-- Retrospective chart review assessing Acthar Gel treatment utilization and patterns in 92 patients suggests improvement in symptoms across three disease states in a real-world setting --

STAINES-UPON-THAMES, United Kingdom, March 4, 2020 /PRNewswire/ --Mallinckrodt plc(NYSE: MNK), a global biopharmaceutical company, today announced findings from a retrospective medical record analysis to assess practice patterns and outcomes of Acthar Gel (repository corticotropin injection) in the treatment of the immune-mediated diseases rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and dermatomyositis/polymyositis (DM/PM). Results of the study were recently published online in Open Access Rheumatology: Research and Reviews.

Acthar Gel is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides. Acthar Gel is approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in RA, including juvenile RA (selected cases may require low-dose maintenance therapy), and for use during an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis).1Please see Important Safety Information for Acthar Gel below.

The study, titled "Treatment with Repository Corticotropin Injection in Patients with Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Dermatomyositis/Polymyositis," examined 92 adult patients (18 years of age) 54 with RA, 30 with SLE and 8 with DM/PM who were treated at 14 U.S. clinical sites with Acthar Gel between January 1, 2011 and February 15, 2016. Researchers collected data on patient demographics, disease and treatment history; Acthar Gel dosing, frequency and duration; concomitant medication use; and physicians' assessments of outcomes and adverse events. Results of the analysis showed that across all three patient populations, the most frequently reported reasons for initiating treatment with Acthar Gel were inadequate response to prior therapies, acute exacerbation or flare of disease, and need for an alternative therapy. The findings also suggest that patients' symptoms improved with Acthar Gel as reported by physicians' impression of overall change after treatment initiation and over the course of the study. Among 57 patients with data on physician impression of change, 78.1 percent of patients with RA, 94.7 percent of patients with SLE and 66.7 percent of patients with DM/PM had a rating of improved. Further, the mean time to best impression of change was 3.42.5 months for RA, 4.32.7 for SLE, and 3.41.6 for DM/PM.

"All three immune-mediated diseases examined in this study can be difficult to manage, and patients can often experience debilitating disease flares and exacerbations," said Tunde Otulana, M.D., Senior Vice President and Chief Medical Officer at Mallinckrodt. "The study suggests that Acthar Gel may have been associated with an improvement in disease exacerbations and symptoms, and it provides insights into real-world practice patterns and outcomes associated with Acthar Gel therapy that may help inform decision-making among clinicians in managing these conditions."

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Further, the study builds on the company's Phase 4 study of Acthar Gel in RA patients (open-label portion, n=259; randomized, placebo-controlled, blinded, withdrawal portion, n=154) presented at the European Congress of Rheumatology 2019 (EULAR), June 12-15 in Madrid. The randomized, placebo-controlled, double-blind two-part study demonstrated that significantly more patients with persistently active RA who met response criteria at week 12 (63 percent of patients in the open-label period who achieved low disease activity (LDA) as assessed by Disease Activity Score 28-joint count Erythrocyte Sedimentation Rate (DAS28-ESR) of <3.2 at 12 weeks) maintained LDA with Acthar Gel (62 percent) versus placebo (43 percent, P<0.05) at week 24. In the double-blind period of the study (weeks 12-24), adverse events (AEs) were reported in 33 percent of the Acthar Gel treatment group and 40 percent of the placebo group. In the open-label period of the study (weeks 0-12), AEs were reported in 38 percent of patients. Overall AEs observed in the study were consistent with previous trials of Acthar Gel. The study was subject to study limitations, including that the results may not be solely attributable to Acthar Gel.

Key Findings:2

Study Limitations:2

The study was funded by Mallinckrodt.

About Rheumatoid ArthritisRA is an autoimmune disease. It is a chronic condition that causes pain, stiffness, and swelling of the jointsall symptoms and signs caused by inflammation.3 An estimated 1.5 million U.S. adults are living with RA.4 Treatment is aimed at stopping inflammation to put the disease in remission and relieve symptoms.5 Nonsteroidal anti-inflammatory drugs are used to ease symptoms whereas corticosteroids, disease-modifying anti-rheumatic drugs and biologics are used to slow down the disease activity.5

About Systemic Lupus ErythematosusSLE is an autoimmune disease in which the immune system produces antibodies to cells within the body leading to widespread inflammation and tissue damage.6 It is the most common form of lupus, a condition that impacts an estimated 1.5 million Americans.7 Ninety percent of those diagnosed with lupus are women, often between the ages of 15-44.8 Lupus is characterized by periods of illness "flares" and remissions and the disease can affect the joints, skin, brain, lungs, kidneys, and blood vessels. Symptoms and signs may include fatigue, pain or swelling in joints, skin rashes, and fevers.6

About Dermatomyositis/PolymyositisDM/PM are rare inflammatory diseases that cause progressive muscle weakness.9 For instance, muscle weakness associated with PM involves those in the hips, thighs, shoulders, upper arms and neck.10 DM also causes skin rashes.9 People of all ages can be affected, though it usually occurs in adults between the ages of 45-60 and is more common in women.11,[12]

ActharGel (repository corticotropin injection) Indications

Acthar Gel (repository corticotropin injection) is indicated for:

IMPORTANT SAFETY INFORMATION

Contraindications

Warnings and Precautions

Adverse Reactions

Other adverse events reported are included in the full Prescribing Information.

Please see fullPrescribing Informationfor additional Important Safety Information.

ABOUT MALLINCKRODTMallinckrodt is a global business consisting of multiple wholly owned subsidiaries that develop, manufacture, market and distribute specialty pharmaceutical products and therapies. The company's Specialty Brands reportable segment's areas of focus include autoimmune and rare diseases in specialty areas like neurology, rheumatology, nephrology, pulmonology and ophthalmology; immunotherapy and neonatal respiratory critical care therapies; analgesics and gastrointestinal products. Its Specialty Generics reportable segment includes specialty generic drugs and active pharmaceutical ingredients. To learn more about Mallinckrodt, visit http://www.mallinckrodt.com.

Mallinckrodt uses its website as a channel of distribution of important company information, such as press releases, investor presentations and other financial information. It also uses its website to expedite public access to time-critical information regarding the company in advance of or in lieu of distributing a press release or a filing with the U.S. Securities and Exchange Commission (SEC) disclosing the same information. Therefore, investors should look to the Investor Relations page of the website for important and time-critical information. Visitors to the website can also register to receive automatic e-mail and other notifications alerting them when new information is made available on the Investor Relations page of the website.

CAUTIONARY STATEMENTS RELATED TO FORWARD-LOOKING STATEMENTSThis release includes forward-looking statements concerning Acthar Gel including its potential impact on patients and anticipated benefits associated with its use. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; issues with product quality, manufacturing or supply, or patient safety issues; and other risks identified and described in more detail in the "Risk Factors" section of Mallinckrodt's most recent Annual Report on Form 10-K and other filings with the SEC, all of which are available on its website. The forward-looking statements made herein speak only as of the date hereof and Mallinckrodt does not assume any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.

CONTACTSFor Trade Media InquiriesCaren BegunGreen Room Communications201-396-8551caren@greenroompr.com

For Financial/Dailies Media InquiriesJim HeinsH+K Strategies212-885-0463jim.heins@hkstrategies.com

Investor Relations Daniel J. Speciale, CPAVice President, Investor Relations and IRO314-654-3638daniel.speciale@mnk.com

Mallinckrodt, the "M" brand mark and theMallinckrodt Pharmaceuticalslogo are trademarks of aMallinckrodtcompany. Other brands are trademarks of aMallinckrodtcompany or their respective owners.2020Mallinckrodt.US-2000329 03/20

References

1 Acthar Gel (repository corticotropin injection) [prescribing information]. Mallinckrodt ARD LLC.2Ho-Mahler N, Turner B, Eaddy M, Hanke ML, Nelson WW. Treatment with repository corticotropin injection in patients with rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis/polymyositis. Open Access Rheumatology: Research and Reviews. 2020:12 21-29.3Mayo Clinic website. Rheumatoid Arthritis. Overview. Available at: https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648. Accessed November 5, 2019.4Arthritis Foundation. What is Rheumatoid Arthritis? Available at: http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/what-is-rheumatoid-arthritis.php. Accessed November 5, 2019.5Arthritis Foundation. Rheumatoid Arthritis Treatment. Available at: http://www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/treatment.php. Accessed November 5, 2019.6The Centers for Disease Control and Prevention. Systemic lupus erythematosus (SLE or lupus). Available at: https://www.cdc.gov/lupus/facts/detailed.html. Accessed March 21, 2019.7Kabadi S, Yeaw J, Bacani AK, Tafesse E, Bos K, Karkare S, et al. Healthcare resource utilization and costs associated with long-term corticosteroid exposure in patients with systemic lupus erythematosus. Lupus. 2018;27:1799-1809. doi: 10.1177/0961203318790675.8Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010; 39(4):257268.9Medline Plus. Myositis. https://medlineplus.gov/myositis.html. Accessed November 3, 2016.10 Mayo Clinic. Polymyositis. http://www.mayoclinic.org/diseases-conditions/polymyositis/basics/symptoms/con-20020710. Accessed November 3, 2016.11Bernatsky S, Joseph L, Pineau CA, et al. Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences. Ann Rheum Dis. 2009;68:1192-1196.12Cheeti A, Panginikkod S. Dermatomyositis and Polymyositis. [Updated 2019 Nov 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532860/.

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Anxiety disorders, which affect 40 million U.S. adults every year, are often characterized by nervousness, near-constant worry, racing thoughts, and other consuming mental health symptoms. But anyone who lives with anxiety knows that it not only affects their mental well-being but their physical comfort, too, from their digestion to their likelihood of getting a decent nights sleep.

Here, well look at some of the ways in which anxiety can affect your physical health and what you can do to reduce its impact on your everyday life.

RELATED: 5 Simple Ways to Be Less Stressed at Work

Gastrointestinal issues, such as indigestion, nausea, diarrhea, cramping, or heartburn, are some of the most common ways in which anxiety manifests itself physically, explains Rebecca Hedrick, M.D., a psychiatrist at Cedars-Sinai. Anxiety triggers the same fight-or-flight reaction in the brain that mortal danger triggered in our prehistoric ancestors, and when those instincts kick in, more blood flows to our muscles and away from our GI tract. As a result, our normal digestive processes slow down or stop. Back in the prehistoric era, wed have a chance to return to a state of rest after confronting a stressor like a predator, but nowadays our stressors come in the form of social media, the 24-hour news cycle, or financial woes theyre chronic, as Dr. Hedrick describes them, and can be too prevalent to avoid.

In addition to chronic gut issues caused by existing in this constant state of responsiveness, rather than rest, there's another factor at play. Digestive issues can also spike with anxiety because when the bodys main stress hormone, cortisol, increases in production, so does stomach acid, explains Michael E. Ford, M.D., an internal medicine physician with NewYork-Presbyterian Medical Group Hudson Valley. Taking an antacid (like Pepcid) should help mitigate this issue, Dr. Ford says.

Again, anxietys effect on sleep is closely tied to that fight-or-flight response when the body is in survival mode, sleep is not a priority. And, as described earlier, living with anxiety means that you shift into that mode pretty easily, and have a hard time shifting out of it. The brain is turned on to either fight or escape, and patients often times awake with ruminative or excessive worry about events in their life, preventing them from falling back asleep, Dr. Ford explains.

Naturally, sleep disturbances can lead to excessive tiredness when youre awake, and thats on top of the fatigue that mental distress naturally causes. Anxiety takes a lot of brain power. It burns a lot of calories; it uses a lot of energy to have all of those anxious thoughts, Dr. Hedrick says. She points out that many people will try to address this problem with caffeine, which only makes their anxiety worse. Instead, she suggests practicing healthy sleep habits like avoiding caffeine, alcohol, and screens before bed, and using a sleep mask or earplugs if needed.

RELATED: Here's How Weighted Blankets Actually Work for Anxiety and Insomnia

According to Jessica Chan, M.D., an assistant professor and ob-gyn specializing in reproductive endocrinology at Cedars-Sinai, anxiety can contribute to irregular periods, fertility issues, and even worse symptoms of menopause. Its impact on menstruation in particular is once again due to the fight-or-flight response that awakens when we feel anxious. That same increase in cortisol that messes with our GI tract also decreases our levels of reproductive hormones, which leads to a lack of ovulation and, in turn, irregular periods, Dr. Chan explains. She adds that if your period has been irregular for three months, you should get in touch with your gynecologist.

The relationship between anxiety and fertility is more complex, Dr. Chan says. On one hand, research shows that people dealing with fertility experience anxiety, stress, and depression at higher rates than those who arent. On the other hand, Dr. Chan believes pre-existing anxiety can lead to issues with fertility, considering anxietys effect on ovulation and menstruation, for one thing. Beyond that, she notes that anxiety can have a negative impact on couples relationships and even lower sufferers libidos, which makes simply having sex, the initial step to conceiving, difficult.

Finally, anxiety can intensify such menopausal symptoms as sleep disturbances and hot flashes (which, Dr. Chan says, can feel very similar to an anxiety attack), as a result of the reproductive hormones estrogen and progesterone decreasing in production. Dr. Chan also says people who had been living with anxiety prior to transitioning into menopause may notice that their anxiety worsens at this point.

This symptom usually crops up as soon as a bout of anxiety begins and it can set off a vicious cycle that only makes those feelings of anxiety worse. Once somebodys heart rate starts racing, a lot people will have palpitations they feel the fluttery feeling of their heartbeat and that feeling itself can trigger worsening anxiety, which can trigger a full panic attack, Dr. Hedrick says. This is yet another side effect of the bodys survival mode, which can be addressed with therapy and practiced relaxation more on that below.

Right off the bat, Dr. Hedrick says to get in the habit of practicing any of the following relaxation techniques: diaphragmatic breathing, where you breathe into your belly as opposed to your chest; progressive muscle relaxation, where you tense and relax your main muscles one at a time; body scanning, where you simply observe the sensations surrounding your body from head to toe; and, finally, mindfulness, in which you observe your feelings and environment in the moment without judgment. Try them out when you dont feel particularly stressed, so that when your anxiety does rise to the surface, you have these techniques down pat.

RELATED: How to Meditate If You Have Anxiety

Itll be incredibly useful to have these tools in your back pocket, but you should also make an appointment with a mental health care professional to learn more about the roots of your anxiety. And, if youre experiencing these physical symptoms on top of anxious thoughts, visit your primary care provider as well as a therapist. Even though anxiety can contribute to issues around sleep, menstruation, and digestion, its important to make sure there isnt an underlying physical condition or illness thats causing them, too.

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How Your Anxiety Might Be Affecting You Physically and What to Do About It - Yahoo Lifestyle

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Dr. Brian Coleisa nationally acclaimed orthopedic surgeon and sports-medicine doctor who cohosts the popular radio showSports Medicine Weekly.Whether you want to know about bunions, better sleep, or running your first marathon without getting hurt, Dr. Cole can offer an experts take. Eric Haunschild, his research assistant, also contributes to this column.Have a question? Email AskADoctor@outsideim.com. The doctor is in.

I keep hearing conflicting things about ibuprofen. My doctor prescribed a steady dose400 milligrams in the morning and 400 in the eveningfor tendonitis, but I always thought it was something to take on an as-needed basis for pain. And 800 milligrams a day sounds like a lot! Also, isnt it bad for my stomach lining? Whats the best, safest way to use ibuprofen?

It sounds like you and your doctor are both right. Ibuprofen can be used to reduce pain and inflammation, but the way you dose depends on which effect you are predominantly trying to achieve. The pain-reducing effects of ibuprofen begin rapidly, usually within 30 minutes of taking a dose, so you can take it as needed, whether you have a headache or an achy knee. To reduce inflammation, ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and Aleve need to be taken regularly over days to quiet the bodys inflammation-producing pathways. For persistent relief of joint pain, you should follow your doctors instructions and take a regular dose as prescribed, even if you arent feeling pain right at that moment.

Its true that ibuprofen can be bad for your stomach and intestines. This is because the same pathway in your body that generates pain and inflammation also produces the mucus in your stomach that protects it from stomach acid. NSAIDs work by blocking cyclooxygenase enzymes, which play a role in producing a type of lipid called prostaglandins, which in turn act like a hormone throughout the body to initiate myriad biologic processes. In particular, they initiate the sensitization of our nerves to send pain signals to the brain, the generation of inflammation in areas where white blood cells signal them to do so, the inhibition of platelet aggregation needed for blood to clot, and the production of the mucous needed to line the stomach. When you take an NSAID, you alter all of these mechanisms, which can, over long periods of time, lead to stomach ulcers and bleeding. Thats why people with gastrointestinal conditions like peptic ulcer disease or Crohns disease, as well as people over the age of 65, shouldnt take NSAIDs without first talking to a doctor. More commonly, taking ibuprofen can cause a mild upset stomach. If you get queasy, take it with food.

As a rule of thumb, you should opt for smaller, more frequent doses when taking NSAIDs. A usual dose is 200 to 400 milligrams every six to eight hours for no more than two weeks. If you miss a dose, dont double up on the next one. Just continue dosing as usual. If you have any questions related to the safety or specific use of NSAIDs, you should consult your physician.

I roll my ankles all the timeon the trail, in heels, when Im just running on the sidewalk. Why? Does this mean I have weak ankles? Are there exercises I can do to make them stronger?And should I be wearing special shoes?

Tweaking your ankle is incredibly common: Americans make more than a million emergency-room visits each year for fractures and sprains of the joint. The ligaments of your ankle are exposed to a lot of stress. They can be torn or strained from a bad ankle roll, but theyre also prone to wear and tear over time with normal movements like walking. Every time you twist your ankle, you contribute to a snowball effect: the ligaments become weaker and more stretched out, which then increases your risk of rolling your ankle again. Without proper treatment, you can develop chronic instability, pain, and degeneration.

Physical therapy that targets and strengthens your ankle stabilizers can go a long way in ensuring your ankle heals correctly. Simple exercises that promote ankle movement in all directions, such as drawing the alphabet in the air with your toes, can help restore range of motion. Calf raises, balancing on one foot, and heel walks can all help strengthen the joint. Once you progress through these exercises, you can further strengthen the ankle with hopping exercises and training with other movements specific to your sport or activity. Find a physical therapist to help you develop your ownpersonalized program.

There arent many conclusive studies about the role of shoe selection in reducing the risk of rolling your ankles. High-top shoes are thought to provide more support, but a number of studies comparing ankle sprains in athletes havent found a meaningful difference between high-top or low-top shoes. There are a number of ankle bracesand taping techniques that can offer supplemental help in stabilizing the ankle. If you feel that additional support helps, theres no reason not to use itbut remember that strong ankle stabilizers are much more critical in preventing future ankle rolls.

For more expert advice, you can follow Dr. Cole on Instagram, Facebook, and Twitter.

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Are You Overdosing on Ibuprofen? - Outside

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If youre looking for a mainstream, or allopathic, physician, there are many ways to find one through a referral from your family doctor, from your health insurance plans network, or from various directories and its easy to check their credentials.

But when seeking practitioners in naturopathic, holistic, integrative and non-Western health care, the search is not so straightforward.

A group of Berks County practitioners in these fields are beginning to solve that problem with Downtown Wellness Berks, or DWB, an organization officially started in November 2018 to create a network of local affiliates, including both practitioners and suppliers of related products such as organic and locally sourced foods. It will share resources, hold informational events and provide a directory for people seeking to live a healthier life.

DWB is the brainchild of Courtney Shober, a certified integrative health coach and other local practitioners who gathered around the Farmhouse Kitchen, a restaurant in West Reading owned by Martie Samuel.

Shober calls the restaurant the gold standard when it comes to clean eating, and it has become a gathering place not only for dining, but for learning about healthful food.

Shober, as the Farmhouse Kitchens educational coordinator, has been facilitating speakers and moderating panel discussions at the Farmhouse Classroom in the restaurant since returning to Berks County three years ago after a 10-year absence.

The 2001 Schuylkill Valley High School graduate had earned a bachelors degree in music industry studies and worked in that field in the New York City area. Finding herself dissatisfied with her career, she decided to make a change, focusing on helping others achieve a healthier life. She enrolled in the Institute for Integrative Nutrition in New York and earned her certification.

When her husband was hired as a teacher in the Reading School District, they moved into the GoggleWorks Apartments in Reading, and Shober embarked on her new career. She quickly found many friends and colleagues in various integrative health fields in the area, and began inviting them to speak at the Farmhouse events.

It was at these events that she and her colleagues saw how hungry their audiences were for information on how to find various healers and places to shop for healthful, organic foods.

Around 2017, they started discussing how they could help with this problem, and, thanks to a suggestion by another of their colleagues, naturopathy practitioner Dr. Henriette Alban, Living in Balance, 103 S. Fifth St., they came up with a plan to establish Humanitarian Social Innovations, a Bethlehem, Northampton County nonprofit, as their fiscal sponsor. They applied for support and were accepted.

