]]> High costs, data management issues and recruitment problems are some of the main challenges for personalised medicine in clinical development. Credit: US Air Force/Kemberly Groue Genome sequencing costs are falling fast, opening the playing field for developing highly personalised drug candidates. Personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

The importance of the individual has been widely established in medicine since time immemorial. The well-worn adage that physicians should treat the patient, not the disease has been around since the 19th century, and the awareness of that message is far older than that. Even Hippocrates, the father of Western medicine who treated patients in the fifth century BC, stressed the importance of treating each patient as an individual.

For the sweet [medicines] do not benefit everyone, nor do the astringent ones, nor are all patients able to drink the same things, Hippocrates wrote.

Hippocrates might have tailored his rudimentary treatments based on the patients age, physique and other easily observable factors, but personalised medicine in the 21st century offers the promise of therapies customised based on the study of what truly makes us unique: our DNA.

Advancements in genomics, proteomics, data analysis and other fields both medical and technical are gradually facilitating the development of laser-focused drugs, as well as the ability to predict peoples personal risk factors for particular diseases and how individual responses to various treatments might differ.

After years of anticipation, there is now evidence that governments around the world have clocked the importance of personalised medicine and are driving efforts to the build the genetic data sets and biobanks that are required to push the science forward. Former US President Barack Obama launched the Precision Medicine Initiative to great fanfare in 2015; the scheme has since evolved into the All of Us research programme, which aims to gather health data from more than a million US volunteer-citizens to unlock new insights.

In the UK, the 100,000 Genomes Project reached its goal of sequencing 100,000 whole genomes from 85,000 NHS patients with cancer or rare diseases. Genomics England has noted that so far, analysis of this data has revealed actionable findings in around one in four rare disease patients, while about 50% of cancer cases suggest the potential for a therapy or clinical trial.

You can match a blood transfusion to a blood type that was an important discovery, said Obama at the launch of the Precision Medicines Initiative, summarising the broad appeal of personalised therapies and diagnostics. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?

The stage might be set for personalised healthcare to dramatically transform public health, but few in the medical field would deny that the world is hardly ready yet. Transitioning from the traditional one-cure-fits-all treatment model to new processes that leverage patients genetics, lifestyles and environmental risk factors is an immense task that presents challenges in both the laboratory and the clinic.

Oncology is, by a landslide, the field that has been most impacted by developments in precision medicine; around 90% of the top-marketed precision treatments approved in 2018 were cancer therapies, while other therapeutic areas have lagged far behind. The majority of approved precision medicines in oncology achieve something of a halfway house between the old way and the new they fall short of being tailored to a specific individual, but they allow for more detailed stratification of patients by the oncogenic mutations of their tumours, which may be driving cancer cell survival and growth.

Common examples of these mutations are HER-2 in certain breast and stomach cancers, BRAF in melanoma and EGFR in lung cancer. High expression of these proteins at cancer sites can be targeted by precision treatments, such as Roches monoclonal antibody Herceptin (trastuzumab) for HER-2, Genentechs BRAF inhibitor Zelboraf (vemurafenib), and Roches EGFR inhibitor Tagrisso (osimertinib). Regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are also increasingly approving tumour-agnostic treatments the first and most famous of which is Mercks immunotherapy Keytruda (pembrolizumab) which target specific biomarkers regardless of tumour location.

But despite the availability of a growing menu of personalised cancer treatments, actually matching patients up to the right therapy can be difficult. According to a survey of US acute care organisations conducted by Definitive Healthcare and published in December 2019, just over 20% had established precision medicine programmes. Investment in genomic testing is vital to quickly get patients on the best treatment course, but financial and operational barriers remain.

The foremost among these is the cost associated with genomic sequencing and the use of companion diagnostic devices, cited by 28% of Definitive Healthcares respondents as the biggest challenge for already-established precision medicine schemes. Lack of expertise is another obstacle, as many physicians may struggle to accurately interpret test results without specialist assistance another major cost driver for clinics and hospital departments trying to build pathology teams that are up-to-date with the newest tests. A 2018 survey of 160 oncologists by Cardinal Health found that 60% of physicians who dont use genomic tests avoid them because of the difficulty of interpreting the data.

In clinical research and development, too, there are growing pains associated with moving the pharmaceutical pipeline towards drugs targeting smaller patient sub-groups. Again, cost is a central issue companion diagnostics dont come cheap, finding and validating biomarkers to guide targeted therapies is a lengthy task, and analysing vast amounts of data often requires new teams with specialised knowledge.

The expense of incorporating a host of new processes into innovative trial designs not to mention the cost of manufacturing cell and gene therapies obviously has an impact on the list price of personalised drugs that win approval. This is most clearly seen in the eye-watering prices of some of the worlds first truly individualised cancer treatments, chimeric antigen receptor T-cell (CAR-T) therapies.

Treatments such as Novartiss Kymriah and Gileads Yescarta remove T-cells from the patients blood, modify them to target tumour cell antigens and then infuse them back into the blood stream. These therapies have achieved impressive results in rare and advanced cancers, but cost upwards of $400,000 per patient, limiting their reimbursement options among both private and public payers. Promising advances in CAR-T manufacturing and potential off-the-shelf T-cell production could help bring these costs down in the years to come, but for now the problem remains.

As for the broader clinical trial eco-system, these studies have been historically set up to assess a drug candidates safety and efficacy in an increasingly large segment of the patient population, building evidence towards the regulatory approval process. Bringing a personalised medicine through the clinical development process is a new paradigm in a number of ways; as well as the aforementioned cost drivers, there can be an extra enrolment burden to identify and recruit patients this is already a common cause of trial failure, but its all the more difficult when youre looking to access a small patient sub-group with the appropriate biological profile.

The difficulty of providing sufficient evidence of safety and efficacy can also present issues where current regulations struggle to accommodate new innovations in personalised medicine. Smaller trial designs present statistical problems in terms of understanding a drugs definitive risk-benefit profile, and while some personalised applications can be discovered as part of larger trials that fail to meet their endpoints outside of a select patient group with particular biomarkers, many current regulations dont accept post hoc analysis and would require an entirely new trial.

Personalised medicine developers desire better guidance on how best to design a successful clinical trial for a personalised therapy, because absent guidance, they risk presenting suboptimal evidence regarding stratification options, reads a 2017 study on personalised medicine barriers, published in the Journal of Law and Biosciences. Designing clinical trials for differently responding subgroups (for example, biomarker-positive and biomarker-negative groups) requires additional time and resources. Companies are reluctant to make this investment without a commensurate increase in the certainty of regulatory approval.

The increasing use of surrogate endpoints, conditional approvals and real-world data is helping to address these issues, but theyre not yet an ideal solution. Conditional approvals rely on very careful post-marketing observation and analysis, while the value of surrogate endpoints has been questioned, adding to the tension between accelerating approvals and ensuring patient safety.

The ultimate benefits of creating more personalised treatments are clear, and their advantages for human health could, in the long-term, be matched by their economic returns. After all, quickly treating patients with the right therapy for them or, even better, using knowledge of a patients genetic risk profile to prevent illness in the first place would be a huge financial gain for overburdened health systems.

Todays costs are gradually falling, as NIH data on DNA sequencing costs demonstrate. But there is still a long way to go before we can wave goodbye to the blanket drug development that has dominated modern pharma for decades, even in the advanced field of oncology, let alone other therapeutic areas. Only a sustained and holistic push from regulators, drug developers, clinicians, governments and others will be enough to bring us over the line.

Read more from the original source:
Precision medicine in 2020: what barriers remain for drug developers? - pharmaceutical-technology.com

Recommendation and review posted by Bethany Smith

On February 26, United Therapeutics (UTHR) came out with earnings results for the fourth quarter of 2019. The companys revenues of $311.11 million were down YoY by 18.43% and fell short of the consensus by $46.06 million. The companys fourth-quarter non-GAAP EPS (earnings per share) of $1.96 also missed the consensus by $1.43.

Subsequently, the stock is down by 11.97% from $112.86 on February 25 to $100.79 on February 27. I believe that this is an investor overreaction, considering that the dip in revenues and EPS is associated with a one-time event of inventory destocking by a distributor in the fourth quarter. Earlier in 2019, this distributor had placed larger-than-normal orders for the companys products due to an error in its patient utilization data. Hence, the smaller-than-normal order in the fourth quarter was an attempt to normalize inventory levels.

Besides this small glitch, the company boasts of robust fundamentals. Today, we will see why United Therapeutics can prove to be an attractive opportunity in 2020.

United Therapeutics is a biotechnology company focused on developing novel, life-extending therapies in lung disease, oncology, and organ manufacturing indications. The company commercializes therapies including an infused formulation of the prostacyclin analog treprostinil, Remodulin; an inhaled formulation of treprostinil, Tyvaso, and a tablet dosage form of treprostinil, Orenitram; and an oral PDE-5 inhibitor, Adcirca, in PAH (pulmonary arterial hypertension) indication. The company also offers Unituxin, a monoclonal antibody for treating neuroblastoma.

United Therapeutics is now working on developing next-generation technologies for Remodulin, Tyvaso, and Orenitram. The companys R&D pipeline also has investigational novel biologics and NCEs (new chemical entities) targeting various lung, oncology, and organ manufacturing indications.

In July 2002, the company secured FDA approval for Remodulin as a continuous subcutaneous infusion for the treatment of PAH patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. Despite the launch of a generic treprostinil in early 2019, Remodulins sales were only 2% down YoY to $587 million in 2019. In fact, the company reported the highest number of new Remodulin starts in the last ten years.

The YoY decline in Remodulin sales was attributed to a small number of patients switching to the generic drug, as well as to the fact that new patients start on lower dosages of Remodulin and then begin the process of titrating to their effective dose. Since the patient switching trend has all but trickled down, the company now expects U.S. Remodulin patient demand as well as sales to jump up YoY in 2020.

