of Pennsylvanias Perelman School of Medicine. Hed published over 100 peer-reviewed articles, and had served as editor and author on multiple textbooks about mood disorders. He was a working psychiatrist, a lecturer and professor, and a full-time researcher.

Amsterdam received his MD in 1974 from Jefferson Medical College in Philadelphia. While still a post-doc, he began working almost immediately with the top researchers investigating treatments for mood disorders. William Dysonone of the early promoters of lithium for bipolar disorderwas one of Amsterdams mentors, as was Dysons colleague, Joseph Mendels. Dyson opened the bipolar disorder clinic that Amsterdam would eventually run.

In the early 1980s, hormone function was one of the chief hypotheses in mood disorders, and Amsterdam became a leading researcher in the burgeoning field of psychoendocrine studies. He conducted a number of studies on melatonin, among many other hormones. By the mid-1980s, Amsterdam was working under Karl Rickels, an ex-Nazi soldier who had been one of the chief investigators on pharmacological treatments for mental health since the 1950s. Amsterdam describes Rickels as a brusque, almost abrasive figure who worked almost exclusively with pharmaceutical industry money, investigating the efficacy of the drugs, but who remained proud of the fact that he did not have his papers ghostwritten. You should always write your own articles, he told Amsterdam. You know, no one has ever written an article for me.

During this time, Amsterdam was investigating various pharmaceutical treatments for depression and bipolar disorder, including tricyclic antidepressants, lithium, and newer SSRI antidepressants like fluoxetine (Prozac). By the late 1980s, Amsterdam had become a leading researcher in psychoimmunovirology, conducting some of the earliest studies on the hypothesis that exposure to viral disease was a cause of psychological disorders. While its unlikely that this is a cause for most psychological problems, some viral diseases like the Borna disease virus and the Epstein-Barr virus have been correlated with a slight increase in the likelihood of psychological problems. He began studying whether lithium might work by suppressing the effects of viral disease.

By 1993, Amsterdams mentor Dyson had passed away, and Amsterdam became the director of the bipolar disorders clinic at Penn. At the time, his clinic was a perfect fit for the needs of the pharmaceutical industry. It was large, so he had a pool of potential participants for trials. Amsterdam also describes the clinic as offering access to treatment-nave, or drug-free, patients with depression and bipolar disorders, who were good enrollees in industry studies.

Amsterdam was happy to work with the industry at that time. One year, he offered his entire crop of mood disorder research participants to Eli Lilly for their study on fluoxetine (Prozac) for relapse prevention. According to Amsterdam, he told them theyd have to pay all his operating costs for the year. Well take care of you, Lillys spokesperson responded. Amsterdam says, I gave them 139 patients, well-diagnosed, well-treated. And actually, my clinic was the only site that differentiated Prozac from placebo for relapse prevention. I really gave them their moneys worth.

Amsterdam was also on industry panels for over a dozen pharmaceutical companies, giving sponsored talks. It wasnt until the early 2000s that industry representatives began urging him to deviate from his prepared talks. Once he began to experience pressure to spin his results in favor of the drug, he said, I stopped giving talks.

But he never saw it as systemic corruption. Instead, each time, it looked like one company, or one representative, was under pressure to deliver better results, and so put the pressure on him to tell a better story about the companys drug. I was never anti-pharma, he said. He was happy to take their money, as long as he could continue to deliver accurate data.

In the 1990s, all was going well for Amsterdam. And he thought little about it when, in 1995, Rickels asked if he could help out a junior colleague at Penn, Laszlo Gyulai. Gyulai was involved in a study for GlaxoSmithKline (then SmithKlineBeecham) of paroxetine (Paxil) to see if it would improve depressive symptoms in patients with bipolar disorder who were already taking lithium. According to Amsterdam, Gyulais clinic had less than a dozen patients, so it was no surprise that he was struggling to recruit participants for the study. Rickels framed it as a favorhe was embarrassed by Gyulais recruitment numbers and wanted Amsterdams help.

I (told Rickels) that I would be willing to be an investigator on the study, Amsterdam recalled. I said that I would be willing to recruit patients and help him if I am the co-principal investigator, if my names listed as co-principal investigator on the consent form, if Laszlo turns over 80% of the revenue for each patient I recruit. If I end up being one of the principal recruiters in the study, I want to be acknowledged as an author, I want to see the data, I want to co-write the paper.

Rickels agreed, and soon GSKs people contacted Amsterdam and helped set up his clinic as the 19th site for the research study. Gyulai had recruited just seven patients over a few years. Amsterdam recruited 12 in just a few monthsno surprise again, since his clinic served over a thousand patients.

Amsterdam was deeply involved in the work with those 12 patients, prescribing their medications, checking their dose, giving the assessment measures to see how well the medications were working. Then, just a few months later, the study was cancelled by GSK.

Amsterdam called up his contact at GSK, research director Cornelius Pitts. But Pitts just told him to stop enrolling participants. I couldnt get any information about why it came to an end, Amsterdam said.

Even a year later, when Amsterdam asked Gyulai where the data from that study was, Gyulai told him we dont have it yet. Amsterdam moved on with his life. It was just one of many projects I was working on.

In 2001, Amsterdam was working on a grant proposal to the NIMH to study fluoxetine (Prozac) as a treatment for bipolar disorder when a member of his research lab mentioned that a study was about to be published in The American Journal of Psychiatry on a similar subjectSSRIs for bipolar disorderthat could provide solid background for the grant-writing process.

Amsterdam hunted down the paper, and quickly realized that some of the listed authors were from his own department at Penn. One was Dwight Evans, chair of psychiatry at Penn. Another was Laszlo Gyulai.

Amsterdam called Evans office and requested a copy of the article from his secretary. Soon the fax machine spit out the cover page, which had a handwritten note at the top. Dear Jay, with compliments. Dwight.

As Amsterdam read the study, he was overwhelmed by a sense of dj vu. I started reading the abstract, and I said to myself, this sounds really familiar. And then I kept reading and Im thinkingI did this study! And Im looking and looking, and I cant find my name. And then I began to get suspicious.

The lead author on the study was Charles Nemeroff, and while Nemeroff had yet to become publicly identified for his regular participation in ghostwriting exercises, Amsterdam knew that he was part of what many liked to call the psychiatric mafia,psychiatrists that had close ties to industry. So that aroused his questions about the integrity of the article. Even more to the point, he couldnt understand why Gyulai was listed as an author.

As far as Amsterdam knew, Gyulai had only enrolled a handful of patients, and so he wondered whether Gyulai had somehow overstated his involvement in the study. Had he falsified data, or plagiarized another researchers work to do so?

Amsterdam called up his department chairDwight Evansto report his concerns. The universitys policy required that the provost or assistant provost for research be informed that such a concern had been raised and should be investigated. But in this instance, Evans told him that he and Rickels would investigate the matterno need, apparently, to take this matter to the university higher-ups. Evans asked Amsterdam what he wanted from the investigation.

I said, Id like an apology and I want Laszlo Gyulai to be sanctioned for plagiarism, Amsterdam told him.

In a letter dated April 3, 2001, Rickels informed Amsterdam of what he had learned from his investigation. Yes, Amsterdam was a co-investigator in the trial, and he had enrolled more patients than Gyulai; and yes a ghostwriting firm, STI, had written two drafts of the paper before it asked Gyulai if he would agree to be the papers first author; yes, STI had later replaced Gyulai with Nemeroff as the first author; and yes, there were academic investigators in the trial who had never reviewed or even seen the submitted manuscript.

Although the letter seemed like an admission of scientific fraud, given the evident ghostwriting of the paper, there was no departmental censure of Gyulai. Amsterdam then wrote both Evans and Rickels to express his displeasure. Am I to assume that it is okay in this department for a junior faculty member to abscond with data from a full professor and publish it without any ramifications? he asked.

Although Gyulai was never sanctioned, he did send Amsterdam a letter of apology. In it, Gyulai wrote that he understood Amsterdams concerns about plagiarism, but stated that he (Gyulai) was the primary investigator of the Penn site and did some work on early drafts of the article. Gyulai complained that first authorship was taken away from me and that he wished that GlaxoSmithKline had allowed Amsterdam to have input on the paper.

At that point, Amsterdam let it go. He wouldnt revisit the study again until 2010, when his own professional life came under attack.

In 2008, Senator Charles Grassley (R-Iowa) of the US Senate Finance Committee began to investigate financial conflicts of interest in scientific research. Paul Thacker, an investigative journalist, was the point man for Grassleys investigation and his 2010 committee report, which resulted in significant changes to the rules used by academic institutions to define research misconduct.

The picture of corruption that emerged thanks to Grassleys investigation, and other investigations into industry-funded trials, told of how academic medicine had been horribly corrupted, with psychiatry the specialty that was most compromised.

Pharmaceutical companies would hire ghostwriting firms to manipulate data and write articles spinning the results. The drug companies would then get academic psychiatrists, who were described by the companies as thought leaders, to agree to be the authors of the study in order to lend credibility to those misleading results. These same experts would then be paid to give talks promoting the companys drug. They would be paid handsomelyin some cases, hundreds of thousands of dollarsto serve the pharmaceutical companys commercial interests in this way.

Charles Nemerofflead author on the study 352 paperbecame the poster boy for this type of research misconduct. At the time, Nemeroff was an internationally-famous researcher with hundreds of publications and awards. He was chair of the psychiatry department at Emory University.

Grassleys investigation helped put a dollar amount on this corruption. He reported that Nemeroff was receiving millions of dollars from the pharmaceutical industry, and failing to disclose that pay according to conflict-of-interest rules. As reported in The New York Times, Nemeroff was found in 2008 to have violated federal research ethics rules by hiding $1.2 million, which, if appropriately disclosed, would have prevented him from being the primary investigator on the government grants he was also receiving.

It was business-as-usual for Nemeroff, whod already weathered two scandals in which hed promoted new treatments in scientific journals without disclosing in one case that he owned the patent on that treatment or that in the second case that he was being paid by the company behind the treatment.

After yet another investigation, Nemeroff was found to have violated Emorys policies, and was forced to resign from his position there. But he immediately moved to the University of Miami, where he soon began the process again.

According to Thacker, Nemeroff continued to receive tens of thousands of dollars from various pharmaceutical companies, while also receiving additional government grant money to test their products. In his case, it seemed that there was little financial penalty for violating federal rules and engaging in research misconduct.

In the 2000s, Amsterdam was becoming increasingly ill. He was almost completely blind, as he suffered from a severe form of glaucoma, but he was still trying to lecture, conduct research, and see patients. During this time, he conducted research on the class of antidepressants known as MAOIs (monoamine oxidase inhibitors), which have been less utilized due to concern about drug interactions with other antidepressants and certain cold medicines, and dietary restrictions such as alcohol and cheese. However, Amsterdam believes that MAOIs are less dangerous than previously believed.

In 2003, he was working with Somerset Labs to test their MAOIs. He did a trial that showed the drug beat the placebo, and they wanted to publish the results. He began to draft the article, but they suggested he outsource it to a ghostwriting company. They told him they were paying this company $30,000 to write the article, so there was no need for him to do it. But Amsterdam remembered Rickels advice: always write your own articles. He wrote the article himself, then sent it to the company.

It was during this time that he began to slowly move away from taking pharmaceutical industry money. He began to drop off the industry panels, as the reps asked him to spin his results more and more when giving talks. This pressure went against his grain as an objective academic.

I could see that pharma had changed. My respect for it had changed, too, he says. I dont want to do shitty research, which is what the drug company research is now.

Science is not the discovery of that new drug. Thats hubris. Science is the replication of that finding, over and over again. I hear colleagues saying we want to show that this drug works. I say, no, you want to show that the placebo theyre testing it against doesnt work. And when I started to say that to industry people, they stopped giving me studies.

By 2006, Amsterdam had had enough. He was done taking pharmaceutical industry money, and funded his research after that entirely with government grant money.

He also began to investigate iatrogenic harms of antidepressantsthe notion that the drugs used to treat the condition are, instead, making it more chronic and resistant to future treatment. He began asking questions: Why did those who continued to take the drug long-term have more risk of relapse than those who decided to stop taking the drug? Why did those who tried more drugs have higher risk of relapse?

According to Amsterdam, People that get repeated antidepressant treatment develop a tolerance to drugs, and, probably as a result of this, weve created the field of treatment resistant depression.

He says that would have been an unthinkable conclusion when he was taking industry money: The pharmaceutical industry would have shut down that research in every way possible.

In the spring of 2010, Amsterdams professional life began to fall apart. Later that year, as he struggled to understand why his career at Penn suddenly came under attackan attack seemingly led by his chairman Dwight Evanshe came to see it as connected to the complaint hed made nine years earlier about the ghostwriting of study 352.

The first shot was fired on April 6, 2010, when Evans suddenly called Amsterdam and told him to go to the Office of Affirmative Action immediately. What did I do? Amsterdam asked. Evans responded by telling him not to ask questions. Just go there.

At his meeting with the head of the affirmative action office, Amsterdam was told he was being investigated for several complaints made against him. However, the head of the office wouldnt tell him any details. Youll learn in due time, Amsterdam was told. I have nothing in writing but youll know from the questions youre asked.

This was the start of what became something of a Kafkaesque experience for Amsterdam. A flood of complaints were suddenly directed at him, all of them emanating from Evans office, and yet he was never formally told of these complaints, or their specifics. Instead, he would be called into the Office of Affirmative Action and questioned about numerous different subjects. Amsterdam inferred from these sessions that the complaints included allegations of retaliation against his staff, racial discrimination, unapproved research activities, photocopying sensitive documents, continuing medical education fraud, and sexual harassment against staff members.

One of the more bizarre episodes occurred on May 13, 2010. Amsterdam was summoned to the affirmative action office by associate director Patrice Miller. As she wrote later that day in an official letter, she did not find any information to support a finding of sexual harassment. While Amsterdam may have been glad to hear this, he was also perplexed. This was the first time that he was aware that a complaint of this type had been made.

The most serious complaint made against Amsterdam was that hed had an inappropriate relationship with a female patient. If this complaint were substantiated, he could have lost his license to practice.

Mad in America spoke to that woman. She confirmed every aspect of Amsterdams relating of this matter to MIA. She is a professional artist and asked that MIA not use her name.

She first met Jay Amsterdam around 1993, when she became his patient through the clinic. Severely depressed, she was a participant in many clinical trials of different drugs as they attempted to find something that worked for her. Most drugs didnt, although some worked for a time before their effects wore off. Eventually, after escaping an emotionally abusive relationship and continuing drug trials, she found her mental health becoming more stable. She attributes a lot of her improvement to Amsterdam. He was such a great doctor, she said. He saved my life, you knowfinally not being depressed.

Because she had been in treatment for many years, she remained in contact with Amsterdam, whom she describes as approachable, friendly, and very professional. Amsterdam was a fan of her artwork, and bought some of her paintings.

In 2010, she learned about the allegations against Amsterdam that supposedly involved her. I was absolutely floored, she said. Nauseated, floored. You know, I considered him a dear friend. He saved my life.

According to both this woman and Amsterdam, the allegation arose from a misrepresentation of some off-the-cuff language he had used in an email to her. Amsterdam had recently purchased one of her paintings, and in the email, he referred to the painting as booty (colloquially, to refer to an item of value). The investigative committee pointed to that word as having a sexual connotation, and thus evidence that Amsterdam had an inappropriate relationship with this female patient.

More than anything I felt terrible for Jay and [his wife] Debbie, she told MIA. This was ridiculous. It was uncalled for, mean-spirited, fabricated.

She wanted to sue Penn, but couldnt find lawyers willing to take on a case like this against the stone wall of Penns legal team. They defamed me, she said, and they should have been punished for it.

Furthermore, during Penns investigation of this matter, someone in Evans office photocopied and circulated her private medical information to various members of the university administration. This, of course, was a violation of HIPAA laws. They stole my emails, my health records, the woman said.

Amsterdam provided Mad in America with documents detailing the history of allegations and complaints made against him, and written records showing that there was an absence of any resolution substantiating the complaints. Even so, the stress of the situation, the sheer volume of complaints, and the feeling that everyone in the university was targeting him for some unknown reason led to a worsening of Amsterdams health in 2011. Acting upon his doctors advice, he took a medical leave.

Once on leave, Amsterdam struggled to figure out why his professional life had suddenly collapsed around him. Although he was now unable to see, his wife Debbie helped him search the internet for information about Penn and Evans. One day, she found an article about a court case in Philadelphia that led him into a larger dive into Evans involvement in the ghostwriting scandal.

In this case, a child had been born with a congenital heart defect after the mother used paroxetine while pregnant. The family sued GSK, accusing the company of hiding data about the harms of the drug. GSK lost the case, and ended up paying a $2.5 million penalty.

GSK, it seemed, had engaged in research misconduct. That article led Amsterdam and his wife to other articles citing UK psychiatrist David Healy, who had testified against GSK in the trial. In one article, Healy named several academic researchers who were on pharmaceutical executives speed-dial lists. One name immediately jumped out to Amsterdam as soon as his wife read it aloud: Dwight Evans.

Now, for Amsterdam, the light bulb was starting to turn on.

In the spring of 2010, when Amsterdam had been hit by the first complaint, Senator Charles Grassley was readying the release of his report on medical ghostwriting. In that report, which was released on June 24, 2010, Grassley noted that during his investigation he had asked Penn Medical School about its policies on ghostwriting, and Penn had informed Grassley that it had policies against plagiarism and it considered [ghostwriting] to be the equivalent of plagiarism.

This inquiry from Grassley surely would have raised anxiety in Penns psychiatry department. Not only had Amsterdam charged Gyulai with stealing his data, but Evans was also listed as an author of the Study 352 report, and yet Rickels, in a letter to Amsterdam, had told of how the paper had been ghostwritten by STI.

Moreover, as Evans likely knew in the spring of 2010, Grassley and his lead investigator, Paul Thacker, already had their sights set on him related to another instance of his authoring a ghostwritten paper. This instance of ghostwriting became public that fall, when Thacker, in a letter to NIH director to Francis Collins, told of how Evans had signed off on an editorial written by Scientific Therapeutics Information (STI), with the ghostwriting firm billing GlaxoSmithKline for its services.