They have 21 affiliates who pay $120 a year to be part of DWB, which has a website, http://www.downtownwellnessberks.com, where the affiliates are listed with their contact information and a bit about who they are and what they offer.

These are basically pre-vetted businesses with a shared philosophy and set of values, Shober said. We have spent the past year building a strong foundation, clarifying our mission and establishing committees. Next we will hold community events, probably starting with a Meet the Affiliates night.

Jennifer Dillow, who started Awakened Aloha Health Coaching in Hamburg five years ago, is part of the core group who created DWB.

A Pottsville native who started out as an X-ray technician and taught high school biology, Dillow switched careers when she had her own health problems and was unable to find relief from allopathic physicians.

While studying at the University of Edinburgh in Scotland, she saw that they have a more proactive approach to health care and were open to Eastern and Western medicine. She called this her Aha! moment, and decided to learn about integrative medicine.

She began integrated health coaching about 20 years ago, and is working on a doctorate in natural medicine from Quantum University in Honolulu, Hawaii.

In addition to her own practice, Dillow works for Dr. Jeffrey L. Marrongelle, a nationally known doctor of integrative medicine and owner of Bio Energymed Metabolic Institute, with offices in Schuylkill Haven, Schuylkill County and Fogelsville, Lehigh County.

Ive seen a lot of people who dont have something major going on, she said, but they have chronic fatigue, weight gain where they cant seem to lose any pounds and hormone imbalance. Theres lots of stress, and that wreaks havoc on your body. It affects the pancreas and the thyroid. Once that starts, it sets you up for the perfect storm: the metabolism is off, and all the hormones are affected.

Many people have forgotten what it feels like to feel good. Their body has adapted to accommodate the stress.

Dillow, who is affiliated with Culture Shock Performing Arts Center, a dance studio in Hamburg, encourages clients to do yoga and take classes in the studio, as well as to walk in nature or simply bounce on a trampoline for a while to reduce stress.

She also counsels them, over a six-month period, on healthy eating, the use of essential oils and other tools to maintain their well-being. Each client receives a personalized plan to help them reach their goals. If they wish, she also refers them to specialists in other modalities.

When Dillow was in the process of trying to connect local organic farmers with local eateries, she reached out to Samuel at Farmhouse Kitchen, and stumbled on the community of like-minded people there. She brought in her friend, Crystal Kulpcavage, whose solo practice, A Sense of Purpose, Wyomissing, coaches people in transition.

I help people design and achieve meaningful lives and meaningful careers, Kulpcavage said. No matter how well you eat, how much you exercise or care for your body, youll have difficulty sustaining physical health if something is wrong in your heart and soul.

We all have an inner craving to be proud of who we are and what were doing with our time in this world. My specialty is to help people with their professional wellness.

She said many people want to make a major change in their careers, but inner fears and other barriers keep them stuck. She first helps them with healing practices and character-building practices, developing self-esteem and confidence, and looking at their strengths and weakness and how to improve the latter.

Then she and the client work on setting goals that are both achievable and meaningful. She gives the client support, accountability and motivation as they work together for a minimum of six months.

Kulpcavage said on of her clients, within four months, resigned from a career with which she was unhappy, decided what business to start, got her first paying client, moved across the country, quit smoking and grieved the loss of her father.

Another client, after 35 years in a corporation and many failed attempts at starting a business, within six months retired, chose a business he was proud of and got it off the ground and running. Two years later, he is set to make $500,000 in revenue.

Kulpcavage said she was a software engineer for 12 years, and found herself unsatisfied after some major life-changing events. She went through a program similar to what she does now and added a certification in professional coaching to her bachelors degree in computer science and her MBA.

When she started coming with Dillow to the Farmhouse Kitchen, she was elated to hear about DWB and got on board.

Ive wanted this for a long time, Kulpcavage said. There just wasnt a great place to find out what kind of practitioner people needed to help them. We can refer people. we all understand each other and can match clients with the right practitioner.

Contact Susan L. Pena: specialsections@readingeagle.com.

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Downtown Wellness Berks helps those who seek alternative health care - Reading Eagle

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The one-year major life extension program on the Ocean Surveyor will begin on April 6, 2020.

(Courtesy Damen Shipyards Group)

Offshore staff

GORINCHEM, the Netherlands SGU, Swedens national geological survey agency, has hired Damen Oskarshamnsvarvet for a major life extension program on the survey and research vessel S/V Ocean Surveyor.

It will include the replacement of the all the machinery, bridge, and auxiliary systems including HVAC and a complete overhaul of all remaining equipment. A key aspect of the project will be the conversion of the propulsion and electrical systems from diesel to diesel electric.

According to Damen, the overall objective of the year-long program will be to deliver a modern, low-impact vessel with a good working environment for both the crew and the scientists working on board and better overall accessibility.

Work will begin on the vessel on April 6, 2020 and is scheduled for completion by March 31, 2021.

Built in 1984 in Norway, the Ocean Surveyor is a twin hull, multi-purpose, survey and ROV support vessel constructed using Kevlar / FRP composite for operations mainly in coastal waters.

Measuring 38 m (125 ft) long and 12 m (39 ft) across, the vessel has accommodation for 15 personnel across 12 cabins and is equipped with DPS as well as various fixed hydroacoustic measuring systems. There are two laboratories on board; a wet lab for sediment and environmental sample analysis, and a space with a gamma spectrometer and sediment x-ray for the detailed study of samples.

Bjrn Bergman, operations manager at SGU, said: Ocean Surveyor is a key platform for many marine surveys conducted in Sweden, not only for SGU, but also for other operators hiring the vessels unique surveying facilities.

Damen Oskarshamnsvarvet won the public tender for the contract.

03/03/2020

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Damen to overhaul Swedish survey vessel - Offshore Oil and Gas Magazine

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TAMPA, FLThink of what plastic packaging has done for entire categories. From seedless cucumbers to grapes, and especially berries.

Fresh-cut fruit wouldnt exist without plastic packaging.

Plastic packaging serves many functions grouping, protection, and shelf life extension, said Natalie Shuman, director of trade and retail marketing for Apeel Sciences, Galena, CA. There reality is that we cant eliminate all packaging, but there are areas where we can reduce reliance.

Before joining Apeel, a company working to reduce food waste through shelf life extension technology, Shuman helped to introduce the stand up pouch bag to the grape category under the Sun World brand.

When we launched that bag that is now ubiquitous across the produce department, we were thrilled because of what it did for merchandising and sales, she said. But I didnt think we were thinking, at the time, about what it was doing to contribute to this issue of plastic waste.

Shuman participated in a panel discussion of The Plight of Plastic at the Southeast Produce Councils Southern Exposure conference on Feb. 28.

Over the past few decades, single-use plastic packaging has increased tremendously, said Anabella de Freeman senior manager of sustainability for produce for Walmart Inc., Bentonville, AR. Packaged produce now accounts for more than 50% of produce sales at retail, she said.

And whats more, she said, millennial consumers prefer packaged produce.

Walmart has issued guidelines for the supplier community to meet, including reducing plastic and recycling metrics, but it can be difficult.

Why?

What we think of as recyclable often isnt. The numbered guide on many plastic packages (think, No. 1 through No. 7) denotes the type of plastic, not that facilities exist to recycle it.

Everybody thinks that clamshells are recycled, said Janis McIntosh, director of marketing innovation and sustainability for Naturipe Farms, Salinas, CA. Its called wishcycling. Ive been there. They take it right out and stick it in the landfill.

Most municipal recyclers dont take clamshells because they cant handle paper labels. Paper labels turn to a mush that contaminates the caustic bath used to wash the plastic to prepare it to be sold to plastic manufacturers.

Rigid plastic packaging is an essential component of the berry business, McIntosh said, so the industry is collaborating on efforts to make clamshells recycle-ready with a film label that separates from the plastic.

The panel outlined other types of collaboration the industry can take to minimize the environmental impact, and waste, of plastic packaging.

Brands have to drive demand for the solutions, said Elizabeth Yerecic key account manager for Yerecic Label.

As suppliers we cant do anything to push that without the demand from the brand owners, she says.

Panelists also discussed solutions like top-seal plastic and fiber-based containers, combined with a shelf-life extension like Apeel to reduce reliance on plastic packaging.

The biggest roadblock?

Price. It always comes down to price, McIntosh said.

Film labels cost anywhere from 15% to 40% more than paper labels, and the industry also is looking at challenges due to humidity and temperature that may affect the adhesives shelf life.

When asked what how the market will adapt to the higher cost of these packaging solutions, De Freeman the industry has to work together to mitigate cost.

The easy answer is that nobody wants to pay more for anything else, she said. Thats why we need to come together to really collaborate to find solutions that maybe at first have a cost impact, and investment. We can get a return on that investment by lowering the shrink.

Yerecic Label debuted the following video about the challenge of recycling plastic clamshells at Southern Exposure.

Continued here:
The Plight of Plastics in fresh produce - Produce Blue Book

Recommendation and review posted by Bethany Smith

Global Artificial Intelligence in Life Extension Market Size, Status and Forecast 2020-2027

The Artificial Intelligence in Life Extension Market 2020 report includes the market strategy, market orientation, expert opinion and knowledgeable information. The Artificial Intelligence in Life Extension Industry Report is an in-depth study analyzing the current state of the Artificial Intelligence in Life Extension Market. It provides a brief overview of the market focusing on definitions, classifications, product specifications, manufacturing processes, cost structures, market segmentation, end-use applications and industry chain analysis. The study on Artificial Intelligence in Life Extension Market provides analysis of market covering the industry trends, recent developments in the market and competitive landscape.

It takes into account the CAGR, value, volume, revenue, production, consumption, sales, manufacturing cost, prices, and other key factors related to the global Artificial Intelligence in Life Extension market. All findings and data on the global Artificial Intelligence in Life Extension market provided in the report are calculated, gathered, and verified using advanced and reliable primary and secondary research sources. The regional analysis offered in the report will help you to identify key opportunities of the global Artificial Intelligence in Life Extension market available in different regions and countries.

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Top Key players: Sydney-based IMF Bentham Ltd., Apex Litigation Finance, and Many More.

The report scrutinizes different business approaches and frameworks that pave the way for success in businesses. The report used Porters five techniques for analyzing the Artificial Intelligence in Life Extension Market; it also offers the examination of the global market. To make the report more potent and easy to understand, it consists of info graphics and diagrams. Furthermore, it has different policies and development plans which are presented in summary. It analyzes the technical barriers, other issues, and cost-effectiveness affecting the market.

Global Artificial Intelligence in Life Extension Market Research Report 2020 carries in-depth case studies on the various countries which are involved in the Artificial Intelligence in Life Extension market. The report is segmented according to usage wherever applicable and the report offers all this information for all major countries and associations. It offers an analysis of the technical barriers, other issues, and cost-effectiveness affecting the market. Important contents analyzed and discussed in the report include market size, operation situation, and current & future development trends of the market, market segments, business development, and consumption tendencies. Moreover, the report includes the list of major companies/competitors and their competition data that helps the user to determine their current position in the market and take corrective measures to maintain or increase their share holds.

What questions does the Artificial Intelligence in Life Extension market report answer pertaining to the regional reach of the industry

A short overview of the Artificial Intelligence in Life Extension market scope:

Reasons for Buying this Report

TABLE OF CONTENT:

1 Report Overview

2 Global Growth Trends

3 Market Share by Key Players

4 Breakdown Data by Type and Application

5 United States

6 Europe

7 China

8 Japan

9 Southeast Asia

10 India

11 Central & South America

12 International Players Profiles

13 Market Forecast 2020-2027

14 Analysts Viewpoints/Conclusions

15 Appendix

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Huge opportunity in Litigation Funding Investment Market 2020-2027 with Sydney-based IMF Bentham Ltd., Apex Litigation Finance - News Times

Recommendation and review posted by Bethany Smith

As climate change concerns grow, worldwide efforts to transition to a low-carbon future have also intensified. And although industry analysts agree that the global energy transformation is happening, they are quick to point out that oil exploration activities should not be written off just yet.

Investments in renewable energy have dwarfed upstream spend in recent years. By the end of 2019, investors poured in more than USD 2.5 trillion in increasing global renewable energy capacity, based on estimates by the United Nations Environment Programme (UNEP).

Meanwhile, investment in exploration stood at just USD 60 billion in the same year, as spending in the sector almost halved between 2014 and 2018, according to the International Energy Agency (IEA).

But Bart Cornelissen, who leads Deloitte Middle Easts Energy, Resources and Industrials consulting efforts, believes there is still room for exploration in the low-carbon transition. Exploration will decline over time. But for the time being, it is still very much needed, he says.

As the paradigm shift towards renewable energy shapes oil producers and investors appetite for exploration, Cornelissen also underscores the importance of distinguishing between the short- and long-term perspectives on the industry.

If we look at the longer term, there is an increasing role for less carbon-intensive energy. However, in the near term, we still need a tremendous amount of oil- and gas-related investments, and this is very much driven by the fact that a normal oil field depletes about 7- to 8 percent per year, he explains.

So even if the volume of oil produced remains stable, there is still a need to do a lot of exploration to fill that annual gap. The question is not around oil eventually being taken over by renewables. It is about timing.

Given that certain sectors, such as transportation, are entirely dependent on oil, the world cannot quit fossil fuels right away, he says.

What we need to understand is that even if every car sold today is an electric car,it would still take around 20 to 30 years before all conventional cars are phased out. In that sense, I would say that the future of energy is an evolution, not a revolution, he adds.

Abhay Bhargava, director of Industrial Practice for the Middle East and South Asia at Frost & Sullivan, says the trend of innovating to zero has been a key factor in influencing a reduction in future investments in oil exploration. However, he believes it is incorrect to attribute the decline entirely on the advent of renewables.

Countries will continue their march towards diversifying their energy mix, and increasingly adopt renewables, impacting oil consumption, Bhargava says. We however expect an even greater impact coming from the thrust towards decarbonisation, wherein the world moves towards reducing its carbon footprint, and embracing a circular economy, across all forms of consumption, ranging from near-term measures like electric vehicles to long-term measures that are focused towards energy and resource efficiency.

As a result, he expects oil consumption, and in turn exploration, to continue witnessing a certain decline over the next decade and beyond.

As the energy transition gathers pace, Bhargava says oil companies will focus on enhancing productivity and efficiency of their existing upstream assets, with deferred investments in capital expenditure, unless absolutely necessary.

We can expect this to continue this year, and in the short term. We can also expect increased investments in the relatively newer areas of carbon capture utilization and storage, energy storage, asset reliability and remnant life extension, and Industry 4.0, [which includes] digitalization, analytics, edge computing, sensors, drones, and blockchains, he notes.

Asked about his projections for the upstream industry, Cornelissen predicts the oil market could post a compound annual growth rate of as much as 1% over the next 10 years.

But he warns that near-term developments, including political conflicts, oil production disruptions, or a possible coronavirus pandemic, could have a massive impact on longer-term consumer behavior and the oil market in general.

Criselda Diala-McBride is a Dubai-based freelance journalist with more than 20 years of experience writing and editing articles on oil and gas, finance, aviation, tourism, retail, technology, and property for a range of print and online publications. She can be reached by email at cdiala@gmail.com.

See the rest here:
How is the Renewables Quest Impacting Exploration Appetites? - Rigzone

Recommendation and review posted by Bethany Smith

The success of approved stem cell therapies has caused a surge in interest of biopharma developers in this field; many innovator companies are currently progressing proprietary leads across different phases of clinical development, with cautious optimism

LONDON, March 4, 2020 /PRNewswire/ -- Roots Analysishas announced the addition of "Global Stem Cells Market: Focus on Clinical Therapies, 20202030 (Based on Source (Allogeneic, Autologous); Origin (Adult, Embryonic); Type (Hematopoietic, Mesenchymal, Progenitor); Lineage (Amniotic Fluid, Adipose Tissue, Bone Marrow, Cardiosphere, Chondrocytes, Corneal Tissue, Cord Blood, Dental Pulp, Neural Tissue Placenta, Peripheral Blood, Stromal Cells); and Potency (Multipotent, Pluripotent))" report to its list of offerings.

There is a growing body of evidence supporting the vast applicability and superiority of treatment outcomes of stem cell therapies, compared to conventional treatment options. In fact, the unmet needs within this domain have spurred the establishment of many start-ups in recent years.

To order this 500+ page report, which features 185+ figures and 220+ tables, please visit this link

Key Market Insights

Over 280 stem cell therapies are under development, most of which are allogeneic products

More than 50% of the pipeline candidates are in the mid to late phase trials (phase II and above), and allogenic therapies (majority of which are derived from the bone marrow) make up 65% of the pipeline.

70% of pipeline candidates are based on mesenchymal stem cells

It is worth highlighting that the abovementioned therapies are designed to treat musculoskeletal (22%), neurological (21%) and cardiovascular (15%) disorders. On the other hand, hematopoietic stem cell-based products are mostly being evaluated for the treatment of oncological disorders, primarily hematological malignancies.

Close to 85% stem cell therapy developers are based in North America and Asia-Pacific regions

Within these regions, the US, China, South Korea and Japan, have emerged as key R&D hubs for stem cell therapies. It is worth noting that majority of the initiatives in this domain are driven by small / mid-sized companies

Over 1,500 grants were awarded for stem cell research, since 2015

More than 45% of the total amount was awarded under the R01 mechanism (which supports research projects). The NCI, NHLBI, NICHD, NIDDK, NIGMS and OD emerged as key organizations that have offered financial support for time periods exceeding 25 years as well.

Outsourcing has become indispensable to R&D and manufacturing activity in this domain

Presently, more than 80 industry / non-industry players, based in different regions across the globe, claim to provide contract development and manufacturing services to cater to the unmet needs of therapy developers. Examples include (in alphabetical order) Bio Elpida, Cell and Gene Therapy Catapult, Cell Tech Pharmed, GenCure, KBI Biopharma, Lonza, MEDINET, Nikon CeLL innovation, Roslin Cell Therapies, WuXi Advanced Therapies and YposKesi.

North America and Asia-Pacific markets are anticipated to capture over 80% share by 2030

The stem cell therapies market is anticipated to witness an annualized growth rate of over 30% during the next decade. Interestingly, the market in China / broader Asia-Pacific region is anticipated to grow at a relatively faster rate.

To request a sample copy / brochure of this report, please visit this link

Key Questions Answered

The USD 8.5 billion (by 2030) financial opportunity within the stem cell therapies market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom stem cell therapies are currently considered to be a promising alternatives for the treatment of a myriad of disease indications, with the potential to overcome challenges associated with conventional treatment options. The report includes detailed transcripts of discussions held with the following experts:

The research covers brief profiles of several companies (including those listed below); each profile features an overview of the company, financial information (if available), stem cell therapy portfolio and an informed future outlook.

For additional details, please visit

https://www.rootsanalysis.com/reports/view_document/stem-cells-market/296.html email sales@rootsanalysis.com

You may also be interested in the following titles:

Contact:Gaurav Chaudhary+1(415)800-3415+44(122)391-1091Gaurav.Chaudhary@rootsanalysis.com

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With Over 280 Therapies Under Evaluation, the Stem Cell Therapy Market is Estimated to be Worth USD 8.5 Billion by 2030, Claims Roots Analysis - P&T...

Recommendation and review posted by Bethany Smith

Graft-versus-host disease can occur any time after a transplant when donor bone marrow or stem cells attack the recipient

CytoDyn Inc (), a late-stage biotechnology company, said Wednesday that it has treated its first patient with its lead drug leronlimab (PRO 140), in its Phase 2 clinical trial for graft-versus-host disease (GvHD) under the modified trial protocol.

Graft-versus-host disease can occur at any time after a transplant. It is a rare condition that typically occurs when donor bone marrow or stem cells attack the recipient.

In a statement, the Vancouver, Washington-based company said the modified protocol now includes reduced intensity conditioning (RIC) patients and an open-label design under which all enrollees receive leronlimab. The modified protocol also provides for a 50% increase in the dose of leronlimab to more closely mimic preclinical dosing.

The next review of data by the independent data monitoring committee (IDMC) will occur after the enrollment of 10 patients under the amended protocol after each patient has been dosed for 30 days, said the company.

CytoDyn CEO Nader Pourhassan pointed out that GvHD is a life-threatening complication following bone marrow transplantation in patients with leukemia, who have compromised immune systems due to treatment with aggressive cancer therapies.

We selected GvHD as one of our immunology indications for leronlimab, as it targets and masks the CCR5 receptor on T cells. This receptor on T cells is an important mediator of inflammatory diseases including GvHD, especially in organ damage that is the most frequent cause of death in these patients, said Dr Pourhassan.

Based upon the compelling results in our preclinical studies, we are optimistic about the opportunities for leronlimab to provide a therapy for transplant patients to mitigate GvHD, he added.