Remodulin demand has been pretty sticky for years. It is a very complex product targeting a very fragile patient population, which places a high premium on years of safety and supply chain reliability.

United Therapeutics is now getting ready to launch the subcutaneous delivery system for Remodulin injections, the RemUnity system, in July 2020. Co-developed by United Therapeutics and Deka Research and Development and cleared by FDA under the FDA 510(K) pathway, the RemUnity system is expected to reduce the risk of bolus dosing due to pump failures and provides wider arrays of notifications, alerts, and alarms than current pumps. Additionally, the RemUnity system will control Remodulin flow rates without the use of a motor. The pump is small and lightweight with a service life of at least three years.

On February 24, the company announced preliminary analysis from Phase 3 INCREASE study evaluating Tyvaso Inhalation Solution in patients suffering from WHO (World Health Organization) Group 3 pulmonary hypertension associated with PH-ILD (interstitial lung disease). The trial met its primary endpoint of demonstrating improvement in 6MWD (six-minute walk distance). In addition to increasing six-minute walk distance by 21 meters versus placebo after 16 weeks of treatment, Tyvaso also demonstrated significant improvements in each of the study's secondary endpoints, including reduction in the cardiac biomarker NT-proBNP, time to first clinical worsening event, change in peak 6MWD at Week 12, and change in trough 6MWD at week 15. Based on the INCREASE results, the company now plans to submit a supplemental new drug application to expand the Tyvasos label in mid-2020.

In June 2019, the company submitted a 505(B)(1) NDA (new drug application) for Trevyent disposable treprostinil pump system. Although the FDA first accepted the application and set PDUFA (prescription drug user fee act) date as April 27, 2020, the agency later included a mid-cycle information request noting several deficiencies in the Trevyent NDA. While the company has already sent its responses to the FDA, based on recent discussions with the FDA, the company expects a delay in the PDUFA date. The company expects this FDA approval in the next 18 months.

United Therapeutics also expects the launch of ISR (Implantable System for Remodulin) codeveloped with Medtronic (MDT) to be delayed to 2021. The delay of the commercial launch is attributable to Medtronic satisfying various conditions to its PMA approval.

United Therapeutics estimates the prevalence of PAH WHO Group 1 in the U.S. to be more than 45,000. The currently approved PAH drugs are for PAH WHO 1 class patients. According to PHA (Pulmonary Hypertension Association), WHO Group 1 refers to pulmonary arterial hypertension (PAH), which is caused when the arteries in the lungs become narrowed, thickened or stiff. The right side of the heart must work harder to push blood through these narrowed arteries. This extra stress can cause the heart to lose its ability to pump enough blood through the lungs to meet the needs of the rest of the body.

However, the prevalence of PAH WHO Group 3 patients in the U.S is even higher, of around more than 130,000 patients. These patients do not have any FDA approved treatment option. Again, according to PHA, WHO Group 3 includes PH due to chronic lung disease and/or hypoxia (low oxygen levels). These lung diseases include obstructive lung disease where the lung airways narrow and make it harder to exhale (e.g. COPD or emphysema); restrictive lung disease in which the lungs have a tough time expanding when one inhales (e.g. interstitial lung disease or pulmonary fibrosis); sleep apnea, and living in an area of high altitude for a long period of time. Arteries in the lungs tighten so that blood can only go to areas of the lungs that are receiving the most air and oxygen. This tightening leads to high blood pressure throughout the lungs.

United Therapeutics is working to increase its total patient base from around 7,500 to 25,000 in the next five years.

Besides Remodulin, Tyvaso and Orenitram also saw the highest patient demand in 2019 as compared to the last four years.

Then again, United Therapeutics expects RemUnity, Trevyent, ISR, and Smart Pump technology to have a very favorable impact on future patient demand and sales of Remodulin. The company also expects label expansion of Tyvaso based on the INCREASE study to increase the addressable U.S. population by more than 30,000 patients. This will also position the Tyvaso as a treatment option for a section of the PAH WHO Group 3 patients, those with interstitial lung disease. The company is studying Tyvaso in COPD (chronic obstructive pulmonary disorder) patients in the Phase 3 PERFECT study. Finally, the expanded label of Orenitram based on the FREEDOM-EV trial highlighting superior morbidity and mortality outcomes is also helping to attract new PAH patients.

United Therapeutics is now studying Tyvaso in PH WHO Group 3 patients, PH COPD patients, in Phase 3 trial PERFECT. The company seems to have high hopes for the success of the trial after robust results from the INCREASE study since inhaled therapies can avoid the VQ (Ventilation Perfusion Mismatch), as is seen in system therapies targeting lung diseases. The PERFECT trial is currently 20% enrolled.

Besides studying already approved products for additional indications, the company also has a slew of investigational NCEs and biologics in its pipeline.

United Therapeutics expects investigational Phase 3 asset, ralinepag, to transform the care of WHO Group I PH patients. The company is also studying a gene therapy study in the Phase 3 trial, SAPPHIRE, to make PH treatment more convenient with just a once quarterly infusion of genetically engineered autologous stem cells from the patient. The company expects enrollment to be completed in 2021, and product launch by 2025. Finally, the company is attempting its hand at the much challenging and lucrative organ manufacturing segment.

The biggest risk weighing down on United Therapeutics valuation is the potential impact of generic erosion of Remodulin. The company depends extensively on its topline on the treprostinil franchise, exposing it to significant business concentration risk.

The company is exposed to R&D failure risk and subsequent contraction in probable growth drivers. The most recent example of such a failed trial is the phase 2/3 DISTINCT study evaluating Unituxin in Injection added to irinotecan compared to irinotecan or topotecan alone in patients with relapsed or refractory SCLC (small cell lung cancer). On February 3, 2020, the company announced that this trial did not meet its primary endpoint of extending OS (overall survival).

According to finviz, the 12-month consensus target price of the company is $122.22. On February 27, Cowen analyst Chris Shibutani upgraded United Therapeutics from Market Perform to Outperform and raised the price target from $119 to $145. On February 25, Wedbush analyst Liana Moussatos raised her price target from $237 to $243 and reiterated Outperform rating for the stock. On February 13, Credit Suisse analyst Martin Auster reiterated the Outperform rating and raised his price target from $113 to $121. On January 31, JPMorgan analyst Jessica Fye revised upwards United Therapeutics rating from Neutral to Overweight and price target from $116 to $120. On December 27, Oppenheimer analyst Hartaj Singh reiterated the Outperform rating and $155 target price.

We see that the overall analyst sentiment and target price have consistently improved for the company since March 2019.

Based on the companys robust product portfolio, strong pipeline, and multiple upcoming catalysts, I believe that $145 is a fair estimate of the true value of the company. I believe that retail investors with above-average risk appetite should consider buying the company on the latest dip in 2020.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Read the original post:
United Therapeutics: Buy The Dip - Seeking Alpha

Recommendation and review posted by Bethany Smith

london-based photographers david vintner and gem fletcher document individuals who form part of the transhumanism culture throughout europe, russia and the united states in their latest collaborative photo series, I want to believe an exploration of transhumanism. the five-year-long project explores the core idea behind transhumanism the belief that human beings are destined to transcend their mortal flesh through technology.

neil harbisson hears color neil harbisson was born with achromatism, a rare disease that renders him colourblind. rather than overcome achromatism, harbisson created a new sense to go beyond the human visual spectrumin 2004 he had an antenna implanted into his skull. the antenna allows him to perceive visible and invisible colours as audible vibrations, including infrareds and ultraviolets.

the photo series by vintner and fletcher illustrates three gradual stages of transhumanism from testing ground, patient zero to humanity 2.0. at the lowest tier, testing ground looks into individuals who have created wearable technology to expand their human abilities, improving everything from concentration to mental health.patient zero studies those who have taken permanent action to become half human and half robot. in the final chapter, humanity 2.0, the transhumanist subjects focus on life extension and immortality.

the work of the individuals in this book demonstrates how optimizing our brains and bodies could revolutionize and redefine humanity. as human architects, we are only limited by our imagination, explains vintner and fletcher.

kevin warrick widely considered as one of the first cyborgs.kevin warrick is a pioneering professor in cybernetics and considered by many as the worlds first cyborg. kevin instigated a series of experiments involving the neuro-surgical implantation of a device into the nerves of his left arm in order to link his nervous system directly to a computer. this enabled him to have a symbiotic connection with a robotic hand. he could control the hand using his own brain signals from anywhere in the world, as well as sense what the robot hand was feeling.

humans are now gods. we are now able to create and design humans, but do humans have the foresight to do it in the right way? questions the photographers.

cyborg arm

for many transhumanists, life extension and immortality is the goal. transhumanism started as early as 1923 and has developed over recent years through the rise of sci-fi themed books, movies and the democratization of technology. as studies on experimental genetic engineering, tissue regeneration and stem cell treatments are also becoming more apparent in todays world, transhumanists hope to extend the life of the human body anywhere from twenty to 500 years longer than the average lifespan.

vintner and fletcher are working together on releasing the photo series as a book, which can be funded on crowd-funding platform kickstarter, here.

moon ribas sensing earthquakesmoon ribas is connected to online seismographs allowing her to perceive the seismic activity of the planet through vibrations in her body. the vibration she feels depends on the intensity of the earthquake. if she is standing in newcastle, she can sense earthquakes happening everywhere from japan to greece. she describes the sensation as having two heartbeats, her biological heartbeat and the earthbeat, which has its own rhythm inside her body.

dr natasha vita-more a leading expert on human enhancement and emerging technologies

dr. aubrey de grey biomedical gerontologist and the chief science 0fficer of SENS research foundation

liz parrish founder of bioviva

dr max more president and CEO of the alcor life extension foundation

patient zero - james young after an accident that left him a double amputee, james young turned to bionics to redesign his body. obsessed with the metal gear solid, he worked with gaming giant konami and prosthetic sculptor sophie de oliveira barata to develop an advanced bionic arm inspired by the computer game.