Thacker wrote:

According to the documents, Sally Laden of STI wrote an editorial for Biological Psychiatry in 2003 for Drs. Dwight Evans, Chairman of the Department of Psychiatry at the University of Pennsylvania School of Medicine, and Dennis Charney, then an employee at the NIH and now Dean of Research at the Mt. Sinai School of Medicine at New York University.

In an email to a GSK employee, Ms. Laden wrote, Is there a problem with my invoice for writing Dwight Evans editorial for the [Depression and Bipolar Support Alliance]s comorbidity issue to Biological Psychiatry? Yet, when published, the authors Evans and Charney only stated, We acknowledge Sally K. Laden for editorial support.

In his letter, Thacker urged Collins to approve new policies that would recognize ghostwriting and plagiarism as research misconduct. He encouraged Collins to consider enforcement mechanisms such as disciplinary action and dismissal for the researchers involved.

Evans was now on the hot seat. Thackers complaint to Collins told of plagiarism for hire. Yet, Penn, in response to Thackers new revelation, took no action against Evans. As Thacker said in a subsequent article published a few months later, Penn just blew it off as though it were a matter of no account.

Thacker, in his latest article, publicly named Evans and Penn as an example of the corruption in academic medicine that needed to be cleaned up. Students should really be pissed off that professors get away with this type of fraud when students receive steep penalties, he wrote. What makes this all even more bizarre and insulting is that Dr. Evans is on the board of Penns Scattergood Program for the Applied Ethics of Behavioral Healthcare, a program dedicated to healthcare ethics.

Once Amsterdam learned of Thackers articles, he could put together a timeline that provided a likely explanation for why he had been hit with all those complaints in the spring of 2010. All of those complaints had emanated from Evans office, at a moment when Evans had reason to be worried about Grassleys investigation of ghostwriting, and if Thacker continued his digging, he might stumble upon the very studystudy 352that Amsterdam had complained about in 2001. And thator so it would seemwould mean big problems for Penn and Evans.

I think what happened is that Evans got all wigged out, Amsterdam said. He remembered the fact that he plagiarized, in 2001, an article in The American Journal of Psychiatry. And he knew that I knew, and that I knew he swept it under the rug by not taking it to the university, with his crony, Rickels. And he knew that if I were called to testify before Congress, I would tell them what happened.

Amsterdam didnt wait for Grassleys call. On July 8, 2011, he filed a whistleblower complaint with the federal Office of Research Integrity (ORI) alleging that Evans and the other authors had committed plagiarism by placing their names on that ghostwritten paper published in 2001.

Given Rickels 2001 letter to Amsterdam, which confessed that STI had written the initial drafts of the article, and that many academic investigators in the trial hadnt reviewed or seen the submitted article, it seemed that Penn would need to censure Evans. The ghostwriting element was clear. Even Gyulai had stated in his letter of apology that the ghostwriting firm had given first authorship to Nemeroff, and Penn had told Grassley that it considered agreeing to author a ghostwritten article to be a form of plagiarism.

But Penn just dismissed Amsterdams complaint with a wave of its institutional hand.

In a letter to Amsterdam dated December 5, 2011, the university admitted that the two researchers had published ghostwritten articles, and while it noted that the ghostwriting firms authors should have been listed on the publications, it decided that there had been no misconduct because Penn, at that time, did not have a formal policy prohibiting faculty and researchers from appending their names to ghostwritten work.

In its statement to the press, the university was even more adamant. A Science article published on March 2, 2012 had this headline: Penn Clears Two Faculty Psychiatrists of Research Misconduct Charges.

There was, the university stated in its press release, no plagiarism and no merit to the allegations of research conduct because Gyulai and Evans had helped conduct the research and analyze the results and contributed to the paper, which had presented the research findings accurately. As for Amsterdam, the university stated, he should not have been listed as a co-author or in the acknowledgements, because his role did not meet the journals guidelines for authorship.

The universitys response to Amsterdams whistleblowing did not impress Thacker and the leaders of the Project on Government Oversight. POGO sent a letter to the office of the President of the United States stating that the president of Penn, Amy Gutmann, had ignored the evidence against Evans. They just blew it off, Thacker wrote.

At that time, Gutmann was the chair of Obamas Bioethics Commission, and Thacker asked how she could be expected to function capably in that position, given this brush-off. Dr. Gutmanns bona fides on bioethicsto borrow a phrase from Penns own spokespersonappear to be unfounded.

After filing his complaint with the federal office of Research Integrity, Amsterdam teamed up with bioethicist Leemon McHenry to write a peer-reviewed article about the 2001 paper. They looked at the way the data from study 352 had been analyzed, and then how it was presented in the article itself. Their article was published in 2012 in the International Journal of Risk & Safety in Medicine. In it, Amsterdam and McHenry wrote that they show how primary and secondary outcome analyses were conflated, turning a negative clinical trial into a positive studywith conclusions and recommendations that could adversely affect patient health.

The study, they wrote, was designed to test GSKs drug, paroxetine (Paxil) against both an older antidepressant, imipramine, and a placebo control. The participants were people with a bipolar disorder diagnosis who were taking a full dose of lithium, but not responding to lithium treatment. The goal was to see if Paxil could improve depression when lithium wasnt working.

However, the study was plagued with problems from the start. The researchers struggled to enroll enough participants (hence the recruitment of Amsterdam, to gain access to his prestigious bipolar disorders clinic). Even with Amsterdams help, the researchers didnt enroll enough participants to meet the original requirement.

Still, GSK continued the study. Each of the 117 participants was randomly assigned to one of three groups: Paxil, imipramine, or placebo. The original test was to see how the groups did, on average, on both the Hamilton Rating Scale for Depression (HRSD, a common measure of depression severity), and the Clinical Global Impression Severity scale (CGI/S, a subjective, 7-point scale of how ill a clinician considers their patient).

The researchers also used the Young Mania Rating Scale (YMRS) to assess whether Paxil caused manic or hypomanic episodesa well-known harmful side effect of SSRIs.

However, the results showed no beneficial effect for either Paxil or imipramine. Improvement was no better than placebo on any of the scales used.

This was a failed study. But rather than publish that finding, GSKs ghostwriters looked for other ways to put a positive spin on the study. Finally, a statistician working for GSK hit on an idea that might produce a positive resultssplitting the participants into two groups, one on high doses of lithium, and one on low doses of lithium.

This was a post-hoc analysis (conducted after the study was over), so the researchers couldnt actually randomize participants to receive a specific dose. Moreover, all the participants were stabilized on a dose that was considered within the normal range. Nonetheless, the statistician arbitrarily separated those with a slightly higher dose from those with a slightly lower dose.

However, even then, the statistician couldnt find an effect when looking at how many people experienced a response to the drugs. Response in this case was defined as having a HDRS score of 7, or a CGI/S score of 2. Neither Paxil nor imipramine were significantly better than placebo and that was true for both the high-lithium and the low lithium group.

However, GSKs statistician still had one more data-mining exercise to try. The average change on the HDRS and the CGI/S scales for both Paxil and imipramine was greater than for placebo, and this difference was statistically significant.

Although the published report of Study 352 did note that no statistically significant differences in response rates were seen among those receiving paroxetine, imipramine, or placebo, it was the average change on the two scales that was featured in the abstract of the article, which was used to support this bottom-line conclusion: Antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium.

This post-hoc data mining is known to be unethical, and if presented as a bottom-line finding, a type of research fraud. The joke within research circles is that if you torture the data long enough you can always find the result you want, and it was that process of data manipulation that Amsterdam and McHenry documented in their analysis of the study.

There were other research sins to be found in the published article. For instance, the researchers didnt report the YMRS data that was used to assess the risk of drug-induced mania/hypomania, which is a scientific sin of omission, one that in company-sponsored trials was regularly used to hide adverse effects of the sponsors drug.

Go here to see the original:
The Whistleblower and Penn: A Final Accounting of Study 352 - James Moore

Recommendation and review posted by Bethany Smith

For the second year in a row, changes to the Abilene City Commission and its staff have been one of the top events of 2019.

This is the second of a two-part series on the top 10 news events of 2019.

The top five which were published Monday were flooding, the Dwight D. Eisenhower Museum, downtown Abilene, economic developments and murals.

The next five include new faces in city government, child care, historical places, Patty OMalley and the Lebold Mansion.

New faces

On May 6 the Abilene City Commission voted 4-0 to terminate the services of its city manager Austin Gilley.

The commission had placed Gilley on paid, indefinite leave at the April 22 meeting.

Just over a month after the termination, the city commission voted Jane Foltz, director of the Abilene Parks and Recreation Department, as interim city manager.

The commission also approved former interim Abilene City Manager Dennis Kissinger as a part-time consultant.

Not only did the city commission change its leadership in 2019, it changed its look.

With the resignation of Terry Chaput, 23-year-old Trevor Witt was appointed in late 2018 to fill the three years left of Chaputs term.

In August Commissioner Sharon Petersen resigned. Former commissioner Angie Casteel was named commissioner.

In the November city commission election, the leading vote getter was Brandon Rein, age 24. Voters also voted incumbents back to the commission, Dee Marshall for four years and Mayor Tim Shafer, two years.

The new commission will be sworn in Jan. 13.

The Abilene Board of Education also has new faces. Greg Brown is the new superintendent. Robert Keener and Veronica Murray were elected to the board in the last election while Gregg Noel and Mark Wilson did not seek reelection.

While their faces have been around the Great Plains Theatre for a while, Mitch Aiello and Layne Roate were introduced as the new co-artistic directors.

Child Care

In early October, 20 families involving 25 children up to the age of 12 were informed that Learn & Grow Depot would no longer provide child care for them starting Jan. 1.

Learn & Grow, a child care facility, planned to continue to provide child care only for employees of Memorial Health System effective Jan. 1.

Learn & Grow is owned and operated by Memorial Health System.

The mission of Learn & Grow Depot has always been to take care of employees children. We currently have employees children on the waiting list and cannot provide that benefit, parents were informed in a letter.

Parents were told that a lack of licensed teachers was the reason Learn & Grow was only going to accept kids from Memorial Health System employees.

Chuck Scott, director of the Dickinson County Economic Development Corporation, told Dickinson County commissioners that child care was at a critical stage with Land Pride starting to add employees at its Abilene West facility.

In a meeting hosted by the economic development corporation, the community was told the number of children needing child care in Dickinson County was estimated at 365 last year.

There is a bigger need than what people recognize, Scott said. It is not a 10 or 20 person need. We are talking in the 300s of children out there that we need to provide a place for.

This is not just a Dickinson County issue, said Tanya Koehn with Child Care Aware. There are meetings like this all over happening.

In mid November it was announced that Robin Hansen, owner of Abilene Childcare Learning Center, was expanding and agreed to lease the Learn & Grow facility to provide child care for hospital staff and members of the community.

Historic Abilene

Both Old Abilene Town and the Dickinson County Historical Society made headlines.

Old Abilene Town hosted can can dancers, gun fighters and evening events in the Alamo Saloon throughout the summer. Just recently it hosted Cowboy Christmas.

The biggest event for Old Abilene Town was another successful Chisholm Trail Days. Much as they did in the 1800s, longhorn cattle were herded through the street and onto rail cars.

In looking a 2020, Old Abilene Town has plans to open a National Old West Trails museum.

We want to move ourselves from not just a tourist destination, but a tourist attraction and all the great things that can happen down in that district, Michael Hook, president of the Historic Abilene, Inc., board of trustees told the Dickinson County Commission.

Several educational programs are planned in 2020, including a Cowboy Camp in July, hosted by OAT and the Community Foundation of Dickinson County.

The Dickinson County Heritage Society changed its name and hosted Heritage Day in September.

A change in the bylaws reducing the number on the Board of Trustees of the Dickinson County Historical Society to seven was voted down by its members during its annual meeting on Nov. 26.

The membership of the society voted to continue to operate under the bylaws adopted in 2018. Those bylaws say the Board of Trustees shall consist of 18 members. It also requires 10 trustees for a quorum.

The membership also elected six new trustees at a standing room only two-hour meeting.

Six new board members were elected at that meeting. Duane Schrag, Cindy Wedel, Gail Whitehair, Mid Hanson, Nanc Scholl and James Holland became board members on Wednesday.

Patty OMalley

More people now are aware that one of the nicest places in Kansas is located in Abilene, thats according to a panel of judges with Readers Digest.

Patty OMalleys Cedar House was named Kansas nominee in the 2019 Nicest Places in America 2019 Readers Digest contest.

Living in the Nicest Place in America means you live in communities that are committed to kindness, trust and health. Life extension is the health solutions expert that is translating scientific research into everyday insights for people wanting to live their healthiest lives. Together, were looking for the community health heroes who are committed to supporting and inspiring communities to live a happier, healthier life, Readers Digest said on its web page in announcing The 50th Nicest Places in America.

Readers Digest tells the story of Patti OMalley and the creation of the rehab center at Cedar House.

It is heartbreaking and heartwarming at the same time, OMalley said. This has been a long six years of a lot of people saying it cant be done. This is some affirmation for all those years. We have made progress and the hope is that now we can do more to help more women.

OMalley built herself a new home while turning what would become Cedar House into a six-bed facility that focuses on hope, healing and giving back to the surrounding community of Abilene, a rural town of some 7,000, famous for being the childhood home of President Dwight D. Eisenhower.

Cedar House now boasts a local food bank and a micro-farm with a greenhouse, which delights locals with its exotic flora.

Lebold Mansion

A killer ghost visited the Lebold Mansion in March.

The vengeful ghost of Mary Wallace haunted the mansion, killing some of its guests.

Those events were in the short film The Haunting of Pottersfield. The film was based on the true story of Lavinia Fisher who is considered to be Americas first female serial killer.

Director and writer Andre Dixon brought actors and a film crew to the mansion.

The film has been nominated for four awards at the Indie Short Fest in Las Angeles: Best Horror Short, Best First Time Director (Andre Dixon), Best Sound Design (Alex Gregson) and Best Special Makeup (Marcus Koch).

But Lebold Mansion events didnt end when the crew left.

Once declared the finest dwelling house west of Topeka by an 1883 history of Kansas, the Lebold Mansion, 106 N. Vine, has had more than its share of ups and downs.

It started as a stone dugout, the first residence in Abilene, built by Timothy Hersey in 1857.

About 40 people crowded into the Dickinson County Commission room in May when the Lebold Mansion and property at 310 S.E. Second Street were sold at a sheriffs office to the Dickinson County Bank of Enterprise for $380,227.78.

This stately mansion boasts as being one of the Eight Architectural Wonders of Kansas. The 10,106 square foot building with five bedrooms and 3-1/2 baths is currently listed for sale.

Contact Tim Horan at editor@abilene-rc.com.

More:
The next five top events of 2019 | News - Abilene Recorder Chronicle

Recommendation and review posted by Bethany Smith

Improved computed tomography (CT) techniques could better recognize manufacturing flaws and structural damage to aerospace composites, improving future aircraft.

University of Texas aerospace engineering researchers will improve reconstruction algorithms and software techniques to produce breakthroughs in computed tomography scanning, which will lead to improved recognition of manufacturing flaws and structural damage of composites. The University of Texas Advanced Materials and Structures Lab uses state-of-the-art facilities.

Andrew Makeev, professor in the University of Texas at Arlingtons Department of Mechanical and Aerospace Engineering, received a $900,000 grant from the Army Research Lab to address the Armys need for better structural diagnostics and life assessment in composite aircraft parts. Makeev, who also directs UTAs Advanced Materials and Structures Lab, will lead the project.

He said UTAs effort will focus on developing effective tools for high-resolution, one-sided computational tomography- or CT-based non-destructive inspection or NDI. One-sided scanning will improve the versatility of CT-based microstructural material characterization and structural diagnostics to virtually unlimited object in-plane dimensions, and help the development of game-changing NDI systems, Makeev said.

Currently, composite aircraft structures are susceptible to damage precursors like porosity and voids, and sustaining fiber-waviness. Those discontinuities may evolve into structural damage in the form of cracks and delamination or composite layer splitting.

X-ray CT has proven to be the only 3D industrial nondestructive inspection which has reliable micro resolution and allows for automated interpretation of the inspection results including the listed flaws. However, the current micro-focus CT technology is based on full scanning or 360 degrees around the object, which limits the technology to small cross sections and prevents accommodation of large structures.

Even small objects, which can be scanned in the existing micro-CT facilities, sometimes do not allow for sufficient magnification of the microstructure during the full scanning. However, available limited-angle reconstructions lose definition and often become erroneous during one-sided inspections.

We believe that to advance composite aircraft structural certification, the analysis must capture manufacturing complexity and variability of flight-critical components and structure, Makeev said. Recent improvement in computing power and advances in X-ray CT reconstruction make it possible to develop high-resolution, one-sided CT inspection technology breaking through the object size limits of X-ray CT. It also offers the long-sought automation for composite aircraft structures.

Inspection of large composite components in a single run addresses a timely and critical need, said Erian Armanios, chair of the Department of Mechanical and Aerospace Engineering. Dr. Makeevs research provides CT software solutions that can combine high degree of automation with high degree of accuracy key end user requirements.

The U.S. Army and helicopter industry are facing the challenge of replacing more than 6,300 military vertical lift aircraft. Earlier this year, Makeev received a separate $600,000 grant from Boeing to assess durability and damage tolerance of composite structures for composite airframe life extension.

Makeev has shouldered many research projects with companies that are especially focused on composite materials and structures. He has current or past grants with Boeing, Lockheed Martin Aeronautics, Sikorsky Aircraft and Bell Helicopter Textron. During his six-year tenure at UTA, Makeev has been conducting pioneering theoretical and experimental work sponsored by the U.S. Army, U.S. Navy, U.S. Air Force and aerospace industry at an average rate of $1 million per year in external funding. His work includes integration of design and manufacturing processes to improve performance of composites, advanced material technologies, material characterization, structural diagnostics and prognostics.