A preclinical study by Dr Denis R Burger, CytoDyns former chief science officer, and Daniel Lindner, from the Department of Translational Hematology and Oncology Research, at The Cleveland Clinic, was published in the peer-reviewed journal called the Biology of Blood and Marrow Transplantation.

The US Food and Drug Administration earlier granted orphan drug designation to leronlimab for the prevention of GvHD. The designation provides CytoDyn with various incentives and benefits including seven years of US market exclusivity for leronlimab in GvHD, subject to FDA approval for use in this indication.

Leronlimab was earlier granted Fast Track status by the FDA for the treatment of HIV in combination with the cocktail known as highly active antiretroviral therapy (HAART), and for metastatic triple-negative breast cancer, a rare variety which doesnt respond to some treatments.

Leronlimab has completed nine clinical trials and has been given to 800 patients in HIV treatment programs, without a single drug-related serious adverse event. CytoDyn is developing leronlimab to battle multiple diseases. The company has also filed an IND application and a Phase 2 clinical trial protocol with the FDA to treat patients with NASH - damage caused by a build-up of fat in the liver.

Contact the author Uttara Choudhury at[emailprotected]

Follow her onTwitter:@UttaraProactive

Continued here:
CytoDyn treats first patient with leronlimab in Phase 2 trial for GvHD under modified protocol - Proactive Investors USA & Canada

Recommendation and review posted by Bethany Smith

INTRODUCTION

In recent years, organoids have emerged as powerful tools for basic research, drug screening, and tissue engineering. The organoids formed in vitro show many features of the structural organization and the functional hallmarks of adult or embryonic anatomical structures (1). In addition, the formation of organoids alleviates the need to perform animal studies and provides an attractive platform for robust quantitative studies on the mechanisms regulating organ homeostasis and tissue repair in vivo (1). The formation of organoids usually starts with populations of stem cells. They are therefore expected to be heterogeneous because pluripotent stem cells [induced pluripotent stem cells (pscs) or embryonic stem cells] have been shown to dynamically and stochastically fluctuate from ground to differentiated state (2). In the same vein, LGR5+ intestinal stem cells are reported to contain several distinct populations (3). As such, the formation of organoids involves the inherent capacity of these heterogeneous populations to self-sort and self-pattern to form an organized three-dimensional (3D) architecture (4). However, the rules underlying organoid formation as well as the contribution of intrinsic population heterogeneity to the organoid self-assembly remain poorly understood (5). Consequently, there is a need for novel quantitative approaches at the single-cell level to reliably understand the mechanisms of spatial tissue patterning in 3D organoids, for which microfluidic and quantitative image analysis methods are well suited.

In this work, we use mesenchymal progenitors, alternatively named mesenchymal stromal cells (MSCs), which constitute a self-renewing population with the ability to differentiate into adipocytes, chondrocytes, and osteoblasts (5). Although human MSCs (HMSCs) express high levels of undifferentiation markers (e.g., CD105, CD44, CD73), they constitute a heterogeneous population of cells that exhibit considerable variation in their biophysical properties and epigenetic status, as well as the basal level of expression of genes related to differentiation, immunoregulation, and angiogenesis (6, 7). Nonetheless, their aggregation leads to the formation of highly cohesive 3D spherical structures [which we designate hereafter as mesenchymal bodies (MBs)] with improved biological activities in comparison to 2D cultures (8). However, little is known on how HMSCs self-organize or whether the intrinsic heterogeneity of the population regulates MB formation and individual cell functions in 3D.

The self-aggregation of HMSCs into MBs can recapitulate the early stages of mesenchymal condensation, and it promotes the secretion of paracrine molecules taking part in the process of ossification (9). During mesenchymal condensation in vivo, mesenchymal progenitors self-aggregate and form dense cell-cell contacts that lead to the initiation of bone organogenesis through endochondral (necessitating a chondrogenic intermediate) and intramembranous (direct osteogenic differentiation) ossification (10). In addition, the formation of these 3D MBs in vivo is associated with the secretion of important paracrine molecules such as prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF), which participate in the recruitment of endogenous osteoblasts, osteoclasts, and blood vessels, leading to the initiation/restoration of bone homeostasis (11, 12). In these two ossification processes, the induction of nuclear factor B (NF-B) target genes, such as cyclooxygenase-2 (COX-2), and their downstream products (e.g., PGE2 and VEGF) plays a critical role as developmental regulators of ossification and bone healing (13). However, while mesenchymal condensation is critical for bone organogenesis, there is still a limited understanding on how the cellular spatial organization within 3D MBs regulates the individual cells endocrine functions (14).

In the present work, we interrogate the influence of phenotypic heterogeneity within a population of stem cells on the mechanisms of self-assembly and functional patterning within 3D organoids using HMSCs as a model of heterogeneous progenitor cell population. This is performed using a novel microfluidic platform for high-density formation of mensenchymal bodies, combined with the analysis of individual cells by quantitative image analysis. Our study reveals that the progenitor cell population self-assembles in a developmentally hierarchical manner. We also find that the structural arrangement in mensenchymal bodies is linked with the functional patterning in 3D, through a modulation of the activity of regulatory molecular signaling at a local scale. This study demonstrates the interplay between cell size and differentiation status, which mediates cellular spatial rearrangement in 3D, leading to the regionalized activation of unique biological functions while forming aggregates.

HMSCs are known to constitute a heterogeneous population (6, 7). In this study, fetal HMSCs were derived from the Whartons jelly of the umbilical cord (UC). UC-derived HMSCs are considered to be more primitive than HMSCs derived from adult bone marrow because of their higher proliferative capacity, their ability to form colony-forming unitfibroblast, as well as their lower degree of basal commitment (15). To examine the cellular diversity within the population, HMSCs were first characterized by their expression of membrane markers. Most of the HMSC population consistently expresses CD73, CD90, CD105, and CD146, but not CD31 (an endothelial cell marker), CD34 (a hematopoietic cell marker), CD14 (an immune cell marker), or human leukocyte antigenDR (HLA-DR) (a type of major histocompatibility complex II) (Fig. 1, A to F, and fig. S1, A to C). However, a deeper analysis of the flow cytometric data shows that the HMSC population contains cells of heterogeneous size [coefficient of variation (CV) = 33 to 37%] (Fig. 1, G and I), having a broad distribution in the expression of CD146 (Fig. 1F). Of note, the CD146 level of expression was linked to the size of the cells: The highest levels of CD146 were found for the largest cells (Fig. 1, H and J). Similar correlations with cell size were also observed for CD73, CD90, and CD105 (fig. S1, D to F). In addition, upon specific induction, the HMSC population used in this study successfully adopted an adipogenic (Fig. 1K), an osteogenic (Fig. 1L), or a chondrogenic (Fig. 1M) phenotype, demonstrating their mesenchymal progenitor identity.

(A) Percentage of positive cells for CD31, CD73, CD90, CD105, and CD146 (n = 3). Representative histograms of the distribution of the CD31 (B), CD73 (C), CD90 (D), CD105 (E), and CD146 (F) level of expression are shown. (G) Representative histogram of the forward scatter (FSC) distribution. (H) Correlation between cell size [FSC and side scatter (SSC)] and the level of CD146 expression. (I) Representative histogram of the cell projected area distribution. (J) Representative histogram of the size distribution of the CD146dim, CD146int, and CD146bright (ImageSteam analysis). (K) Representative images of hMSCs differentiated toward adipogenic lineage (Oil Red O staining). (L) Representative images of UC-hMSCs differentiated toward osteogenic lineage in (Alizarin Red S staining). (M) Representative images of UC-hMSCs differentiated toward chondrogenic lineage (Alcian Blue staining in 2D and cryosectioned micromass cultures). Scale bars, 50 m. The images were acquired using a binocular. FITC-A, fluorescein isothiocyanateA; APC-A, allophycocyanin-A.

To interrogate contribution of cellular heterogeneity (i.e., in terms of size and levels of CD marker expression) in the self-organization of HMSCs in 3D, MBs were formed at high density on an integrated microfluidic chip. This was done by encapsulating cells into microfluidic droplets at a density of 380 cells per droplet, with a CV of 24% (fig. S2, A and B). The drops were then immobilized in 250 capillary anchors in a culture chamber, as previously described (Fig. 2, A and B) (16). The loading time for the microfluidic device was about 5 min, after which the typical time for complete formation of MBs was about 4 hours (movie S1), as obtained by measuring the time evolution of the projected area (Fig. 2, C and D) and circularity of individual MBs (Fig. 2E and movie S2). The protocol resulted in the formation of a single MB per anchor (fig. S2C) with an average diameter of 158 m (Fig. 2F), when starting with a seeding concentration of 6 106 cells ml1. The diameter of the aggregates can easily be tuned by modulating the concentration of cells in the seeding solution (fig. S2, A and B). In addition, the complete protocol yielded the reproducible formation of a high-density array of fully viable MBs ready for long-term culture (for the images of the individual fluorescent channel, see Fig. 2G and fig. S2D), as described previously (16). Of interest, the CV of the MB diameter distribution was lower than the CV of the individual cell size and of the cell number in droplets (CV MB diameter = 13.3%, CV cell number per drop = 24%, and CV cell size = 35%), which demonstrates that the production of MBs leads to more homogeneous size conditions, compared with the broad heterogeneity in the cell population.

(A) Chip design. Scale bar, 1 cm. (B) Schematized side view of an anchor through the MB formation and culture protocol. (C) Representative time lapse of an MB formation. Scale bar, 100 m. (D and E) Measurement of the time evolution of the projected area (D) and circularity of each aggregate (E). n = 120 MBs. (F) Distribution of the MB diameter normalized by the mean of each chip (n = 10,072 MBs). (G) Top: Representative images of MBs after agarose gelation and oil-to-medium phase change. Bottom: The same MBs are stained with LIVE/DEAD. Scale bar, 100 m. (H) Representative images of MBs formed in the presence of EDTA, an N-cadherin, or a CD146-conjugated blocking antibody (Ab) (the red color shows the position of the CD146 brightest cells, and the dilution of the antibody was 1/100 and remain in the droplet for the whole experiment). Scale bar, 100 m. The images were acquired using a wide-field microscope.

To gain insight into the cellular components required to initiate the self-organization of HMSCs in 3D, the MB formation was disrupted by altering cell-cell interactions. This was first performed by adding EDTA, a chelating agent of the calcium involved in the formation of cadherin junctions, to the droplet contents. Doing so disrupted the MB formation, as shown in Fig. 2H, where the projected area of the cells increased and the circularity decreased in the presence of EDTA compared with the controls, as previously reported (17). The role of N-cadherins among different types of cadherins was further specified by adding a blocking antibody in the droplets before MB formation. This also led to a disruption of the MB formation, demonstrating that N-cadherin homodimeric interactions are mandatory to initiate the process of HMSC aggregation. CD146 [melanoma cell adhesion molecule (M-CAM)] plays important dual roles: as an adhesion molecule (that binds to Laminin 411) (18) and a marker of the commitment of HMSCs (19). We, thus, interrogate its contribution to MB formation. The addition of a CD146-conjugated blocking antibody also disrupted the formation of the MB (Fig. 2H), demonstrating that cell-cell interactions involving CD146 are also required during MB formation, as reported with other cell types (18). Of note, the brightest signal from the CD146-stained cells was located in the core of the cellular aggregates (Fig. 2H), suggesting that HMSCs self-organize relatively to their degree of commitment.

We found that the population of HMSCs constituted of cells of broad size and expressing different levels of undifferentiated markers [i.e., CD90, CD73, CD105, and CD146 are known to be down-regulated upon differentiation; (20)] and that the cells are capable of self-organizing cohesively in 3D. To better understand how the heterogeneous cells organized within the MBs, we measured how the different cell types composing the population self-assembled spatially in 3D by investigating the role of CD146. For this purpose, the CD146dim and CD146bright cells were separated from the whole HMSC population by flow cytometry (Fig. 3, A and B). The cells were then reseeded on a chip for the MB formation after fluorescently labeling the brighter and/or the dimmer CD146 populations. Image analysis revealed that the CD146bright cells were mostly located in the center of the cellular aggregates, while CD146dim cells were found at the boundaries of the MBs (Fig. 3, C to E, figs. S3A and S5A for confocal images, and movie S1). This organization was stable for a 3-day culture (fig. S3B).

(A) Representative dot plot of the hMSC population separation based on the level of CD146: The CD146dim constitutes 20% of the population expressing the highest levels of CD146; the CD146bright constitutes the 20% of the population expressing the lowest levels of CD146. (B) Fluorescence signal distribution in the CD146dim and CD146bright populations after cell sorting. (C) After cell sorting, the CD146bright or the CD146dim was stained with Vybrant Dil (red) or Vybrant DiO (green), remixed together and allowed to form MBs. Representative images of the CD146bright and CD146dim within the MBs. Scale bar, 100 m (n = 185 MBs). (D) The position of the CD146bright and CD146dim was quantified by correlating the fluorescence signal of the different stained cells as a function of their radial position within the MBs, after the staining of individual population with Vybrant Dil (CD146bright) = 500 and CD146dim (MBs; CD146bright = 85). Error bars show the SD. (E) Schematized representation of the structural organization of MBs. (F and G) RT-qPCR analysis of the relative RUNX-2, CEBP/, and SOX-9 expression to glyceraldehyde-3-phosphate dehydrogenase (GADPH) [Ct (cycle threshold) (D) and relative RNA expression (E)] in the CD146bright and CD146dim populations (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001.

As we found that the CD146bright cells were larger than the CD146dim cells, the cells from the HMSC population were also separated on the basis of their relative size (a parameter that also discriminates the CD90, CD105, and CD73bright from the CD90, CD105, and CD73dim cells; fig. S1, D to F). After reseeding on the chip, the MBs were composed of large cells in the core, while the smallest cells were located at the boundaries, as expected from the previous experiments (fig. S3A). Moreover, we found that the speed of self-assembly of each population is not related to the rearrangement of CD146dim and CD146bright cells in 3D, because the mixing of dissociated cells or the fusion of aggregates made each population give rise to the same structural organization (21). It is well established that CD146bright defines the most undifferentiated HMSCs (20). The heterogeneity in level of commitment between the two subpopulations was therefore checked by reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis to quantify differences in the expression of differentiation markers. The analysis showed that the CD146dim cells expressed higher levels of osteogenic differentiation markers (i.e., RUNX-2) than the CD146bright cells (Fig. 3, F and G).

The level of RUNX-2 expression was also quantified at the protein level using immunocytochemistry and image analysis of the MBs on the microfluidic device by developing a layer-by-layer description of the MBs. This mapping was constructed by estimating the boundaries of each cell in the image from a Voronoi diagram, built around the positions of the cell nuclei stained with 4,6-diamidino-2-phenylindole (DAPI) (Fig. 4A) (22). These estimates were then used to associate the fluorescence signal from each cell with one of the concentric layers (Fig. 4B). Such a mapping provides better resolution for discriminating the spatial heterogeneity of protein expression than simply assigning a fluorescence signal to a defined radial coordinate (fig. S4). Moreover, the reliability of the measurements by quantitative image analysis was confirmed by performing several control experiments. In particular, we verified (i) the specificity of the fluorescence labeling, (ii) the absence of limitation for antibody diffusion, and (iii) the absence of the light path alteration in the 3D structure (fig. S5 and Materials and Methods). Consistent with the qPCR data, we found that HMSCs located at the boundaries of the MBs expressed higher levels of the protein RUNX-2 than the cells located in the core (see Fig. 4, C and D, and fig. S7 for individual experiments).

(A and B) The detection of nuclei within MBs enables the construction of a Voronoi diagram (A) that allows the identification of concentric cell layers (B) within the MBs. (C and D) Representative image (C) and quantitative analysis (D) (error bars represent the SD) of RUNX-2 staining within the cell layers of the MB (Nchips = 3 and nMBs = 458). N.S., nonsignificant. (E to H) Quantitative analysis (E) and representative images (F to H) of N-cadherin staining after methanol/acetone (F) (Nchips = 3 and nMBs = 405), after PFA/Triton X-100 fixation and permeabilization (G) (Nchips = 3 and nMBs = 649), and F-actin staining with phalloidin (H) (Nchips = 3 and nMBs = 421). Scale bars, 20 m. The images were acquired using a wide-field microscope. ***P < 0.001. (I) Schematized representation of the structural organization of MBs.

Thus, as CD146 defines the most undifferentiated and clonogenic cells as well as regulates the trilineage differentiation potential of HMSCs, the results indicate that HMSCs self-organize within MBs based on their initial commitment. The most undifferentiated and largest cells are found in the core (r/R < 0.8), while more differentiated cells positioned in the outer layers of the MBs (r/R > 0.8) (Fig. 4, C to E). In addition, these data reveal that HMSCs are conditioned a priori to occupy a specific location within the MBs.

The commitment of HMSCs is known to regulate their level of CD146 expression and the type of cell-cell adhesion molecules (23), which plays a fundamental role in the structural cohesion of the MBs (Fig. 2H). For this reason, we interrogated the organization of cell-cell junctions after the MB formation through measurements of the N-cadherin and F-actin fluorescence signal distribution. Two different protocols were used to discriminate several forms of N-cadherin interactions. First, paraformaldehyde (PFA) fixation and Triton X-100 permeabilization were used, because they were reported to retain in place only the detergent-insoluble forms of N-cadherin. Alternatively, ice-cold methanol/acetone fixation and permeabilization enabled the detection of all forms of N-cadherins (26). The results show a higher density of total N-cadherins in the core of the MBs (Fig. 4, E and F), while a higher density of F-actin was found in the cell layers located near the edge of the MBs (Fig. 4, E and H). The pattern of F-actin distribution was not related to the agarose gel surrounding the MBs (fig. S5B). These results are consistent with the theories of cell sorting in spheroids that postulate that more adhesive cells (i.e., expressing more N-cadherin or CD146) should be located in the core, while more contractile cells (i.e., containing denser F-actin) are located at the edge of the MBs (24). Moreover, our observations are in accordance with recent results demonstrating that HMSCs establishing higher N-cadherin interactions show reduced osteogenic commitment than HMSCs making fewer N-cadherin contacts, potentially through the modulation of Yap/Taz signaling and cell contractility (23).

In contrast, the most triton-insoluble forms of N-cadherins were located at the boundaries of the HMSC aggregates (Fig. 4, E and G), at the same position as the cells containing the denser F-actin. These results demonstrate that different types of cellular interactions were formed between the core and the edges of the MBs, which correlated with the degree of cell commitment that apparently stabilize the adherens junctions (Fig. 4I) (25).

We found above that the degree of commitment was linked with the pattern of HMSC self-organization in MBs (i.e., formation of adherens junctions), which may also regulate their paracrine functions (26). We therefore interrogated the functional consequences of the cellular organization in MBs by investigating the distribution of VEGF- and PGE2-producing cells.

The specific production of COX-2, VEGF, and two other molecules regulating bone homeostasis such as tumor necrosis factorinducible gene 6 (TSG-6) (27) and stanniocalcin 1 (STC-1) (28) was evaluated by RT-qPCR analysis. An increased transcription (20- to 60-fold) of these molecules was measured in 3D in comparison to the monolayer culture (Fig. 5, A and B). Consistent with this observation, while a very limited level of secreted PGE2 and VEGF was measured by enzyme-linked immunosorbent assay (ELISA) in 2D culture, they were significantly increased (by about 15-fold) upon the aggregation of HMSCs in 3D (Fig. 5C). In addition, to interrogate the specific role of COX-2 [the only inducible enzyme catalyzing the conversion of arachidonic acid into prostanoids; (29)] in PGE2 and VEGF production, indomethacin (a pan-COX inhibitor) was added to the culture medium. Indomethacin abrogated the production of PGE2, and it significantly decreased VEGF secretion (Fig. 5C), which suggests an intricate link between COX-2 expression and the secretion of these two molecules (30, 31).

(A and B) RT-qPCR analysis of the relative TSG-6, COX-2, STC-1, and VEGF expression to GADPH (Ct) (A) and relative RNA expression (B) in the 3D and 2D populations (n3D = 3 and n2D = 3). (C) Quantification by ELISA of the PGE-2 and VEGF secreted by hMSCs cultivated in 2D, as MBs or as MBs treated with indomethacin (nchips = 3 and n2D = 3). (D and E) Representative image (D) and quantitative analysis (E) of COX-2 (Nchips = 13 and nMBs = 2936) and (F) VEGF-A (Nchips = 3 and nMBs = 413) staining within the cell layers of the MBs (error bars represent the SD). Scale bars, 50 m. The images were acquired using a wide-field microscope *P < 0.05; ***P < 0.001; a and b: P < 0.05. (G) Schematized representation of the structural organization of MBs.