carbon fibre bionic limb

patient zero - rob spence known as the eyeborg, rob spence lost an eye as a child while playing with his grandfather's shotgun. inspired by a love of the bionic man and his interest in documentary filmmaking, spence created an eye with a wireless video camera inside. the camera is not connected to his optic nerve but sends footage to a remote receiver. over the years, he has created several different aesthetics for the eye, from a realistic 'hidden camera' version to a terminator inspired glowing red version.

patient zero - neil harbisson neil harbisson was born with achromatism, a rare disease that renders him colourblind. rather than overcome achromatism, harbisson created a new sense to go beyond the human visual spectrumin 2004 he had an antenna implanted into his skull. the antenna allows him to perceive visible and invisible colours as audible vibrations, including infrareds and ultraviolets.

image out of rob spence's eyes

new ways of seeing - EYEsect the experimental device aims to recreate the experience of seeing the world like a chameleon, with two single steerable eyes. in changing the way we perceive the world around us, eyesect alters our version of reality enabling new ways to sense and experience our environment.

new ways of seeing - north sense created by liviu babitz and scott cohen, north sense is a small matchbox-sized artificial sense organ that delivers a short vibration every time the user faces north, similar to the biological abilities of migratory birds, extending the human perception of orientation.

new ways of seeing - aisen caro chacin / echolocation the echolocation headphones are a pair of goggles that aid human echolocation. it is designed to substitute the users vision augmenting our spatial awareness with sound, similar to the abilities of bats and whales. the device has both the potential to aid the visually impaired and provide sighted individuals with a new sense.

project info:

title:I want to believe an exploration of transhumanism

artistic director: gem fletcher

photographer: david vintiner

kick starter page: I want to believe

See the original post:
cyborgs, robots, and biohackers: the first-ever survey of transhumanism - Designboom

Recommendation and review posted by Bethany Smith

Are These Penny Stocks On Your Watch List Right Now As Coronavirus Fuels Headlines?

Over the weekend, global headlines continued to see countless mentions of coronavirus cases. While many compare it to the average flu, its global spread hasnt been ignored. While the death toll among young, healthy individuals hasnt become a major concern, the fact that mortality is an issue, has been a focal point. Meanwhile, the broader markets are coming off the worst week since the financial crisis.

However, if you are an active reader of PennyStocks.com, it was actually a huge week for coronavirus penny stocks. Last week saw many of these coronavirus stocks reach highs that were well out of penny stock range. Some even blew clear past $40 per share at times.

While the S&P and Dow posed a comeback at the end of the day, we cant ignore continued concerns over the weekend. The first U.S. death has been recorded while new states are reporting their first cases. Meanwhile, weve got a big week of economic data ahead.

Coming up first, weve got China PMI data to consider. It showed the fastest contraction in factory activity ever in February. This was even worse than during the financial crisis. Meanwhile, the likelihood of a Fed rate cut just got that much greater. Slower non-farm payroll figures from Friday didnt help either.

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Consensus forecasts showed payrolls gaining 175,000, which slowed from 225,000 in January. While the U.S. economy appears increasingly vulnerable to the outbreak, the Fed has said it will act as appropriate in response to evolving risks. On another note, The Bank of Canada will also hold a policy meeting this week.

Some analysts think that the Bank could pre-emptively cut rates. This may be a further indication of whats to come for other central banks. The BoC has been known to move early in certain instances, so further market risk could be in play and in favor of certain penny stocks like gold if this is the case.

Then weve got Super Tuesday to think about. A total of 14 states will cast ballots in favor of their optimal Democratic candidate. Bernie Sanders has been said to hold the lead heading into the week. But Super Tuesday will further shed light on what American Democrats want in a candidate, this week. Given everything at work, there are certain sectors that those investing in penny stocks could be focusing on this week.

First, though gold stocks have dipped amid coronavirus concerns, it doesnt mean they will be counted out by any means. Certainly, broader sector stocks felt the brunt of the latest outbreak. However, given the financial uncertainty and economic shifts, gold stocks have historically presented safe-haven options in the market. There are several gold penny stocks that either held a trend or saw a late-Friday bounce last week.

First, IMC International Mining Inc. (IMIMF Free Report)(IMCX) was one of the only gold penny stocks that didnt pull back aggressively last week. In fact, for most of February, shares traded within a range of high $0.30s to low $0.40s. While its U.S. listing is only about a month old, its Canadian listing shows that momentum has built since the beginning of the year. Around January 8th, the stock traded around $0.25 CAD and managed to reach highs of $0.50 CAD.

In February, the company reported several big developments that could be in focus this month. Aside from appointing a new CFO, IMC International also entered into the early phases of a potential acquisition. IMC signed a letter of intent to acquire Thane Minerals, owners of the Cathedral property in northern British Columbia. The Cathedral Project is in an area called the Quesnel Terrane which is rich in mineralization perfect for gold discovery.

The fact that Cathedral is still in a relatively unexplored portion of the northern Quesnel Terrane could signal an opportunity for the company. Considering the proposed acquisition is in its early phases, the market may be watching closely to see if IMC will formally close. It would present immediate access to the Quesnel Terrane via the Catherdral property. The area hosts past and planned production of 50 billion pounds of copper and 28 million ounces of gold.

Next, Yamana Gold stock (AUY Free Report) could be one of the potentially oversold gold penny stocks to watch next week. Shares plummeted last week as coronavirus fears put a stranglehold on the market. After hitting fresh highs of $4.94 on the 24th, Yamana gold stock pulled back to lows it hadnt seen since mid-January.

Aside from last weeks market fueled sell-off, Yamana has actually performed well. That goes from a price and a fundamental perspective. The companys created a pipeline of highly viable exploration projects and created significant positions across the globe with producing assets. But the next move has Yamana focusing on the longer-term.

Yamana has always taken a long-term strategic perspective. We believe that investing in a generative exploration program today will secure our future tomorrow. We have strong prospects in mine-friendly jurisdictions that we know well, and we are confident that they will become a cornerstone of Yamanas next generation of mines.

Yamana has also further optimized its portfolio by shedding assets. For example, last month the company sold off its portfolio of royalty interests and contingent payments from the Deep Carbonates project for $65 million. This is broken up into a $20 million cash component and $45 million share position of which Yamana can further benefit from the potential success of the project.

Similar to Yamana and unlike IMC International, Hecla Mining (HL Free Report) saw its stock drop last week. For Hecla, it was a dip to new 2020 lows. However, in a similar fashion to other gold stocks, HL stock rebounded by the end of the day on Friday. Overall, the sentiment surrounding the company hasnt been bearish.

Earlier last month, the company announced fourth-quarter and full-year 2019 results. Sales for Q4 came in at $225 million with full-year sales hitting $673.3 million marking the highest in company history. Silver production from Hecla came in at 12.6 million ounces along with record gold production of 272,873 ounces. Hecla also reported record reserves for silver, lead, and zinc. Aside from this, the company was able to decrease its net debt by $136 million.

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In 2020, at current prices, we expect continued strong cash flow generation with the ongoing solid performance at Greens Creek, the ramp-up of Lucky Friday, expected improvements at Casa Berardi and the potential mine life extension at San Sebastian from the Hugh Zone, said Phillips S. Baker, Jr., President and CEO of Hecla. During after-hours trading on February 28, Hecla gold stock traded higher at $2.79, which may be something to note if its one of the names on your penny stocks watch list for this week.

After last week, theres no question that biotech penny stocks have taken a spotlight. While some stock saw their biggest drops in recent weeks, many biotech penny stocks reached record highs. In fact, many of these coronavirus penny stocks have been covered consistently for some time now. We put an article out getting everyone up to speed last week Coronavirus Madness: Stocks That Scored Big For Investors. Could these penny stocks to watch join the list this week?

First, Biocept Inc. (BIOC Free Report) was one of the biotech penny stocks discussed in January. At the time the company announced that its Target Selector assays were available to doctors. The focus is for doctors to use the product to evaluate cerebrospinal fluid of patients in checking for tumors. Earlier last month the company reported that it entered into an agreement with a California-based physician association to provide testing services to physicians and patients in that network.

Considering that testing could become a big focus during this outbreak, Biocept appears to have gained attention. On Friday, BIOC stock saw one of its biggest days yet. Shares traded from an open of $0.285 as we focused on the company. By the closing bell, the penny stock was at $0.78. While there hasnt been much coronavirus-specific news, as weve seen speculation played a big role with the latest boom in coronavirus penny stocks.

If Biocept is one of the names on your list of penny stocks, keep this information in mind. Hype may need to be factored into this equation. If BIOC is falling into the coronavirus stock category, take particular consideration in the fact that its pipeline is focused on testing for cancerous tumors. Also, keep in mind that BIOC made a dramatic move on Friday and profit-taking could also be something to keep mindful of in the week ahead.

Another one of the coronavirus penny stocks to watch might be Heat Biologics (HTBX Free Report). While most coronavirus stocks have been taking off for days, HTBX stock seems to have just caught attention on February 28. This came after a downtrend for most of the year. Theres no recent news and no new filings. But several popular message board sites are paring HTBX stock with coronavirus-related news.

Similar to Biocept, Heat Biologics focuses on cancer and T-cell stimulation. Nothing on its site nor in its previous updates were related to coronavirus or the common flu. Meanwhile, back in December, the company reported that it had dosed its first patient in a Phase 1 trial of its t-cell treatment, HS-130. Something else to note is that on the corporate site, it shows the company held a 2020 Special Meeting of Stockholders on February 27.

So, while the market digests the latest coronavirus data, HTBX could find itself in the conversation apparently. In a company 8-K filing, the results of the special meeting showed shareholders agreed to each of Heats proposals. This included an increase to authorized shares from 100m to 250m, effecting a reverse split of common stock, as well as updates to its stock incentive plan. The company also approved authorization to issue undesignated preferred stock. In regard to the reverse split, the company gave a ration within a range of 1 share of Common Stock for every 2-50 shares of Common Stock.