For more information: http://www.uta.edu

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Recommendation and review posted by Bethany Smith

Analysts forecast that Sealed Air Corp (NYSE:SEE) will post sales of $1.30 billion for the current quarter, according to Zacks. Three analysts have made estimates for Sealed Airs earnings, with the highest sales estimate coming in at $1.30 billion and the lowest estimate coming in at $1.29 billion. Sealed Air reported sales of $1.26 billion in the same quarter last year, which would suggest a positive year over year growth rate of 3.2%. The business is expected to announce its next quarterly earnings report on Thursday, February 6th.

On average, analysts expect that Sealed Air will report full-year sales of $4.79 billion for the current financial year, with estimates ranging from $4.78 billion to $4.80 billion. For the next financial year, analysts expect that the business will report sales of $5.01 billion, with estimates ranging from $4.91 billion to $5.20 billion. Zacks Investment Researchs sales calculations are an average based on a survey of research analysts that follow Sealed Air.

Sealed Air (NYSE:SEE) last posted its quarterly earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share (EPS) for the quarter, topping the Thomson Reuters consensus estimate of $0.62 by $0.02. The firm had revenue of $1.22 billion for the quarter, compared to analyst estimates of $1.23 billion. Sealed Air had a net margin of 7.55% and a negative return on equity of 135.60%. The firms quarterly revenue was up 2.7% compared to the same quarter last year. During the same quarter in the previous year, the business posted $0.61 earnings per share.

In other news, CFO James M. Sullivan bought 5,000 shares of the stock in a transaction on Thursday, November 7th. The shares were purchased at an average price of $38.75 per share, for a total transaction of $193,750.00. Following the completion of the purchase, the chief financial officer now directly owns 17,028 shares of the companys stock, valued at approximately $659,835. The purchase was disclosed in a filing with the SEC, which is available through this link. 0.53% of the stock is currently owned by company insiders.

Several institutional investors and hedge funds have recently bought and sold shares of the company. Evoke Wealth LLC bought a new stake in shares of Sealed Air in the 3rd quarter valued at approximately $1,469,000. Man Group plc increased its stake in shares of Sealed Air by 91.7% during the 3rd quarter. Man Group plc now owns 125,245 shares of the industrial products companys stock worth $5,199,000 after purchasing an additional 59,911 shares during the last quarter. Michael & Susan Dell Foundation increased its stake in shares of Sealed Air by 28.7% during the 3rd quarter. Michael & Susan Dell Foundation now owns 14,760 shares of the industrial products companys stock worth $613,000 after purchasing an additional 3,294 shares during the last quarter. Squarepoint Ops LLC bought a new position in shares of Sealed Air during the 3rd quarter valued at $4,082,000. Finally, Voloridge Investment Management LLC increased its holdings in shares of Sealed Air by 391.5% during the 3rd quarter. Voloridge Investment Management LLC now owns 41,538 shares of the industrial products companys stock valued at $1,724,000 after acquiring an additional 33,087 shares during the last quarter. 94.05% of the stock is owned by institutional investors.

Shares of NYSE:SEE opened at $38.26 on Friday. The companys fifty day moving average is $38.61 and its two-hundred day moving average is $41.11. The company has a market cap of $5.91 billion, a P/E ratio of 15.30, a price-to-earnings-growth ratio of 1.31 and a beta of 1.03. Sealed Air has a 12-month low of $34.92 and a 12-month high of $47.13.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air Corp (NYSE:SEE) Expected to Announce Quarterly Sales of $1.30 Billion - Slater Sentinel

Recommendation and review posted by Bethany Smith

Sealed Air Corp (NYSE:SEE) has been assigned an average rating of Hold from the fourteen brokerages that are currently covering the stock, MarketBeat reports. Three research analysts have rated the stock with a sell rating, eight have assigned a hold rating and two have given a buy rating to the company. The average twelve-month price objective among analysts that have issued a report on the stock in the last year is $44.61.

Several research firms recently issued reports on SEE. Robert W. Baird reaffirmed a buy rating and set a $50.00 price target on shares of Sealed Air in a research note on Monday, November 18th. ValuEngine downgraded shares of Sealed Air from a sell rating to a strong sell rating in a research note on Thursday. KeyCorp raised shares of Sealed Air from an underweight rating to a sector weight rating in a research note on Wednesday, November 6th. They noted that the move was a valuation call. Wells Fargo & Co reaffirmed a hold rating on shares of Sealed Air in a research note on Monday. Finally, Citigroup dropped their price target on shares of Sealed Air from $45.00 to $42.00 and set a neutral rating on the stock in a research note on Thursday, October 17th.

In related news, CFO James M. Sullivan acquired 5,000 shares of the firms stock in a transaction on Thursday, November 7th. The stock was bought at an average cost of $38.75 per share, with a total value of $193,750.00. Following the acquisition, the chief financial officer now directly owns 17,028 shares in the company, valued at $659,835. The acquisition was disclosed in a document filed with the Securities & Exchange Commission, which is available through this link. 0.53% of the stock is owned by company insiders.

A number of hedge funds have recently made changes to their positions in the business. Motco acquired a new position in shares of Sealed Air in the 2nd quarter valued at about $29,000. Doyle Wealth Management acquired a new position in shares of Sealed Air in the 2nd quarter valued at about $40,000. CSat Investment Advisory L.P. boosted its holdings in shares of Sealed Air by 34.1% in the 2nd quarter. CSat Investment Advisory L.P. now owns 1,234 shares of the industrial products companys stock valued at $53,000 after buying an additional 314 shares during the period. Penserra Capital Management LLC boosted its holdings in shares of Sealed Air by 556.0% in the 3rd quarter. Penserra Capital Management LLC now owns 1,804 shares of the industrial products companys stock valued at $74,000 after buying an additional 1,529 shares during the period. Finally, Massey Quick Simon & CO. LLC acquired a new position in shares of Sealed Air in the 3rd quarter valued at about $96,000. 94.07% of the stock is owned by institutional investors.

Sealed Air stock traded down $0.16 during midday trading on Friday, hitting $38.54. 30,675 shares of the stock were exchanged, compared to its average volume of 972,233. Sealed Air has a 1 year low of $32.33 and a 1 year high of $47.13. The firm has a market cap of $5.99 billion, a P/E ratio of 15.42, a P/E/G ratio of 1.41 and a beta of 1.00. The company has a 50 day moving average price of $39.18 and a two-hundred day moving average price of $41.51.

Sealed Air (NYSE:SEE) last released its quarterly earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share (EPS) for the quarter, topping the Thomson Reuters consensus estimate of $0.62 by $0.02. Sealed Air had a net margin of 7.55% and a negative return on equity of 135.60%. The firm had revenue of $1.22 billion for the quarter, compared to the consensus estimate of $1.23 billion. During the same quarter in the previous year, the firm posted $0.61 EPS. The firms quarterly revenue was up 2.7% on a year-over-year basis. On average, equities research analysts anticipate that Sealed Air will post 2.78 EPS for the current fiscal year.

The business also recently disclosed a quarterly dividend, which will be paid on Friday, December 20th. Shareholders of record on Friday, December 6th will be issued a dividend of $0.16 per share. This represents a $0.64 annualized dividend and a yield of 1.66%. The ex-dividend date is Thursday, December 5th. Sealed Airs dividend payout ratio is currently 25.60%.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air Corp (NYSE:SEE) Receives Average Recommendation of Hold from Brokerages - Riverton Roll

Recommendation and review posted by Bethany Smith

Sealed Air (NYSE:SEE)s stock had its hold rating restated by analysts at Wells Fargo & Co in a report issued on Monday, December 9th, AnalystRatings.com reports.

A number of other analysts have also weighed in on SEE. KeyCorp upgraded Sealed Air from an underweight rating to a sector weight rating in a report on Wednesday, November 6th. They noted that the move was a valuation call. Citigroup reduced their price target on Sealed Air from $45.00 to $42.00 and set a neutral rating on the stock in a research report on Thursday, October 17th. ValuEngine raised Sealed Air from a strong sell rating to a sell rating in a research report on Tuesday, November 19th. Finally, Robert W. Baird reaffirmed a buy rating and set a $50.00 price target on shares of Sealed Air in a research report on Monday, November 18th. One equities research analyst has rated the stock with a sell rating, eight have given a hold rating and three have given a buy rating to the companys stock. Sealed Air currently has a consensus rating of Hold and an average price target of $44.33.

Sealed Air stock traded down $0.61 during mid-day trading on Monday, reaching $38.26. 1,144,692 shares of the company were exchanged, compared to its average volume of 989,617. The business has a fifty day moving average of $38.61 and a 200 day moving average of $41.11. The firm has a market cap of $5.91 billion, a P/E ratio of 15.30, a PEG ratio of 1.31 and a beta of 1.03. Sealed Air has a 12-month low of $34.92 and a 12-month high of $47.13.

Sealed Air (NYSE:SEE) last posted its earnings results on Wednesday, November 6th. The industrial products company reported $0.64 earnings per share for the quarter, topping analysts consensus estimates of $0.62 by $0.02. The company had revenue of $1.22 billion during the quarter, compared to analyst estimates of $1.23 billion. Sealed Air had a negative return on equity of 135.60% and a net margin of 7.55%. Sealed Airs revenue was up 2.7% on a year-over-year basis. During the same quarter in the prior year, the business earned $0.61 earnings per share. As a group, equities research analysts predict that Sealed Air will post 2.78 EPS for the current fiscal year.

In other news, CFO James M. Sullivan bought 5,000 shares of the businesss stock in a transaction that occurred on Thursday, November 7th. The shares were purchased at an average cost of $38.75 per share, with a total value of $193,750.00. Following the transaction, the chief financial officer now directly owns 17,028 shares in the company, valued at $659,835. The transaction was disclosed in a legal filing with the Securities & Exchange Commission, which is accessible through this link. 0.53% of the stock is owned by corporate insiders.

Several hedge funds and other institutional investors have recently added to or reduced their stakes in SEE. FMR LLC increased its position in shares of Sealed Air by 3.1% in the 1st quarter. FMR LLC now owns 88,646 shares of the industrial products companys stock valued at $4,083,000 after acquiring an additional 2,697 shares during the period. Steward Partners Investment Advisory LLC acquired a new stake in Sealed Air during the 2nd quarter worth about $152,000. Los Angeles Capital Management & Equity Research Inc. grew its position in Sealed Air by 4.6% during the 2nd quarter. Los Angeles Capital Management & Equity Research Inc. now owns 143,346 shares of the industrial products companys stock worth $6,132,000 after purchasing an additional 6,285 shares during the period. First Trust Advisors LP acquired a new stake in Sealed Air during the 2nd quarter worth about $3,762,000. Finally, Aperio Group LLC grew its position in Sealed Air by 1.7% during the 2nd quarter. Aperio Group LLC now owns 64,135 shares of the industrial products companys stock worth $2,743,000 after purchasing an additional 1,064 shares during the period. 94.05% of the stock is currently owned by hedge funds and other institutional investors.

About Sealed Air

Sealed Air Corporation provides food safety and security, and product protection solutions worldwide. It operates in two segments, Food Care and Product Care. The Food Care segment offers integrated packaging materials and equipment solutions to provide food safety, shelf life extension, and total cost optimization for perishable food processors in the fresh red meat, smoked and processed meats, poultry, and dairy markets under the Cryovac, Cryovac Grip & Tear, Cryovac Darfresh, Cryovac Mirabella, Simple Steps, and Optidure brands.

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Sealed Air (NYSE:SEE) Stock Rating Reaffirmed by Wells Fargo & Co - Riverton Roll

Recommendation and review posted by Bethany Smith

(CN) When the U.S. Fish and Wildlife Service takes a species off the endangered list, the move is typically greeted with effusive praise from wildlife conservation groups and offered as proof that conservation in concert with recovery programs works.

But the delisting of the Kanab ambersnail, which makes its home in the Grand Canyon, is different.

The snail was delisted not because its numbers have rebounded dramatically, but because scientists have concluded the creature in question is likely not that genetically different from other ambersnails distributed throughout the high deserts of southern Utah and northern Arizona.

Available genetic evidence suggests that at least one population identified as Kanab ambersnail is more closely related to other nearby Oxyloma populations than it is to the other two Kanab ambersnail populations, the service said in the final act document released Friday.

In other words, at least one of the Kanab ambersnail populations, which was historically found in three distinct springs in Utah and Arizona, is more related to another ambersnail population found outside the region in question than they are to each other. Oxyloma is the scientific name for ambersnails, which are characterized by translucent shells that appear amber when empty.

They were first discovered by biologist James Ferriss in 1909. Biologists at the time believed the ambersnails in question were genetically distinct but acknowledged more research was required to establish their taxonomic independence.

When the Kanab ambersnails were first listed under the endangered species act in 1992, they were thought to only exist in three separate spots Kanab Creek Canyon and Three Lakes in Utah as well as Vaseys Paradise in Arizona.

Vaseys Paradise is a small spring or seep located about 33 miles downstream from Lees Ferry on the Colorado River. Located squarely within Grand Canyon National Park, it has been protected from development and copious groves of poison ivy deter potential visitors.

But the snail has struggled due to frequent flooding, sometimes caused by water managers releasing large amounts of water from the Glen Canyon Dam situated just upstream.

In Utah, livestock managers entirely depleted a small spring at the Kanab Creek Canyon location outside of the small town, causing the local extinction of the snail there. The species at Three Lakes near Kanab has fared better.

Kanab is a small town on the eastern flank of Zion National Park and on the doorstep of the Grand Staircase-Escalante National Monument, serving as a headquarters for tourists to explore the spectacular scenery of Utahs unique high desert.

While the species recovered somewhat in both places and was introduced to Upper Elves Canyon, also located in the Grand Canyon National Park about 83 miles downstream from Vaseys Paradise, their recovery isnt the reason for delisting as much as additional scientific studies have raised doubt as to whether the Kanab ambersnail is actually distinct from other ambersnail populations that flourish throughout the region.

Specifically, a research team studied the morphology and mitochondrial DNA patterns of the three distinct populations in questions and compared it with those of eight other populations found in Utah and Arizona.

The authors concluded that the three populations of Kanab ambersnail are not a valid subspecies of Oxyloma haydeni and should instead be considered part of the same taxa as ambersnails from the eight other populations of Oxyloma in Utah and Arizona that were sampled for comparison, the service wrote.

The delisting of species on taxonomic reasons is rare but not unheard of. The International Union for Conservation of Nature recognizes such delistings as non-genuine reasons rather than genuine reasons involving the reduction of threats and the introduction of conservation measures such as habitat restoration.

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Genetic Testing Leads to End of Protections for Grand Canyon Snail - Courthouse News Service

Recommendation and review posted by Bethany Smith

As we enter our third decade in the 21st century, it seems appropriate to reflect on the ways technology developed and note the breakthroughs that were achieved in the last 10 years.

The 2010s saw IBMs Watson win a game of Jeopardy, ushering in mainstream awareness of machine learning, along with DeepMinds AlphaGO becoming the worlds Go champion. It was the decade that industrial tools like drones, 3D printers, genetic sequencing, and virtual reality (VR) all became consumer products. And it was a decade in which some alarming trends related to surveillance, targeted misinformation, and deepfakes came online.

For better or worse, the past decade was a breathtaking era in human history in which the idea of exponential growth in information technologies powered by computation became a mainstream concept.

As I did last year for 2018 only, Ive asked a collection of experts across the Singularity University faculty to help frame the biggest breakthroughs and moments that gave shape to the past 10 years. I asked them what, in their opinion, was the most important breakthrough in their respective fields over the past decade.

My own answer to this question, focused in the space of augmented and virtual reality, would be the stunning announcement in March of 2014 that Facebook acquired Oculus VR for $2 billion. Although VR technology had been around for a while, it was at this precise moment that VR arrived as a consumer technology platform. Facebook, largely fueled by the singular interest of CEO Mark Zuckerberg, has funded the development of this industry, keeping alive the hope that consumer VR can become a sustainable business. In the meantime, VR has continued to grow in sophistication and usefulness, though it has yet to truly take off as a mainstream concept. That will hopefully be a development for the 2020s.

Below is a decade in review across the technology areas that are giving shape to our modern world, as described by the SU community of experts.

Dr. Tiffany Vora | Faculty Director and Vice Chair, Digital Biology and Medicine, Singularity University

In my mind, this decade ofastounding breakthroughs in the life sciences and medicinerests on the achievement of the$1,000 human genome in 2016.More-than-exponentially falling costs of DNA sequencinghave driven advances in medicine, agriculture, ecology, genome editing, synthetic biology, the battle against climate change, and our fundamental understanding of life and its breathtaking connections. The digital revolution in DNA constituted an important model forharnessing other types of biological information, from personalized bio data to massive datasets spanning populations and species.

Crucially, by aggressively driving down the cost of such analyses, researchers and entrepreneurs democratized access to the source code of lifewith attendantfinancial, cultural,andethical consequences. Exciting, but take heed: Veritas Geneticsspearheaded a $600 genomein 2019, only to have to shutter USA operations due to amoney trail tangled with the trade war with China. Stay tuned through the early 2020s to see the pricing of DNA sequencing fall even further and to experience the many ways that cheaper, faster harvesting of biological data will enrich your daily life.

Alex Gladstein | Chief Strategy Officer, Human Rights Foundation

The past decade has seen Bitcoin go from just an idea on an obscure online message board to a global financial network carrying more than 100 billion dollars in value. And were just getting started. One recent defining moment in the cryptocurrency space has been a stunning trend underway in Venezuela, where today, the daily dollar-denominated value of Bitcoin traded now far exceeds the daily dollar-denominated value traded on the Caracas Stock Exchange. Its just one country, but its a significant country, and a paradigm shift.

Governments and corporations are following Bitcoins success too, and are looking to launch their own digital currencies. China will launch its DC/EP project in the coming months, and Facebook is trying to kickstart its Libra project. There are technical and regulatory uncertainties for both, but one thing is for certain: the era of digital currency has arrived.

Pascal Finnette | Chair, Entrepreneurship and Open Innovation, Singularity University

For me, without a doubt, the most interesting and quite possibly ground-shifting development in the fields of entrepreneurship and corporate innovation in the last ten years is the rapid maturing of customer-driven product development frameworks such as Lean Startup, and its subsequent adoption by corporates for their own innovation purposes.