To further interrogate the link between the COX-2 and the VEGF-producing cells, their location was analyzed by quantitative image analysis at a layer-by-layer resolution. These measurements showed significantly higher levels of COX-2 in the first two layers, compared with the successive layers of the MBs (Fig. 5, D and E), with a continuous decrease of about 40% of the COX-2 signal between the edge and the core. This pattern of COX-2 distribution was not affected by the MB diameter (fig. S7B). Similar observations were made with VEGF (Fig. 5, D and F), demonstrating that cells at the boundaries of the MBs expressed both COX-2 and VEGF (Fig. 5G). Taken with the measurements of Fig. 5C, these results imply that COX-2 acts as an upstream regulator of PGE2 and VEGF secretion. Conversely, oxygen deprivation was unlikely to occur within the center of the MBs because no hypoxic area was detected through the whole MBs (fig. S5). Consequently, it is unlikely that hypoxia-inducible factor1 (HIF-1) signaling mediates the increase in VEGF expression at the boundaries of the MBs. Note that finding the link between these three molecules requires the 3D format, because the molecules are not detected in 2D. Here, the combination of population-scale measurements (Fig. 5C) and cell layer analysis (Fig. 5, E and F) provides strong evidence for this pathway.

Because variations of COX-2 and adherens junction distribution are colocalized within the MBs (Figs. 4, E to G, and 5, D and E), the results point to a link between the quality of cell-cell interactions and the spatial distribution of the COX-2high cells in 3D. The mechanisms leading to the spatial patterning of COX-2 expression in the MBs were therefore explored using inhibitors of the signaling pathways related to anti-inflammatory molecule production and of the molecular pathways regulating the structural organization (table S3): (i) 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) that inhibits NF-B, a critical transcription factor regulating the level of COX-2 expression (32); (ii) N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) that inhibits the canonical Notch pathway, modulating cell-cell interactions and several differentiation pathways; (iii) Y-27632 (Y27) that inhibits ROCK involved in the bundling of F-actin (i.e., formation of stress fibers) to assess the role of actomyosin organization; and (iv) cytochalasin D (CytoD) that inhibits the polymerization of actin monomers.

While the addition of DAPT had virtually no effect on the ability of the cells to form MBs, Y27 led to MBs with more rounded cells, and both QNZ and CytoD strongly interfered with the MB formation process (Fig. 6, A to C). The results indicate that NF-B activation and the promotion of actin polymerization are critical signaling steps initiating the process of MB formation by HMSCs.

(A) Representative images of MBs formed 1 day after the droplet loading. Scale bar, 100 m. Inhibitors are added to the culture medium before the MB formation. (B and C) Quantitative analysis of the aggregates projected area (B) and shape index (C) in the presence of the different inhibitors. Red lines represent the mean value for each condition. (D and E) Representative images (D) (contrast is adjusted individually for a better visualization of the pattern; scale bar, 100 m; the images were acquired using a wide-field microscope) and quantitative analysis (E) of the COX-2 fluorescence signal intensity normalized by the control value with the different inhibitors. For these longer culturing times, QNZ and CytoD are only added during the phase change to allow the MB formation. Small dots represent one MB. Large dots represent the average normalized COX-2 fluorescence signal per chip. Each color corresponds to a specific chip. *P < 0.05. (F) Estimation of inhibitor effect in the cell layers with the COX-2 signal normalized by the control value. Control: Nchips = 11 and nMBs = 2,204; QNZ: Nchips = 6 and nMBs = 1215; DAPT: Nchips = 3 and nMBs = 658; Y27: Nchips = 4 and nMBs = 709; CytoD: Nchips = 3 and nMBs = 459. *P < 0.05; **P < 0.01; ***P < 0.001. (G) Proposed mechanisms regulating the MB formation and the patterning of their biological functions. (i) Regulation of the formation of MBs. (ii and iii) Spatial patterning of hMSC biological properties within MBs.

To assess the role of NF-B and actin polymerization in the pattern and the level of COX-2 expression in the MBs, QNZ and CytoD were added 1 day after the cell seeding, once the MBs were completely formed. In contrast, Y27 and DAPT were included in the initial droplets and maintained in the culture medium for the whole culture period. Typical images showing the COX-2 signal in these different conditions are shown in Fig. 6D (see also fig. S7 for quantification of the individual experiments). Of note, none of the inhibitors had an effect on Casp3 activation, indicating that they do not induce apoptosis at the concentration used in this study (fig. S8). The levels of COX-2 expression in MBs, after 3 days in culture, were significantly reduced with QNZ, also decreasing after the addition of CytoD (Fig. 6E). By contrast, Y27 and DAPT had no effect on the levels of COX-2 expression. As a consequence, the results demonstrate that a sustained NF-B activity after the MB formation is required to promote COX-2 expression. Moreover, the induction of actin polymerization in MBs constitutes a mandatory step to initiate COX-2 production.

To get a deeper understanding on the local regulation of these signaling pathways, we analyzed at the single-cell resolution the distribution of COX-2 within the MBs. The spatial mapping revealed that the COX-2 fluorescence intensity was mostly attenuated at the edge of the MBs treated with CytoD and QNZ, while more limited change in the pattern of its expression was observed in the presence of Y27 and even less so with DAPT (Fig. 6F). Consequently, the results revealed a strong link between cell phenotype, the capability to form functional adherens junctions, and the local regulation of NF-B and actin polymerization leading to the increased expression of PGE2 and VEGF that are mediated by COX-2 in 3D (Fig. 6G). Together, the results indicate that in 3D cell aggregates, the spatial organization has some implications on the specific activation of signaling pathways, resulting in local functional heterogeneity.

Understanding the mechanisms of the formation and the spatial tissue patterning within organoids requires a characterization at single-cell level in 3D. In this study, we used a novel microfluidic and epifluorescence imaging technology to obtain a precise quantitative mapping of the structure, the position, and the link with individual cell functions within MBs. The image analysis provided quantitative data that were resolved on the scale of the individual cells, yielding measurements on 700,000 cells in situ within over 10,000 MBs.

While the microfluidic technology developed here is very efficient for high-density size-controlled MB formation, the method is prone to some limitations. Chief among them, the cultivation in nanoliter-scale drops may subject the cells to nutrient deprivation and by-product accumulation under static culture conditions. This limits the duration of the culture to a few days, depending on the cell type and droplet size. To overcome this limitation, it is possible to continuously perfuse the chip with fresh culture medium after performing the oil-aqueous phase exchange, as we demonstrated previously (16). Alternatively, it is also possible to maintain the cells in liquid droplets (without using a hydrogel) by resupplying culture medium through the fusion of additional drops at later times. This operation requires, however, a new design of the anchors and additional microfluidic steps (21).

The second major drawback of the method emerges from the large distance between the MBs and the microscope objective, which requires the use of very large working distance objectives. This compounds the difficulty of applying different confocal techniques by limiting the fluorescence intensity of the images, which, in turn, reduces the throughput when 3D image stacks are required. Although we have shown above that wide-field imaging can be used to obtain spatial mappings of spheroid structure and cell functions, true single-cell measurements will need to overcome the limitations on imaging in the future.

A Voronoi segmentation was used to categorize the cells into concentric layers, starting from the edge of the MBs and ending with the cells in the central region (22), which allowed us to measure variations in the structural organization and in the protein expressions on a layer-by-layer basis within the 3D cultures. The MBs were found to organize into a core region of undifferentiated cells, surrounded by a shell of committed cells. This hierarchical organization results from the spatial segregation of an initially heterogeneous population, as is generally the case for populations of pluripotent and somatic stem cells (2, 3, 33). The process of aggregation of HMSCs obtained within a few hours takes place through different stages (Fig. 6G): The first steps of the aggregation of MBs are mediated by N-cadherin interactions. In parallel, NF-B signaling is activated, promoting cell survival by preventing anoikis of suspended cells (34, 35). At later stages, the formation of polymerized F-actin and, to a lesser extent, stress fibers mediates the MB compaction, mainly at the edge of the MBs where the cellular commitment helps the stabilization of adherens junctions. The formation of adherens junctions facilitates the cohesion of the 3D structure, probably through the enhanced - and -catenin availability in the CD146dim/RUNX-2+ cells (36, 37, 38), which are recruited in the CCC complexes of the adherens junctions to promote the stable coupling of the F-actin to the N-cadherin (39), which become more insoluble to Triton X-100 than unbounded N-cadherins.

A functional phenotype that correlates with this hierarchical segregation is an increase in endocrine activity of the cells located at the boundaries of the MBs. COX-2 expression is increased in the outer layers of the MBs, which also contain more functional adherens junctions as well as a sustained NF-B activity in this region. The promoter of COX-2 contains RUNX-2 and NF-B cis-acting elements (40). While RUNX-2 is required for COX-2 expression in mesenchymal cells, its level of expression does not regulate the levels of COX-2 (40). The increased COX-2 expression is, in turn, due to the unbundled form of F-actin (i.e., a more relaxed form of actin, in comparison to the dense stress fibers observed in 2D) near the edge of the MBs, which was reported to sustain NF-B activity (41) and to down-regulate COX-2 transcriptional repressors (42). Therefore, NF-B has a high activity in the outer layers of the MB, where it locally promotes COX-2 expression.

These results show that the 3D culture format may provide some insights to understand the mesenchymal cell behavior in vivo, because we found that the expression of key bone regulatory molecules is spatially regulated as a function of the structural organization of the MBs. The 3D structure obtained here recalls some of the conditions found at the initial steps of intramembranous ossification that occurs after mesenchymal condensation (i.e., no chondrogenic intermediate was found in the MBs). In the developing calvaria, the most undifferentiated mesenchymal cells (e.g., Sca-1+/RUNX-2 cells) are located in the intrasutural mesenchyme, which is surrounded by an osteogenic front containing more committed cells (e.g., Sca-1/RUNX-2+ cells) (43, 44). Similarly, we observed that undifferentiated HMSCs (i.e., CD146bright/RUNX-2 HMSCs) were surrounded by osteogenically committed cells (i.e., CD146dim/RUNX-2+ HMSCs), which also coexpressed pro-osteogenic molecules, namely, COX-2 and its downstream targets, PGE2 and VEGF. While the link between COX-2 and PGE2 is well established, there is also evidence that COX-2 can induce the production of VEGF in different cell types, e.g., colon cancer cells (45), prostate cancer cells (46), sarcoma (47), pancreatic cancer cells (48), retinal Mller cells (49), gastric fibroblasts (50), skin or lung fibroblasts (51). In these cases, the mechanism for VEGF production through COX-2 induction is thought to be linked to PGE-2, either in an autocrine/paracrine manner (52) or in an intracrine manner (53).

Beyond HMSCs, spatial organization related to the level of differentiation and cell size has been documented in growing embryoids and organoids, with more committed cells being positioned in the outer layers (54, 55, 56). Our results show that a similar hierarchical structure can also be obtained through the aggregation of a mixed population of adult progenitors. This suggests that cell sorting, based on the size and commitment, plays a dominant role in organizing stem cell aggregates. This data-driven approach of combining high-throughput 3D culture and multiscale cytometry (16) on complex biological models can be applied further for getting a better understanding of the equilibria that determine the structure and the function of cells within multicellular tumor spheroids, embryoid bodies, or organoids.

HMSCs derived from the Whartons jelly of the UC (HMSCs) [American Type Culture Collection (ATCC) PCS-500-010, LGC, Molsheim, France] were obtained at passage 2. Four different lots of HMSCs were used in this study (lot nos. 60971574, 63739206, 63516504, and 63739206). While the lots were not selected a priori, we found consistent results for COX-2 and CD146 distribution within MBs. HMSCs from the different lots were certified for being CD29, CD44, CD73, CD90, CD105, and CD166 positive (more than 98% of the population is positive for these markers) and CD14, CD31, CD34, and CD45 negative (less than 0.6% of the population is positive for these markers) and to differentiate into adipocytes, chondrocytes, and osteocytes (ATCC, certificates of analysis). HMSCs were maintained in T175 cm2 flasks (Corning, France) and cultivated in a standard CO2 incubator (Binder, Tuttlingen, Germany). The culture medium was composed of modified Eagles medium (-MEM) (Gibco, Life Technologies, Saint Aubin, France) supplemented with 10% (v/v) fetal bovine serum (FBS) (Gibco) and 1% (v/v) penicilin-streptomycin (Gibco). The cells were seeded at 5 103 cells/cm2, subcultivated every week, and the medium was refreshed every 2 days. HMSCs at passage 2 were first expanded until passage 4 [for about five to six population doublings (PDs)], then cryopreserved in 90% (v/v) FBS/10% (v/v) dimethyl sulfoxide (DMSO), and stored in a liquid nitrogen tank. The experiments were carried out with HMSCs at passages 4 to 11 (about 24 to 35 PDs, after passage 2).

HMSCs were harvested by scrapping or trypsinization from T175 cm2 flasks. Then, the cells were incubated in staining buffer [2% FBS in phosphate-buffered saline (PBS)], stained with a mouse anti-human CD146Alexa Fluor 647 (clone P1-H12, BD Biosciences), a mouse anti-human CD31Alexa Fluor 488 (BD Biosciences, San Jose, CA) antibody, a mouse anti-human CD105Alexa Fluor 647 (BD Biosciences, San Jose, CA), a mouse anti-human CD90fluorescein isothiocyanate (FITC) and a mouse anti-human CD73allophycocyanin (APC) (Miltenyi Biotec, Germany), a CD14-APC (Miltenyi Biotec), a CD34-FITC (BioLegend), and an HLA-DRAPC (BD Biosciences).

The percentages of CD73-, CD90-, CD105-, CD146-, CD31-, CD34-, and HLA-DRpositive cells were analyzed using a FACS LSRFortessa (BD Biosciences, San Jose, CA) or an ImageStream (Amnis) flow cytometer. To validate the specificity of the antibody staining, the distributions of fluorescently labeled cells were compared to cells stained with isotype controls: mouse immunoglobulin G1 (IgG1), k-PE-Cy5 (clone MOPC-21, BD Biosciences), and mouse IgG2a K isotype control FITC (BD Biosciences, San Jose, CA). Alternatively, HMSCs were sorted on the basis of their level of expression of CD146 or their size [forward scatter (FSC) and side scatter (SSC)] using a FACSAria III (BD Biosciences, San Jose, CA).

To induce adipogenic differentiation, UC-HMSCs were seeded at 1 104 cells/cm2 in culture medium. The day after, the culture medium was switched to StemPro Adipogenesis Differentiation medium (Life Technologies) supplemented with 10 M rosiglitazone (Sigma-Aldrich) for 2 weeks. To visualize the differentiated adipocytes, the cells were stained with Oil Red O (Sigma-Aldrich). As a control, UC-HMSCs were maintained in culture medium for 2 weeks and stained with Oil Red O, as above.

To induce osteogenic differentiation, UC-HMSCs were seeded at 5 103 cells/cm2 in culture medium. The day after, the culture medium was switched to StemPro Osteogenesis Differentiation medium (Life Technologies) supplemented with 2-nm bone morphogenetic protein 2 (BMP-2) (Sigma-Aldrich) for 2 weeks. To visualize the differentiated osteoblasts, the cells were stained with Alizarin Red S (Sigma-Aldrich). As a control, UC-HMSCs were maintained in culture medium for 2 weeks and stained with Alizarin Red S, as above.

To induce chondrogenic differentiation, UC-HMSCs were seeded at 1 106 cells/ml in a 15-ml conical tube to promote micromass culture. The medium consisted of StemPro Chondrogenic Differentiation medium (Life Technologies). After 3 weeks in culture, the pellets were fixed and cryosectioned and then stained for Alcian Blue 8GX (Sigma-Aldrich). As a control, UC-HMSCs were maintained in 2D using culture medium for 3 weeks and stained with Alcian Blue, as above.

The color images were acquired using a binocular (SMZ18, Nikon) equipped with a camera (D7500, Nikon).

Standard dry-film soft lithography was used for the flow-focusing device (top of the chip) fabrication, while a specific method for the fabrication of the anchors (bottom of the chip) was developed. For the first part, up to five layers of dry-film photoresist consisting of 50-m Eternal Laminar E8020, 33-m Eternal Laminar E8013 (Eternal Materials, Taiwan), and 15-m Alpho NIT215 (Nichigo-Morton, Japan) negative films were successively laminated using an office laminator (PEAK pro PS320) at a temperature of 100C until the desired channel height, either 135, 150, 165, or 200 m, was reached. The photoresist film was then exposed to ultraviolet (Lightningcure, Hamamatsu, Japan) through a photomask of the junction, the channels, and the culture chamber boundaries. The masters were revealed after washing in a 1% (w/w) K2CO3 solution (Sigma-Aldrich). For the anchor fabrication, the molds were designed with RhinoCAM software (MecSoft Corporation, LA) and were fabricated by micromilling a brass plate (CNCMini-Mill/GX, Minitech Machinery, Norcross). The topography of the molds and masters was measured using an optical profilometer (Veeco Wyco NT1100, Veeco, Mannheim, Germany).

For the fabrication of the top of the chip, poly(dimethylsiloxane) [PDMS; SYLGARD 184, Dow Corning, 1:10 (w/w) ratio of curing agent to bulk material] was poured over the master and cured for 2 hours at 70C. For the fabrication of the bottom of the chip, the molds for the anchors were covered with PDMS. Then, a glass slide was immersed into uncured PDMS, above the anchors. The mold was lastly heated on a hot plate at 180C for 15 min. The top and the bottom of the chip were sealed after plasma treatment (Harrick, Ithaca). The chips were filled three times with Novec Surface Modifier (3M, Paris, France), a fluoropolymer coating agent, for 30 min at 110C on a hot plate.

HMSCs were harvested with TrypLE at 60 to 70% confluence, and a solution containing 6 105 cells in 70 l of medium was mixed with 30 l of a 3% (w/v) liquid low-melting agarose solution (i.e., stored at 37C) (Sigma-Aldrich, Saint Quentin Fallavier, France) diluted in culture medium containing gentamicin (50 g/ml; Sigma-Aldrich) (1:3, v/v), resulting in a 100-l solution of 6 106 cells/ml in 0.9% (w/v) agarose.

HMSCs and agarose were loaded into a 100-l glass syringe (SGE, Analytical Science, France), while Fluorinert FC-40 oil (3M, Paris, France) containing 1% (w/w) PEG-di-Krytox surfactant (RAN Biotechnologies, Beverly, USA) was loaded into a 1- and 2.5-ml glass syringes (SGE, Analytical Science). Droplets of cell-liquid agarose were generated in the FC-40 containing PEG-di-Krytox, at the flow-focusing junction, by controlling the flow rates using syringe pumps (neMESYS Low-Pressure Syringe Pump, Cetoni GmbH, Korbussen, Germany) (table S1). After complete loading, the chips were immersed in PBS, and the cells were allowed to settle down and to organize as MBs overnight in the CO2 incubator. Then, the agarose was gelled at 4C for 30 min, after which the PEG-di-Krytox was extensively washed in flushing pure FC-40 in the culture chamber. After washing, cell culture medium was injected to replace the FC-40. All flow rates are indicated in table S1. Further operations were allowed by gelling the agarose in the droplets, such that the resulting beads were retained mechanically in the traps rather than by capillary forces (Fig. 2G). This step allowed the exchange of the oil surrounding the droplets by an aqueous solution, for example, to bring fresh medium for long-term culture, chemical stimuli, or the different solutions required for cell staining.

For the live imaging of the MB formation, the chips were immersed in PBS and then were incubated for 24 hours in a microscope incubator equipped with temperature, CO2, and hygrometry controllers (Okolab, Pozzuoli, Italy). The cells were imaged every 20 min.

2D cultures or MBs were washed in PBS and incubated with a 5 M NucView 488 caspase-3 substrate (Interchim, Montluon, France) diluted in PBS. After washing with PBS, HMSCs were fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. The samples were blocked with 5% (v/v) FBS in PBS for 30 min and incubated with a rabbit polyclonal antiCOX-2 primary antibody (ab15191, Abcam, Cambridge, UK) diluted at 1:100 in 1% (v/v) FBS for 4 hours. After washing with PBS, the samples were incubated with an Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS for 90 min. Last, the cells were counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

The same protocol was used for the staining of VEGF-Aexpressing cells using a rabbit anti-human VEGF-A monoclonal antibody (ab52917, Abcam, Cambridge, UK), which was revealed using the same secondary antibody as above. RUNX-2positive cells were similarly stained using a mouse anti-human RUNX-2 monoclonal antibody (ab76956, Abcam, Cambridge, UK), which was revealed using an Alexa Fluor 488 goat anti-mouse IgG2a secondary antibody (A-21131, Life Technologies, Saint Aubin, France), both diluted at 1:100 in 1% (v/v) FBS.

To measure potential induction of hypoxia within the core of the MBs, the cells were stained with Image-iT Red Hypoxia Reagent (Invitrogen) for 3 hours and then imaged using a fluorescence microscope. As a positive control, the chips containing the MBs were immersed into PBS, incubated overnight in an incubator set at 37C under 3% O2/5% CO2, and lastly imaged as above.