Finally, Oragenics Inc. (OGEN Free Report) was one of the top penny stocks to watch in February. Last Friday, that momentum continued to push shares to new 11-month highs after the market close. OGEN stock reached $0.90 after closing the regular session just under $0.75.

The biotech penny stock started moving as it approached an industry presentation date in early February. We also highlighted all of the FORM 4s filed that showed insider movement in the stock. But there could be a few things at work right now to take notice of, mainly the companys focus on infectious diseases. Oragenics reported the completion of enrollment of its Phase 2 clinical trial for AG013 in Oral Mucositis. More specifically, the company previously reported that it plans to deliver the results of its study early this year.

While coronavirus penny stocks are in focus, timing is of importance. Thats also considering the timeline given in recent CDC press conferences too. Given Fridays momentum will OGEN continue to be one of the coronavirus stocks to watch this week? On its website, the company even states:

Oragenics, in collaboration with Precigen, is in the process of developing lantibiotics, a novel class of antibiotics that are known to be active against several life-threatening infectious agents, toward the goal of commercialization for the treatment of infectious diseases in humans.

Pursuant to an agreement between Midam Ventures LLC and IMC International Mining Corp.(CSE: IMCX), Midam has been paid $200,000 for a period from January 7, 2020, to February 14, 2020. Midam has been paid an additional $200,000 and extended its period of coverage to March 14, 2020. We may buy or sell additional shares of IMC International Mining Corp.(CSE: IMCX) in the open market at any time, including before, during or after the Website and Information, to provide public dissemination of favorable Information about IMC International Mining Corp. (CSE: IMCX).Full disclaimer here.

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If you ever end up in an emergency room, the first thing that happens is a doctor or nurse will check your critical vitals: your temperature, blood pressure, respiratory rate, and pulse. If those indicate your life is at risk, your care is prioritized over others who have already been waiting or who have been seen by a doctor but require additional testing (e.g. an x-ray or blood test) or a specialist to review their symptoms. This process, called triaging, is the global standard for allocating resources in emergency care.

Triaging is a marvel of modern healthcare if it is abundantly clear that you are on deaths door. But if theres no textbook description of your condition, it can leave you needlessly suffering while the experts try to figure it out. Thats often the case for those with rare diseases, a group of conditions that are not individually common, but combined, affect an estimated 10% of the global population, some 475 million people. An estimated 80% of the 7,000 identified rare diseases are caused by DNA mutations that occur during pregnancy, meaning most of those with this category of illness are born with it. In many cases, these babies emerge from the womb with life-threatening conditions that doctorsworking the triage systemwill immediately address. However, this also tends to lead doctors to then ignore the underlying rare diseasean unnecessary medical expenditure, in the triage system framework.

I am one of the people living with a rare disease.

I was born with a number of symptoms and signs that put my life at risk a collapsed lung, a premature exit from my mothers body after only six months, and malnutrition from a hole in my amniotic sac. These problems were all treated and resolved over a multiple month stay in the hospital dictated by the triage system. I was allocated hospital resources for my life-threatening conditions until I was deemed stable enough to go home: the point at which I wouldnt die if I left the care of the hospital.

But there was another problem that was overlooked, and which wasnt diagnosed until I was five years old.

Every bone in my body was bent and every muscle atrophied or non-existent. I couldnt move my neck away from shoulder; I couldnt straighten my legs, knees, arms, wrists, ankles, toes, hands, or fingers beyond fixed, fully bent positions.

The triage system worked at saving my life, but never addressed how I would live day to day or even physically move from a single location by myself. It never addressed the underlying issue and root of the problem: a rare orthopedic genetic disease.

The life or death triage standard is one of the primary reasons that it takes, on average, seven years for people with a rare disease to get a diagnosis in the U.S.and

I am one of the lucky ones. Serendipitously, a Because of these surgeries, and additional ones Ive had since, I could feed myself, live free from a wheelchair, go to school through the post-graduate level, and hold a full-time job.

The orthopedic surgeries I neededover 29 of them in less than 30 yearshave cost millions of dollars. And these costs grow each year as I undergo additional exploratory surgery in the absence of any cure. However, these costs are still lower than what I would have incurred had I been left as the triage system deemed stable as an infant. I would have required 24-hour in-home care my entire life. I would never have been able to use the bathroom alone, to get dressed alone or to even leave the house alone. The lifetime value of a working individual according to the US Office of Management and Budget is on average $7 million to $9 million. The cost of a full-time caregiver is on average $40,320 a year; if a rare-disease patient reaches the average US life expectancy of 78 years old, the lifetime cost of full-time care is at least $3 million.

Our healthcare system needs to weigh the long-term costs of leaving behind people with rare disease, and, more specifically, evaluate the economic consequences that follow at a global scale.

Even more so, we need to weigh the costs of creating a pipeline to fill the treatment gap facing people with rare disease., Using genomic sequencing, clinicians can holistically understand the genetic roots of rare disease and even potentially cure rare disease through gene therapy, which modifies and permanently fixes abnormal genes that cause a specific rare disease at birth.

Nonetheless, identifying the root genetic cause of rare disease is the only way to begin to cure a rare disease rather than just treating the symptoms in an ad hoc fashion. While certain pharmaceutical drugs can be developed from the findings in a genomic sequence to help mitigate or lessen symptoms, the science suggests the only way to cure a rare disease is to administer an even newer science called gene therapywhich modifies and permanently fixes genes that are abnormal. Considered to be the most expensive option, a However, this nascent science is costly: gene therapy costs around $2 million for current US Food and Drug Administration (FDA)-approved options.

Insurance plans in the US rarely pay for clinical-grade whole-genomic sequencing (which can carry a price tag of up to $9,000)let alone gene therapies. Yet if the most expensive cost to cure a rare disease is $2 million, thats still far less than $3 million for a lifetime of full-time care (which excludes additional expenses). And new studies, like one the World Economic Forum released in the lead up to this years International Rare Disease Day, show that we can ultimately save money in the long term by funding more treatments and, as an added benefit, potentially develop more cures by learning when treatments work and when treatments dont work.

We cant create clinical pathways for the more than 7,000 rare diseases overnight, but we need a standard of care that goes beyond using death as the primary barometer of focus, over-simplifies the complexity of what it means to be healthy, and only considers short term costs. An economically effective, new model could center on allocating resources with the end goal to allow people to reach a level of health that provides basic mobility or basic independencea level of health allowing economic productivity. We are living in a time of unprecedented medical innovation, and our system of coverage needs to catch up. We can do better than just keeping people alive.

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The Bad Economics of the U.S. Health Care System Shows Up Starkly in its Approach to Rare Diseases - TIME

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In recent years in the world of medical genetics has been a real breakthrough. New medicines through which have learned to treat disease, cure which recently even anticipated. As far as the development of the Russian medical genetics corresponds to the global trends?

Sergey Kutsev: In the world, indeed, occurred very serious changes in the field of genetics. They happen literally before our eyes, and we are talking primarily about new approaches in the treatment of orphan genetic diseases. First of all there is to say about classical gene therapy. She has nearly 30 years, and the long development has led to the fact that, for example, a few years ago appeared the first drug for the treatment of a very rare hereditary disease (1 case per 1 million), which is characterized by increase in triglycerides in the blood. The disease is accompanied by acute pancreatitis and can lead to death. Unfortunately, not all of the goals the developers of the drug have been achieved, widespread it is not found, and the high cost of treatment was unjustified.

However, development of such drugs continued. The result is a drug that can be called a real breakthrough in the world of genetics, used for treatment of spinal muscular atrophy. From this disease the child dies, as a rule, in the second year of life. So today, a single administration of this drug leads to an almost complete cure of such a severe hereditary disease. Therefore, despite the high cost of treating one child more than $2 million the price of the drug is justified.

And now of course we see great prospects of this direction, because in addition to these drugs at present, there are already a number of advanced clinical trials for the treatment of the same gene-therapy methods and other hereditary orphan diseases, among which phenylketonuria, hemophilia, some hereditary diseases WSOena.

If we talk about the domestic developments, I would say that our pharmaceutical industry is now turning its attention to the problems of patients with orphan diseases, and we follow the global developments. With regard to diagnosis and early diagnosis very important for treatment of rare diseases, it in our country is organized on a global level. And the issue here is not only in the availability of genetic diagnosis, but also in the fact that in addition to conventional methods, such as molecular genetics, we use the latest technology of massive parallel sequencing (sequencing of the new generation). These technologies allow us to diagnose a wide range of hereditary diseases.

In April last year at the Federal level was approved by the scientific-technical program of development of genetic technologies. As far as its content corresponds, in your opinion, the needs of medical genetics in Russia?

Sergey Kutsev: the Program of development of genetic technologies is quite extensive. Very important for us section on the creation in Russia of centers of genomic research at the international level. To date, three such centres: one of them is engaged in Biosafety (this refers to infectious agents), the second genetic technology in agriculture, and the third genetic technologies in medicine. Under the program, as a basic guideline deals with the editing of the genome. This decision of the government we support with both hands, because it is aimed at fostering research in the field is very promising technology, the technology of genome editing. This is the next phase in medical genetics. It is how to get the cells directly from the patient to edit the genome, that is, to correct the defect that arose in these cells, and transplanting them back to the cells subsequently multiply and, accordingly, began to produce the necessarynecessary body substances. This approach is very promising, it relates to the gene-cell technology. And, of course, the development of these technologies it is necessary to invest now, because thats the future.

You have repeatedly said that the qualification of Russian geneticists are highly valued on a global level. At the same time, the personnel issue is one of the most serious in todays genetics in Russia. Suffice it to say, doctors-geneticists, who are involved in the identification of orphan diseases in the country, only about 350. How is this problem solved at the Federal level?