Tools and frameworks like the Business Model Canvas, agile (software) development and the aforementioned Lean Startup methodology fundamentally shifted the way we think and go about building products, services, and companies, with many of these tools bursting onto the startup scene in the late 2000s and early 2010s.

As these tools matured they found mass adoption not only in startups around the world, but incumbent companies who eagerly adopted them to increase their own innovation velocity and success.

Ramez Naam | Co-Chair, Energy and Environment, Singularity University

The 2010s were the decade that saw clean electricity, energy storage, and electric vehicles break through price and performance barriers around the world. Solar, wind, batteries, and EVs started this decade as technologies that had to be subsidized. That was the first phase of their existence. Now theyre entering their third, most disruptive phase, where shifting to clean energy and mobility ischeaper than continuing to useexistingcoal, gas, or oil infrastructure.

Consider that at the start of 2010, there was no place on earth where building new solar or wind was cheaper than building new coal or gas power generation. By 2015, in some of the sunniest and windiest places on earth, solar and wind had entered their second phase, where they were cost-competitive fornewpower. And then, in 2018 and 2019, we started to see the edge of the third phase, as building new solar and wind, in some parts of the world, wascheaper thanoperatingexisting coal or gas power plants.

Liz Specht, Ph. D | Associate Director of Science & Technology, The Good Food Institute

The arrival of mainstream plant-based meat is easily the food tech advance of the decade. Meat analogs have, of course, been around forever. But only in the last decade have companies like Beyond Meat and Impossible Foods decided to cut animals out of the process and build no-compromise meat directly from plants.

Plant-based meat is already transforming the fast-food industry. For example, the introduction of the Impossible Whopper led Burger King to their most profitable quarter in many years. But the global food industry as a whole is shifting as well. Tyson, JBS, Nestle, Cargill, and many others are all embracing plant-based meat.

Jody Medich | CEO, Superhuman-x

The breakthrough moment for augmented and virtual reality came in 2013 when Palmer Lucky took apart an Android smartphone and added optic lenses to make the first version of the Oculus Rift. Prior to that moment, we struggled with miniaturizing the components needed to develop low-latency head-worn devices. But thanks to the smartphone race started in 2006 with the iPhone, we finally had a suite of sensors, chips, displays, and computing power small enough to put on the head.

What will the next 10 years bring? Look for AR/VR to explode in a big way. We are right on the cusp of that tipping point when the tech is finally good enough for our linear expectations. Given all it can do today, we cant even picture whats possible. Just as today we cant function without our phones, by 2029 well feel lost without some AR/VR product. It will be the way we interact with computing, smart objects, and AI. Tim Cook, Apple CEO, predicts it will replace all of todays computing devices. I cant wait.

Alix Rbsaam | Faculty Fellow, Singularity University, Philosophy of Technology/Ethics of AI

The last decade has seen a significant shift in our general attitude towards the algorithms that we now know dictate much of our surroundings. Looking back at the beginning of the decade, it seems we were blissfully unaware of how the data we freely and willingly surrendered would feed the algorithms that would come to shape every aspect of our daily lives: the news we consume, the products we purchase, the opinions we hold, etc.

If I were to isolate a single publication that contributed greatly to the shift in public discourse on algorithms, it would have to be Cathy ONeils Weapons of Math Destruction from 2016. It remains a comprehensive, readable, and highly informative insight into how algorithms dictate our finances, our jobs, where we go to school, or if we can get health insurance. Its publication represents a pivotal moment when the general public started to question whether we should be OK with outsourcing decision making to these opaque systems.

The ubiquity of ethical guidelines for AI and algorithms published just in the last year (perhaps most comprehensively by the AI Now Institute) fully demonstrates the shift in public opinion of this decade.

Ola Kowalewski | Faculty Fellow, Singularity University, Data Innovation

In the last decade we entered the era of internet and smartphone ubiquity. The number of internet users doubled, with nearly 60 percent of the global population connected online and now over 35 percent of the globe owns a smartphone. With billions of people in a state of constant connectedness and therefore in a state of constant surveillance, the companies that have built the tech infrastructure and information pipelines have dominated the global economy. This shift from tech companies being the underdogs to arguably the worlds major powers sets the landscape we enter for the next decade.

Darlene Damm | Vice Chair, Faculty, Global Grand Challenges, Singularity University

The biggest breakthrough over the last decade in social impact and technology is that the social impact sector switched from seeing technology as something problematic to avoid, to one of the most effective ways to create social change. We now see people using exponential technologies to solve all sorts of social challenges in areas ranging from disaster response to hunger to shelter.

The worlds leading social organizations, such as UNICEF and the World Food Programme, have launched their own venture funds and accelerators, and the United Nations recently declared that digitization is revolutionizing global development.

Raymond McCauley | Chair, Digital Biology, Singularity University, Co-Founder & Chief Architect, BioCurious; Principal, Exponential Biosciences

CRISPR is bringing about a revolution in genetic engineering. Its obvious, and its huge. What may not be so obvious is the widespread adoption of genetic testing. And this may have an even longer-lasting effect. Its used to test new babies, to solve medical mysteries, and to catch serial killers. Thanks to holiday ads from 23andMe and Ancestry.com, its everywhere. Testing your DNA is now a common over-the-counter product. People are using it to set their diet, to pick drugs, and even for dating (or at least picking healthy mates).

And were just in the early stages. Further down the line, doing large-scale studies on more people, with more data, will lead to the use of polygenic risk scores to help us rank our genetic potential for everything from getting cancer to being a genius. Can you imagine what it would be like for parents to pick new babies, GATTACA-style, to get the smartest kids? You dont have to; its already happening.

Neil Jacobstein | Chair, Artificial Intelligence and Robotics, Singularity University

The convergence of exponentially improved computing power, the deep learning algorithm, and access to massive data resulted in a series of AI breakthroughs over the past decade. These included: vastly improved accuracy in identifying images, making self driving cars practical, beating several world champions in Go, and identifying gender, smoking status, and age from retinal fundus photographs.

Combined, these breakthroughs convinced researchers and investors that after 50+ years ofresearch and development, AI was ready for prime-time applications. Now, virtuallyevery field of human endeavor is being revolutionized by machine learning. We still have a long way to go to achieve human-level intelligence and beyond, but the pace of worldwide improvement is blistering.

Hod Lipson | Professor of Engineering and Data Science, Columbia University

The biggest moment in AI in the past decade (and in its entire history, in my humble opinion) was midnight, Pacific time, September 30, 2012: the moment when machines finally opened their eyes. It was the moment when deep learning took off, breaking stagnant decades of machine blindness, when AI couldnt reliably tell apart even a cat from a dog. That seemingly trivial accomplishmenta task any one-year-old child can dohas had a ripple effect on AI applications from driverless cars to health diagnostics. And this is just the beginning of what is sure to be a Cambrian explosion of AI.

Divya Chander | Chair, Neuroscience, Singularity University

If the 2000s were the decade of brain mapping, then the 2010s were the decade of brain writing. Optogenetics, a technique for precisely mapping and controlling neurons and neural circuits using genetically-directed light, saw incredible growth in the 2010s.

Also in the last 10 years, neuromodulation, or the ability to rewire the brain using both invasive and non-invasive interfaces and energy, has exploded in use and form. For instance, the Braingate consortium showed us how electrode arrays implanted into the motor cortex could be used by paralyzed people to use their thoughts to direct a robotic arm. These technologies, alone or in combination with robotics, exoskeletons, and flexible, implantable, electronics also make possible a future of human augmentation.

Image Credit: Image by Jorge Guillen from Pixabay

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Tech's Biggest Leaps From the Last 10 Years, and Why They Matter - Singularity Hub

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Fleetwood Macs Stevie Nicks: Did she help to inspire Daisy Jones and the Six?GETTY IMAGES

FICTION

Frankissstein: A Love Story by Jeanette Winterson A trans woman doctor starts an affair with the scientist Victor Stein, who is planning to reanimate the head of a man frozen in a cryonics facility. The recently divorced Ron Lord is marketing talking sex dolls for lonely men. And in 1816 Mary Shelley is plotting a new novel . . . This fast-paced tale has fun with the Frankenstein story.Vintage, 8.99

Daisy Jones and the Six by Taylor Jenkins Reid A rocknroll soap opera. The rise and drug-addled fall of a fictional pop group definite shades of Fleetwood Mac told in glorious Seventies detail.Arrow, 8.99

Reasons to be Cheerful by Nina Stibbe Nina Stibbe won the Bollinger Everyman Wodehouse prize for comic literature

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Pills, Powder and Smoke by Antony Loewenstein a war waged against human nature

How the Brain Lost its Mind by Allan Ropper and BD Burrell when science was left in two minds

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The best paperbacks coming out in January | Saturday Review - The Times

Recommendation and review posted by Bethany Smith

This weeks Cardio Round-up features a look back at what you may have missed during the holidays, as well as some of the big 2019 cardiology stories.

The past year saw some big stories like the Apple Heart study, presented at ACC.19, which essentially validated the ability of a wearable device (an Apple iWatch) equipped with a tachogram-tracking algorithm was able to detect pulse irregularities associated with atrial fibrillation. Icosapent ethyl also featured prominently, gaining an FDA approval for the reduction of cardiovascular disease risk as an add-on to statin therapy in high-risk patients with hypertriglyceridemia. Dapagliflozin (highlighted in the DAPA-HF study) also was shown to be an effective treatment for heart failure in both diabetic and non-diabetic patients.

2019 In Cardiology: Apple Heart Study Lands; Icosapent Ethyl Gets FDA Nod for New Indication; Dapagliflozin For Nondiabetics; and More

A new observational study published inEuropacesuggests it is possible to monitor and predict individual progression ofatrial fibrillation (AFib) using pacemakers or defibrillators.We aimed to study the progression of AER in individual patients with implantable devices and AFib episodes, the paper authors wrote. The study results indicated that the slope of AAR changes during the progression of AFib showed patient-specific patterns correlating with the time-to-completion of AER (R2 = 0.85). This technology opens up enormous possibilities in personalized medicine for AFib patients because it allows us to determine the progression rate of the arrhythmia in each individual and to optimize the timing of medical intervention with current treatment options, one of the researchers said in a press release.

Personalized Medicine for AFib: How Electric Activity in the Heart Can Predict Individual Progression of Atrial Fibrillation

A research team, publishing the study in the Journal of Molecular and Cellular Cardiology, worked on converting adipogenic mesenchymal stem cells, which reside within fat cells, into cardiac progenitor cells. The ensuing cardiac progenitor cells can be programmed to aid heartbeats as a sinoatrial node (SAN), which is part of the electrical cardiac conduction system.We are reprogramming the cardiac progenitor cell and guiding it to become a conducting cell of the heart to conduct electrical current, said study co-author Bradley McConnell, associate professor of pharmacology, in a press release. Results of this study show that the SHT5 combination of transcription factors can reprogram CPCs into Pacemaker-like cells.

The Next Generation of Biologic Pacemakers? New Discovery in Stem Cells from Fat Creates Another Alternative Treatment

Diabetes mellitus is an independent predictor for heart failure, according to the findings of a study published inMayo Clinic Proceedings. In this study, using the Rochester Epidemiology Project, researchers assessed the long-term impact ofdiabeteson the development of heart failure by including 116 study subjects with diabetes, who were matched 1:2 based on age, hypertension, sex, coronary artery disease and diastolic with 232 participants without diabetes. The results showed that that diabetes is an independent risk factor for the development of heart failure. Over the duration of 10 years, 21% of participants with diabetes developed heart failure, independent of other causes. The researchers observed that by comparison, only 12% of patients without diabetes developed heart failure. The key takeaway is that diabetes mellitus alone is an independent risk factor for the development of heart failure, wrote one of the authors.

Diabetes is an Independent Predictor for Heart Failure

A new study suggests that regularly getting a good nights sleep isnt just a helpful overall health recommendation but is also an essential way to keep risk for heart disease and stroke down. The paper, published in theEuropean Journal of Cardiology, included more than 300,000 participants initially free of cardiovascular disease (CVD) from UK Biobank. According to the results, there were 7,280 documented cases of incident CVD (4,667 coronary heart disease and 2,650 stroke) cases. Participants with a sleep score of 5 had a 35% reduced risk for CVD, a 34% reduced risk for coronary heart disease, and a 34% reduced risk for stroke when compared to participants with a score of 0-1.As with other findings from observational studies, our results indicate an association, not a causal relation, one of the authors said in a press release. However, these findings may motivate other investigations and, at least, suggest that it is essential to consider overall sleep behaviors when considering a persons risk of heart disease or stroke.

Getting Quality Sleep, and the Right Amount, Can Offset Genetic Susceptibility for Heart Disease and Stroke Risk

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Cardio Round-up: Look Back at 2019, The Importance of Sleep, and More - DocWire News

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Colleen LeCours lay in a hospital bed at the General campus of The Ottawa Hospital on August 12, 2016, waiting for the only thing that could save her life a stem cell transplant from a stranger.

The donor could be anywhere in the world if a related blood donor cant be found, the call to find a match goes out to registries all over the globe and the donated stem cells are rushed across international borders.

What LeCours didnt know is that her donor, an 18-year-old Carleton University student named Timothy White, was just one floor below. Similarly, White didnt know that his recipient was in the same hospital.

There are currently more than 450,000 people on the Canadian Blood Services Stem Cell Registry formerly known as OneMatch and 36 million on affiliated international registries. Still, some people never find a match. There are more than 900 Canadians in need of a transplant who have not found a match anywhere in the world.

What were the odds that the match for LeCours, now 57, would be found in the same city?

Astronomical, she said.

The chances that White would even ever be asked to donate were also very low only about one in a thousand. After he agreed to donate, he was not told where the recipient might be. I was told the recipient could be anywhere. They could be in Africa, said White, now 22 and a recent graduate in computer science.

White had signed up for the registry through a cheek swab booth at ComiCon less than six months earlier. A smart place to recruit would-be stem cell donors, he notes. The optimal donor is a male between the age of 17 and 35 and thats the ComiCon demographic.

He decided to register as a potential donor because he grew up in the scouting movement. One of the main philosophies is to do a good turn every day, he said.

The donation was a non-surgical procedure in which Whites blood was removed though a needle, the stem cells were separated from his blood and the remaining blood components returned to his body through another needle. The procedure started at about 8 a.m. and was over by about 5 p.m.

I figured if I gave someone a day for a thousand more days (of life) then I felt it was a fair trade. I have many years of life. Why not spend one day? said White.

LeCourss medical journey started in 2009 with an emergency room visit for abdominal pain. She was eventually diagnosed with Stage 4 follicular lymphoma, a blood cancer that affects infection-fighting white blood cells. At the time, LeCours was working for Gov.-Gen. Michalle Jean and was able to stay on the job most of the time during her six months of treatment.

Four years later, the lymphoma returned. It was back again two years after that, in a more aggressive form. The only treatment was stem cell transplant.

There are two main kinds of stem cell transplants autologous and allogenic. In an autologous transplant, stem cells are collected from a patients own blood and reintroduced after being treated to remove cancer cells. In an allogenic stem cell transplant, the stem cells come from a donor.

At this point, LeCours was a candidate for an autologous transplant. Once again, she underwent aggressive chemotherapy. A year later, the cancer returned.

Doctors told LeCours there wasnt much else they could do and advised her to get her affairs in order. But the hospitals transplant team felt she could be a candidate for an allogenic transplant. Theres risk rejecting donated stem cells can be fatal to the patient.

LeCours learned that her brother was a match. But the medical work-up would last about three months and she couldnt wait that long.

I wasnt sure I wanted to do it but I didnt have much choice, she said. They said, We have someone waiting in the wings.

And I said, He probably has wings.

After the transplant, LeCours recovered as an outpatient in the home of her brother and sister-in-law. It took three months to rebuild her immune system. Her only rejection symptoms were a bit of skin irritation.

In January 2018, LeCours received an email asking if she would like to exchange contact information with her donor. She replied that she would.

A few months later, she got a message with Whites co-ordinates and was astonished to find that her donor was in Ottawa. It took her a few weeks to formulate an email.

I didnt want to scare him. I just wanted him to know how incredibly grateful I was. And I wanted to pay it forward, said LeCours.

After careful consideration, she sent White an email on Oct. 8, 2018.

Today, being Thanksgiving, I have so much to be thankful for, namely you giving your stem cells and saving my life and the success of the stem cells grafting to my bone marrow, LeCours wrote. I cant thank you enough for your wonderful selfless act.

Stem cell donor 18-year-old Carleton University student Timothy White at The Ottawa Hospital, General campus, donating stem cells for Colleen LeCours in August 2016. At the time he did not know that LeCours would be the recipient. Courtesy Timothy White.jpg

She added that she didnt know anything about him except for his name and email address, and asked if they could meet. They got together for the first time over lunch in a burger restaurant.

As soon as I saw him, I broke down, said LeCours.

It has been three and a half years since the transplant and LeCours remains in remission. She invited White to her familys Thanksgiving this year, and the two meet to catch up every few months. Its one of the quirks of stem cell donation that the recipient assumes the blood type of the donor. LeCours, once O-positive, now has blood type A-negative, like White.

Im a grandmother. The fact that my grandson has his moma is huge.

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ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa - Ottawa Sun

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Military personnel walk past the Raytheon Missile stand.

Carl De Souza | AFP | Getty Images

Check out the companies making headlines in midday trading:

Raytheon, Lockheed Martin, L3Harris Equity of major aircraft and weapons manufacturers Raytheon, Lockheed Martin and L3Harris rose 1.6%, 3.8% and 3.3%, respectively, in midday trading as U.S.-Iranian tensions flare in the Middle East. The U.S. confirmed it was responsible for a drone strike in Baghdad on Friday that killed Iranian Gen. Qasem Soleimani, Tehran's top military commander and a prominent political fixture in the region.

Incyte Shares of Incyte plunged 10% Friday after the company announced that a Phase III study showed one of its developmental drugs failed to show results that were statistically superior to a placebo. The drug was aimed at treating a disease that arises when donated bone marrow or stem cells attack their new host.