To interrogate the contribution of signaling related to anti-inflammatory molecule production (COX-2 and NF-B) or molecular pathways regulated by the cell structural organization (Notch, ROCK, and F-actin), several small molecules inducing their inhibition were added to the culture medium (table S1). For all the conditions, the final concentration of DMSO was below 0.1% (v/v) in the culture medium.

The cell viability was assessed using LIVE/DEAD staining kit (Molecular Probes, Life Technologies). The MBs were incubated for 30 min in PBS containing 1 M calcein AM and 2 M ethidium homodimer-1, in flushing 100 l of the solution. The samples were then washed with PBS and imaged under a motorized fluorescence microscope (Nikon, France).

For the detection of the functional forms of N-cadherins (i.e., the N-cadherins closely linked to the actin network, which are PFA insoluble), the MBs were fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. Alternatively, the aggregates were incubated for 5 min with 100% cold methanol followed by 1 min with cold acetone, for the detection of total N-cadherins (i.e., the PFA-soluble and PFA-insoluble forms).

Then, the samples were blocked with 5% (v/v) FBS in PBS for 30 min and incubated with a rabbit polyclonal antiN-cadherin primary antibody (ab18203, Abcam, Cambridge, UK) diluted at 1:100 in 1% (v/v) FBS for 4 hours. After washing with PBS, the samples were incubated with an Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS for 90 min. Last, the cells were counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

For the quantification of the polymerized form of actin (F-actin), the MBs were first fixed with a 4% (w/v) PFA (Alpha Aesar, Heysham, UK) for 30 min and permeabilized with 0.2 to 0.5% (v/v) Triton X-100 (Sigma-Aldrich) for 5 min. The samples were then blocked with a 5% (v/v) FBS solution and incubated for 90 min in a 1:100 phalloidinAlexa Fluor 594 (Life Technologies) diluted in a 1% (v/v) FBS solution. The cells were then counterstained with 0.2 M DAPI for 5 min (Sigma-Aldrich) and then washed with PBS.

To ensure the specificity of the antibody to COX-2 and N-cadherin, control UC-HMSCs were permeabilized, fixed, and incubated only with the secondary antibody (Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG), as above. The absence of fluorescence signal indicated the specific staining for intracellular COX-2 and N-cadherin.

Next, to validate that the distribution of the fluorescence intensity was not related to any antibody diffusion limitation, the MBs were fixed and permeabilized, as above. For this assay, the MBs were not subjected to any blocking buffer. The cells were incubated for 90 min with the Alexa Fluor 594conjugated goat polyclonal anti-rabbit IgG secondary antibody (A-11012, Life Technologies, Saint Aubin, France) diluted at 1:100 in 1% (v/v) FBS. Then, the cells were counterstained for DAPI, as above. Last, the MBs were collected from the chip, deposed on a glass slide, and imaged.

For the analysis of COX-2 expression by flow cytometry, the total MBs were recovered from the chip. The MBs were then trypsinized and triturated to obtain single-cell suspension. UC-HMSCs were stained for COX-2, as above. The percentage of COX-2positive cells was quantified on 5 103 dissociated UC-HMSCs using a Guava easyCyte Flow Cytometer (Merck Millipore, Guyancourt, France). The results were compared to the fluorescence intensity distribution obtained by image analysis.

To interrogate the influence of the MB opacity in the COX-2 and N-cadherin fluorescence signals, the samples were treated by the Clear(T2) method after immunostaining (57). Briefly, the MBs were incubated for 10 min in 25% (v/v) formamide/10% (w/v) polyethylene glycol (PEG) (Sigma-Aldrich), then for 5 min in 50% (v/v) formamide/20% (w/v) PEG, and lastly for 60 min in 50% (v/v) formamide/20% (w/v) PEG, before their imaging. The fluorescence signal distribution was compared with the noncleared samples.

The MBs were collected from the chip and then fixed using PFA, as above. The MBs were incubated overnight in a 30% sucrose solution at 4C. Then, the sucrose solution was exchanged to O.C.T. medium (optimal cutting temperature; Tissue-Tek) in inclusion molds, which were slowly cooled down using dry ice in ethanol. The molds were then placed at 80C. On the day of the experiments, the O.C.T. blocks were cut at 7 m using a cryostat (CM3050 S, Leica). The cryosections were placed on glass slides (SuperFrost Plus Adhesion, Thermo Fisher Scientific), dried at 37C, and rehydrated using PBS. The cryosections were permeabilized and stained for COX-2, as above. The slides were lastly mounted in mounting medium containing DAPI (Fluoromount-G, Invitrogen).

All the images used for the quantitative analysis were taken using a motorized wide-field microscope (Ti, Eclipse, Nikon), equipped with a CMOS (complementary metal-oxide semiconductor) camera (ORCA-Flash4.0, Hamamatsu) and a fluorescence light-emitting diode source (Spectra X, Lumencor). The images were taken with a 10 objective with a 4-mm working distance (extra-long working distance) and a 0.45 numerical aperture (NA) (Plan Apo , Nikon).

For control experiments, images were taken using a motorized (Ti2, Nikon) confocal spinning disc microscope equipped with lasers (W1, Yokogawa) and the same camera and objective as above. Alternatively, the samples were imaged with a multiphoton microscope (TCS SP8 NLO, MP, Leica). The objective was an HCX PL APO CS 10, 0.40 NA, working distance of 2.2 mm (Leica).

All immunostained samples were counterstained with DAPI, and most of the images (i.e., for N-cadherin, COX-2, VEGF-A, and F-actin) were taken using red light excitation that is known to penetrate deeper into the 3D objects than dyes emitting at lower weight length (e.g., DAPI, FITC). For wide-field microscopy, the focal plane was defined as the area containing the maximal number of DAPI-stained nuclei covering the focal area, while z stacks were taken for the whole in-focus planes containing DAPI-stained nuclei using spinning discs and two-photon confocal microscopy.

Wide-field imaging is sensitive for the emission of fluorescence from inside and outside the focal plane (i.e., from the out-of-focus upper and bottom planes of the spheroids) (58). Consistently, more DAPI signal from nuclei is emitted from the core than in the edges of MBs using epifluorescence microscopy (fig. S5I). We confirmed that our interpretation of the signal distribution from epifluorescence images was consistent with confocal and two-photon microscopy by comparing with images taken from the median z plane and the maximal z projection (fig. S5, N to P).

Consequently, the results unambiguously demonstrate that even if there are more cells in the z plane of the middle area of the MBs, the contribution of the out-of-focus signal from N-cadherin, COX-2, VEGF-A, and F-actin staining in this area of the MBs is minimal using wide-field imaging. Because of the higher throughput of wide-field microscopy, this method was chosen to quantitatively analyze the distribution of these immunolabeled proteins within MBs.

The culture supernatants of six-well plates were collected, while the total medium content of the chip was recovered by flushing the culture chamber with pure oil. A PGE2 human ELISA kit (ab133055, Abcam, Cambridge, UK) was used for the quantification of PGE2 concentration in the culture supernatant, following the manufacturers instructions. Briefly, a polynomial standard curve of PGE2 concentration derived from the serial dilution of a PGE2 standard solution was generated (r2 > 0.9). The absorbance was measured using a plate reader (Chameleon, Hidex, Finland).

A VEGF-A human ELISA kit (Ab119566, Abcam, Cambridge, UK) was used for the quantification of VEGF-A concentration in the culture supernatant of 2D cultures or from the chips. A linear standard curve of VEGF-A concentration derived from the serial dilution of a VEGF-A standard solution was generated (r2 > 0.9). The absorbance was measured using a plate reader (Chameleon, Hidex, Finland).

The total MBs of a 3-day culture period were harvested from the chips, as described above. Alternatively, cells cultured on regular six-well plates were recovered using trypsin after the same cultivation time; CD146dim and CD146bright isolated cells were immediately treated for RNA extraction after sorting. The total RNA of 1 104 cells were extracted and converted to complementary DNA (cDNA) using SuperScript III CellsDirect cDNA Synthesis System (18080200, Invitrogen, Life Technologies), following the manufacturers instructions. After cell lysis, a comparable quality of the extracted RNA was observed using a bleach agarose gel, and similar RNA purity was obtained by measurement of the optical density at 260 and 280 nm using a NanoDrop spectrophotometer (Thermo Fisher Scientific, Wilmington, DE) between total RNA preparations from 2D and on-chip cultures.

The cDNA was amplified using a GoTaq qPCR Master Mix (Promega, Charbonnieres, France) or a FastStart Universal SYBR Green Master Mix (containing Rox) (Roche) and primers (Life Technologies, Saint Aubin, France or Eurofins Scientific, France) at the specified melting temperature (Tm) (table S2) using a MiniOpticon (Bio-Rad) or a QuantStudio 3 (Thermo Fisher Scientific) thermocycler. As a negative control, water and total RNA served as template for PCR. To validate the specificity of the PCR, the amplicons were analyzed by dissociation curve and subsequent loading on a 2.5% (w/v) agarose gel and migration at 100 V for 40 min. The PCR products were revealed by ethidium bromide (Sigma-Aldrich) staining, and the gels were imaged using a transilluminator. The analysis of the samples not subjected to reverse transcription (RT) indicated negligible genomic DNA contamination (i.e., <0.1%), while no amplification signal was observed for the water template (no template control). The amount of TSG-6, COX-2, STC-1, VEGF-A, RUNX-2, CEBP-, and SOX-9 transcripts was normalized to the endogenous reference [glyceraldehyde-3-phosphate dehydrogenase (GADPH)], and the relative expression to a calibrator (2D cultures) was given by 2Ct calculation. At least five biological replicates of 2D and on-chip cultures were analyzed by at least duplicate measurements. The standard curves for GADPH, TSG-6, COX-2, and STC-1 were performed using a five serial dilution of the cDNA templates and indicated almost 100% PCR efficiency.

The image analysis allowed us to perform a multiscale analysis (16) of the MBs. For each chip, single images of the anchors were acquired automatically with the motorized stage of the microscope. The analysis was conducted on a montage of the detected anchors using a custom MATLAB code (r2016a, MathWorks, Natick, MA). Two distinct routines were used: one with bright-field detection and one for the fluorescence experiments.

For the bright field-detection described previously (16), the cells were detected in each anchor as pixels with high values of the intensity gradient. This allowed for each cell aggregate to compute morphological parameters such as the projected area A and the shape index SI that quantifies the circularity of an objectSI=4APwhere P is the perimeter. Shape index values range from 0 to 1, with 1 being assigned for perfect disk.

The MB detection with fluorescence staining (DAPI/Casp3/COX-2, DAPI/phalloidin, DAPI/N-cadherin, or LIVE/DEAD) was performed as described previously (16). First, morphological data were extracted at the MB level, such as the equivalent diameter of the MBs or the shape index. Also, the mean fluorescence signal of each MB was defined as the subtraction of the local background from the mean raw intensity.

At the cellular level, two different methods were used, both relying on the detection of the nuclei centers with the DAPI fluorescence signal. On the one hand, each cell location could be assigned to a normalized distance from the MB center (r/R) to correlate a nuclear fluorescence signal with a position in the MB, as previously described (16). On the other hand, the cell shapes inside the MBs were approximated by constructing Voronoi diagrams on the detected nuclei centers. Basically, the edges of the Voronoi cells are formed by the perpendicular bisectors of the segments between the neighboring cell centers. These Voronoi cells were used to quantify the cellular cytoplasmic signal (COX-2, F-actin and N-cadherin, VEGF and RUNX-2). In detail, to account for the variability of the cytoplasmic signal across the entire cell (nucleus included), the fluorescence signal of a single cell was defined as the mean signal of the 10% highest pixels of the corresponding Voronoi cell.

Image processing was also used to get quantitative data on 2D cultures, as previously described (16). Last, different normalization procedures were chosen in this paper. When an effect was quantified compared with a control condition, the test values were divided by the mean control value, and the significance was tested against 1. For some other data, the values were simply normalized by the corresponding mean at the chip level to discard the interchip variation from the analysis.

*P < 0.05; **P < 0.01; ***P < 0.001; NS, nonsignificant. Details of each statistical test and P values can be found in table S4.

Acknowledgments: C. Frot is gratefully acknowledged for the help with the microfabrication, and F. Soares da Silva is gratefully acknowledged for the help in flow cytometry. The group of Biomaterials and Microfluidics (BMCF) of the Center for Innovation and Technological Research as well as the Center for Translational Science (CRT)Cytometry and Biomarkers Unit of Technology and Service (CB UTechS is also acknowledged for the access to the microfabrication and flow cytometry platform at the Institut Pasteur). Funding: The research leading to these results received funding from the European Research Council (ERC) grant agreement 278248 Multicell. Author contributions: S.S., C.N.B., and A.C. conceived the experiments. S.S. performed the experiments. R.F.-X.T. wrote the image processing code and performed the image analysis. R.F.-X.T., S.S., G.A., and A.B. performed the image and data analyses. S.S., C.N.B., and A.C. discussed the results and wrote the manuscript. All authors discussed the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Mapping the structure and biological functions within mesenchymal bodies using microfluidics - Science Advances

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By Partnered Content Mar 2, 2020

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Most of you reading this would have probably never heard of such a disease. My hope is, after taking time to read this, that you will know what myeloma is and have a better understanding of bone marrow cancer in general.

So, lets get started!

Your bone marrow is the factory where all your blood cells are made. This includes red blood cells (they carry the oxygen in your blood), white blood cells (your bodys defence against infections) and platelets (small fragments that prevent and stop bleeding).

The production of these cells by the bone marrow is very well controlled by your body, both in terms of the amount and the type of cells produced. If you have an infection, for instance, your body tells the stem cells in your bone marrow to make more white blood cells to help fight the infection. In such instances, an immature, baby cell gets produced in your bone marrow which then needs to go through various stages of growth and development to become a mature white blood cell. It is then released from the bone marrow into your bloodstream to go and do the job it was destined for, to fight the infection.

This process usually runs quite smoothly, but things can, unfortunately go horribly wrong. Sometimes your body makes a mistake in the production of a white blood cell, almost like a programming error which occurs in the DNA (blueprint) of the cell. It often recognizes its mistake and corrects it, but occasionally this abnormal cell has the ability to hide from your bodys defences, doesnt listen to your bodys commands anymore and can start to increase in number without anything controlling it. This causes a variety of problems and is then called cancer.

Depending on the type of white blood cell and where in its development the programming error occurs, a person can either develop a type of bone marrow cancer (usually leukaemia or myeloma) or lymphoma (glandular cancer), which is also a type of cancer that develops from an abnormal white blood cell.

That brings us to myeloma (also called multiple myeloma or plasma cell myeloma). Myeloma is a type of bone marrow cancer that develops when a programming error occurs in the development of a specific type of white blood cell, called a plasma cell. To understand myeloma better, it is important to understand what role a plasma cell plays under normal circumstances.

They are indeed an integral part of your bodys immune system. Any infection that you may develop gets recognized by your plasma cells. They respond by rapidly producing small proteins called antibodies, which are almost like homing missiles, programmed to go and destroy only that specific virus or bacteria that is making you ill.

After an infection, some of the antibodies remain in your bloodstream and if you are exposed to that exact virus or bacteria again, they are ready to attack immediately, thereby limiting the infection. This is the rationale behind childhood vaccination; to stimulate the production of antibodies which patrol your bloodstream and protect you when you get exposed to infections like measles, polio and many others.

If these plasma cells become cancerous however, they rapidly increase in number, taking over the bone marrow and producing a massive amount of an abnormal antibody which can cause a whole array of problems. This increase in antibody levels in the bloodstream can be measured with a blood test and is also used to monitor the response to treatment.. What are thesymptoms of myeloma?

The abnormal plasma cells in the bone marrow overwhelms the normal bone marrow which most commonly leads to an inability to produce enough red blood cells. This is called anaemia. Symptoms of anaemia are related to the bodys inability to carry sufficient oxygen to your organs and include worsening fatigue, shortness of breath and dizziness.

The abnormal plasma cells also have the ability to weaken your bones. This can either be a generalized loss of bone strength (called osteoporosis), or it can lead to numerous holes being eaten in your bones. This can be seen on an X-Ray or other types of scans. It often results in significant bone pain or even worse, severe fractures with minimal- or even no trauma at all.

Bones are rich in calcium, and if they are being eaten away, their calcium content is released into the bloodstream causing an elevated blood calcium level. This can lead to dehydration, kidney failure and numerous other symptoms.

As mentioned before, the plasma cells in the bone marrow releases a massive amount of abnormal antibodies into the bloodstream. They can clog up your kidneys and cause significant- and often irreversible kidney failure. This can seriously complicate the management of the disease.

These are by far the most common features of myeloma:

Anaemia, bone lesions or fractures, hypercalcaemia and kidney failure.There are numerous other symptoms which can occur, albeit less common.

Is myeloma treatable?

Myeloma is indeed a treatable condition, but there are a couple of important treatment principles to understand.

For most people, myeloma is not a curable disease. It can, however, be carefully managed and the aim of treatment is to provide a good quality of life for as many years as possible. No patients disease is the same and where we sometimes have patients with myeloma living in excess of ten years after being diagnosed, other patients are unfortunately less fortunate and have a form of the disease that is resistant to treatment which can take its toll after only a couple of months.

We perform DNA-tests on the cancer cells and look at various other blood results in an attempt to identify those patients with high-risk disease, who potentially need more intense treatment than others.

The goal of treatment is to destroy as many abnormal plasma cells in the bone marrow as possible. This leads to recovery of the normal bone marrow and minimises the risk of any further complications, giving the body a chance to recover from any complications caused prior to treatment.

For many decades, the backbone of the treatment for myeloma was a combination of two different type of drugs: Chemotherapy and high dosages of cortisone. This is usually quite well tolerated.

The last couple of years, however, have seen an explosion of newer therapies for the treatment of myeloma. This started years ago with the discovery that Thalidomide, was extremely effective for the treatment of myeloma. Soon, more of these so-called novel therapies were developed, leading to a significant increase in the survival of patients who have access to these drugs.

The latest and most impressive of these treatments are certainly the development of monoclonal antibodies and CAR-T cells, both of which are extremely effective even in high risk or resistant myeloma. There is so much excitement about all the newer therapies, but access remains a challenge in theSouth African market.

A strong collaborative effort is required amongst pharmaceutical companies, government and medical schemes, to improve the current access of newer drugs. Nevertheless, some of these drugs have been around for many years and the costs have come down considerably, making it accessible to more people.

The initial treatment of myeloma generally consists of varying combinations of these drugs depending on the patients age, physical condition and of course, the available funding.

We usually use 3 different drugs in combination (a so-called triplet regimen) which has been proven to be very effective. Once the treatment is started, we take blood regularly to monitor the abnormal antibody levels in the blood which, as mentioned earlier, is a surrogate indicator of the number of cancer cells remaining in the bone marrow.

If we dont see a significant downward trend, the disease is likely resistant to that specific treatment combination and treatment should be adjusted accordingly. However, if the antibody levels come down significantly, we are on the right track and can continue with the same treatment until an optimal response is obtained or the development of side-effects forces us to make an adjustment.

After 4-6 months of treatment, the hope is to see no sign of any abnormal antibodies or cancer cells anymore (we call this a remission), or at least a dramatic reduction. We do however know that although we sometimes dont pick up any sign of residual disease, it is merely because the available tests are not sensitive enough. There will always be some cancer cells that remain.

As a general principle, however, the less residual disease, the longer it usually takes before it causes problems again. Because of this, we usually treat younger patients more aggressively in an attempt to obtain a deeper remission. The biggest difference in younger patients is the use of an autologous stem cell transplant as a 2nd phase of treatment to try and obtain or deepen a remission.

We harvest the patients bone marrow stem cells and keep them frozen until needed. We then administer a single high dose chemotherapy which destroys many of the remaining cancer cells, but in the process, it also destroys the normal bone marrow, without which you cannot survive. The patients stem cells are then thawed and given back to them like a blood transfusion.

After about two weeks of close monitoring in the hospital, the stem cells start to function and the patient subsequently has his/her own bone marrow back, hopefully with significantly less myeloma. The age cut-off for such a procedure is arbitrary because it largely depends on the physical condition of the patient. Most people in South Africa, however, use the age of 70 as a cut off, sometimes a bit older if the patient is in exceptional condition for his/her age.

The median age of people diagnosed with myeloma worldwide is about 70 years. The available data, however, suggests that the median age in South Africa is considerably younger, somewhere around the age of 60 years. Due to this, as well as the problems with drug availability in South Africa, we often rely quite heavily on stem cell transplantation as an important part of treatment. If enough stem cells are harvested and cryopreserved, such a transplant can be repeated on numerous occasions to improve disease control.

After a transplant, as well as for those patients who are not candidates for a transplant, a form of low-intensity maintenance therapy is often started as the next phase of treatment in an attempt to keep the disease under control for as long as possible. This duration varies considerably. We hope for a couple of years, but it is unfortunately sometimes just a couple of months before the disease worsens, after which more intense treatment needs to be restarted again and the above cycle repeats itself. The remission duration gives us a good indication regarding the nature and prognosis of the disease.