Sergey Kutsev: the Shortage of personnel in genetics in Russia is pretty decent. In some regions of the country there are only one to two doctors-genetics in the region. Frames for genetics to prepare necessary. Needed professionals, especially doctors-genetics, doctors genetics laboratory.

in addition, there is a problem in the education of doctors of all specialties neurologists, nephrologists, ophthalmologists, cardiologists and so on. In practice, any doctor can meet a genetic disease. Therefore, genetics, ranging from inheritance laws to the clinical manifestations of some diseases, doctors of different specialties just have to know. The fact that undergraduate education of doctors is paid to genetics now, few hours of study. On the other hand, specialists for teaching genetics in more than 50 medical universities in the country is also not enough.

What is the output?

Sergey Kutsev: In early February at the meeting of the academic Council approved my proposal to create a large scientific and educational centre on the basis of our Medico-genetic scientific center named after academician N. P.Bochkova. We planned for 2020, the establishment of more than 15 departments in our centre and already certain areas, among which neurogenetics, ophthalmic genetics, cardiogenetics and so on. These chairs will be required to take the advanced training of physicians of different SPEcelesta in the field of genetics. So now we are talking about postgraduate education simply because the urgent need to train people who are already in practice, who would now be able to work and to identify patients with hereditary diseases at an early stage. Of course, it is necessary to engage students, education at undergraduate level, but I think now we have to extinguish the fire. And gradually increase the share of education in genetics for students of all medical universities. For refresher training were going to have about 100 of geneticists who could teach. And of course, intend to look for partners among medical universities in the country.

what are the main directions currently your genetic center?

Sergey Kutsev: Our institution is primarily a scientific center, which is the study of the etiology, pathogenesis, development of diagnostic approaches, prevention hereditary, including orphan diseases. Despite the fact that we diagnose a disease, we can diagnose any of the hereditary diseases described in the world practice.

our Second destination medicine. Every year we take more than 11 thousand patients. And when you consider that advise usually the whole family, it is more than 20 thousand people per year. Speaking of laboratory studies, in the year we spend more than 70 thousand genetic research, and on this indicator are the largest centre in Europe. According to my calculations, about 90% of diagnoses of hereditary diseases in the country were set in the walls of our institution.

And third we focus on education. To us comes more and more residents and graduate students. Now, if you count in all the courses, internship and graduate school trained more than 50 people. Thats a lot. Im sure it will be a high level of doctors and scientists.

You have repeatedly talked about the need to expand screening to 41 nosology. What has been achieved in this direction today? How effective it can be in terms of preventing the development of illness and subsequent disability of the patient?

Sergey Kutsev: At the end of December last year, we almost agreed on a program of extending screening up to 39 diseases. Of course, it is difficult to expand screening to more than 1.65 million newborns per year. But this program will allow us to annually identify more than 2 thousand children, you can help. To make it clear those children who could die in the first year of life or during childhood, or become disabled. If we identify hereditary diseases in the first days of life, in most cases we can help them to avoid death and disability.

If we talk about pharmacoeconomics, the treatment of children in these cases are relatively inexpensive and can become a large financial burden for the state. The treatment of one such patient is estimated to be worth about 500 thousand rubles.

So even those who say that the treatment of orphan diseases is expensive and costly, I can assure you that the state advantageous to have an economically active citizen than many years, to include the disabled. This path is calculated and passed in many States. In addition, the screening in this case is one of the mechanisms capable of improving the demographic indicators of the country. We hope that an expanded screening across the country will be able to start in the last quarter of 2021.

the impression that in the last year or two orphan diseases are increasingly get into the focus of attention of both society and government. In particular, it greatly expanded the list of orphan diseases of the WNV program. How do you assess the prospects for federalization, and that more needs to be done to improve the situation with rare diseases in Russia?

Sergey Kutsev: Attention to orphan diseases from the state the actubut I grew up. First, there is more understanding that this is a great medical and economic problem that needs to be addressed. By the way, according to one study, about 40% of the seats in childrens hospitals today takes children with a serious hereditary, including orphan, diseases. And expansion of screening in this case is one of the tools to change these statistics for the better. Secondly, a social problem that society can not bear to look on the suffering of children, especially when there are ways to help children with serious illnesses to remain in society and thrive together with their peers.

In my opinion, the most important thing now is to improve the skills of physicians-geneticists, laboratory geneticists, and strengthen medical genetic service in all regions. This will help to put the correct diagnosis in patients with orphan diseases. Next, we need to address questions about the creation of domestic products, modern technological approaches, classical gene therapy to develop genome editing.

on the question of the extension of the list of high-cost nosologies (VZN) that is financed at the Federal level, I am sure that gradually we have to include all orphan diseases for which treatment today there are drugs. So today on the queue can be diseases such as disease, Niemann-pick, Fabry, and others. Federalization would not only reduce the financial burden on the regions, but also will allow to solve the problem of early diagnosis of orphan diseases, and therefore, the assistance provided and the patient and his family will become more effective. In the end, with timely start of treatment, patients with these diagnoses remain economically active, reduced social burden on the budget.

in addition, under this system, a much higher control over the correctness of appointments, expensive medications and monitoring their effectiveness. A fixed price for drugs under centralized procurement havedischarges are much lower than what we saw in procurement in the regions. I believe that the government will not be able to get away from this problem and definitely solve it. Theres no other way.

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one of last years sittings of the chamber of regions, the Chairman of the Federation Council Valentina Matvienko said that the purchase of medicines for treatment of orphan (rare) diseases will be funded from the Federal budget in 2021. There is the prospect that in 2020 we will close another five diseases and in 2021 will complete the transfer of funding for the procurement of medicines for people with orphan diseases in full at the Federal level, promised the Chairman of the Federation Council.

Since the formation of the list it was 7 nosologies. Last year, the list of WNV were added to the 5 diseases that have moved from the so-called List-24, containing a list of orphan diseases, drugs for the treatment of which can be purchased at the expense of regional budgets. The necessity of transferring diseases from the List of 24 at the Federal level due to the fact that regions do not always cope with the task timely and complete provide patients with appropriate drugs, there were difficulties and the threat of treatment interruption for orphan patients. According to the Executive Director of the Union of patients and patient organisations on rare diseases Denis Belyakov, despite the fact that the availability of therapy with the diagnosis from the regional list of 24 nosology in Russia enshrined in law, the situation with treatment is not very favourable: there were cases, when, for example, the patient diagnosed with Fabry prescribed therapy is needed, but the regional authorities have not always managed to Finance the provision of medication and treatment was interrupted.

today in the regional list there were 19 diseases, among which, besides the above-mentioned Fabry disease, Niemann-pick disease, arterial LeJonker hypertension, idiopathic thrombocytopenic purpura (ITP), phenylketonuria (PKU) and others. This is a severe genetic disease, leading to disability and often to death.

Experts say that the introduction of rare diseases in the WNV program will allow patients to get necessary drugs fully. In addition, the federalization of orphan diseases provides pricing transparency in the procurement of products and flexibility of a regional supply of medicines. It is very important that patients even with severe orphan diagnoses whose treatment begins in a timely manner, throughout their life are able to remain economically active members of society, is no different from a healthy person.

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Recent developments in the field of stem cell research are paving a path towards a radical shift in the way we diagnose and treat dementia. Stem cells have excited scientists for years and research groups across the globe are using them to advance modern medicine. Using stem cells to aid the fight against dementia is perhaps one of the most critical applications of the technology. Dementia is the leading cause of death in the UK, sixth in US and fifth globally, with an estimated 50 million people currently affected.

The term dementia does not relate to a single disease, but more an array of symptoms that can arise from multiple conditions. The most common is Alzheimers disease (AD) which accounts for up to 80% of all cases. Dementia itself is caused by the death of cells that make up the complex circuitry of our brains and an eventual loss of large portions of the brain. Patients suffering with dementia often exhibit the same general symptoms such as confusion, memory loss and an inability to perform day to day functions. It is a debilitating condition that often strikes the most vulnerable members of society and, consequently, many research groups around the globe work to try to understand dementia-causing diseases to provide better diagnostic and treatment platforms.

In 2007, a research group at Kyoto University in Japan published a study with the potential to change the face of research into dementia along with many other fields. Professor Shinya Yamanaka and his research team developed a method whereby stem cells (cells that can be transformed/differentiated into cells from any tissue) could be generated from a sample of skin. The study, which resulted in a 2012 Nobel Prize for Prof. Yamanaka, demonstrated that skin cells could be isolated from a patient and genetically reprogrammed into induced pluripotent stem cells (iPSCs). In short, this technology made it possible to generate and study brain cells from a patient with dementia without having to remove any of their brain. All they would need to do is provide scientists with a sample of skin.

Since this development, research groups around the globe have started using iPSCs from many patients with dementia in order to understand the biological mechanisms that underlie disease. Dr Eric Hill runs a research group at Aston University in the UK that specializes in iPSCs for dementia research and he had the following to say about the technology:

Its really exciting because it allows us to study cells with genetic mutations that are patient specific. We can get a much better picture of what is actually happening in the brains of these patients. We can now generate all the different cell types found in the human brain and understand how they function together and map the changes that result in disease.

The latter was perhaps most powerfully demonstrated in a study published by a team at the University of North Carolina, led by Professor Hansang Cho. The team was able to generate three key cell subtypes that play important roles in brain function; study the impact of mutations associated with Alzheimers disease; and even replicate some of the core malfunctions found to trigger disease in the brains of patients.

Studies like this are of significance because a large part of the focus in dementia research is on trying to understand how such changes in function arise. When a patient is diagnosed with a disease such as Alzheimers it is often too late for effective treatment. Scientists, instead, seek to elucidate those early changes in brain cell function in order to diagnose patients earlier to give more time for treatment. It is very much a case of prevention being better than a cure. Dr Hill provided an encouraging statement regarding this:

When we generate brain cells from iPSCs the cells we get are developmentally very young. What is interesting is the fact we still see differences between cells from dementia patients versus healthy patients suggesting we could find markers to help us detect and prevent disease some years before it develops.