Tesla Tesla's stock climbed 3.8% on Friday after the automaker reported better-than-expected deliveries for its most recent quarter. The electric car company delivered 112,000 vehicles during the fourth quarter, topping consensus estimates of 106,000. Tesla delivered roughly 367,500 vehicles for the full year, a 50% increase from 2018 and within the range that it had given as guidance.

Bank of America Shares of the top U.S. bank fell 1.5% in afternoon trading after BMO Capital Markets downgraded the equity to market perform from outperform, telling clients its valuation re-rating has "run its course." Analyst James Fotheringham added that Bank of America shares now trade at a premium to their long-term average and suggested investors look to cheaper names like Citi and Morgan Stanley in the big-bank space.

Concho Resources, Apache, Devon Energy Shares of Concho, Apache and Devon all traded higher, following crude prices, after the U.S. killed a top Iranian military leader in an airstrike. Concho and Apache each traded higher by more than 1% while Devon advanced 0.8%.

L Brands Shares of L Brands rose nearly 8% after Bank of America upgraded the retail and apparel company to buy from neutral. The bank's analysts cited a strong Bath & Body Works business, potential for a more stable Victoria's Secret and a high dividend yield as reasons for the upgrade. The bank also raised its price target on the stock to $25 per share from $21, which would be a 49% increase from where the stock closed on Thursday.

Humana Humana rose 1.5% after Goldman Sachs added the health care company to its "Conviction Buy" list and told clients it sees sizable upward revisions to earnings estimates due to the recent repeal of a fee on health insurers.

CNBC's Fred Imbert and Jesse Pound contributed to this report.

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more - CNBC

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INTRODUCTION

Programmed cell death protein 1 (PD-1) is a major inhibitor of T cell responses expressed on activated T cells. It is also expressed on natural killer cells, B cells, regulatory T cells, T follicular helper cells, and myeloid cells (1). The current model supports that a key mechanism dampening antitumor immune responses is the up-regulation of PD-1 ligands in cancer cells and antigen-presenting cells (APCs) of the tumor microenvironment (TME), which mediate ligation of PD-1 on tumor-infiltrating CD8+ T cells, leading to the development of T incapable of generating antitumor responses (2). Therapeutic targeting of the PD-1 pathway with antibodies blocking the PD-1 receptor or its ligands induces expansion of oligoclonal CD8+ tumor-infiltrating lymphocytes that recognize tumor neoantigens (3). Thus, in the context of cancer, PD-1 is considered a major inhibitor of T effector cells, whereas on APC and cancer cells, emphasis has been placed on the expression of PD-1 ligands. PD-1 ligand-1 expression in the TME is often a prerequisite for patient enrollment to clinical trials involving blockade of the PD-1 pathway. However, responses do not always correlate with PD-L1 expression, and it remains incompletely understood how the components of the PD-1:PD-L1/2 pathway suppress antitumor immunity.

Recent studies indicated that PD-1 can be induced by Toll-like receptor (TLR) signaling in macrophages (M) and negatively correlates with M1 polarization (4). PD-1 expression in macrophages plays a pathologic role by suppressing the innate inflammatory response to sepsis (5) and inhibiting Mycobacterium tuberculosis phagocytosis in active tuberculosis (6). Our knowledge about the function of PD-1 on myeloid cells in the context of cancer is very limited. However, similar to its role in infections, PD-1 expression inversely correlates with M1 polarization and phagocytic potency of tumor-associated M (TAM) against tumor (7, 8). The mechanisms of PD-1 expression in myeloid cells and the role of PD-1expressing myeloid cells in tumor immunity remain unknown.

The rapid increase in myeloid cell output in response to immunologic stress is known as emergency myelopoiesis. Terminally differentiated myeloid cells are essential innate immune cells and are required for the activation of adaptive immunity. Strong activation signals mediated by pathogen-associated molecular pattern or danger-associated molecular pattern molecules lead to a transient expansion and subsequent differentiation of myeloid progenitors to mature monocytes and granulocytes to protect the host. In contrast, during emergency myelopoiesis mediated by continuous low-level stimulation mediated by cancer-derived factors and cytokines, bone marrow common myeloid progenitors (CMPs) but, predominantly, granulocyte/macrophage progenitors (GMPs) undergo modest expansion with hindered differentiation, and a fraction of myeloid cells with immunosuppressive and tumor-promoting properties, named myeloid-derived suppressor cells (MDSCs), accumulates. MDSCs suppress CD8+ T cell responses by various mechanisms (9). In the mouse, MDSCs consist of two major subsets, CD11b+Ly6ChiLy6G (thereafter named CD11b+Ly6C+) monocytic (M-MDSC) and CD11b+Ly6CloLy6G+ (hereafter named CD11b+Ly6G+) polymorphonuclear (PMN-MDSC) (10). These cells have similar morphology and phenotype to normal monocytes and neutrophils but distinct genomic and biochemical profiles (9). In humans, in addition to M-MDSC and PMN-MDSC, a small subset of early-stage MDSC has been identified (10).

Although PMN-MDSCs represent the major subset of circulating MDSC, they are less immunosuppressive than M-MDSC when assessed on a per cell basis (1113). Current views support the two-signal requirement for MDSC function. The first signal controls MDSC generation, whereas the second signal controls MDSC activation, which depends on cues provided by the TME and promotes MDSC differentiation to TAM (14). Proinflammatory cytokines and endoplasmic reticulum stress response in the TME contribute to pathologic myeloid cell activation that manifests as weak phagocytic activity, increased production of reactive oxygen species and nitric oxide (NO) and expression of arginase-1 (ARG1), and convert myeloid cells to MDSC (9). MDSCs are associated with poor outcomes in many cancer types in patients and negatively correlate with response to chemotherapy, immunotherapy, and cancer vaccines (1519).

In the present study, we examined how PD-1 regulates the response of myeloid progenitors to cancer-driven emergency myelopoiesis and its implications on antitumor immunity. We determined that myeloid progenitors, which expand during cancer-driven emergency myelopoiesis, express PD-1 and PD-L1. PD-L1 was constitutively expressed on CMPs and GMPs, whereas PD-1 expression displayed a notable increase on GMPs that arose during tumor-driven emergency myelopoiesis. PD-1 was also expressed on tumor-infiltrating myeloid cellsincluding M-MDSCs and PMN-MDSCs, CD11b+F4/80+ M, and CD11c+major histocompatibility complex class II-positive (MHCII+) dendritic cells (DCs) in tumor-bearing miceand on MDSCs in patients with refractory lymphoma. Ablation of PD-1 signaling in PD-1 knockout (KO) mice prevented GMP accumulation and MDSC generation and resulted in increase of Ly6Chi effector monocytes, M and DC. We generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared with T cellspecific ablation of PD-1, myeloid-specific PD-1 ablation more effectively decreased tumor growth in various tumor models. At a cellular level, only myeloid-specific PD-1 ablation skewed the myeloid cell fate commitment from MDSC to effector Ly6Chi monocytes M and DC and induced T effector memory (TEM) cells with improved functionality. Our findings reveal a previously unidentified role of the PD-1 pathway and suggest that skewing of myeloid cell fate during emergency myelopoiesis and differentiation to effector APCs, thereby reprogramming T cell responses, might be a key mechanism by which PD-1 blockade mediates antitumor function.

For our studies, we selected the murine B16-F10 melanoma tumor model because it has been informative in dissecting mechanisms of resistance to checkpoint immunotherapy (20). First, we examined whether B16-F10 induces tumor-driven emergency myelopoiesis similarly to the MC17-51 fibrosarcoma, a mouse tumor model well established to induce cancer-driven emergency myelopoiesis (21). We assessed the expansion of myeloid progenitors in the bone marrow and the increase of CD11b+CD45+ myeloid cells in the spleen and tumor (figs. S1 and S2). Both tumor types induced increase of myeloid progenitors in the bone marrow and systemic increase of CD45+CD11b+ myeloid cells (fig. S3), providing evidence that B16-F10 melanoma is an appropriate tumor model to study tumor-driven emergency myelopoiesis and its consequences in tumor immunity. In the spleen of nontumor-bearing mice, few myeloid cells constitutively expressed very low levels of PD-L1, whereas PD-1 was very low to undetectable (Fig. 1, A and B). In B16-F10 tumor-bearing mice, expression of PD-1 and PD-L1 was up-regulated on myeloid cells of the spleen (Fig. 1, C to F). PD-1 and PD-L1 were also expressed on myeloid cells at the tumor site (Fig. 1, G to I). All subsets of myeloid cells expanding in tumor-bearing mice including M-MDSCs, PMN-MDSCs, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs expressed PD-1 (Fig. 1, D and G). Kinetics studies of PD-1 expression on myeloid cells in the spleen of tumor-bearing mice showed a gradual increase over time (Fig. 1, J to M).

(A and B) Expression of PD-1 and PD-L1 on CD11b+Ly6C+ monocytes and CD11c+MHCII+ DC in the spleen of nontumor-bearing C57BL/6 mice. FMO, fluorescence minus one. (C) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and at the indicated time points, expression of PD-1 was examined by flow cytometry in the spleen after gating on the indicated myeloid populations; contour plots depicting the percentage of positive cells are shown. On day 16 after tumor inoculation, expression of PD-1 and PD-L1 was assessed in the spleen (D) and the tumor site (G) after gating on the indicated myeloid populations. (D and G) Fluorescence-activated cell sorting (FACS) histograms and contour plots depicting the percentage of positive cells and bar graphs (E, F, H, and I) of mean SEM positive cells. Results are representative of 12 independent experiments with six mice per group. (J to M) Kinetics of PD-1 up-regulation on CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ of the spleen after tumor inoculation. **P < 0.01, ***P < 0.005, ****P < 0.001.

Because myeloid cells that give rise to MDSC and TAM are generated from myeloid progenitors in the bone marrow during tumor-driven emergency myelopoiesis, we examined PD-1 and PD-L1 expression in these myeloid progenitors. In nontumor-bearing mice, PD-1 was detected at very low levels on GMPs (Fig. 2A), whereas PD-L1 was constitutively expressed in CMPs but mostly on GMPs (Fig. 2B). In tumor-bearing mice, PD-L1 was up-regulated in CMPs and GMPs, and its expression levels remained elevated during all assessed time points (Fig. 2, F to J). PD-1 expression was induced on CMPs but more prominently on GMPs (Fig. 2, C to I). Kinetics studies showed that PD-1 expression on GMPs peaked early after tumor inoculation (Fig. 2, C, E, and I), at a time point when tumor growth was not yet measurable. Thus, induction of PD-1 expression in myeloid progenitors is an early event during tumor development.

(A and B) Expression of PD-1 and PD-L1 on CMPs and GMPs of nontumor-bearing mice. (C to J) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and expression of PD-1 and PD-L1 on CMPs and GMPs was examined on days 9, 12, 14, and 16 after implantation. FACS histograms (C and F) and contour plots (D, E, G, and H) indicating the percentage of positive cells and bar graphs of mean SEM positive cells (I and J) are shown. Results are representative of four independent experiments with six mice per group. (K and L) Kinetics of PD-1 (K) and PD-L1 (L) expression on CMPs (blue) and GMPs (orange) during tumor-driven emergency myelopoiesis. Results are representative of four separate experiments with six mice per group. *P < 0.05, ***P < 0.005, ****P < 0.001.

To determine whether PD-1 expression on GMPs was mediated by growth factors regulating emergency myelopoiesis, we cultured bone marrow cells from nontumor-bearing mice with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony growth factor (GM-CSF), and the TLR4 ligand lipopolysaccharide. PD-1 that was constitutively expressed at low levels in GMPs was up-regulated by culture with each of these factors (fig. S4A), consistent with our findings that PD-1 expression was rapidly induced on GMPs of tumor-bearing mice in vivo (Fig. 2, C, E, and I). Quantitative polymerase chain reaction (qPCR) in purified Linneg bone marrow cells showed that PD-1 mRNA was constitutively expressed in myeloid progenitors and was up-regulated by culture with G-CSF or GM-CSF (fig. S4B). Together, these in vivo and in vitro studies provide evidence that PD-1 expression on myeloid progenitors is regulated by a direct cell-intrinsic effect of factors driving cancer-mediated emergency myelopoiesis.

To examine whether PD-1 was expressed in MDSCs in humans, we used samples from healthy donors and patients with malignant non-Hodgkins lymphoma (NHL) (figs. S5 and S6). A high level of PD-1expressing M-MDSCs was detected in the peripheral blood of three patients with treatment-refractory NHL but not in two patients who responded to treatment or five healthy donors (fig. S6). These results show that PD-1 expression is detected in human MDSCs and serve as a paradigm, suggesting that PD-1 expression in MDSCs of patients with cancer might be a clinically relevant event.

To examine whether PD-1 might have an active role in tumor-induced stress myelopoiesis, we used PD-1deficient (PD-1/) mice. PD-1 deletion, which resulted in decreased tumor growth (Fig. 3, A and B), substantially altered tumor-induced stress myelopoiesis (Fig. 3, C to E). Although accumulation of CMPs was comparable, accumulation of GMPs was significantly diminished in PD-1/ mice (Fig. 3, C and D), indicating that GMPs might be a key target on which PD-1 mediated its effects on myeloid progenitors (Fig. 3E). Kinetics studies showed sustained GMP expansion in wild-type (WT) tumor-bearing mice. In contrast, in PD-1/ tumor-bearing mice, GMPs displayed a rapid expansion and subsequent decline (fig. S7). In parallel, in PD-1/ mice, there was an increase of differentiated CD11b+Ly6Chi monocytic cells not only in the tumor (Fig. 3H) but also in the spleen and the small intestine, which also displayed an increase in CD11c+MHCII+ DCs (Fig. 3, F and G). Moreover, at these sites, there was a significant increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 3, I to K), indicating a shift of myelopoiesis output toward monocytic lineage dominance. These Ly6Chi monocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs in PD-1/ tumor-bearing mice expressed interferon (IFN) regulatory factor 8 (IRF8), and all myeloid subsets had elevated expression of the retinoic acid receptor-related orphan receptor (RORC or ROR) (Fig. 3, L to N, and fig. S8). Similar results were observed in two additional tumor models, the MC38 colon adenocarcinoma and the MC17-51 fibrosarcoma model (fig. S9), both of which induced cancer-driven emergency myelopoiesis (fig. S3).

(A and B) WT and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). Mice were euthanized on day 16, and tumor weight was measured (B). Data shown are means SEM of six mice per group and are representative of six independent experiments. (C) Mean percentages SEM of LSK (Linneg, Sca1pos, CD127neg, c-kitpos) and LK (Linneg, Sca1neg, CD127neg, c-kitpos) hematopoietic precursors, CMP, and GMP in the bone marrow of nontumor-bearing and tumor-bearing WT and PD-1/ mice. GMPs in PD-1/ mice were significantly lower compared with GMPs in WT mice (**P < 0.01). (D) Representative contour plots of FACS analysis for CMP and GMP in the bone marrow of tumor-bearing WT and PD-1/ mice. (E) Schematic presentation of myeloid lineage differentiation. The arrowhead indicates GMP, the key target population of PD-1 during emergency myelopoiesis. HSC, hematopoietic stem cells; MPP, multi-potent progenitor; MDP, monocyte/macrophages and DC precursors; CDP, common dendritic cell progenitors; CLP, common lymphoid progenitors. (F to H) Mean percentages of CD45+CD11b+, CD11b+Ly6C+, CD11b+Ly6G+, and CD11c+MHCII+ in the spleen (F), small intestine (G), and B16-F10 site (H) of tumor-bearing WT and PD-1/ mice. (I to K) Representative plots of FACS analysis for CD11b+Ly6Chi and CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen (I), small intestine (J), and B16-F10 site (K). (L to N) Mean percentages SEM of RORC and IRF8 expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD45+CD11b+ gate in the spleen (L), small intestine (M), and B16-F10 site (N). Data from one representative experiment of three independent experiments with six mice per group are shown. (O and P) Diminished suppressive activity (O) and NO production (P) of CD11b+Ly6C+ cells isolated from PD-1/ tumor-bearing mice. CD11b+Ly6C+ cells were isolated from tumor-bearing WT and PD-1/ mice and cultured at various ratios with OTI splenocytes stimulated with OVA257264. Data show means SEM of one representative of two experiments (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001).

IRF8 regulates myeloid cell fate to monocyte/macrophage and DC differentiation versus granulocyte differentiation (22, 23), explaining the increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio that we observed in tumor-bearing PD-1 KO mice. IRF8 is designated as one of the terminal selectors that control the induction and maintenance of the terminally differentiated state of these myeloid cells (22, 23). Moreover, IRF8 shifts the fate of myeloid cells away from immature MDSC, which are characterized by a restriction in IRF8 expression (24, 25). Retinoid-related orphan nuclear receptors not only are required for myelopoiesis and are mediators of the inflammatory response of effector Ly6Chi monocytes and macrophages (21, 26) but also can be expressed by MDSC (21). For these reasons, we examined the functional properties of CD11b+Ly6C+ cells in PD-1/ tumor-bearing mice. A key mechanism by which CD11b+Ly6C+ M-MDSCs mediate suppression of T cell responses involves the production of NO (27). We assessed the immunosuppressive function and found diminished NO production and diminished suppressor capacity of CD11b+Ly6C+ myeloid cells isolated from tumor-bearing PD-1/ mice compared with their counterparts isolated from tumor-bearing WT control mice (Fig. 3, O and P). Thus, PD-1 ablation switches the fate and function of myeloid cells away from immunosuppressive MDSC and promotes the generation of differentiated monocytes, M, and DC. The expansion of CD11b+Ly6Chi monocytes, the increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio, and the up-regulation of RORC in myeloid cells of the spleen of PD-1/ mice were already observed on day 9 after tumor inoculation, when tumors were not yet measurable, and on day 12, when tumors in WT and PD-1/ mice had comparable size (fig. S10). These results indicate that the effects of PD-1 ablation on the myeloid compartment of PD-1/ tumor-bearing mice preceded the differences in tumor growth.