There is so much more detail about myeloma to share, but the bottom line is this: Although myeloma is not a curable cancer and can lead to devastating complications, there is good treatment available which can help many patients enjoy a good quality of life for many years.

It is important to diagnose myeloma early, so if you have some of the symptoms mentioned earlier, please contact your General Practitioner for further investigation. If any abnormalities are detected, your GP can refer you to aClinical Haematologist, who specialises in bone marrow cancers and are best equipped to treat your myeloma.

We are all very excited about the future of myeloma treatment and hope that the treating physicians, pharmaceutical companies and government can take hands to ensure proper treatment for all the people in South Africa who suffer from this disease.

This article was compiled by Dr. Hannes Koornhof (Chairman of SACHAS)MBChB, FCP (SA), Dip HIV Man (SA), Cert Clin Haematology (SA) PhysSponsored by JANSSEN PHARMACEUTICA(PTY) LTD/(EDMS) BPK. (Reg. No./Regnr. 1980/011122/07); No 2, Medical Road, Halfway House, Midrand, 1685.www.janssen.com.

Medical Info Line: 0860 11 11 17. EM-27036

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Everything you need to know about Myeloma - IOL

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After performing well on the stock market last year -- with shares climbing by 37.3% -- Incyte's (NASDAQ:INCY) stock is down by 11% year to date. And while it would be easy to attribute this poor performance to the COVID-19 epidemic -- which has now spread to more than 50 countries and is hurting the stock market -- the fact is, Incyte's struggles predate these developments.In early January, before most of us had even heard of the coronavirus, Incyte's shares dropped by about 12% after the company reported disappointing results from a pivotal phase 3 clinical trial.

The clinical trial investigated the efficacy of itacitinib and corticosteroids as a combination treatment for treatment-naive acute graft-versus-host disease (GVHD), a condition that can develop in a patient following a stem cell transplant. The treatment failed to meet its primary or secondary endpoints. Despite this setback, Incyte has a plan to get back on the right track, and here are two things that could help the company do just that.

Image source: Getty Images.

Incyte's top selling-product is Jakafi, which treats several conditions, including a rare bone marrow cancer called myelofibrosis. Jakafi also treats patients with polycythemia vera, a condition that leads to an abnormal increase in the production of red blood cells.Lastly, in May 2019, the U.S. Food and Drug Administration (FDA) approved Jakafi for the treatment of steroid-refractory acute GVHD, a condition that occurs when a patient receives a stem cell transplant and the donor's cells trigger an immune response and attack the recipient's organs.Incidences of this condition number about 5,700 cases a year.

Also, steroid-refractory acute GVHD has a one-year mortality rate of about 70%.Jakafi is the first and only FDA-approved treatment for steroid-refractory acute GVHD. Thanks to this relatively new indication, sales of Jakafi could continue growing, as they have been doing for the past few years. During the fourth quarter, Jakafi's net product revenue was $466.5 million, 23% higher than the year-ago period. For the full year, Jakafi's net product revenue was $1.7 billion, a 21% increase compared to 2018.According to Incyte's executive vice president, Barry P. Flannelly, "Patient demand continued to drive the uptake of Jakafi and growth was strong across all three indications."

Furthermore, Incyte collects royalty revenues from Novartis (NYSE:NVS), which holds the rights to Jakafi outside the U.S. Incyte's royalty revenue for Jakafi for the fourth quarter and the full year were $65 million and $225.9 million, respectively, which represented an increase of 17% for the fourth quarter and 16% for the full year.

According to Incyte, Jakafi has been growing its revenue at a compound annual growth rate of 29% since 2016. And the company hopes its crown jewel will continue performing well in the future. Incyte's CEO Herve Hoppenot said, "On the commercial side, we will work to drive continued Jakafi growth in all three indications."

While Jakafi is performing well, Incyte does rely heavily on this product. During the fourth quarter, Jakafi's net product revenue accounted for about 80.5% of the company's total revenue. Fortunately, Incyte is trying to decrease its top-line exposure to its top-selling drug. In February, Incyte submitted capmatinib to the FDA as a potential treatment for an aggressive type of non-small cell lung cancer (NSCLC) called metastatic MET exon 14 skipping (METex14) mutated NSCLC.

There are currently no approved therapies that specifically target this type of NSCLC, which occurs in 3% to 4% of advanced NSCLC cases. Lung cancer is the most common type of cancer in the world, and NSCLC is the most common form of lung cancer. The FDA granted capmatinib a priority review designation, which means the review process for this drug will go faster than usual.

Also, in November 2019, Incyte submitted a New Drug Application to the FDA for pemigatinib as a potential treatment for cholangiocarcinoma, a rare cancer that affects about 0.3 to 3.4 per 100,000 people in North America and Europe. The FDA also granted pemigatinib priority review.In addition to those products that are currently being reviewed by regulatory authorities, Incyte boasts several more pipeline candidates for a variety of other conditions.This could help the company become less reliant on Jakafi in the future.

Incyte's heavy reliance on Jakafi remains a concern, and for that reason, Incyte probably isn't a strong buy. However, Jakafi's revenue should continue climbing, and unless Incyte runs into regulatory roadblocks, it should have several more products to drive its sales even higher. In short, investors should keep an eye on this biotech company.

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These 2 Things Will Help Incytes Stock Rebound - Motley Fool

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The latest Stem Cell Therapy market study offers an all-inclusive analysis of the major strategies, corporate models, and market shares of the most noticeable players in this market. The study offers a thorough analysis of the key persuading factors, market figures in terms of revenues, segmental data, regional data, and country-wise data. This study can be described as most wide-ranging documentation that comprises all the aspects of the evolving Stem Cell Therapy market.

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Stem cell therapy is a technique which uses stem cells for the treatment of various disorders. Stem cell therapy is capable of curing broad spectrum of disorders ranging from simple to life threatening. These stem cells are obtained from different sources, such as, adipose tissue, bone marrow, embryonic stem cell and cord blood among others. Stem cell therapy is enables to treat more than 70 disorders, including degenerative as well as neuromuscular disorders. The ability of a stem cell to renew itself helps in replacing the damaged areas in the human body.

MARKET DYNAMICSIncrease in the number of stem cell banking facilities and rising awareness on the benefits of stem cell for curing various disorders are expected to drive the market during the forecast period. Rise in number of regulations to promote stem cell therapy and increase in number of funds for research in developing countries are expected to offer growth opportunities to the market during the coming years.

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Stem Cell Therapy Market 2020 To 2027-Expanding Worldwide with Top Players Future Business Scope and Investment Analysis Report - Monroe Scoop

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Results Surpass FDA-Agreed Efficacy Threshold

Omeros Corporation (Nasdaq: OMER) today reports an update on clinical data from its pivotal trial of narsoplimab in the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), markedly exceeding the FDA-agreed threshold for the primary efficacy endpoint. While an overview of preliminary data submitted to FDA was made public on December 4, 2019 in a press release from the company, all patients have now completed treatment and trial enrollment has been closed. Narsoplimab is Omeros human monoclonal antibody targeting mannan-binding lectin-associated serine protease 2 (MASP-2).

In recent meetings with FDA focused on clinical as well as chemistry, manufacturing and controls (CMC) data, FDA confirmed important aspects of Omeros rolling Biologics License Application (BLA) for narsoplimab in HSCT-TMA. The BLA continues on its clear path to completion.

The efficacy threshold agreed with FDA, the updated results from the 28-patient trial, and highlights of the recent FDA meetings are the following:

Primary Endpoint

Secondary Endpoints

Safety

The treated population had multiple high-risk features that portend a poor outcome, including the persistence of HSCT-TMA despite modification of immunosuppression (which was a criterion for entry into the trial), graft-versus-host disease, significant infections, non-infectious pulmonary complications and neurological findings. Patients in the trial had a high expected mortality rate, with 93% of them having multiple risk factors.

"The efficacy and safety data from the pivotal trial with narsoplimab are encouraging," said Miguel-Angel Perales, M.D., Deputy Chief of the Adult Bone Marrow Transplantation Service and Director of the Adult Stem Cell Transplantation Fellowship at Memorial Sloan Kettering Cancer Center. "Given the trials stringent response criteria across laboratory markers and organ function, the complete response rate seen with narsoplimab is remarkable, as is the 100-day survival. There currently is no approved treatment for HSCT-TMA. Current therapy is generally limited to supportive care and withdrawal of drugs critical for GVHD prophylaxis. Not only could narsoplimab become central to the treatment of HSCT-TMA, it might well allow us to maintain that needed GVHD prophylaxis."

Complete clinical trial data will be presented by Dr. Perales later this month at the Annual Meeting of the European Society for Blood and Marrow Transplantation in Madrid.

Recent FDA Meeting Highlights and CMC Updates

"The non clinical sections of our BLA have been submitted, our CMC campaign is progressing well with process validation and commercial lots already manufactured, and our pivotal trial is complete," stated Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros. "The efficacy threshold agreed with FDA reflects both the primary endpoints stringent response criteria and the poor outcomes expected in the patients enrolled in our trial. Of course, were very pleased that the response rates and confidence intervals seen with narsoplimab are well above that efficacy threshold. We look forward to continuing to work closely with regulators to make the drug commercially available to transplanters and their patients in the U.S. and internationally as quickly as possible."

In addition to its HSCT-TMA program, Omeros is enrolling its narsoplimab Phase 3 clinical trials for immunoglobulin A (IgA) nephropathy and atypical hemolytic uremic syndrome (aHUS). Narsoplimab has been granted, for both HSCT-TMA and IgA nephropathy, FDAs breakthrough therapy designation as well as orphan drug designations from FDA and the European Medicines Agency. The drug also holds FDAs fast-track designation for aHUS.

Primary Efficacy Endpoint

To be considered a responder, a patient must achieve the primary endpoint of complete HSCT-TMA response defined by improvement in laboratory markers and improvement in clinical status.

Laboratory Markers

Clinical Status

About Omeros Corporation

Omeros is an innovative biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market as well as orphan indications targeting complement-mediated diseases, disorders of the central nervous system and immune-related diseases, including cancers. In addition to its commercial product OMIDRIA (phenylephrine and ketorolac intraocular solution) 1%/0.3%, Omeros has multiple Phase 3 and Phase 2 clinical-stage development programs focused on complement-mediated disorders and substance abuse. In addition, the company has a diverse group of preclinical programs including GPR174, a novel target in immuno-oncology that modulates a new cancer immunity axis recently discovered by Omeros. Small-molecule inhibitors of GPR174 are part of Omeros proprietary G protein-coupled receptor (GPCR) platform through which it controls 54 new GPCR drug targets and their corresponding compounds. The company also exclusively possesses a novel antibody-generating platform.

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About HSCT-TMA

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a significant and often lethal complication of stem cell transplants. This condition is a systemic, multifactorial disorder caused by endothelial cell damage induced by conditioning regimens, immunosuppressant therapies, infection, GvHD, and other factors associated with stem cell transplantation. Endothelial damage, which activates the lectin pathway of complement, plays a central role in the development of HSCT-TMA. The condition occurs in both autologous and allogeneic transplants but is more common in the allogeneic population. In the United States and Europe, approximately 25,000 to 30,000 allogeneic transplants are performed annually. Recent reports in both adult and pediatric allogeneic stem cell transplant populations have found an HSCT-TMA incidence of approximately 40 percent, and high-risk features may be present in up to 80 percent of these patients. In severe cases of HSCT-TMA, mortality can exceed 90 percent and, even in those who survive, long-term renal sequalae are common. There is no approved therapy or standard of care for HSCT-TMA.

About Narsoplimab

Narsoplimab, also known as "OMS721," is an investigational human monoclonal antibody targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a novel pro-inflammatory protein target and the effector enzyme of the lectin pathway of complement. Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Omeros controls the worldwide rights to MASP-2 and all therapeutics targeting MASP-2.

Phase 3 clinical programs are in progress for narsoplimab in hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA), in immunoglobulin A (IgA) nephropathy, and in atypical hemolytic uremic syndrome (aHUS). The FDA has granted narsoplimab breakthrough therapy designations for HSCT-TMA and for IgA nephropathy; orphan drug status for the prevention (inhibition) of complement-mediated thrombotic microangiopathies, for the treatment of HSCT-TMA and for the treatment of IgA nephropathy; and fast track designation for the treatment of patients with aHUS. The European Medicines Agency has granted orphan drug designation to narsoplimab for treatment in HSCT and for treatment of primary IgA nephropathy.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, which are subject to the "safe harbor" created by those sections for such statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "can," "could," "estimate," "expect," "goal," "intend," "likely", "look forward to," "may," "on track," "plan," "potential," "predict," "project," "prospects," "scheduled," "should," "slated," "targeting," "will," "would" and similar expressions and variations thereof. Forward-looking statements, including statements regarding anticipated regulatory submissions, expectations regarding regulatory exclusivities, the timing and results of ongoing or anticipated clinical trials, and the therapeutic application of Omeros investigational product, are based on managements beliefs and assumptions and on information available to management only as of the date of this press release. Omeros actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, availability and timing of data from clinical trials and the results of such trials, unproven preclinical and clinical development activities, regulatory oversight, intellectual property claims, competitive developments, litigation, and the risks, uncertainties and other factors described under the heading "Risk Factors" in the companys Annual Report on Form 10-K for the year ended December 31, 2019, filed with the Securities and Exchange Commission on March 2, 2020. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the company assumes no obligation to update these forward-looking statements, whether as a result of any new information, future events or otherwise, except as required by applicable law.

Dr. Miguel-Angel Perales has received compensation from Omeros for advisory services.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200302005938/en/

Contacts

Jennifer Cook WilliamsCook Williams Communications, Inc.Investor and Media Relations360.668.3701jennifer@cwcomm.org

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Omeros Corporation Reports Updated Results from Narsoplimab HSCT-TMA Clinical Trial and Highlights from Recent Clinical and CMC Meetings with FDA -...

Recommendation and review posted by Bethany Smith

Why is it that when a woman runs for an office or does something remarkable so very often the first thing people say is look at her hair or WHAT is she wearing! Well, there is a woman whose photos adorn the halls of the volunteer organization where I volunteer. And because she is the founder of the organization there are lots of photos in the office and in books about the history of the organization. The organization is Hadassah, The Womens Zionist Organization of America. The woman, the founder, is Henrietta Szold (1860-1945).

When I look at her photos, I dont focus on her hair, which changed little over the decades of her work. I dont look at the black pocketbook she often carried which seems not to have changed over the decades of her work. I dont think about her shoes, which were sturdy and usually black. Nope when I look at Miss Henrietta Szolds photo the first thing I think of look at how strong she is, look at the determination and purpose in her eyes, look at what those eyes have seen and those hands have touched. The rest unimportant and anecdotal.

As we are commemorating Womens History and Womens Empowerment Month in March, its very appropriate to tell you that even before Henrietta started Hadassah in a New York City synagogue in 1912 with a study group, she had, in her young life, already broken gender barriers and established institutions. Henrietta started the first night school for immigrants in the US and she studied at the Jewish Theological Seminary in an era when the idea of a female rabbi was unthinkable. An empowered woman look no further absolutely.

When Henriettas eyes first saw the disease and living conditions of the Jews in pre-state Israel on a trip with her mother in 1911, her mission of practical Zionism and her purpose were born. When you read her letters looking for funding or in subsequent years, letters between her and the nurses she sent over to provide pasteurized milk to babies and new moms, and to set up public health stations in Jerusalem to fight off the flies on the eyes of children suffering from trachoma, her words are full of determination and, excuse the old fashioned word gumption. This woman had moxie, this woman had chutzpah, this woman had guts. And thank G-d she did. Because she and her womens organization built the State of Israel. Hadassah created the medical infrastructure of Palestine and continues to do so today in Israel, a mere 108 years later. When there is purpose to what you are committed to and that purpose is accompanied by action there can be longevity. How about an organization that looks forward to the next 100 years? How about volunteers that are active for decades?

They say the proof is in the pudding, that you can judge something only once you have used or experienced it. So: Been there. Done that. Doing it.

Ive been a life member of Hadassah for 54 years, worked in just about every capacity and position at every possible level of the organization. I have gone to Israel so many times but when I juxtapose the memories of my first visit in 1966 with my most recent visit in 2018, WOW, the differences are staggering. Close to the top of the list are the ongoing changes at Hadassah Hospitals and Youth Villages. In the early years, beginning in 1913 when Henrietta sent over the first two nurses, Hadassah Hospitals and Clinics covered the map and over the years. Hadassah and the Hadassah Medical Organization (HMO) created many firsts the first medical school, dental school, nursing school, cancer institute, childrens hospice, ambulatory surgery center, ER unit for premature babies, and trauma treatment center in Israel.

Today the two hills of healing stand at opposite ends of Jerusalem Mt. Scopus (opened in 1939, closed in 1948, reopened in 1975) and the Ein Kerem campus, a tertiary care facility, built in 1961 as Ben Gurion told Hadassah to build in the southwest outskirts of Jerusalem and the city would grow out to it. Which is just what happened. Today, a light rail and bus bring people from all over the area to the hospital. In 2012, the Sarah Wetsman Davidson Hospital Tower opened adding 500 beds and 20 operating theaters. In 2020, Hadassah is re-imagining and re-energizing the campus with its 360 Degrees of Healing Campaign.

Hadassah Hospitals were first in Israel with heart, liver, lung and bone marrow transplants, computer-guided hip replacement (first in the world), macular degeneration clinical trial using embryonic stem cells to repair vision (second in the world) and bone marrow registry for Arabs (only one in the world). Hadassah Medical Organization (HMO) triage procedures and surgical techniques developed by Hadassah doctors were used following the Boston Marathon bombing. HMO doctors and nurses have been first responders in the Philippines, Haiti, Indonesia and Thailand in the wake of natural disasters. Hadassah doctors recently brought humanitarian spinal surgery to Ethiopia.

No rest for this woman she found more purpose and then, more purpose, as time went on.

As a 70-year-old woman, Henrietta was a member of the Palestine Zionist Executive, the Jewish Agency Executive and the Vaad Leumi. Photos show her as often being the only woman in the room. In these capacities she directed the health/educational development and social services of the population. And then, Henrietta took over the daily operations of Youth Aliyah in Palestine. Youth Aliyah was created to bring Jewish children out of Nazi Germany and bring them to Palestine.

In 1943, Henrietta waited in the cold at the Atlit Detention Camp as 750 children from Iran disembarked a train (120 followed a few months later), saved from the atrocities of Nazi Germany. Hadassah joined the life-saving work of Youth Aliyah and continues to be a major supporter to this day. Today, Hadassah-supported youth villages, Meir Shfeyah, Ramat Hadassah Szold and Hadassah Neurim, set at-risk children in Israel on the road to success and since its beginning, more than 300,000 young people from 80 lands have graduated from Youth Aliyah.

Always with an eye to the future, Henrietta Szolds connection to Young Judaea, began in 1909, when she prompted the Federation of American Zionists to call for a junior Zionist convention of delegates from Zionist youth societies. Young Judaea was formally established as a national Zionist youth organization at that New York convention. And then, under the leadership of Henrietta Szold, the department of education was formed by the Zionist Organization of America (ZOA), which briefly sponsored Young Judaea from 1918 to 1921. Over the years, there were many different connections between Henrietta, Hadassah and Young Judaea. Today, Hadassah and Young Judaea continue their connection through their shared mission to forge a strong commitment to Jewish life, instill a love of Israel and Zionism, connect American kids to Israel through education and programs, develop leaders for the Jewish community, and advocacy. Henrietta Szold and Hadassah in the room!

Today Hadassah has 300,000 members, Associates and supporters. It is the largest Jewish womens membership organization in the United States. With members in every Congressional district, Hadassahs advocacy work in spear-heading important legislation, most recently, the Never Again Education Act working to ensure Holocaust education in public schools, is a direct modern-day application of Henriettas legacy and an illustration of purpose with action. Hadassah women are in the room!

So, I think you can see that Henrietta started a run a run of practical Zionism that stretches across decades and centuries. A run I am proud to be part of since it has enabled me to work for Israel while living here in New York. It has allowed me to make differences around the world through medical research and protocols that are shared. Four generations of life members in my family. Three generations of Hadassah Presidents in my family. Once I make our new grandson an Associate, five generations of men affiliated with Hadassah. For me, personally, Hadassah is a family affair.

Today Hadassah strives to empower women of all ages to make a difference and to become leaders in the Jewish community by continuing Henriettas legacy of Practical Zionism through our work in Israel, our advocacy here in the US, on issues that affect Israel, the Jewishcommunity and health. Henrietta asked the artist of her sculpture to make my eyes look to the future. A most meaningful and purposeful statement.

Boy, I would love to know what Henrietta carried in that black bag of hers, or better yet, what her bag would hold today. I can only imagine that shewasthe one with the tissues to wipe the eyes of the young children as they disembarked the train. Shewould bethe one with the cell phone to reach out to anyone who would listen to her pleas for assistance and for funding to facilitate medical research and care of youth. Shewould bethe one with the small flashlight to bring a big light unto the nations. Over the years I have implored our members to release their inner Henrietta. A woman of purpose and perseverance to emulate for sure.