Despite such promise, however, iPSCs have yet to provide the field of dementia research with that big break. Multiple treatments have progressed into clinical trials since the technology first emerged but no therapies have been approved. Drugs that show promise in the lab fail to deliver on their potential in patient clinical trials, sending researchers back to square one.

We should not be disheartened by this, however, and should instead view it as space into which the technology of using iPSCs to study dementia can grow. A lot of drugs fail in clinical trials because the platforms used to run initial tests dont provide scientists with a wide enough perspective of how those drugs will influence human cells. Additionally, many preclinical studies use animals with dementia-causing disease artificially induced into them. Studies like this often fail to translate into humans because the initial data is not from a human perspective. This is where researchers like Dr. Hill think iPSCs can provide us with an advantage:

iPSCs could provide us with much better platforms for screening drugs to treat and prevent these diseases. They can really add to what we already have, and while we might not be able to grow a full human brain, we can generate the cells that provide the building blocks for one. They give us the chance to screen new therapies more efficiently, better test their effectiveness and reduce the amount of animal use in dementia research.

Dr Hill is not alone in seeing the promise of using iPSCs to find better treatments for preventing the progression of dementia. Multiple research groups around the world have shown the potential of iPSC-derived brain cells for studying the effectiveness of new therapies.

In the last 12 months we have observed a wave of new studies using iPSCs to try to develop better treatments for diseases like Alzheimers, Parkinsons, Huntingtons disease and ALS. From studies in the University of California identifying cholesterol metabolism as a potential target to treating Alzheimers to studies in Luxembourg helping us find better treatments for Parkinsons, it is easy to see why the global effort to get that big break from iPSCs continues to gain interest. We might still be waiting for that next Noble Prize-winning discovery that will improve the lives of millions of patients but the collective effort of iPSC research groups across the world brings us a step closer with every study they publish. Dementia may, one day, be a thing of the past and iPSC research will likely be a significant part in getting us there.

Sam Moxon has a PhD in regenerative medicine and is currently involved in dementia research. He is a freelance writer with an interest in the development of new technologies to diagnose and treat degenerative diseases. Follow him on Twitter @DrSamMoxon

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For years, scientists have predicted that 3-D printingwhich has been used it to make toys, homes, scientific tools and even a plastic bunny that contained a DNA code for its own replicationcould one day be harnessed to print live, human body parts to mitigate a shortage of donor organs. So far, researchers also used 3-D printing in medicine and dentistry to create dental implants, prosthetics, and models for surgeons to practice on before they make cuts on a patient. But many researchers have moved beyond printing with plastics and metalsprinting with cells that then form living human tissues.

No one has printed fully functional, transplantable human organs just yet, but scientists are getting closer, making pieces of tissue that can be used to test drugs and designing methods to overcome the challenges of recreating the bodys complex biology.

A confocal microscopy image showing 3-Dprinted stem cells differentiating into bone cells

The first 3-D printer was developed in the late 1980s. It could print small objects designed using computer-aided design (CAD) software. A design would be virtually sliced into layers only three-thousandths of a millimeter thick. Then, the printer would piece that design into the complete product.

There were two main strategies a printer might use to lay down the pattern: it could extrude a paste through a very fine tip, printing the design starting with the bottom layer and working upward with each layer being supported by the previous layers. Alternatively, it could start with a container filled with resin and use a pointed laser to solidify portions of that resin to create a solid object from the top down, which would be lifted and removed from the surrounding resin.

When it comes to printing cells and biomaterials to make replicas of body parts and organs, these same two strategies apply, but the ability to work with biological materials in this way has required input from cell biologists, engineers, developmental biologists, materials scientists, and others.

So far, scientists have printed mini organoids and microfluidics models of tissues, also known as organs on chips. Both have yielded practical and theoretical insights into the function of the human body. Some of these models are used by pharmaceutical companies to test drugs before moving on to animal studies and eventually clinical trials. One group, for example, printed cardiac cells on a chip and connected it to a bioreactor before using it to test the cardiac toxicity of a well-known cancer drug, doxorubicin. The team showed that the cells beating rate decreased dramatically after exposure to the drug.

However, scientists have yet to construct organs that truly replicate the myriad structural characteristics and functions of human tissues. There are a number of companies who are attempting to do things like 3-D print ears, and researchers have already reported transplanting 3-D printed ears onto children who had birth defects that left their ears underdeveloped, notes Robby Bowles, a bioengineer at the University of Utah. The ear transplants are, he says, kind of the first proof of concept of 3-D printing for medicine.

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Bowles adds that researchers are still a ways away from printing more-complex tissues and organs that can be transplanted into living organisms. But, for many scientists, thats precisely the goal. As of February 2020, more than 112,000 people in the US are waiting for an organ transplant, according to the United Network for Organ Sharing. About 20 of them die each day.

For many years, biological engineers have tried to build 3-D scaffolds that they could seed with stem cells that would eventually differentiate and grow into the shapes of organs, but to a large extent those techniques dont allow you to introduce kind of the organization of gradients and the patterning that is in the tissue, says Bowles. There is no control over where the cells go in that tissue. By contrast, 3-D printing enables researchers with to very precisely direct the placement of cellsa feat that could lead to better control over organ development.

Ideally, 3-D printed organs would be built from cells that a patients immune system could recognize as its own, to avoid immune rejection and the need for patients to take immunosuppressive drugs. Such organs could potentially be built from patient-specific induced pluripotent stem cells, but one challenge is getting the cells to differentiate into the subtype of mature cell thats needed to build a particular organ. The difficulty is kind of coming together and producing complex patternings of cells and biomaterials together to produce different functions of the different tissues and organs, says Bowles.

To imitate the patterns seen in vivo, scientists print cells into hydrogels or other environments with molecular signals and gradients designed to coax the cells into organizing themselves into lifelike organs. Scientists can use 3-D printing to build these hydrogels as well. With other techniques, the patterns achieved have typically been two-dimensional, Eben Alsberg, a bioengineer at the University of Illinois, tells The Scientist in an email. Three-dimensional bioprinting permits much more control over signal presentation in 3D.

So far, researchers have created patches of tissue that mimic portions of certain organs but havent managed to replicate the complexity or cell density of a full organ. But its possible that in some patients, even a patch would be an effective treatment. At the end of 2016, a company called Organovo announced the start of a program to develop 3-D printed liver tissue for human transplants after a study showed that transplanted patches of 3-D printed liver cells successfully engrafted in a mouse model of a genetic liver disease and boosted several biomarkers that suggested an improvement in liver function.

Only in the past few years have researchers started to make headway with one of the biggest challenges in printing 3-D organs: creating vasculature. After the patches were engrafted into the mouses liver in the Organovo study, blood was delivered to it by the surrounding liver tissue, but an entire organ would need to come prepared for blood flow.

For any cells to stay alive, [the organ] needs that blood supply, so it cant just be this huge chunk of tissue, says Courtney Gegg, a senior director of tissue engineering at Prellis Biologics, which makes and sells scaffolds to support 3-D printed tissue. Thats been recognized as one of the key issues.

Mark Skylar-Scott, a bioengineer at the Wyss Institute, says that the problem has held back tissue engineering for decades. But in 2018, Sbastian Uzel, Skylar-Scott, and a team at the Wyss Institute managed to 3-D print a tiny, beating heart ventricle complete with blood vessels. A few days after printing the tissue, Uzel says he came into the lab to find a piece of twitching tissue, which was both very terrifying and exciting.

For any cells to stay alive, [the organ] needs that blood supply, so it cant just be this huge chunk of tissue.

Courtney Gegg, Prellis Biologics

Instead of printing the veins in layers, the team used embedded printinga technique in which, instead of building from the bottom of a slide upwards, material is extruded directly into a bath, or matrix. This strategy, which allows the researchers to print free form in 3-D, says Skylar-Scott, rather having to print each layer one on top of the other to support the structure, is a more efficient way to print a vascular tree. The matrix in this case was the cellular material that made up the heart ventricle. A gelatin-like ink pushed these cells gently out of the way to create a network of channels. Once printing was finished, the combination was warmed up. This heat caused the cellular matrix to solidify, but the gelatin to liquify so it could then be rinsed out, leaving space for blood to flow through.

But that doesnt mean the problem is completely solved. The Wyss Institute teams ventricle had blood vessels, but not nearly as many as a full-sized heart. Gegg points out that to truly imitate human biology, an individual cell will have to be within 200 microns of your nearest blood supply. . . . Everything has to be very, very close. Thats far more intricate than what researchers have printed so far.

Due to hurdles with adding vasculature and many other challenges that still face 3-Dprinted tissues, laboratory-built organs wont be available for transplant anytime soon. In the meantime, 3-D printing portions of tissue is helping accelerate both basic and clinical research about the human body.

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

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On the Road to 3-D Printed Organs - The Scientist

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Top Manufacturers Listed in the Atmospheric Water Generator Market Report are:

U.S. STEM CELL, INC.Brainstorm Cell TherapeuticsCytoriDendreon CorporationFibrocellLion BiotechnologiesCaladrius BiosciencesOpexa TherapeuticsOrgenesisRegenexxGenzymeAntriaRegeneusMesoblastPluristem Therapeutics IncTigenixMed cell EuropeHolostemMiltenyi Biotec

By Types:

Embryonic Stem CellResident Cardiac Stem CellsAdult Bone MarrowDerived Stem CellsUmbilical Cord Blood Stem Cells

By Applications:

Neurodegenerative DisordersAutoimmune DiseasesCancer and TumorsCardiovascular Diseases

Covering Region:

1. South America Backup Software Market Covers Colombia, Brazil, and Argentina.2. North America Backup Software Market Covers Canada, United States, and Mexico.3. Europe Backup Software Market Covers UK, France, Italy, Germany, and Russia.4. The Middle East and Africa Backup Software Market Covers UAE, Saudi Arabia, Egypt, Nigeria, and South Africa.5. Asia Pacific Backup Software Market Covers Korea, Japan, China, Southeast Asia, and India.