To determine the potential therapeutic relevance of these findings, we examined whether changes in the myeloid compartment might be detected during treatment with PD-1blocking antibody. Compared with the control treatment group, mice receiving antiPD-1 antibody (fig. S11A) had diminished accumulation of GMP in the bone marrow (fig. S11B) and increased expansion of Ly6C+ monocytes and DC in the tumor site (fig. S11D), with effector features characterized by the expression of RORC, IRF8, and IFN- (fig. S11, E to G and I). In contrast, cells expressing interleukin-4 receptor (IL-4Ra), a marker of MDSC (10, 28), were significantly decreased (fig. S11H). Thus, treatment with antiPD-1blocking antibody promotes the differentiation of myeloid cells with effector features while suppressing expansion of MDSC in tumor-bearing mice.

To determine whether these changes on myeloid cell fate in PD-1/ mice were mediated by myeloid cellintrinsic effects of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) (fig. S12A) and crossed them with mice expressing cre recombinase under the control of the lysozyme (LysM) promoter to induce selective ablation of the Pdcd1 gene in myeloid cells (PD-1f/fLysMcre) or with mice expressing cre recombinase under the control of the CD4 promoter to induce selective ablation of the Pdcd1 gene in T cells (PD-1f/fCD4cre) (fig. S12, B and C). In PD-1f/fLysMcre mice, tumor growth was significantly diminished (Fig. 4, A and B), indicating that despite the preserved PD-1 expression in T cells, myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice was sufficient to inhibit tumor growth. Tumor-driven emergency myelopoiesis was selectively affected in PD-1f/fLysMcre mice. Although myeloid-specific PD-1 ablation resulted in expansion of CMPs, accumulation of GMPs was prevented (Fig. 4C). In contrast, no change on cancer-driven emergency myelopoiesis was detected in PD-1f/fCD4cre mice, which had comparable expansion of CMP and GMP to PD-1f/f control mice (Fig. 5A).

(A and B) PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). After mice were euthanized, tumor weight was measured (B). (C) Mean percentages SEM of CMP and GMP in the bone marrow of tumor-bearing PD-1f/f and PD-1f/fLysMcre mice. (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen of tumor-bearing mice. (E) Mean percentages SEM of CD11b+CD45+, CD11b+Ly6C+, and CD11b+Ly6G+ cells and (F) representative contour plots of FACS analysis for CD11b+CD45+ and CD11b+Ly6C+ cells at the tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (G) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, and CD80+ cells and IFN-expressing myeloid cell subsets within the CD45+CD11b+ gate in B16-F10 tumors from PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (H) Mean percentages SEM and (I) FACS histograms of IL-4Ra, CD206, and ARG1 expression in CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD11b+CD45+ gate in the spleen of tumor-bearing PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. Data are from one representative of three independent experiments with six mice per group are shown in all the panels (*P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001).

PD-1f/f and PD-1f/fCD4cre mice were inoculated with B16-F10 melanoma. (A) On day 16, mice were euthanized, and bone marrow CMPs and GMPs were examined by flow cytometry. Mean percentages SEM of CMP or GMP are shown. (B and C) Tumor size was assessed every other day from inoculation (B). On the day of euthanasia, tumor weight was measured (C). (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+ and CD11b+Ly6G+ populations within the CD11+CD45+ gate in the spleen. (E) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ cells within the CD11b+CD45+ gate in the tumor site. (F) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, CD80+, and IFN- expression in the indicated myeloid subsets (CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+) within the CD11b+CD45+ gate in the tumor site. (G to J) Mean percentages SEM of CD4+ and CD8+ TCM and TEM (G), as well as IFN-, IL-2, and IL-17 (H to J) expression in CD4+ and CD8+ TEM and TCM at the tumor site, and respective contour plots (K to M). Results are from one representative of two independent experiments with six mice per group are shown (*P < 0.05 and **P < 0.01).

Myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice not only shifted the differentiation of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid subsets and increased the CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen and tumor site as in PD-1/ mice (Fig. 4, D to F) but also resulted in a notably different immunological profile of CD11b+Ly6C+ monocytic myeloid cells, consistent with effector myeloid function as indicated by the expression of effector myeloid cell markers including CD80, CD86, CD16/32 (Fc receptor II/III), and CD88 (C5aR) (Fig. 4G). Consistent with the improved function of myeloid cells, PD-1f/fLysMcre mice also had higher levels of IFN-expressing CD11b+Ly6Chi monocytes and CD11b+F4/80+ Ms (Fig. 4G and fig. S13, A and B) and increase of IRF8+ and RORC+ CD11b+Ly6Chi monocytes (fig. S13, C and D). In contrast, cells expressing IL-4Ra, CD206, and ARG1which are markers of MDSC, immunosuppressive neutrophils, and tolerogenic DCs (2933)were diminished (Fig. 4, H and I). Thus, myeloid-intrinsic PD-1 ablation skews the fate of myeloid cells away from immunosuppressive MDSCs; promotes the differentiation of functional effector monocytes, Ms, and DCs; and has a decisive role in systemic antitumor immunity despite PD-1 expression in T cells.

We studied antitumor responses in mice with T cellspecific PD-1 ablation and found that PD-1f/fCD4cre mice had diminished antitumor protection (Fig. 5, B and C). Consistent with the causative role of myeloid cellspecific PD-1 targeting in the differentiation and function of myeloid cells, T cellspecific PD-1 ablation did not induce expansion of CD11b+CD45+ leukocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs and increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 5, D and E) or immunological features of functional effector myeloid cells (Fig. 5F) in PD-1f/fCD4cre tumor-bearing mice, compared with control tumor-bearing mice. Moreover, despite PD-1 ablation, tumor-bearing PD-1f/fCD4cre mice did not have quantitative differences in tumor-infiltrating TEM cells compared with control tumor-bearing mice (Fig. 5G) or features of enhanced effector function as determined by assessment of cytokine-producing cells (Fig. 5, H to M).

Similar outcomes to those observed with B16-F10 tumor in the differentiation of myeloid cells toward myeloid effectors versus MDSC were obtained when PD-1f/fLysMcre and PD-1f/fCD4cre mice were inoculated with MC38 colon adenocarcinoma cells (Fig. 6, B to I). Moreover, PD-1f/fLysMcre but not PD-1f/f CD4cre mice inoculated with MC38 had functional differences in tumor-infiltrating TEM and T central memory (TCM) cells compared with control tumor-bearing mice (Fig. 6, J to L). In the context of this highly immunogenic tumor, PD-1 ablation in myeloid cells resulted in complete tumor eradication, whereas mice with PD-1 ablation in T cells showed progressive tumor growth (Fig. 6A). Together, these results suggest that by preventing the differentiation of effector myeloid cells and promoting generation of MDSC, myeloid-specific PD-1 expression has a decisive role on T cell function. Thus, although PD-1 is an inhibitor of T cell responses (2, 34, 35), ablation of PD-1 signaling in myeloid cells is an indispensable requirement for induction of systemic antitumor immunity in vivo.

(A) PD-1f/f, PD-1f/fCD4cre, and PD-1f/fLysMcre mice were inoculated with MC38 colon adenocarcinoma, and tumor size was monitored daily. Mice were euthanized on day 21, and mean percentages SEM of CD45+CD11b+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen (B) and tumor site (C) were determined. (D) Mean percentages SEM of RORC- and IRF8-expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F/480+, and CD11c+MHCII+ myeloid cells and (E) mean percentages SEM of ARG1, IL-4Ra, CD88, and CD80 cells within the same myeloid subsets in the spleen. (F and G) Representative flow cytometry plots for RORC and IRF8 expression. (H) Mean percentages SEM and (I) representative flow cytometry plots of IFN- and ARG1-expressing CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells at the tumor site. (J to L) Mean percentages SEM of CD4+ and CD8+ TCM and TEM cells (J) and IFN-expressing CD4+ and CD8+ TEM and TCM at the tumor site (K) and respective contour plots (L). Data are from one representative of three experiments with six mice per group (*P < 0.05, **P < 0.01, and ***P < 0.001).

To further investigate the direct effects of PD-1 on myeloid cell fate in the absence of T cells, we used recombination activating gene 2 (RAG2) KO mice (lacking mature T cells and B cells). Treatment of RAG2 KO tumor-bearing mice with antiPD-1blocking antibody resulted in decreased accumulation of GMPs during tumor-driven emergency myelopoiesis (fig. S14A), myeloid cell expansion in the spleen and tumor site (fig. S14, B and C), and enhanced generation of effector myeloid cells (fig. S14, D to G), providing evidence that blockade of PD-1mediated signals skews myeloid lineage fate to myeloid effector cells in a myeloid cellintrinsic and T cellindependent manner. In RAG2 KO mice treated with antiPD-1 antibody, despite the absence of T cells, a decrease of tumor growth was also observed (fig. S14, H and I), suggesting that ablation of PD-1 signaling promotes myeloid-specific mechanisms that induce tumor suppression, one of which might involve increased phagocytosis (8).

To understand mechanisms that might be responsible for the significant differences of myeloid cell fate commitment induced by myeloid-specific PD-1 targeting, we examined whether PD-1deficient bone marrow myeloid progenitors might have distinct signaling responses to the key hematopoietic growth factors that mediate cancer-driven emergency myelopoiesis, which also induced PD-1 expression in GMP during in vitro culture. To avoid any potential impact of bone marrowresiding PD-1/ T cells or mature myeloid cells on the signaling responses of myeloid progenitors, we used Linneg bone marrow from PD-1f/fLysMcre mice because LysMcre is expressed in CMPs and GMPs (36), allowing us to take advantage of the selective deletion of PD-1 in these myeloid progenitors. PD-1deficient GMPs (fig. S15) had enhanced activation of extracellular signalregulated kinase 1/2 (Erk1/2), mammalian target of rapamycin complex 1 (mTORC1), and signal transducer and activator of transcription 1 (STAT1) in response to G-CSF, a main mediator of emergency myelopoiesis (37, 38). These results are notable because each of these signaling targets has a decisive role in the differentiation and maturation of myeloid cells while preventing the generation of immature immunosuppressive MDSC (3942). These findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis.

Metabolism has a decisive role in the fate of hematopoietic and myeloid precursors. Stemness and pluripotency are regulated by maintenance of glycolysis (43). Switch from glycolysis to mitochondrial metabolism and activation of oxidative phosphorylation and trichloroacetic acid (TCA) cycle are associated with differentiation (44). This is initiated by glycolysis-mediated mitochondrial biogenesis and epigenetic regulation of gene expression (43). The structural remodeling of the mitochondrial architecture during differentiation is characterized by increased replication of mitochondrial DNA to support production of TCA cycle enzymes and electron transport chain subunits, linking mitochondrial metabolism to differentiation (45).

We examined whether PD-1 ablation, which promoted the differentiation of myeloid cells in response to tumor-mediated emergency myelopoiesis, might affect the metabolic properties of myeloid precursors. Linneg bone marrow myeloid precursors were cultured with the cytokines G-CSF/GM-CSF/IL-6 that drive tumor-mediated emergency myelopoiesis in cocktail (Fig. 7, A and B) or individually (Fig. 7, C and D). Hematopoietic stem cell differentiation was documented by decrease of Linneg, which was more prominent in the cultures of PD-1deficient bone marrow cells, and coincided with increase of CD45+CD11b+ cells (Fig. 7, A and B). Ly6C+ monocytic cells dominated in the PD-1f/fLysMcre cultures, whereas Ly6G+ granulocytes were decreasing compared with PD-1f/f control cultures (Fig. 7, C and D), providing evidence for a cell-intrinsic mechanism of PD-1deficient myeloid precursors for monocytic lineage commitment. Glucose uptake, but more prominently, mitochondrial biogenesis, was elevated in PD-1deficient CMP and GMP (Fig. 7, E and F). Bioenergetics studies showed that PD-1deficient cells developed robust mitochondrial activity (Fig. 7G) and increase of oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio during culture (Fig. 7H), indicating that mitochondrial metabolism progressively dominated over glycolysis. This bioenergetic profile is consistent with metabolism-driven enhanced differentiation of hematopoietic and myeloid precursors (45, 46).

(A and B) Linneg bone marrow from PD-1f/f and PD-1f/fLysMcre mice was cultured with GM-CSF, G-CSF, and IL-6 for the indicated time intervals. Mean percentages SEM of CD11b+CD45+ (A) and Linneg cells (B) are shown. (C and D) Bone marrow cells purified as in (A) and (B) were cultured with the indicated growth factors, and mean percentages SEM of CD11b+Ly6C+ and CD11b+Ly6G+ cells were examined after 48 hours of culture. (E to H) Bone marrow cells were prepared and cultured as in (A) and (B), and at 48 hours of culture, glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) (E), and mitochondrial biogenesis was assessed by MitoGreen staining and flow cytometry (F). (G) At 24, 48, and 72 hours of culture, OCR and ECAR were measured by a Seahorse extracellular flux analyzer, and mitostress responses at each time point of culture were examined. (H) OCR/ECAR ratio was measured at these time points, and the increase of OCR/ECAR ratio during stimulation was calculated. (I) Linneg bone marrow cells from PD-1f/f and PD-1f/fLysMcre mice were cultured with G-CSF and GM-CSF for 48 hours, and metabolite analysis was performed by mass spectrometry. The unsupervised hierarchical clustering heat map of the top 50 metabolites is shown. (J) At 24, 48, and 72 hours of culture with G-CSF and GM-CSF, mRNA was extracted and analyzed for the expression of the indicated genes by qPCR. Results of the 48-hour culture are shown and are presented as the fold increase over the mRNA level expressed by PD-1f/f cells. Results are from one of three independent experiments. (K to M) At 24 hours of culture with GM-CSF, G-CSF, or IL-6, the content of neutral lipid droplets, including triglycerides and cholesterol esters, was assessed by flow cytometry using boron-dipyrromethene (BODIPY) 493/503. Mean percentages SEM (K) of BODIPY 493/503positive cells within the CD11b+CD45+ gate, representative contour plots (L), and histograms of FACS analysis (M) are shown. (N) PD-1f/f and PD-1f/fLysMcre DC were differentiated in the presence of B16-F10 tumor supernatant, and the content of neutral lipids was assessed. Mean percentage SEM of BODIPY 493/503positive DC within the CD45+CD11b+ gate is shown. Results are representative of three experiments. *P < 0.05, **P < 0.01, and ***P < 0.005.

We performed unbiased global metabolite analysis to determine whether PD-1deficient myeloid precursors developed a distinct metabolic program. Compared with control, PD-1deficient cells had elevated metabolic intermediates of glycolysis and pentose phosphate pathway (PPP), acetylcoenzyme A (coA), and the TCA cycle metabolites citrate and -ketoglutarate, but the most prominent difference was the elevated cholesterol (Fig. 7I, figs. S16 and S17, and table S1). Abundant cytosolic acetyl-coA can be used for fatty acid and cholesterol biosynthesis (fig. S17) (43). Moreover, mTORC1 activates de novo cholesterol synthesis via sterol regulatory element-binding protein 1 (SREBP1), which regulates transcription of enzymes involved in cholesterol synthesis (47, 48). Because acetyl-coA was elevated (Fig. 7I and fig. S17) and mTORC1 activation was enhanced in PD-1deficient myeloid progenitors in response to growth factors driving emergency myelopoiesis (fig. S15), we examined whether activation of the mevalonate pathway that induces cholesterol synthesis (fig. S18A) might be involved. In PD-1deficient myeloid progenitors cultured with growth factors of emergency myelopoiesis, mRNA of genes regulating cholesterol synthesis and uptake was increased, mRNA of genes promoting cholesterol metabolism was decreased (Fig. 7J and fig. S18B), whereas cellular cholesterol and neutral lipid content was elevated (Fig. 7, K to M). PD-1deficient DC not only differentiated in vitro in the presence of B16-F10 tumor supernatant but also had a significant increase of cholesterol and neutral lipids compared with similarly differentiated DC from control mice (Fig. 7N). Consistent with these in vitro findings, glucose uptake and content of cholesterol and neutral lipids were elevated in GMPs of tumor-bearing PD-1 KO mice compared with control mice at days 7 or 9 after tumor inoculation, respectively, when tumors were not yet detectable or tumors in WT and PD-1 mice had equal size (fig. S19). Thus, features associated with metabolism-driven differentiation of myeloid progenitors are enhanced early in tumor-bearing PD-1 KO mice.

In addition to cholesterol synthesis, mevalonate also leads to the synthesis of isoprenoids, including geranylgeranyl pyrophosphate (GGPP) (fig. S17), which is required for protein geranylgeranylation catalyzed by geranylgeranyltransferase and has an active role in the up-regulation of RORC expression (49). Our metabolite analysis showed increased GGPP (Fig. 7I), providing a mechanistic explanation for the up-regulation of RORC in PD-1deficient myeloid cells. Cholesterol accumulation is associated with skewing of hematopoiesis toward myeloid lineage and monocytosis, induces a proinflammatory program in monocytes/macrophages and DC, and amplifies TLR signaling (5052). Together, these results unravel a previously unidentified role of PD-1 targeting in regulating myeloid lineage fate commitment and proinflammatory differentiation of monocytes, macrophages, and DC during tumor-driven emergency myelopoiesis, through metabolic reprogramming.

Previously, it was determined that monocyte/macrophage terminal differentiation is controlled by the combined actions of retinoid receptors and the nuclear receptor peroxisome proliferatoractivated receptor (PPAR), which is regulated by cholesterol and promotes gene expression and lipid metabolic processes, leading to terminal macrophage differentiation (26, 53). Because our in vitro studies showed that PD-1deficient myeloid progenitors developed a distinct metabolic program with elevated cholesterol metabolism, we examined whether PD-1 ablation might alter the expression of PPAR in addition to RORC. We found that the expression of PPAR was elevated in CD11b+Ly6C+ monocytic cells and M isolated from tumors of PD-1/ and PD-1f/fLysMcre mice (Fig. 8, A to C). Because PD-1deficient myeloid progenitors developed robust mitochondrial activity during culture in vitro (Fig. 7, G and H) and PPAR is involved in mitochondrial function (53), we examined whether myeloid cells in tumor-bearing mice have improved mitochondrial metabolism, a feature that has an important role in supporting antitumor function of other immune cells (54). Monocytes, M, and DC isolated from tumor of PD-1/, and PD-1f/fLysMcre mice had increased mitochondrial membrane potential compared with myeloid cells from control tumor-bearing mice, consistent with enhanced mitochondrial metabolism (Fig. 8, D to G).