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A Woman of Purpose and Perseverance - Thrive Global

Recommendation and review posted by Bethany Smith

For the first time, doctors have attempted to cure blindness by gene-hacking a patientwith CRISPR technology.

A team from Oregon Health & Science Institute injected three droplets of fluid that delivered the CRISPR DNA fragments directly into a patients eyeball, The Associated Press reports, in hopes that it will reverse a rare genetic condition called Leber congenital amaurosis, which causes blindness early in childhood.

We literally have the potential to take people who are essentially blind and make them see, Charles Albright, chief scientific officer of Editas Medicine, told the AP. Editas is one of the biotech companies that actually developed the treatment. We think it could open up a whole new set of medicines to go in and change your DNA.

While some genetic conditions can be treated with conventional gene therapy, which would replace the entire mutated gene rather than editing it, patients with Leber congenital amaurosis were out of luck. The gene associated with the disease is too large to replace, so doctors turned to CRISPR in a bid to edit out the faulty mutation.

Once the cell is edited, its permanent and that cell will persist hopefully for the life of the patient, Eric Pierce, a doctor at Massachusetts Eye and Ear who worked on the project, told the AP.

It will take about a month for doctors to know whether this first experiment worked, the AP reports. If it does, the team has plans to gene-hack 18 more patients kids and adults with the condition.

Excerpt from:
CRISPR Scientists Hack Patient's Genes in Bid to Cure Blindness - Futurism

Recommendation and review posted by Bethany Smith

Read about the biggest pharmaceutical development and pricing stories from the past week in KHN's Prescription Drug Watch roundup.

Stat:Drug Prices Rose Three Times Faster Than Inflation, Despite DiscountsAmid intensifying anger over the rising cost of medicines, a key piece of data has been missing from the debate the actual prices after accounting for rebates and discounts offered by drug makers to payers. Now, a new analysis has come up with some numbers and the results are illuminating: Over a recent 11-year period, net prices for hundreds of drugs rose 60%, which was 3.5 times the inflation rate. (Silverman, 3/3)

Medscape:Drug Prices In US Continue To Soar; Are Profits Too High?Three studies and two editorials in Journal of the American Medical Association tackle the issue of the relentless rise in prices of new drugs and ask: Is the pharma industry making too much profit? (Nelson, 3/3)

The Washington Post:Why Facebook Is Filled With Pharmaceutical AdsJordan Lemasters keeps seeing ads in his Facebook app for an attention-deficit/hyperactivity disorder drug called Vyvanse. When the Chicago-based audio branding consultant recently clicked on the ads drop-down menu and selected Why Am I Seeing This Ad, a pop-up said it was because of his age range, because he lives in the United States and because he may have visited Vyvanse.com. But Lemasters felt spooked. The 29-year-old had used another ADHD drug, Adderall, but never publicized it. The ads just felt invasive, says Lemasters, who says he quit Adderall in 2017 because it made him feel like a zombie. What bothers me is how powerful those drugs are and how its pushed, rather than a doctor actually assessing a patient and suggesting a proper solution." (Tiku, 3/4)

The Wall Street Journal:Insulin Giant Aims To Unlock Elusive Obesity-Drug MarketThe worlds biggest insulin maker is betting it can unlock a multibillion-dollar market that has largely eluded the drug industry: obesity. Denmarks Novo Nordisk makes one of the worlds few approved drugs aimed specifically at battling obesity, but weight-loss treatments are typically a tough sell. Many doctors are convinced that lifestyle changes, not drugs, are a better answer. The sector is also relatively new: Obesity was first recognized as a disease by the American Medical Association in 2013. Many insurers still dont cover obesity drugs, and some previous treatments didnt win approval or were withdrawn from the market after problems arose. (Roland, 3/3)

Stat:One Woman's Complicated Journey To A Canada All For Cheaper InsulinJust after Emma Kleck turned 26, she started looking up flights to Canada. Kleck, who has type 1 diabetes, knew shed be paying a hefty sum each year for the test strips, body sensors, and insulin vials she needs to manage her disease once she switched from her parents insurance to the high-deductible plan her job offers. She was determined to see if she could find a cheaper option. (Florko and Jaques, 3/4)

Reuters:Two In Five U.S. Diabetics Struggle With Medical BillsMany working-age U.S. adults with diabetes struggle to pay their medical bills, according to a study that suggests health insurance offers inadequate protection from financial hardship. Among adults under age 65 with diabetes, 60% of those without insurance struggled to pay for care, as did 40% of people with coverage. (Rapaport, 3/3)

The CT Mirror:Lawmakers Rally Support For Wide-Ranging Drug BillBolstered by national efforts and the financial concerns of their constituents, legislators are pushing a measure that includes several provisions aimed at capping or lowering the price of prescription medication. The sweeping drug billfeatures a plan to import medicine from Canada, a proposal to cap the monthly cost of prescription pharmaceuticals at $250 for people with fully insured health plans, a ban on pay to delay a practice that postpones the introduction of cheaper, generic drugs into the market, and a prohibition on mid-year changes to drug formularies. (Carlesso, 3/4)

Reuters:U.S. Sues Mallinckrodt, Accuses Drugmaker Of Defrauding MedicaidThe United States sued a unit of the drugmaker Mallinckrodt Plc on Tuesday, accusing it of defrauding Medicaid out of hundreds of millions of dollars as a result of "meteoric" price increases for its biggest-selling drug, Acthar Gel. Joining a civil whistleblower lawsuit filed in Boston federal court, the government said Mallinckrodt ARD LLC violated the federal False Claims Act by withholding Medicaid rebates related to Acthar, which now costs nearly $40,000 per vial. (Stempel, 3/3)

Stat:Mallinckrodt Sued Over 'Hundreds Of Millions Of Dollars' In Medicaid RebatesA simmering feud between the federal government and Mallinckrodt (MNK) took a new turn as the Department of Justice filed a lawsuit accusing the company of deliberately underpaying hundreds of millions of dollars in Medicaid rebates, which were tied to the price of its most important medication, the Acthar Gel treatment. Under federal law, drug makers are required to pay quarterly rebates to state Medicaid programs in exchange for coverage of their medicines. These rebates include a provision that is designed to insulate the programs from price hikes that outpace inflation, and companies must pay rebates based on 1990 pricing or whenever a medicine was first marketed. (Silverman, 3/3)

Reuters:Gilead Buys Forty Seven For $4.9 Billion To Bolster Cancer Drug PipelineGilead Sciences Inc said on Monday it would buy Forty Seven Inc for $4.9 billion in cash, adding an experimental treatment that targets blood cancer to its portfolio of oncology drugs. Shares of Forty Seven jumped 62%, trading slightly below the offer price of $95.50 per share. Gilead shares were up 2.3% at $70.95 in early morning trading. (Mishra and Roy, 3/2)

The Wall Street Journal:Gilead Sciences To Buy Forty Seven For $4.9 BillionThe deal is the first major outright acquisition under Gilead Chief Executive Daniel ODay, who took over the company a little over a year ago with a mandate to jump-start sales growth and turn around the companys sagging stock price. The transaction will deepen Gileads pipeline of cancer drugs. Gilead, based in Foster City, Calif., is grappling with a sharp decline in revenue from its hepatitis C drug franchise and the threat of generic competition to its HIV drugs. (Walker, 3/2)

Stat:These 4 Startups Got Venture Funding A Year Ago. Where Are They Now?Every quarter, the CEO of a public biotech company can expect to spend an hour or two on the phone, describing her companys progress to shareholders and reporters and answering questions from analysts. But CEOs of early-stage, privately held biotech companies are allowed to play their cards much closer to the vest. There are no earnings calls or SEC filings; these CEOs can choose when to update the world with a press release or an interview. (Sheridan, 3/2)

Stat:This Biotech Went Public During The Stock Markets Worst Week Since 2008Concerns about the coronavirus outbreak made last week one of the markets worst since the 2008 financial crisis. But Philadelphia-based gene therapy company Passage Bio (PASG) still launched its initial public offering in the middle of that mess and the company did just fine. (Sheridan, 3/4)

Stat:TG Therapeutics Cops To Another Blood Cancer Drug Trial Delay, As Excuses Wear ThinTG Therapeutics (TGTX) on Tuesday delayed yet again the readout from its most important blood cancer clinical trial. And like the previous delay of study results disclosed in September 2018, the biotechs CEO is papering over the very real risk of failure. (Feuerstein, 3/3)

Bloomberg:Health-Care Banker Chris Hite Leaves Citi For Royalty PharmaChris Hite, a top Citigroup Inc. health-care dealmaker, is leaving the firm. Hite, head of the New York-based banks global health-care group for 12 years, will join Royalty Pharma, according to people familiar with the matter, who asked to not be identified because the matter is private. Royalty Pharma is a private company that invests in revenue streams from drugs. (Ahmed and Hammond, 2/27)

Carroll County Times:Insurers Wont Pay For A Hampstead Child To Get Treatment For A Rare Syndrome. A Maryland Bill Could Force Them To.In 2017, 4-year-old Jackson Mattoon of Hampstead could not have been more excited to start preschool, according to his mother Molly. He was one of those kids that just wanted to be around kids so bad, she said. The first day of preschool, we dropped him off and he ran in and didnt even look back. And then one day, Molly got a call from Jacksons teacher. He was inconsolable. (Kelvey, 3/4)

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Drugmakers Have Long Insisted Reports On Skyrocketing Rates Don't Take Into Account Rebates. Study Shows It Doesn't Matter. - Kaiser Health News

Recommendation and review posted by Bethany Smith

FLORIDA TODAY's Rob Landers brings you some of today's top stories on the News in 90 Seconds. Florida Today

Get ready to rumble Friday night. And that's not just because it's Friday and it's time to party.

SpaceX is poised to launch its Falcon 9 rocket and cargo Dragon capsule from Cape Canaveral Air Force Station Launch Complex 40 no earlier than 11:50 p.m. Friday.

From there it will head on a three-day journey to the International Space Station where Dragon will deliver science experiments, cargo and supplies to the crew onboard.

This will mark the aerospace company's 20th flight under NASA's Commercial Resupply Services contract as well as the last time SpaceX uses its Dragon 1 capsule before retiring it to make way to its newer, more advanced spacecraft: Dragon 2.

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The newer spacecraft is not only equipped to carry supplies to and from the space station, but it is also certified to refly up to five times (Dragon 1 for instance, was only certified for three re-flights) and can also carry humans, which could happen as soon as May for NASA's Commercial Crew Program.

"Some of the accomplishments of SpaceX under the CRS One program includesthe first U.S. Commercial provider toberth the ISS ... With that we're looking forward to SpaceX continuing on the CRS Two contract with SpaceX-21," said Jennifer Buchli, deputy chief scientist for NASA's International Space Station Program Science Office during a media teleconference.

SpaceX launched a Falcon 9 rocket with cargo for the International Space Station on Thursday, Dec. 5, 2019. Cape Canaveral hosted the liftoff. Florida Today

For this mission, Dragon 1 will deliver several science experiments including:

ACE-T-Ellipsoids: Researchers from the New Jersey Institute of Technology will examine colloids small particles suspended within a fluid in microgravity to not only understand fluid physics more but to advance space-based additive manufacturing, an area of great interest to NASA and other agencies in the U.S.

MVP Cell-03: Emory University School of Medicine will study whether microgravity increases the production of heart cells from specific stem cells, called "human-induced pluripotent stem cells." Those specific cells have the potential to be used toreplenish cells that are damaged or lost due to cardiac diseases.

Flow Chemistry in Microgravity: Researchers from Boston University will study the effects of microgravity on chemical reactions as a step toward on-demand production of chemicals and materials in space.

Droplet Formation Study: Delta Faucet Company will study water droplet formation and water flow in microgravity to gain a better understanding on how to improve its showerhead technology in an effort to create better performance while also conserving water and energy.

Dragon will also deliver the European external payload hosting facility called Bartolomeo that will be an enhancement to the space station's European Columbus Module.

Contact Jaramillo at321-242-3668or antoniaj@floridatoday.com. Follow her onTwitterat@AntoniaJ_11.

Get the latest space news by becoming a subscriber.

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SpaceX set to launch Falcon 9 rocket and Dragon capsule from Cape Canaveral this week - Florida Today

Recommendation and review posted by Bethany Smith

TMRR, in its recent market report, suggests that the Stem Cell Therapy market report is set to exceed US$ xx Mn/Bn by 2029. The report finds that the Stem Cell Therapy market registered ~US$ xx Mn/Bn in 2018 and is spectated to grow at a healthy CAGR over the foreseeable period.

The Stem Cell Therapy market research focuses on the market structure and various factors (positive and negative) affecting the growth of the market. The study encloses a precise evaluation of the Stem Cell Therapy market, including growth rate, current scenario, and volume inflation prospects, on the basis of DROT and Porters Five Forces analyses. In addition, the Stem Cell Therapy market study provides reliable and authentic projections regarding the technical jargon.

In this Stem Cell Therapy market study, the following years are considered to project the market footprint:

The content of the Stem Cell Therapy market report includes the following insights:

Request For Discount On This Report @ https://www.tmrresearch.com/sample/sample?flag=D&rep_id=1787&source=atm

On the basis of solution, the global Stem Cell Therapy market report covers the following solutions:

Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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The Stem Cell Therapy market study answers critical questions including:

All the players running in the global Stem Cell Therapy market are elaborated thoroughly in the Stem Cell Therapy market report on the basis of R&D developments, distribution channels, industrial penetration, manufacturing processes, and revenue. In addition, the report examines, legal policies, and comparative analysis between the leading and emerging Stem Cell Therapy market players.

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Stem Cell Therapy Market Opportunity Analysis and Industry Forecast up to 2017 2025 - Jewish Life News

Recommendation and review posted by Bethany Smith

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WERNERSVILLE, PA (WPMT) A Berks County mother is battling with insurance companies to get her son the treatment he needs. Doctors have prescribed the toddler the most expensive drug in the world. Yet, his insurance companies deny coverage.

What is my childs life worth to you, asked Jacqueline Brewer, of Berks County.

Brewer has been in a fight with her almost two-year-old son Johns insurance companies for nine months.

Were not giving up, said Brewer.

John was a happy, healthy baby for the first six months of his life.

He was drinking from a bottle, he was nursing, he was great until he picked up a viral infection, said Brewer. it was just a simple cold.

A cold that took a turn for the worse very quickly, appearing to trigger something even worse in John.

Being in the ICU and being intubated and the doctors coming in and saying were going to do more tests and more tests and more tests and theres still nothing coming up, said Brewer. And then they said theyd like to do a genetic panel.

The genetic panel revealed John has spinal muscular atrophy, also known as SMA. Its a muscle wasting disease caused by a mutated chromosome gene.

It goes on and on and on until he basically cant move, said Brewer. He wouldnt be able to move his tongue. His diaphragm would no longer work. And its terrifying.

Johns been receiving a drug called Spinraza every four months, it helps build the proteins his body needs.

Its a little much, it takes a toll on him, said Brewer. Hes getting a stronger. Now, hes able to hold his head up a little bit.

Spinraza has a price tag of more than $100,000 per injection and is covered by Johns insurance. But, since May of 2019, theres something new on the market.

Now theres Zolgensma. Thats the one we need and that would stop the regression, said Brewer.

Zolgensma is the most expensive drug in the world, with a $2.1 million price tag, but John would only need to receive it once. The one-time treatment is actually less expensive than receiving Spinraza for five years.

It would stop where hes at, said Brewer. He would never get any worse and thats what we need.

Yet, insurance companies Aetna and Ameri-Health have continuously denied coverage of the drug.

Every doctor he comes across is saying its medically necessary for this child to have it but theyre [insurance companies] saying no, said Brewer.

Brewer has continued to receive denials letters from Johns insurance companies all saying the same thing: The request for Zolgensma was denied completely because we are not able to establish medical necessity.

Theyre saying its not medically necessary because hes already being supported, said Brewer. Hes already on a ventilator and the Spinraza injections are enough.

But, Brewer says other children with advanced stages of SMA with other insurance providers have been approved for Zolgensma.

Time is also running out for John to receive Zolgensma. The FDA only approved it for children under two-years-old. John turns to March 24th.

Its terrifying because what if they say no and dont budge and hes gonna turn two and theyre not going to budge, said Brewer. But, Im still going to call everyday, his doctors are still calling everyday, they will do everything they can. Were not going to give up. Even if he turns 2, Im not going to give up.

Brewer says she will continue to fight Johns insurance companies every single day, and if he doesnt receive the drug before he turns two, shell look for clinical trials to somehow get John this drug.

I need to know what this innocent childs life is worth, said Brewer

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Berks County mother fights insurance companies to cover $2 million gene therapy drug for son - KTVZ

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A University of Virginia biomedical engineering student is trying to tackle the worlds No. 1 cause of death on a genetic level.

Rita Anane-Wae, from Ghana by way of Glendale, Arizona, and a third-year biomedical engineering student, is using a 2019 Harrison Undergraduate Research grant to seek a genetic solution to atherosclerosis, or the build-up of plaque in ones arteries, which impedes blood flow.

There are cells that will try to fix this problem by covering them and basically pushing the plaque down to allow blood flow, she said. These cells will try to reduce that plaque so that there is correct blood flow. In very serious cases, the plaque can harden and break off. Once it breaks, it can get lodged somewhere and cause a stroke or a heart attack.

Created through a gift from the late David A. Harrison III and his family, the Harrison Undergraduate Research Awards fund outstanding undergraduate research projects. Selected by a faculty review committee, awardees receive as much as $4,000 apiece to pursue their research interests, under the direction of a faculty mentor.

Anane-Wae started working in a laboratory run by Mete Civelek, an assistant professor of biomedical engineering, as a second-year student.

Civelek had already altered her life. Anane-Wae came to UVA to be a chemical engineer. She met Civelek when she signed up as a first-year student for a program that offered faculty mentoring.

At the time I was a chemical engineering major with an interest in biomedical engineering, Anane-Wae said. After talking with him, he was able to assuage my fears about biomedical engineering.

Biomedical engineering is a relatively new field and as such, I did not believe there were many jobs out there, and my parents were worried for the same reason, she said. Mete has a chemical engineering undergrad degree and a masters and Ph.D. in biomedical engineering, so he was the perfect person for me to talk to. He explained the two fields in a unique way, unlike what I had read and seen on YouTube.

Honestly, I love biomedical engineering. When I switched into biomedical engineering, literally in my first class, I though Oh, my God, this is home. I am learning about anatomy, physiology, genes and cells, and it is still all really exciting for me.

Civelek also suggested Anane-Wae participate in the research trip to Uganda through the UVA Minority Health & Health Disparities International Research Training program to perform research on congestive heart failure. While in Uganda, Anane-Wae made rounds with a doctor at a local hospital and met a 17-year-old girl suffering from congestive heart failure.

Her legs were all swollen, Anane-Wae said. She had edema and her stomach was filled with fluid. I was looking at her and thinking, This girl cant lay down because of all the swelling and she cant even be at rest. And I was thinking, She is about my age and I am fortunate enough to be traveling the world and she is here stuck in this hospital bed.

Her encounter with the girl became part inspiration to her and part reminder that congestive heart failure is not just for older patients.

I have a hard time accepting what I am capable of doing, Anane-Wae said. Being here, being in Uganda, working in the lab, it has taught me that I am basically capable of making change. I know what I am supposed to be doing with my time and my future and I know that doing it makes me happy and will make other people better.

In her lab work, Anane-Wae studies a specific gene melanoma inhibitor activity 3, or MIA3 that affects smooth muscle cells.

Smooth muscle cells are able to basically cover the plaque in that disease state, Anane-Wae said. We are running experiments to see how us modulating MIA3 affects the disease.

She said she and members of the research team in the lab also performed experiments knocking out the MIA3 gene from the cells, which led to a more serious disease state.

I think experiments like these are really important because we are not yet at the stage where we can do gene therapy on a person, Anane-Wae said. If you knock out specific genes, it will affect things that we dont understand yet.

Anane-Wae is working on a small section of a large field, but she thinks there is promise in the work she is doing.

The genome-wide association studies show that 161 different genes so far have been associated with coronary artery disease, she said. And we are studying just one. There is so much further that we have to go.

The path is really long, but we are trying to understand the mechanism by which one gene affects the disease and if we actually figure out that mechanism, we can try to apply it to the other genes and maybe understand the bigger picture.

Research can lead her down many blind alleys, which she understands. Anane-Wae is also very conscious of the law of unintended consequences, and how something that solves one problem can create other problems in the process.

We can say that about everything, she said. I think that is the way with all new development. You fix problems and new ones will arise, and then you fix those, too. So we can only do so much. But I think what I have learned is that I have found something about which I am passionate. I have found something that I enjoy and here at UVA, I have found a community of people who will help me develop my skills.