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Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market Provides An In-Depth Insight Of Sales Analysis -Regenexx, Genzyme - Fashion...

Recommendation and review posted by Bethany Smith

Cells of 114-year-old converted to young pluripotent stem cells

Evidence of reversal of the telomere aging clock in a supercentenarian

Supports hypothesis of no upper age limit for reprogramming cellular aging

Introduces possibility of identifying the underlying biology of extreme human lifespan and healthspan

AgeX Therapeutics, Inc. ("AgeX"; NYSE American: AGE), a biotechnology company focused on developing therapeutics for human aging and regeneration, announced a new paper co-authored by two AgeX scientists that could lead to new insights into the fundamental mechanisms of aging and why super-centenarians not only live the longest, but also experience extraordinary healthspans; an extension of the healthy years of life that compresses morbidity to a very short period near the end of life. The paper, "Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells," is published online in the peer-reviewed scientific journal "Biochemical and Biophysical Research Communications" from Elsevier. The senior author is Dana Larocca, PhD, VP of Discovery Research at AgeX, and the first author is Jieun Lee, PhD, Scientist at AgeX.

"Clearly, we can learn a lot about aging and longevity from the longest of the long-lived, the supercentenarians, and we hope that this paper accelerates such research," commented Dr. Larocca. "Now that we have converted the cells of one of the longest-lived people in history, a deceased 114-year-old American woman, to a young pluripotent state, researchers can do so with cells from other supercentenarians. The goal is to understand specifically how these "extreme agers" manage to avoid the major chronic illnesses of aging better than any other age group including centenarians. We can essentially put their cells in a time machine and revert them to an earlier state, then study their biology to help unlock the mysteries of super-longevity. Scientists have long wondered, and now we know that we can indeed reset the developmental state and cellular age in the oldest of the old."

Story continues

By way of comparison, the paper also describes undertaking a similar process with cells from two other donors: an eight-year-old with a rapid-aging syndrome commonly known as Progeria, and a 43-year-old, healthy disease-free control (HDC) subject. The paper notes that the supercentenarians cells reverted to induced pluripotent stem (iPS) cells at the same rate as the HDC subject and the Progeria patient. However, there may be some negative impact of extreme age on telomere resetting as this did not occur as frequently in the supercentenarian as in the other two donors.

The donated cells were from "the longevity collection," a cell bank established by the NIHs National Institute on Aging.

About AgeX Therapeutics

AgeX Therapeutics, Inc. (NYSE American: AGE) is focused on developing and commercializing innovative therapeutics for human aging. Its PureStem and UniverCyte manufacturing and immunotolerance technologies are designed to work together to generate highly-defined, universal, allogeneic, off-the-shelf pluripotent stem cell-derived young cells of any type for application in a variety of diseases with a high unmet medical need. AgeX has two preclinical cell therapy programs: AGEX-VASC1 (vascular progenitor cells) for tissue ischemia and AGEX-BAT1 (brown fat cells) for Type II diabetes. AgeXs revolutionary longevity platform induced Tissue Regeneration (iTR) aims to unlock cellular immortality and regenerative capacity to reverse age-related changes within tissues. AGEX-iTR1547 is an iTR-based formulation in preclinical development. HyStem is AgeXs delivery technology to stably engraft PureStem cell therapies in the body. AgeX is developing its core product pipeline for use in the clinic to extend human healthspan and is seeking opportunities to establish licensing and collaboration agreements around its broad IP estate and proprietary technology platforms.

For more information, please visit http://www.agexinc.com or connect with the company on Twitter, LinkedIn, Facebook, and YouTube.

Forward-Looking Statements

Certain statements contained in this release are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not historical fact including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates" should also be considered forward-looking statements. Forward-looking statements involve risks and uncertainties. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the business of AgeX Therapeutics, Inc. and its subsidiaries particularly those mentioned in the cautionary statements found in more detail in the "Risk Factors" section of AgeXs Annual Report on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commissions (copies of which may be obtained at http://www.sec.gov). Subsequent events and developments may cause these forward-looking statements to change. AgeX specifically disclaims any obligation or intention to update or revise these forward-looking statements as a result of changed events or circumstances that occur after the date of this release, except as required by applicable law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200228005122/en/

Contacts

Media Contact for AgeX:

Bill Douglass Gotham Communications, LLCbill@gothamcomm.com (646) 504-0890

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AgeX Therapeutics Researchers Publish Paper on the Age Reprogramming of Super-Centenarian Cells - Yahoo Finance

Recommendation and review posted by Bethany Smith

When an animal, such as a dog or cat, is sick or unwell, its first natural instinct is to refuse food. Their body automatically cuts down appetite till they recover. They may drink water, but nothing else. This is bodys intelligence taking over to heal and recover.Intuitive eatingHumans arent any different. At least, intuitively. All of us are products of nature and we have been designed the same. When we call in sick, the first thing that happens is that our appetites shut down too. Our taste of mouth changes and our sensitivity to smell and taste is numbed. This is our bodys intelligence and subtle biofeedback trying to tell us that its time we give our body some rest.

This is fasting in a way and has been practised since the longest time across all religions. Fasting is inbuilt in us and is considered medicinal if you actually go back and read its history. It is our bodys uncomplicated way of cleaning and healing. Unfortunately, we have moved too far from nature and our natural instincts. We are constantly eating and munching even when sick, thereby compromising our own immunity and masking the inbuilt mechanism to heal.Take a break

Originally posted here:
Dont feed sickness - Times of India

Recommendation and review posted by Bethany Smith

DUBLIN, Feb. 27, 2020 /PRNewswire/ -- The "Stem Cell Banking - Market Analysis, Trends, and Forecasts" report has been added to ResearchAndMarkets.com's offering.

The growing interest in regenerative medicine which involves replacing, engineering or regenerating human cells, tissues or organs, will drive market growth of stem cells. Developments in stem cells bioprocessing are important and will be a key factor that will influence and help regenerative medicine research move into real-world clinical use. The impact of regenerative medicine on healthcare will be comparable to the impact of antibiotics, vaccines, and monoclonal antibodies in current clinical care. With the global regenerative medicine market poised to reach over US$45 billion by 2025, demand for stem cells will witness robust growth.

Another emerging application area for stem cells is in drug testing in the pharmaceutical field. New drugs in development can be safely, accurately, and effectively be tested on stem cells before commencing tests on animal and human models. Among the various types of stem cells, umbilical cord stem cells are growing in popularity as they are easy and safe to extract. After birth blood from the umbilical cord is extracted without posing risk either to the mother or the child. As compared to embryonic and fetal stem cells which are saddled with safety and ethical issues, umbilical cord is recovered postnatally and is today an inexpensive and valuable source of multipotent stem cells. Until now discarded as waste material, umbilical cord blood is today acknowledged as a valuable source of blood stem cells. The huge gap between newborns and available cord blood banks reveals huge untapped opportunity for developing and establishing a more effective banking system for making this type of stem cells viable for commercial scale production and supply. Umbilical cord and placenta contain haematopoietic blood stem cells (HSCs). These are the only cells capable of producing immune system cells (red cells, white cells and platelet).

HSCs are valuable in the treatment of blood diseases and successful bone marrow transplants. Also, unlike bone marrow stem cells, umbilical cord blood has the advantage of having 'off-the-shelf' uses as it requires no human leukocyte antigen (HLA) tissue matching. Developments in stem cell preservation will remain crucial for successful stem cell banking. Among the preservation technologies, cryopreservation remains popular. Development of additives for protecting cells from the stresses of freezing and thawing will also be important for the future of the market. The United States and Europe represent large markets worldwide with a combined share of 60.5% of the market. China ranks as the fastest growing market with a CAGR of 10.8% over the analysis period supported by the large and growing network of umbilical cord blood banks in the country. The Chinese government has, over the years, systematically nurtured the growth of umbilical cord blood (UCB) banks under the 'Developmental and Reproductive Research Initiation' program launched in 2008. Several hybrid public-private partnerships and favorable governmental licensing policies today are responsible for the current growth in this market.

Competitors identified in this market include:

Companies Mentioned

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Global Stem Cell Market Poised for Strong Growth as Global Regenerative Medicine Market Poised to Reach US$45 billion by 2025 - P&T Community

Recommendation and review posted by Bethany Smith

A bone marrow donor registry drive on Texas A&M Universitys campus brought more than 400 students to Duncan Dining Hall on Friday.

Participants swabbed their mouths to provide DNA samples and have their names added to Be the Matchs national bone marrow registry, which will help people in need of bone marrow connect with donors. The event was a collaborative effort between the A&M Corps of Cadets, the Kidz1stFund and Be the Match.

If anyone is matched, Community Engagement Representative for Be the Match Gulf Coast Benita Davis said they will need to have additional blood work done before donating.

A&M senior and Cadet 1st Lt. Mitchell Moore said his attendance on Friday was motivated in part by his interest in the medical field, since he is aiming to go to medical school.

Its minimum to no risk for you and not too much time, Moore said about donating. A small time on your part can make a huge difference and extend someones life by years.

A&M football coach Jimbo Fisher and Candi Fisher started Kidz1stFund in 2011 to raise money for research about fanconi anemia, which is a rare blood disorder that their teenage son was diagnosed with. Fisher stopped by Fridays event to speak with organizers and meet participants.

Its amazing how many great people there are in this world who are willing to help other people, Fisher said. These young men and women out here are actually saving lives.

Davis said donating is not as painful as many people often think, especially since about 80% of donations can be made with the nonsurgical method of giving peripheral blood stem cells. The other 20% of donations involve marrow being removed from the hip while the donor is asleep under general anesthesia. According to the Be the Match website, about one in 430 people on the registry end up donating.