(A to C) Expression of PPAR in myeloid cells at the B16-F10 site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by flow cytometry. Mean percentages SEM (A), representative histograms (B), and contour plots (C) of PPAR-expressing CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets. (D to G) Mitochondrial metabolic activity of myeloid cells at the B16-F10 tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by assessing mitochondrial membrane potential using MitoRed. Mean fluorescence intensity (MFI) SEM of MitoRedpositive CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets within the CD45+CD11b+ gate (D to F) and representative plots of FACS analysis (G) are shown. (H to L) In parallel, expression of IFN-, IL-17A, IL-2, IL-10, RORC, and ICOS in CD8+ TCM and TEM isolated from B16-F10bearing PD-1f/f and PD-1f/fLysMcre mice was assessed by flow cytometry. Representative histograms (H), contour plots (I and K), and mean percentages SEM (J, L, and M) within the CD44hiCD62Lhi gate (for TCM) and CD44hiCD62lo gate (for TEM) cells are shown. Data are from one representative of four independent experiments (*P < 0.05, **P < 0.01, and ***P < 0.005).

We investigated whether these significant immunometabolic changes of myeloid cells, induced by myeloid-specific PD-1 targeting, affected immunological properties of T cells that have key roles in their antitumor function. Compared with control PD-1f/f tumor-bearing mice, PD-1f/fLysMcre tumor-bearing mice had no quantitative differences in CD4+ or CD8+ TEM and TCM cells (fig. S20A) but had significant functional differences. There was an increase of IFN-, IL-17, and IL-10producing CD8+ TEM cells and IL-2producing CD8+ TCM cells (Fig. 8, H to J). Inducible T cell costimulator (ICOS) and lymphocyte-activation gene 3 (Lag3) were elevated in T cells from PD-1f/fLysMcre tumor-bearing mice but cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and mucin domain 3 (Tim3), CD160, and PD-1/PD-L1 were comparable in T cells from PD-1f/f and PD-1f/fLysMcre tumor-bearing mice (Fig. 8, K to M, and fig. S20B). These findings are significant because IL-17producing T helper cell 17 (TH17)/ T cytotoxic cell 17 (Tc17) cells have enhanced antitumor function and mediate durable tumor growth inhibition (55). Moreover, T cells with a hybrid phenotype producing both IFN- and IL-17 might have superior antitumor properties by combining the enhanced effector function of TH1/Tc1 and the longevity and stemness of TH17/Tc17 cells (56). In our studies, these properties of TEM cells correlated with improved antitumor function in PD-1f/fLysMcre mice.

To examine experimentally whether PD-1deficient myeloid cells differentiated in tumor-bearing mice in vivo have improved capacity of inducing antigen-specific T cell responses, we assessed responses of the same primary CD4+ or CD8+ T cells to antigen-loaded DCs isolated from PD-1/ or control mice bearing B16-F10 tumors (fig. S21A). DCs isolated from the spleen of tumor-bearing WT and PD-1/ mice were pulsed with ovalbumin (OVA) and cocultured with OVA-specific CD4+ or CD8+ T cells from OTI or OTII T cell receptor (TCR)transgenic mice. DCs from tumor-bearing PD-1/ mice had superior ability to induce OTI and OTII T cell proliferation and IFN- expression (fig. S21, B and C). Together, our data provide evidence that myeloid cellintrinsic PD-1 ablation induces potent antitumor immunity by decreasing accumulation of MDSC and promoting proinflammatory and effector monocytic/macrophage and DC differentiation, thereby leading to enhanced effector T cell responses.

Our present studies reveal a previously unidentified role of the PD-1 pathway in regulating lineage fate commitment and function of myeloid cells that arise from tumor-driven emergency myelopoiesis. These outcomes are mediated by myeloid-intrinsic effects of PD-1 ablation, leading to altered signaling and metabolic reprogramming of myeloid progenitors characterized by enhanced differentiation and elevated cholesterol synthesis. Consequently, the accumulation of immature immunosuppressive and tumor-promoting MDSC is diminished, and the output of differentiated, inflammatory effector monocytes, M, and DC is enhanced. These immunometabolic changes of myeloid cells promote the differentiation of TEM cells and systemic antitumor immunity in vivo despite preserved PD-1 expression in T cells.

We found that PD-1deficient myeloid progenitors had enhanced activation of Erk1/2 and mTORC1 in response to G-CSF. These results indicate that Erk1/2 and mTORC1, a downstream mediator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which are major targets of PD-1 in T cells (2), are subjected to PD-1mediated inhibition in myeloid cells. These results are revealing because Erk1/2 phosphorylation subverts MDSC-mediated suppression by inducing M-MDSCs differentiation to APC (39). Erk and PI3K regulate glycolysis in response to G-CSF (57). PI3K/Akt/mTORC1 signaling is critical in myeloid lineage commitment. Expression of constitutively active Akt in CD34+ cells induces enhanced monocyte and neutrophil development, whereas a dominant negative Akt has the opposite effect (58). mTORC1 is necessary for the transition of hematopoietic cells from a quiescent state to a prepared alert state in response to injury-induced systemic signals (59), for G-CSFmediated differentiation of myeloid progenitors (40), and for M-CSFmediated monocyte/macrophage generation (41). mTORC1 stimulates translation initiation through phosphorylation of 4E (eIF4E)binding protein 1 (4E-BP1) and ribosomal S6 kinases and has a decisive role in the expression of glucose transporters and enzymes of glycolysis and PPP (47). Consistent with these, our studies showed that PD-1deficient myeloid progenitors had elevated expression of glycolysis and PPP intermediates after culture with emergency cytokines in vitro and enhanced monocytic differentiation in tumor-bearing mice in vivo. Together, our findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis. Further studies will identify how receptor-proximal signaling events mediated by hematopoietic growth factors are targeted by PD-1 in a manner comparable to PD-1mediated targeting of signaling pathways in T cells (2, 34, 35).

Our metabolite analysis showed that a notable difference of PD-1deficient myeloid progenitors was the increased expression of mevalonate metabolism enzymes and the elevated cholesterol. mTORC1 activates SREBP1, which induces transcription of enzymes involved in fatty acid and cholesterol synthesis (48), thereby leading to glycolysis-regulated activation of the mevalonate pathway. Our signaling studies showing enhanced mTORC1 activation and our metabolic studies showing enhanced mitochondrial metabolism and increased cholesterol content in PD-1deficient myeloid cells provide a mechanistic link between the altered differentiation of PD-1deficient myeloid progenitors and the altered immunophenotypic and functional program of PD-1deficient monocytes, M, and DC in tumor-bearing mice. Cholesterol drives myeloid cell expansion and differentiation of macrophages and DC (50, 51, 60) and promotes antigen-presenting function (61). These properties are consistent with the metabolic profile and the increased cholesterol of PD-1deficient myeloid progenitors; the inflammatory and effector features of differentiated monocytes, M, and DC; and the enhanced T effector cell activation in tumor-bearing mice with myeloid-specific PD-1 ablation that we identified in our studies. By such mechanism, PD-1 might centrally regulate antitumor immunity, independently of the expression of PD-1 and its ligands in the TME. Our studies showed that PD-1 expression on myeloid progenitors is an early event during tumor-mediated emergency myelopoiesis and indicate that PD-1 blockade at early stages of cancer might have a decisive effect on antitumor immunity by preventing MDSC generation from myeloid progenitors and inducing the systemic output of effector myeloid cells that drive antitumor T cell responses.

In addition to its expression in myeloid progenitors, in the bone marrow, we found that PD-1 is expressed in all myeloid subsets including M-MDSC, PMN-MDSC, CD11b+F4/80+ M, and CD11c+MHCII+ DC in the tumor and the spleen of tumor-bearing mice, albeit at different levels. This difference might be related to gradient of tumor-derived factors responsible for PD-1 induction such as G-CSF and GM-CSF that we found to induce PD-1 transcription in myeloid progenitors. This possibility would be consistent with the gradual up-regulation of PD-1 expression in splenic myeloid cells, determined by our kinetics studies, which correlates with tumor growth that might be responsible for the increase of systemic levels of tumor-derived soluble factors that induce PD-1. Other cues of the TME known to mediate the activation step of MDSC (14) might also be responsible for the induction of higher PD-1 expression level in the tumor versus the splenic myeloid cells. Our findings unravel a previously unidentified role of PD-1 in myeloid cell fate commitment during emergency myelopoiesis, a process that is involved not only in antitumor immunity but also in the control of pathogen-induced innate immune responses and sterile inflammation (62).

An additional important finding of our studies is that the nuclear receptors RORC and PPAR are up-regulated in myeloid cells by PD-1 ablation. RORs were initially considered retinoic acid receptors but were subsequently identified as sterol ligands. RORC not only is induced by sterols and isoprenoid intermediates (49) but also serves as the high-affinity receptor of the cholesterol precursor desmosterol (63, 64), a metabolic intermediate of cholesterol synthesis via the mevalonate pathway that regulates inflammatory responses of myeloid cells (52, 60). Desmosterol and as sterol sulfates function as endogenous RORC agonists and induce expression of RORC target genes (63, 64). Our studies showed that, in addition to cholesterol, the mevalonate metabolism product GGPP that has an active role in the up-regulation of RORC expression (49) was elevated in PD-1deficient myeloid cells, providing a mechanistic basis for our finding of the elevated RORC expression. Retinoid receptors and PPAR together regulate monocyte/macrophage terminal differentiation (26). Although initially thought to be involved in proinflammatory macrophage differentiation, it was subsequently understood that PPAR predominantly promotes macrophage-mediated resolution of inflammation by inducing expression of the nuclear receptor liver X receptor and the scavenger receptor CD36, thereby regulating tissue remodeling (65). PPAR also regulates macrophage-mediated tissue remodeling by efferocytosis and production of proresolving cytokines (66), which can suppress cancer growth (67). The combined actions of RORC and PPAR induced by myeloid-specific PD-1 ablation might be involved in the antitumor function by promoting both proinflammatory and tissue remodeling properties of myeloid cells. Future studies will dissect the specific role of each of these nuclear receptors on the antitumor immunity induced by myeloid cellspecific ablation of PD-1.

In conclusion, our results provide multiple levels of evidence that myeloid-specific PD-1 targeting mediates myeloid cellintrinsic effects, which have a decisive role on systemic antitumor responses. This might be a key mechanism by which PD-1 blockade induces antitumor function. Recapitulating this immunometabolic program of myeloid cells will improve the outcome of cancer immunotherapy.

immunology.sciencemag.org/cgi/content/full/5/43/eaay1863/DC1

Materials and Methods

Fig. S1. Gating strategy of hematopoietic and myeloid precursors in the bone marrow.

Fig. S2. Gating strategy of myeloid subsets in the spleen and tumor site.

Fig. S3. Cancer-induced emergency myelopoiesis in three different mouse tumor models.

Fig. S4. PD-1 expression is induced on myeloid progenitors by emergency cytokines.

Fig. S5. Gating strategy for identification of MDSC in human blood samples.

Fig. S6. PD-1 expression in human MDSC.

Fig. S7. PD-1 ablation alters tumor-driven emergency myelopoiesis.

Fig. S8. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in response to tumor-driven emergency myelopoiesis.

Fig. S9. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in mice-bearing MC38 or MC17-51 tumors.

Fig. S10. PD-1 ablation increases the output of RORChi effector-like myeloid cells at early stages of tumor growth.

Fig. S11. Therapeutic targeting of PD-1 increases effector features of myeloid cells and decreases tumor growth.

Fig. S12. Myeloid-specific and T cellspecific PD-1 deletion.

Fig. S13. Myeloid-specific PD-1 ablation promotes expansion of IRF8hi and RORChi monocytes and IFN-producing monocytes and macrophages in the tumor site.

Fig. S14. Tumor-induced emergency myelopoiesis and myeloid effector differentiation in Rag2-deficient mice treated with PD-1 antibody.

Fig. S15. PD-1 ablation reduces the threshold of growth factormediated signaling in GMP.

Fig. S16. Myeloid-specific PD-1 ablation induces a distinct metabolic profile characterized by elevated cholesterol.

Fig. S17. Metabolic pathways linking glycolysis to PPP, fatty acid, and cholesterol synthesis.

Fig. S18. Schematic presentation of the mevalonate pathway.

Fig. S19. Increase of glucose uptake and neutral lipid content in PD-1deficient myeloid progenitors early after tumor implantation.

Fig. S20. Myeloid-specific PD-1 deletion alters the immunological profile of CD8+ TEM cells.

Fig. S21. PD-1 ablation enhances antigen presentation ex vivo by tumor-matured DC.

Table S1. List of significantly different metabolites.

Table S2. List of antibodies used for surface staining.

Table S3. List of antibodies used for intracellular staining.

Table S4. List of antibodies used for phenotype of human MDSC.

Table S5. Raw data in Excel spreadsheet.

References (6871)

Acknowledgments: Funding: This work was supported by NIH grants CA183605, CA183605S1, and AI098129-01 and by the DoD grant PC140571. Author contribution: L.S. participated in the conceptualization of the project and experimental design, performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. M.A.A.M. performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. J.D.W., N.M.T.-O., A.C., R.P., Q.W., and M.Y. participated in various steps of the experimental studies. J.A. participated in the experimental design of metabolite studies and the formal analysis and the validation of the data and participated in the preparation of the manuscript. N.P. participated in the conceptualization of the project, designed and performed the bioenergetics studies, and participated in experiments, the analysis and validation of the data, and the preparation of the manuscript. V.A.B. had the overall responsibility of project conceptualization, experimental design, investigation, data analysis and validation, and preparation of the manuscript and figures. Competing interests: V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

See more here:
Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

Recommendation and review posted by Bethany Smith

As the chief executive of a big German utility told me, in the 1970s, the future of his countrys energy was going to be nuclear. In the 1980s, it was brown coal. Today it is renewables solar and wind. Looking out on a new decade, as modellers confidently predict energy to 2050, do we really have a good idea what is coming?

International agencies, ministries, oil companies, banks, consultancies and environmental campaigners all put out their long-term forecasts, whether predictions or aspirations. Popular end dates seem to be 2030 or 2035, though 2030 is effectively tomorrow as far as major energy policies and infrastructure are concerned. Long-range forecasts mostly stop in 2050 apart from the ones studying climate change effects, where 2100 is the horizon to show more of the damage we are inflicting on the environment. The next century may seem unimaginably far-off, yet it should be well within the lifespan of children born today, and certainly of our monuments.

The underlying assumptions in these models are fairly similar. Growth of the world population and economy will continue but slow down, with economic expansion in the range 2.5-3.5 percent annually at first before settling at 1.5-2.5 percent. Essentially, the same large countries and global political and economic system will remain. Emerging Asian economies will grow faster than the West and dominate in overall size, but remain poorer per capita, while Africa catches up only slowly. Energy efficiency and technology will improve steadily, but no dramatic new technologies will appear either in energy production or use.

So energy consumption rises, although in some cases of high efficiency it might peak in the 2030s and then fall slowly. The models more attuned to climate and environment phase out coal and oil in favour of renewable energy and battery vehicles, and petroleum consumption goes into decline somewhere in the 2030s. Some oil company forecasts show still-rising demand into the 2040s and beyond, but oil use becomes concentrated in aviation and petrochemicals. Nuclear generally shrinks a little.

Think if we could have made such confident predictions going back eight decades instead of forwards.

Eighty years ago, the world was descending into the full horrors of the Second World War. The US was barely emerging from the Great Depression, the Soviet Union was ruled by a totalitarian Communist state, and all of Africa and much of Asia were in the grip of colonial empires. Some 2.3 billion people, a third of todays level, inhabited this world, and the economy was less than 4 percent the size it is now. The power of the atom, the jet engine and electronics were just emerging; the world was powered by coal supplemented by oil, wood and horses; steaming from England to Australia took a month; and space travel was science fiction.

New methods for producing and using energy, and entirely new political and social phenomena, will surely emerge up to 2050 and 2100. We can imagine five areas of development, which might overlap or might define entirely new paradigms.

In a world of virtualisation and miniaturisation, we might live much more within our minds and within computers. Three-dimensional printing and nanotechnology would produce highly efficient and tailored goods with a minimum of waste, while centralised industry and conventional bricks-and-mortar retail disappears. Vertical farms powered by low-carbon energy, and artificial meat grown without animals, would feed humanity.

Life extension would change demographics. Genetic engineering, manufactured and tailor-grown organs, and artificial intelligence could take life-spans regularly beyond 125 years. Birth-rates may drop but populations rise more as wealthy people live much longer, exacerbating inequality and generational divides.

Super-globalisation would see the hypercharging of our interconnected yet competitive world. The importance of nation states would diminish in favour of self-selecting personal networks, unanchored corporations and activist groups, and supranational unions.

Self-driving electric vehicles and ships, delivery drones and hypersonic planes usher in a new era of mobility. Space travel would be routine, and much industry would be located in orbit. A wealth of unimagined energy-using devices, including universal helper robots, would emerge. Energy consumption could rise much faster than anticipated, even if most of it comes from ubiquitous solar cells, super-compact batteries, hydrogen and small advanced nuclear or fusion reactors, instead of fossil fuels.

Planetary stewardship would demand the repair of our damaged and impoverished environment. Unprecedented global cooperation would see huge areas of land returned to the wild, extinct species and ecosystems resurrected. Biological and technological methods would remove carbon dioxide from the atmosphere while carefully calibrated geoengineering slows global warming.

Finally, there is the prospect of defeat by the forces of entropy and chaos. Ever-worsening climate change would combine toxically with other problems: a slowing and ageing world economy, growing inequality, the dystopian effects of social media and mass surveillance, the confrontation between China and the US, failed states in parts of the Middle East and Africa. Lands made uninhabitable by drought, sea-level rise, wildfires and heat waves, mass migration, militarised borders, conflict and new totalitarian systems would send the global economy into a permanent and deepening depression. Energy demand would fall but be very dirty as countries fall back on coal and oil.