Included in that community, Anane-Wae cited Civelek and Redouane Aherrahrou, an American Heart Association Postdoctoral Fellow with whom she works.

Aherrahrou has known Anane-Wae since she joined the lab in 2018. When she first joined our lab, Rita knew only the fundamental lab skills and methods, he said. After a short amount of training, she learned rapidly and became very familiar with the cell culture techniques and appropriate lab handling. She performed the experiments independently. Her interactions with other lab members are both professional and friendly.

He described Anane-Wae as a diligent researcher, a gifted student, an inspiring person, and enjoyable to be around.

She has a great personality, is open to guidance and responds well to criticism, he said. She wants to apply to Ph.D. programs after she graduates, and I predict a great future in her career as a research scientist.

Civelek said he enjoys having Anane-Wae as part of his team.

She is hard-working, curious and eager to make a scientific impact, he said. I can see the joy in her face when she learns something new. She gets along well with everyone in the lab and is a role model to those who are junior to her. She has a bright future and I am very proud of her accomplishments.

Civelek said Anane-Wae was recently awarded a German Academic Exchange Research Internship in Science and Engineering, which is presented to only 300 students from the U.S. and Canada.

Redouane and Mete both have high standards for me and motivate me to do my very best, Anane-Wae said. They have instilled a confidence in me that I did not have prior to joining the lab, and they continuously push me to achieve great things. I am so fortunate to have these two individuals as mentors, in addition to all of the other members in the laboratory.

A Blue Ridge Scholarship recipient, Anane-Wae is member of the National Society of Black Engineers and the Society of Women Engineers. She also has received a Hugh Bache Scholarship.

Anane-Wae said she is looking at doing big things, such as gene therapy, but realizes that she has to take small steps at first, and that her friends in the lab will help her out when things go wrong.

She has also learned that research is a team effort, not a solo pursuit.

You cant do research by yourself, she said. You wont be able to get anything done. You will have to depend on other people and you have to be able to share what you have learned. You wont get anything done in any amount of time if you dont trust other people and work together.

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First-Year Lab Experience Gave This Student the Confidence to Aim for a Ph.D. - UVA Today

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A wave of new targeted therapies expands the options in acute myeloid leukemia.

As a mother of three, I dont focus on myself a lot, says Hibbard, who lives in Yorba Linda, California, and was then 37. I was having a lot of bone pain in Vegas, but I have scoliosis, so I always have some pain. Everything just multiplied when I got back home.

She rushed to schedule a same-day appointment with her doctor. As someone in the medical field she works as an ultrasound technician Hibbard had no hesitation about learning what could be wrong. Her doctor appeared alarmed about how sick she looked and immediately ordered bloodwork.

Her platelet count was astoundingly low. A normal count ranges from 150,000 to 450,000 platelets per microliter of blood; Hibbards hovered around 20,000. She initially assumed something had gone wrong with her intrauterine device, because she had recently experienced heavy vaginal bleeding abnormal uterine bleeding can be a symptom of certain hematologic cancers.

I thought I was anemic because I had lost a lot of blood. Cancer didnt even cross my mind until the doctor came in and told me I had leukemia, she says.

A week and half after returning from her vacation, Hibbard received a diagnosis of acute myeloid leukemia (AML). This cancer of the blood and bone marrow affects more than 20,000 people each year in the United States.

For years, prognosis remained poor for patients with the disease, which has a 24% five-year survival rate for people ages 20 and older and 67% for those younger than 20, with limited treatment options. But the past two years brought an explosion of new medications approved by the Food and Drug Administration (FDA) to treat AML, particularly therapies targeting specific genomic mutations that may confer a worse prognosis.

For more than 45 years, the treatment for AML only involved intensive chemotherapy, and that was the only chance at a cure, says Amer Zeidan, an associate professor of internal medicine at Yale Cancer Center in New Haven, Connecticut. But since 2017, weve had a revolution in the treatment of AML after many years of no approved agents. I give an analogy in (terms) of before Christ and after Christ because the landscape has changed so much.

WHAT DOES AN AML DIAGNOSIS MEAN?

Historically, chemotherapy for the treatment of AML involves two phases: induction therapy followed by consolidation therapy. Shortly after diagnosis, a patient will undergo induction therapy to rid the body of any signs of the disease.

Most often, patients receive the combination of cytarabine and an anthracycline drug such as Cerubidine (daunorubicin) or Idamycin (idarubicin). Approximately 75% of younger adults with AML and 50% of patients older than 60 achieve complete remission, or disappearance of overt leukemia in the bone marrow, after induction treatment. Once a patient has recovered, consolidation therapy, chemotherapy or a stem cell transplant kills any remaining leukemia cells.

Early signs of AML, which is typically associated with older age (more than 65 years), history of tobacco smoking and certain inherited genetic disorders, include weight loss, fatigue, fever, night sweats, bruising and excessive bleeding. Because AML is generally widespread throughout the bone marrow and possibly other organs, it is not staged like other cancers. About half of patients who achieve remission after initial treatment will relapse.

Genomic testing revealed that Hibbard had a FLT3 mutation. The most common mutation in AML, FLT3 is found in 30% of all cases and associated with a particularly aggressive form of the disease and a higher risk of relapse. My oncologist told me, Bad news you have the FLT3 mutation. But the good news is that they just developed an inhibitor you can take, recalls Hibbard. He said it with a big smile on his face.

In April 2017, the FDA approved Rydapt (midostaurin), the first targeted therapy for AML, combined with chemotherapy to treat adults with a new diagnosis and a FLT3 mutation. The oral medication belongs to a group of drugs called FLT3 inhibitors, which block several enzymes that promote cell growth.

During Hibbards month in the hospital to receive induction chemotherapy, she experienced several life-threatening complications, including a blood clotting disorder, two strokes and a bout of sepsis. Believing she was on her deathbed; she made a video saying goodbye to her children.

Hibbard recovered, returned home and began treatment with Rydapt, which made her nauseated. The drugs other common side effects include low levels of white blood cells with fever (febrile neutropenia), inflammation of the mucous membranes and vomiting.

Hibbard achieved remission following more chemotherapy and a stem cell transplant and remains free of cancer. I was extremely excited about taking Rydapt because I felt truly blessed that there was an inhibitor for my mutation, since it was so aggressive, says Hibbard, who is now 39.

It smells horrible, and its a large pill, but I took it willingly because I knew it would improve my chances of survival.

RIGHT ON TARGET

Rydapt is one of eight drugs for AML that have gained FDA approval since 2017. Xospata (gilteritinib), another type of targeted therapy that inhibits FLT3, was approved in May2019 for adults who stopped responding to treatment or whose disease had relapsed.

The IDH inhibitors Idhifa (enasidenib) and Tibsovo (ivosidenib) target mutations in the IDH1 and IDH2 genes. Daurismo (glasdegib), Venclexta (venetoclax) and Vyxeos (CPX-351) expand the options for older patients who cant be treated with intensive chemotherapy because of its toxicities. Mylotarg (gemtuzumab ozogamicin) can be given to patients who express the CD33 antigen.

We now have a better understanding of the biology behind AML, especially the molecular mutations that drive this disease, and we have developed treatment that targets these mutations, says Dr. Kevin Kelly, an associate professor of clinical medicine at the University of Southern California in Los Angeles. One of the most important mutations is FLT3, targeted by midostaurin and gilteritinib. These drugs specifically target the leukemia cells while being less toxic on the normal tissue of the body.In a large clinical trial, patients with new diagnoses who took Rydapt along with chemotherapy lived longer than those who received chemotherapy alone. After four years, 51.4% in the Rydapt group were still alive compared with 44.3% in the chemotherapy group.

Findings from the ADMIRAL trial showed that Xospata similarly extended survival. Patients who took the FLT3 inhibitor alone had a median overall survival of 9.3 months compared with 5.6 months for those given chemotherapy alone. Though encouraging, these are early findings from new files, and long-term follow-up could bring significantly different results, cautioned experts.

Side effects of Xospata include nausea, vomiting, diarrhea, constipation, pain or sores in the mouth or throat, shortness of breath, muscle or joint pain and dizziness. The drug can also cause differentiation syndrome, a potentially fatal complication believedto be caused by release of cytokines from leukemia cells. It can be treated with steroids, but prompt recognition is key. Symptoms include fever, cough, trouble breathing, bone pain, rapid weight gain and swelling in the arms, legs, underarm, groin or neck.Differentiation syndrome is also a concern for patients treated with Idhifa and Tibsovo. Based on clinical trial results showing that 19% of patients had complete remission for a median of 8.2 months, Idhifa was approved in August 2017 for patients who relapsed or became resistant to treatment for AML. The targeted therapy homes in on mutations in the IDH2 gene, which are found in 8%-19% of patients with AML.

In July 2018, Tibsovo, which targets IDH1 mutations found in 7%-14% of patients with AML, was approved. Roughly two years later, the FDA allowed the drugs use as a first-line treatment for patients who arent eligible for intensive chemotherapy.Another type of targeted therapy, Mylotarg aims at AML cells expressing the CD33 antigen, found in more than 80% of patients. Reapproved by the FDA in September 2017 to treat patients with new diagnoses and those who relapsed or became resistant to therapy, the agent combines the unique targeting of a monoclonal antibody with the cancer-killing ability of a chemotherapy drug.

What is happening now in AML is similar to what already happened with multiple myeloma. Today, proteasome inhibitors and other biological drugs have almost completely replaced chemotherapy for almost all ages and subsets of myeloma, says Dr. Naval Daver, an associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston. With these new targeted therapies, we can improve outcome and survival in AML while reducing the need for chemotherapy and even stem cell transplants.

OPTIONS FOR OLDER PATIENTS

The lack of treatment options for older patients with AML only about half of patients older than 60 receive intensive induction chemotherapy; the rest get either gentler chemotherapy that doesnt aim to cure or supportive care without any chemotherapy has meant that many are undertreated, with poorer clinical outcomes.

Fortunately, the approvals of Venclexta and Daurismo for patients aged 75 and older bring new options. Venclexta, which blocks BCL-2 proteins, was granted accelerated approved by the FDA based on promising results from early-phase clinical trials, but two larger, ongoing studies are examining its effectiveness and safety. The rate of complete remission was up to 54% for Venclexta plus decitabine but varied depending on which chemotherapy drug was given.

There has been dramatic progress in the treatment of AML in recent years, with one of the most important drugs being venetoclax for older AML populations, who have been one of the most difficult populations to treat, Daver says. It works synergistically with low-dose chemotherapy drugs already being used, which is a major breakthrough in the treatment of older patients with AML.

Daurismo targets the smoothened, or SMO, protein that fuels the growth and spread of AML. In a clinical trial, the median overall survival in older patients who received Daurismo along with chemotherapy was 8.3 months compared with 4.3 months for those who got chemotherapy alone.

Vyxeos (CPX-351) can also be used in older patients. It's August 2017 approval was for patients with two types of prognoses: newly diagnosed therapy-related AML, which occurs as a complication of cancer treatment in 8%-10% of patients within five years after chemotherapy or radiation, and AML with myelodysplasia-related changes, characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with these types of AML tend to be older and have additional medical issues.

A study that compared Vyxeos with traditional chemotherapy showed that patients with new diagnoses who took Vyxeos lived longer, with a median overall survival of 9.56 months compared with 5.95 months, respectively.

In addition, an investigational oral therapy, CC-486, has shown a survival benefit in patients with newly diagnosed AML in the maintenance setting. In a phase 3 trial, researchers saw that the drug extended overall survival by 9.9 months compared with placebo.

We have new drugs available for subsets of the disease, which is why the management of AML is becoming more like personalized medicine, Zeidan says. I think we are going in the direction of more targeted therapy, lower toxicity agents, combinations of different oral agents and, hopefully, incremental improvement in outcomes. Im very optimistic about where the field is going.

The wealth of drug approvals certainly gives more hope to patients with AML, especially those with a previously poor prognosis and lack of treatment options. Rapid genetic testing is leading to the early classification of disease subtypes, pushing AML treatment into the realm of precision medicine. Several clinical trials in progress aim to test combinations of the newer agents, such as Venclexta with an IDH inhibitor.

Hibbard remains thankful for the targeted therapy she received. She believes that the trust she had in the newly approved Rydapt and the entire treatment process helped save her life.

I remember being terrified, with people praying over my bedside. But Im very pragmatic, so I was very much like, OK, now what do we do? Whats the next step? Hibbard says. That was my entire battle. Today I am more than a year post-transplant and grateful to kiss my kids goodnight every night.

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Extending the Options for Patients with AML by Making It Personal - Curetoday.com

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TORONTO - The signs were there, but Lidia Vetturetti says her mother refused to consider the possibility she had Alzheimer's.

By the time she was diagnosed five years ago, the disease was so advanced Nicole Vetturetti was forced to enter a full-time care facility the following year.

Lidia Vetturetti believes her mother's rapid decline was accelerated by the belief there was no point seeking help earlier.

But now, she says there's real hope for other patients and their families, thanks to a landmark $16.7-million grant announced Monday that will speed up development of targeted treatments of a variety of brain disorders including Alzheimers, brain cancer and ALS.

Just the prospect that new research could revolutionize the way doctors tackle hard-to-treat conditions is powerful stuff, she says, and would have been enough to make a difference in her own family's life.

"It would have changed everything. I would have pushed her to go (to the doctor) even sooner because I would have said, 'There's trials. As soon as we can, let's try it. It might stop this. It might slow down.' And we might have had longer with her," says Vetturetti.

"She's still here, but she's not really. I lost her a long time ago."

Sunnybrook Hospital says the funds from the W. Garfield Weston Foundation will help create a new type of focused ultrasound device that can more efficiently bypass the blood-brain barrier in delivering treatments.

The Toronto hospital will test the helmet-like device on three brain disorders, including Alzheimer's disease, breast cancer that has spread to the brain, and glioblastoma the deadliest and most common brain tumour.

The blood-brain barrier is a tightly packed network of vessels meant to protect the brain from toxins. But it can also be a major obstacle in many conditions because it prevents potentially helpful agents from entering the brain such as chemotherapy, antibodies, stem cells or gene therapy.

The hospital already does focused ultrasound treatments but neurosurgeon Dr. Nir Lipsman says this new device could allow doctors to deliver medication directly to a brain tumour, and allow more targeted treatment in multiple areas, with less medication and fewer side effects.

For one thing, the helmet-like prototype would be specifically fitted to each patient and wouldn't need an MRI for guidance, which is the current practice.

The new device also wouldn't require a patient to wear a painful frame to immobilize the head as is common now, in which four pins are inserted under local anaesthetic for several hours.

"Many of the treatments that we're envisioning are serial treatments, which means the treatments will happen over time repeatedly. And the more comfortable you can make the procedure, the more streamlined and efficient you can make it, the shorter in duration you can make it, the better it will be for patients," said Lipsman.

The hospital's foundation is trying to raise the rest of its $33-million goal for the Weston Family Focused Ultrasound Initiative.

Research like this can offer powerful hope to patients and families grappling with a frightening diagnosis, adds Vetturetti.

"Hopefully in the future people won't have to go through what I've gone through with my mother or that she has gone through as a result of this illness," she says.

"It gives me hope as well that if, God forbid, I ever was to get this diagnosis, that maybe there would be hope for me, or my children."

This report by The Canadian Press was first published on March 2, 2020

The Canadian Press. All rights reserved.

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Multimillion-grant to speed innovative device for hard-to-treat brain disorders - The Chronicle Journal

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Female pattern baldness, also called androgenetic alopecia, is hair loss that affects women. Its similar to male pattern baldness, except that women can lose their hair in a different pattern than men.

Hair loss in women is normal, especially as you age. Up to two-thirds of women experience hair loss after menopause. Less than half of women will make it past age 65 with a full head of hair.

Female pattern baldness is hereditary. Its more common after menopause, so hormones are likely responsible. If you notice that youre losing hair, see your doctor or a dermatologist. They will be able to determine if youre experiencing female pattern baldness or another type of hair loss.

The sooner you get treated, the faster youll be able to stop the loss and possibly even regrow hair.

In female pattern baldness, the hairs growing phase slows down. It also takes longer for new hair to begin growing. Hair follicles shrink, leading the hair that does grow to be thinner and finer. This can result in hair that easily breaks.

Its normal for women to lose 50 to 100 hairs each day, but those with female pattern baldness can lose many more.

In men, hair loss starts in the front of the head and recedes to the back until they go bald. Women lose hair from all over their head, starting at their part line. Hair at the temples may also recede.

Woman are less likely to go completely bald, but you may have a lot of thinning throughout your hair.

Doctors divide female pattern baldness into three types:

Hair loss is passed down from parents to their children, and many different genes are involved. You can inherit these genes from either parent. Youre more likely to have female pattern baldness if your mother, father, or other close relatives have experienced hair loss.

Female pattern baldness is generally caused by an underlying endocrine condition or a hormone secreting tumor.

If you have other symptoms, such as an irregular period, severe acne, or an increase unwanted hair, consult your doctor. You may be experiencing a different type of hair loss.

Women are less likely to develop female pattern baldness before midlife. Like men, women are more likely to start losing hair once they get into their 40s, 50s, and beyond.

High levels of male sex hormones, called androgens, contribute to hair loss in men. Its generally felt that androgens are also at play in female pattern hair loss.

Smoking may also increase your risk for developing female pattern hair loss.

Check out: Can birth control cause hair loss?

If youve noticed thinning hair on your scalp, see your doctor or a dermatologist. Your doctor will examine your scalp to see the pattern of hair loss. Testing generally isnt needed to diagnose female pattern baldness.

If they suspect another type of hair loss, they may also perform a blood test to check your levels of thyroid hormone, androgens, iron, or other substances that can affect hair growth.

If you have female pattern baldness, you may be able to camouflage the hair loss at first by adopting a new hairstyle. Eventually, you might have too much thinning at the top of your scalp to hide.

Early diagnosis is encouraged, as it can enable you to get on a treatment plan and potentially minimize future hair loss. Your treatment plan will likely consist of one or more medications approved to treat hair loss.

Minoxidil (Rogaine) is the only drug approved by the U. S. Food and Drug Administration (FDA) to treat female pattern baldness. Its available in 2% or 5% formulas. If possible, opt for the 5% formula.

To use, apply minoxidil to your scalp every day. Though it wont fully restore all the hair youve lost, minoxidil can grow back a significant amount of hair and give your hair an overall thicker appearance.

You probably wont start to see results for 6 to 12 months. Youll need to keep using minoxidil to maintain the effect, or it will stop working. If it stops working, your hair may return to its previous appearance.

The following side effects are possible:

Finasteride (Propecia) and dutasteride (Avodart) are FDA-approved to treat hair loss in men. Theyre not approved for women, but some doctors do recommend them for female pattern baldness.

Studies are mixed as to whether these drugs work in women, but some research has shown that they do help regrow hair in female pattern baldness.

Side effects can include headaches, hot flashes, and a decreased sex drive, especially during the first year of use. Women shouldnt get pregnant while on this drug, because it can increase the risk for birth defects.

Spironolactone (Aldactone) is a diuretic, which means it removes excess fluid from the body. It also blocks androgen production, and it may help regrow hair in women.

This drug can cause a number of side effects, including:

You may need to have regular blood pressure and electrolyte tests while you take this drug. If youre pregnant or plan to become pregnant, you shouldnt use this medication. Spironolactone may cause birth defects.

If low iron is contributing to your hair loss, your doctor might prescribe an iron supplement. At this time, there isnt any evidence that taking iron will regrow your hair. Other supplements, such as biotin and folic acid, are also promoted to thicken hair.

One study did show that women developed thicker hair after taking omega-3 fatty acids, omega-6 fatty acids, and antioxidants. However, its best to check with your doctor before taking any supplements to re-grow hair.

Laser combs and helmets are FDA-approved to treat hair loss. They use light energy to stimulate hair regrowth. More research needs to be done to determine if this is truly effective.

Platelet-rich plasma therapy may also be beneficial. This involves drawing your blood, spinning it down, then injecting your own platelets back into your scalp to stimulate hair growth. Though promising, more studies need to be done.

You may be able to conceal hair loss by wearing a wig or using a spray hair product.

A hair transplant is a more permanent solution. During this procedure, your doctor removes a thin strip of hair from one part of your scalp and implants it in an area where youre missing hair. The graft regrows like your natural hair.

Learn more: Menopause hair loss prevention

Female pattern baldness isnt reversible. Proper treatment can stop the hair loss and potentially help regrow some of the hair youve already lost. Treatments can take up to 12 months to start working. Youll need to stay on them long-term to keep from losing your hair again.

Keep reading: 9 tricks for healthier, fuller-looking hair

You cant prevent female pattern baldness, but you can protect your hair from breakage and loss:

Follow this link:
Female Pattern Baldness: Causes, Treatment, and More

Recommendation and review posted by Bethany Smith