Much that is familiar will remain alongside much that seems bizarre or inconceivable today. Its hard for energy companies or energy-rich states to build a strategy in the face of such uncertainties. But it is a reminder that whatever we do today should be robust and flexible, not wedded to a single vision of the future however seductive.

Robin M Mills is CEO of Qamar Energy, and author of The Myth of the Oil Crisis

Updated: December 30, 2019 07:49 AM

Excerpt from:
Energy sector planning needs to be flexible enough to deal with an uncertain future - The National

Recommendation and review posted by Bethany Smith

If you're considering investing in the gene editing sector, it's worth taking some time to look through all the main players in this small but promising biotech market. At the moment, there are just a few noteworthy companies in this space, all of them still at early clinical stages despite commanding market valuations well into the billions of dollars.

CRISPR Therapeutics (NASDAQ:CRSP) is likely the first gene editing stock to come to mind, and it's considered by many to be the leading company in the market, if only by market cap. However, smaller companies, like Sangamo Therapeutics (NASDAQ:SGMO), also have plenty of promise.

If you're wondering which of these two stocks is the better buy, then read below to find out all the details.

Image source: Getty Images.

While different gene editing companies target their own specific conditions, investors will notice that many tend to coalesce around the area of blood disorders. Both CRISPR and Sangamo are working on drug candidates that target sickle cell disease and transfusion-dependent beta thalassemia (TDT), which are disorders that hinder the ability of hemoglobin to carry oxygen around the body.

CRISPR is working on CTX001, which has been used to treat two different patients, one with sickle cell disease and the other with beta thalassemia. Both patients have shown a complete reversal of all key symptoms, with more patients now undergoing CTX001 treatment.

Unlike CTX001, Sangamo has two separate drug candidates, each targeting only one of the blood disorders mentioned above. ST-400 is Sangamo's beta thalassemia drug, while BIVV003 is its sickle cell candidate. Both are being developed alongside Sanofi, which has partnered with Sangamo to develop these drugs.

While BIVV003 is still undergoing early clinical testing, with investors still waiting to see the preliminary results, ST-400 has proven to be an early success so far. Sangamo released data in early December regarding the first three patients treated with ST-400 for TDT, with all of them showing encouraging results with few side effects. Further results are expected to come out in 2020.

Sangamo has a pretty diverse portfolio of drug candidates that are either in preclinical or clinical stages of development, totaling 15 separate projects in comparison to CRISPR's nine. Five of those are in early phase 1/2 trials. Besides Sangamo's sickle cell and beta thalassemia treatments, Sangamo is working on treatments for Fabry disease, Hemophilia A, and Hunter syndrome (also known as mucopolysaccharidosis type 2 or MPS II).

The Hemophilia A treatment, SB-525, showed strong results in its phase 1/2 study earlier this year. Patients with this blood disorder, who experience a lack of a key blood-clotting factor, showed significant improvements in levels of this clotting factor after taking SB-525.

Even patients with severe cases of hemophilia A, which is extremely hard to treat, showed impressive improvements in the levels of this clotting factor. Pfizer, which is partnered with Sangamo to develop SB-525, is now moving toward a new phase 3 trial, which is expected to begin sometime in 2020.

Sangamo's Fabry treatment, ST-920, is still undergoing its own early-stage clinical trials, with little information available at present. The only setback for Sangamo has been in its MPS II drug, SB-913, which ended up failing to significantly help patients with the rare genetic disorder. While the company hasn't given up on SB-913 yet, it's definitely the weak link in an otherwise strong drug portfolio.

CRISPR's drug portfolio is a bit narrower, with only two drugs in clinical testing in comparison to Sangamo's five. Besides the previously mentioned CTX001, CRISPR has a fairly strong cancer immunology lineup. CTX110, CTX120, and CTX130 are its selection of immunology candidates, although CTX110 is the only one in clinical testing at the moment.

Cancer immunology is a massive market that's estimated to reach $127 billion by 2026, and a home run in this area would be a major win for CRISPR. CTX110 is a CAR-T (chimeric antigen receptor T-cell) therapy, a type of treatment in which immune cells are extracted from a patient, retrained outside the body, and later reintroduced into the patient's system in hopes they will perform better. While it's not the only CAR-T therapy being developed, CRISPR's treatment could prove to be much cheaper than current treatments, which cost hundreds of thousands of dollars for a single patient.

CRISPR has had a strong fiscal third quarter, reporting $138.4 million in net income on revenues of $211.9 million. But in 2019, CRISPR has so far only reported $36.3 million in net income, as the earlier quarters reported losses. While it's nice that CRISPR is reporting a profit, something very few early-stage biotech companies can boast, it's still a very small figure considering CRISPR's $3.9 billion market cap.

Sangamo's financials look a lot different. Besides being a fraction of CRISPR's size with a market cap of $970 million, Sangamo's Q3 2019 revenues came in at $21.9 million, while reporting a net loss of $27.4 million for the quarter. However, the company has an impressive $408.3 million in cash and equivalents, enough to last for around four years at the current rate of expenses.

In terms of traditional valuation metrics, it's hard to evaluate clinical-stage biotech stocks by looking at ratios, as their financial figures can change dramatically if a drug candidate receives approval. Currently, CRISPR trades at 16.7 its price to sales (P/S) ratio, but in July, the company was trading at an astronomical 1,800 P/S ratio, meaning that investors were willing to pay extraordinarily high amounts for what little revenue it was making that quarter. In comparison, Sangamo is more moderately priced, with a 12.2 P/S ratio.

Both companies are compelling investments if you're looking for exposure to the gene editing sector. While Sangamo has a broader pipeline of projects, I still think CRISPR is the better choice if you had to pick just one of these companies. CRISPR has not only shown positive clinical results for CTX001 and CTX110, but is also reporting a profit for this most recent quarter, which is pretty rare for early-stage biotech stocks. Meanwhile, Sangamo isn't expected to turn a profit anytime soon.

However, gene-editing drugs are still at an early stage of clinical development, and plenty of things can change over the coming years. Both CRISPR and Sangamo are promising investments for someone who's comfortable buying into early-stage biotech stocks.

Read this article:
Better Buy: CRISPR Therapeutics vs. Sangamo Therapeutics - The Motley Fool

Recommendation and review posted by Bethany Smith

Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the sourcebut significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common Funds Somatic Cell Genome Editing (SCGE) program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing both new CRISPR systems for gene regulation and to regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in using AAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about the Duke Center for Advanced Genomic Technologies.

Read more here:
Duke Researchers Garner Over $6 Million in NIH Funding to Fight Genetic Diseases - Duke Today

Recommendation and review posted by Bethany Smith

The 2010s brought major advancements in every aspect of the life sciences and ushered in an era of collaboration and multidisciplinary approaches. The Scientist spoke with Steven Wiley, a systems biologist at Pacific Northwest National Laboratory and member of TSs editorial board, about what he thinks the recent past indicates about the upcoming decade of research.

Wiley: The next year will be a continuation of the scientific breakthroughs that were present the last couple of years, and whats happened the last couple of years will fundamentally transform the next decade. There are two areas that I think are really posed for an explosive growth, and one is single-cell biology. . . . The second one people know is transformative . . . is CRISPR technologies.

Wiley: Single-cell sequencing, single-cell proteomics, single-cell imagingthese are all part of this new area of single-cell biology which is really going to impact a whole slew of different fields. We'll see a lot of breakthroughs driven by that in the next year, but well see the full impact of this playing out over the next decade.

[Single-cell biology] started [out] driven by single-cell sequencing, and very near on the horizon is going to single-cell proteomics. And then, of course, that complements a lot of the imaging work thats been done, developing a new generation of probes to be able to query whats happening at the single-cell level.

This really brings to the fore the idea that cells in a population are very heterogeneous, and what we see at the population level is a reflection of what the individual cells are doing. And until we understand what the individual cells in a population are doing, we cant deal with issues of, for example, mathematically modeling whats going on in cells.

[Researchers developing] both sequencing technologies and proteomics technology in the last decade have been working on increased sensitivity and speed and precision. This increase in speed and precision and increasingly small sample size has gotten down to a point where now we can look at things like cancer heterogeneity. That is . . . when you treat a cancer you can kill 95 percent of the tumor but theres 5 percent left and that is whats going to come back, and you have a recurrence of the cancer or metastasis. So its the small parts that really cause the problem, and until you can actually understand why those resistant cells are different, youre never going to do things like develop a completely effective cancer treatment.

Now the technology is thereboth sequencing technology and mass spectrometry technologies. It opens up new worlds of what we can look at, and I think thats why this is really being very transformative. Were now at the level where we can look at individual cells. Thats amazing.

Wiley: CRISPR technologieseveryone touts them as a way of editing the genome, which is true. But the true power of that, I believe . . . is the fact that it provides a way of tagging endogenous genes. So for example, you see a number of different papers come out in which people have used CRISPR technologies to insert fluorescent markers into genes. You can look at the dynamics and localization and expression of individual genes and individual cells.

The second thing that CRISPR is really good at is perturbations, being able to turn up genes and down genes, altering the expression of individual genes up and down in a cell with incredible specificity. For example, [with] a genetic disease or in cancer, most of the really significant impactful genetic changes are at the level of increased expression or decreased expression. So the way we think about changing gene expression is: [in] one cell type, the gene is off, [and in] another cell type, the gene is on. But thats not actually true. There are subtle changes in abundance and localization and disposition of individual genes that have enormous regulatory impact on the cells. But weve lacked good tools to [investigate] that.

The ability to manipulate the expression level of genes, to tag them, to make modifications in the individual genes and cells opens up a toolbox of experimental technologies that are just revolutionary.

Editors note: Answers have been edited for length and clarity.

Emma Yasinski is a Florida-based freelance reporter. Follow her on Twitter@EmmaYas24.

Go here to see the original:
The Advances that Will Shape Life Sciences in the 2020s - The Scientist

Recommendation and review posted by Bethany Smith

CRISPR Therapeutics AG [NASDAQ: CRSP] gained by 1.21% on the last trading session, reaching $60.04 price per share at the time. CRISPR Therapeutics AG represents 57.50M in outstanding shares, while the company has a total market value of $3.41B with the latest information.

The CRISPR Therapeutics AG traded at the price of $60.04 with 803450 shares were bought and sold during the latest trading session. Over the period of the last 3 months, the average trading volume of CRSP shares recorded 1.08M.

Its stock price has been found in the range of 27.50 to 74.00. This is compared to its latest closing price of $59.32.

Pay attention to the next-scheduled financial results for this company to be released, which is slated for Mon 24 Feb (In 52 Days).

Now lets turn to look at profitability: with a current Operating Margin for CRISPR Therapeutics AG [CRSP] sitting at -5087.80, this companys Net Margin is now -5.30%. These metrics indicate that this company is not generating as much profit, after accounting for expenses, compared to its market peers.

This companys Return on Total Capital is -54.81, and its Return on Invested Capital has reached -40.70%. Its Return on Equity is -56.89, and its Return on Assets is -43.40. These metrics suggest that this CRISPR Therapeutics AG does a poor job of managing its assets, and likely wont be able to provide successful business outcomes for its investors in the near term.

What about valuation? This companys Enterprise Value to EBITDA is -22.31. The Enterprise Value to Sales for this firm is now 16.31. CRISPR Therapeutics AG [CRSP] has a Price to Book Ratio of 3.78.

Shifting the focus to workforce efficiency, CRISPR Therapeutics AG [CRSP] earns $16,617 for each employee under its payroll. Similarly, this companys Receivables Turnover is 2.30 and its Total Asset Turnover is 0.01. This publicly-traded organizations liquidity data is also interesting: its Quick Ratio is 16.81 and its Current Ratio is 16.81. This company, considering these metrics, has a healthy ratio between its short-term liquid assets and its short-term liabilities, making it a less risky investment.

CRISPR Therapeutics AG [CRSP] has 57.50M shares outstanding, amounting to a total market cap of $3.41B. Its stock price has been found in the range of 27.50 to 74.00. At its current price, it has moved down by -18.86% from its 52-week high, and it has moved up 118.33% from its 52-week low.

This stocks Relative Strength Index (RSI) is at 42.19. This RSI score is good, suggesting this stock is neither overbought or oversold.

Shares of CRISPR Therapeutics AG [CRSP], on the whole, present investors with both positive and negative signals. Wall Street analysts have mixed reviews when it comes to the 12-month price outlook, and this companys financials show a combination of strengths and weaknesses. Based on the price performance, this investment is somewhat risky while presenting reasonable potential for ROI.

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CRISPR Therapeutics AG [CRSP] A Healthcare stock that is highly - The Dwinnex

Recommendation and review posted by Bethany Smith

2019 has seen some astonishing scientific breakthroughs, from the creation of the first ever image of a black hole a feat once thought impossible to the use of DNA splicing technology to treat sickle cell disease.

As the year comes to an end, three of our regular science contributors Daniel Holz of the University of Chicago, Rabiah Mayas of the Museum of Science and Industry and Mark Hammergren of the Adler Planetarium share what they regard as the most significant science stories of the year.

Here are the stories they selected.

Daniel Hotz: First ever image of a black hole

Using the Event Horizon Telescope, scientists obtained an image of the black hole at the center of galaxy M87, outlined by emission from hot gas swirling around it under the influence of strong gravity near its event horizon. (Credits: Event Horizon Telescope collaboration et al.)

In April, an international astronomical team called the Event Horizon Telescope Collaboration produced an image of a black hole for the first time.

Because not even light can escape from the immense gravity well that is a black hole, the idea of imaging a one was once thought impossible. Holz explained that the image the Event Horizon Telescope team produced is actually of super-heated matter about to fall into the black hole.

We are not looking at the black hole itself, what we are doing is seeing stuff fall into the black hole and that stuff gets very, very hot superheated because of the strong gravity and then it glows, said Holz. And what we are seeing is that glow but in the center nothing is glowing and thats because theres a black hole there.

Mayas noted the years of hard work and international collaboration that created what has already become an iconic image. The team used telescopes around the world to, in effect, create one huge telescope the size of the Earth to create the image.

There were scientists and engineers and astronomers from across the globe that came together to generate this image, said Mayas. The shear technology and the instrumentation and the collaboration that led to that is another example of what a career in STEM can look like for young people.

Rabiah Mayas: Gene-edited cells used to treat sickle cell disease

Researchers at the Sarah Cannon Research Institute in Nashville, Tennessee, announced in November that they had used genetically edited cells to treat sickle cell disease a painful and until now incurable condition that impacts millions of people in the United States and around the world.

Doctors used cells from a patients bone marrow that had been modified using CRISPR cas9 gene-splicing technology and reintroduced the cells back into the patients body.

CRISPR cas9 is something that was identified in bacteria as part of a bacterias natural immunity, said Mayas. The way that CRISPR works is that it looks for specific regions of DNA so the genetic information in the cells of many organisms and recognizes the particular sequence. And cas9 is an enzyme that can cut it. So it cuts the DNA, makes a break, and then your cell can put those ends back together.

CRISPR in this case was used to genetically modify the version of hemoglobin which is the protein that is malformed in Sickle Cell and turn it into a different form that is functional, said Mayas.

Within a month, those cells were producing healthy hemoglobin.

Mark Hammergren: Artemis moon mission

NASA is returning to the moon much sooner than it originally planned.

At the direction of President Donald Trump, NASA has been asked to accelerate its Artemis mission and return humans to the moons surface by 2024. The original Artemis schedule would have put humans back on the moon by 2028.

President Trump and his administration have proposed accelerating this return to the moon and came out and said we are going to land humans on the moon a man and a woman on the moon by 2024. And that is the directive given to NASA, said Hammergren. Regardless of what you think of these plans this is a directive to NASA that NASA has to follow.

Mayas noted that although the Artemis mission is to the moon, it is also regarded as a way to answer key questions and test and prove technology that could one day take humans to Mars.

What does it mean to spend time on another solar body? What does it mean to look for water and develop systems on a place that is not Earth in preparation for Mars?

All: Climate change

Activists on the evening of Monday, Oct. 7, 2019 closed down the streets in front of Chicago City Hall and the James R. Thompson Center as they called on Mayor Lori Lightfoot and Gov. J.B. Pritzker to declare a climate emergency. (WTTW News)

Climate change is the defining challenge of our time, according to United Nations Secretary-General Antonio Guterres.

Guterres noted in an introduction to the latest report of the UNs Science Advisory Group, released in September, that the climate is already changing and highlights the far-reaching and dangerous impacts that will unfold for generations to come.

All three of our scientific contributors believe that climate change is one of the top science stories of the year.

I think young people have been telling us for years that they have been concerned about climate change, said Mayas. Young people from indigenous cultures around the world, from black and other marginalized communities in this country and elsewhere have been screaming for a while about climate change in part because we know from data that certain communities suffer the consequences of climate change more than others.

Hammergren said that as a planetary scientist we have to consider the Earth as a system as a whole and that he had seen directly the increase in carbon dioxide in the atmosphere in his astronomical observations.

Holz noted the evidence for global warming was overwhelming at this point.

The last few years have shown just look at the news the wildfires, the storms, the rising sea levels its just this whole parade of disasters. And this is just the beginning, said Holz. I fear for the future.

But Holz also noted that its not yet too late to try and address some of the worst impacts of climate change, particularly as young people around the world have rallied around this issue.

Its not too late, we can all get involved theres lots of things to do and the fact that young people are rising up. It really impacts them the most and we should listen to them, said Holz. Its somewhat embarrassing that we have to have the young, the next generation, to hold us to task.

Related stories:

Field Museums New Meteorite Contains Stardust That Predates the Solar System

Astronomers Take First-Ever Picture of a Black Hole

Climate Simulations Are Mostly Accurate, Study Finds

Climate Activists: The Oceans Are Rising, And So Are We

Excerpt from:
Year in Review: The Top Science Stories of 2019 - WTTW News

Recommendation and review posted by Bethany Smith