The cadets in attendance on Friday were a reflection of who they are as people and students, according to Amy Thompson, assistant commandant, marketing and communications for the Corps of Cadets.

Selfless service is an A&M core value its also a core value for the Corps of Cadets, Thompson said. The commandant really supports and encourages cadets to seek out opportunities to be leaders in selfless service. This is one of those opportunities where we can do that on a very large scale and make a huge impact.

Corps Squadron 1 commander and A&M senior Jacob Svetz donated using stem cells about two years ago. He said he thinks everyone should sign up for the registry.

The few pin pricks that you get Its such a miniscule amount of pain compared to what that family and individual are suffering through, Svetz said. To put yourself into a position to be able to help that for me, it doesnt make sense not to.

Be the Match On Campus President and A&M senior Paige Boone said the organization hosts drives every month. The next one will be March 25 at A&Ms Rudder Plaza. Home swab kits are also an option. To get started, visit join.bethematch.org or text CORPS to 61474. Anyone ages 18 to 44 can participate.

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Jimbo Fisher's Kidz1stFund, Aggie Corps of Cadets team up for Be the Match bone marrow donor registry drive - Bryan-College Station Eagle

Recommendation and review posted by Bethany Smith

CRISPR takes first steps in humans

CRISPR-Cas9 is a revolutionary gene-editing technology that offers the potential to treat diseases such as cancer, but the effects of CRISPR in patients are currently unknown. Stadtmauer et al. report a phase 1 clinical trial to assess the safety and feasibility of CRISPR-Cas9 gene editing in three patients with advanced cancer (see the Perspective by Hamilton and Doudna). They removed immune cells called T lymphocytes from patients and used CRISPR-Cas9 to disrupt three genes (TRAC, TRBC, and PDCD1) with the goal of improving antitumor immunity. A cancer-targeting transgene, NY-ESO-1, was also introduced to recognize tumors. The engineered cells were administered to patients and were well tolerated, with durable engraftment observed for the study duration. These encouraging observations pave the way for future trials to study CRISPR-engineered cancer immunotherapies.

Science, this issue p. eaba7365; see also p. 976

Most cancers are recognized and attacked by the immune system but can progress owing to tumor-mediated immunosuppression and immune evasion mechanisms. The infusion of ex vivo engineered T cells, termed adoptive T cell therapy, can increase the natural antitumor immune response of the patient. Gene therapy to redirect immune specificity combined with genome editing has the potential to improve the efficacy and increase the safety of engineered T cells. CRISPR coupled with CRISPR-associated protein 9 (Cas9) endonuclease is a powerful gene-editing technology that potentially allows the ability to target multiple genes in T cells to improve cancer immunotherapy.

Our first-in-human, phase 1 clinical trial (clinicaltrials.gov; trial NCT03399448) was designed to test the safety and feasibility of multiplex CRISPR-Cas9 gene editing of T cells from patients with advanced, refractory cancer. A limitation of adoptively transferred T cell efficacy has been the induction of T cell dysfunction or exhaustion. We hypothesized that removing the endogenous T cell receptor (TCR) and the immune checkpoint molecule programmed cell death protein 1 (PD-1) would improve the function and persistence of engineered T cells. In addition, the removal of PD-1 has the potential to improve safety and reduce toxicity that can be caused by autoimmunity. A synthetic, cancer-specific TCR transgene (NY-ESO-1) was also introduced to recognize tumor cells. In vivo tracking and persistence of the engineered T cells were monitored to determine if the cells could persist after CRISPR-Cas9 modifications.

Four cell products were manufactured at clinical scale, and three patients (two with advanced refractory myeloma and one with metastatic sarcoma) were infused. The editing efficiency was consistent in all four products and varied as a function of the single guide RNA (sgRNA), with highest efficiency observed for the TCR chain gene (TRAC) and lowest efficiency for the TCR chain gene (TRBC). The mutations induced by CRISPR-Cas9 were highly specific for the targeted loci; however, rare off-target edits were observed. Single-cell RNA sequencing of the infused CRISPR-engineered T cells revealed that ~30% of cells had no detectable mutations, whereas ~40% had a single mutation and ~20 and ~10% of the engineered T cells were double mutated and triple mutated, respectively, at the target sequences. The edited T cells engrafted in all three patients at stable levels for at least 9 months. The persistence of the T cells expressing the engineered TCR was much more durable than in three previous clinical trials during which T cells were infused that retained expression of the endogenous TCR and endogenous PD-1. There were no clinical toxicities associated with the engineered T cells. Chromosomal translocations were observed in vitro during cell manufacturing, and these decreased over time after infusion into patients. Biopsies of bone marrow and tumor showed trafficking of T cells to the sites of tumor in all three patients. Although tumor biopsies revealed residual tumor, in both patients with myeloma, there was a reduction in the target antigens NY-ESO-1 and/or LAGE-1. This result is consistent with an on-target effect of the engineered T cells, resulting in tumor evasion.

Preliminary results from this pilot trial demonstrate that multiplex human genome engineering is safe and feasible using CRISPR-Cas9. The extended persistence of the engineered T cells indicates that preexisting immune responses to Cas9 do not appear to present a barrier to the implementation of this promising technology.

T cells (center) were isolated from the blood of a patient with cancer. CRISPR-Cas9 ribonuclear protein complexes loaded with three sgRNAs were electroporated into the normal T cells, resulting in gene editing of the TRAC, TRBC1, TRBC2, and PDCD1 (encoding PD-1) loci. The cells were then transduced with a lentiviral vector to express a TCR specific for the cancer-testis antigens NY-ESO-1 and LAGE-1 (right). The engineered T cells were then returned to the patient by intravenous infusion, and patients were monitored to determine safety and feasibility. PAM, protospacer adjacent motif.

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCR (TRAC) and TCR (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.

Gene editing offers the potential to correct DNA mutations and may offer promise to treat or eliminate countless human genetic diseases. The goal of gene editing is to change the DNA of cells with singlebase pair precision. The principle was first demonstrated in mammalian cells when it was shown that expression of a rare cutting endonuclease to create double-strand DNA breaks resulted in repair by homologous and nonhomologous recombination (1). A variety of engineered nucleases were then developed to increase efficiency and enable potential therapeutic applications, including zinc finger nucleases, homing endonucleases, transcription activatorlike effector nucleases, and CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 endonuclease) (2). The first pilot human trials using genome editing were conducted in patients with HIV/AIDS and targeted the white blood cell protein CCR5, with the goal of mutating the CCR5 gene by nonhomologous recombination and thereby inducing resistance to HIV infection (3, 4). The incorporation of multiple guide sequences in CRISPR-Cas9 permits, in principle, multiplex genome engineering at several sites within a mammalian genome (59). The ability of CRISPR to facilitate efficient multiplex genome editing has greatly expanded the scope of possible targeted genetic manipulations, enabling new possibilities such as simultaneous deletion or insertion of multiple DNA sequences in a single round of mutagenesis. The prospect of using CRISPR engineering to treat a host of diseases, such as inherited blood disorders and blindness, is moving closer to reality.

Recent advances in CRISPR-Cas9 technology have also permitted efficient DNA modifications in human T cells, which holds great promise for enhancing the efficacy of cancer therapy. T lymphocytes are specialized immune cells that are largely at the core of the modern-day cancer immunotherapy revolution. The T cell receptor (TCR) complex is located on the surface of T cells and is central for initiating successful antitumor responses by recognizing foreign antigens and peptides bound to major histocompatibility complex molecules. One of the most promising areas of cancer immunotherapy involves adoptive cell therapy, whereby the patients own T cells are genetically engineered to express a synthetic (transgenic) TCR that can specifically detect and kill tumor cells. Recent studies have shown safety and promising efficacy of such adoptive T cell transfer approaches using transgenic TCRs specific for the immunogenic NY-ESO-1 tumor antigen in patients with myeloma, melanoma, and sarcoma (1012). One limitation of this approach is that the transgenic TCR has been shown to mispair and/or compete for expression with the and chains of the endogenous TCR (1315). Mispairing of the therapeutic TCR and chains with endogenous and chains reduces therapeutic TCR cell surface expression and potentially generates self-reactive TCRs.

A further shortcoming of adoptively transferred T cells has been the induction of T cell dysfunction or exhaustion leading to reduced efficacy (16). Programmed cell death protein 1 (PD-1)deficient allogeneic mouse T cells with transgenic TCRs showed enhanced responses to alloantigens, indicating that the PD-1 protein on T cells plays a negative regulatory role in antigen responses that are likely to be cell intrinsic (17). The adoptive transfer of PD-1deficient T cells in mice with chronic lymphocytic choriomeningitis virus infection initially leads to enhanced cytotoxicity and later to enhanced accumulation of terminally differentiated T cells (18). Antibody blockade of PD-1, or disruption or knockdown of the gene encoding PD-1 (i.e., PDCD1), improved chimeric antigen receptor (CAR) or TCR T cellmediated killing of tumor cells in vitro and enhanced clearance of PD-1 ligandpositive (PD-L1+) tumor xenografts in vivo (1923). In preclinical studies, we and others found that CRISPR-Cas9mediated disruption of PDCD1 in human T cells transduced with a CAR increased antitumor efficacy in tumor xenografts (2426). Adoptive transfer of transgenic TCR T cells specific for the cancer antigen NY-ESO-1, in combination with a monoclonal antibody targeting PD-1, enhanced antitumor efficacy in mice (27). We therefore designed a first-in-human, phase 1 human clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 genome editing for a synthetic biology cancer immunotherapy application. We chose to target endogenous TRAC, TRBC, and PDCD1 on T cells to increase the safety and efficacy profile of NY-ESO-1 TCRexpressing engineered cells. In principle, this strategy allowed us to increase exogenous TCR expression and reduce the potential for mixed heterodimer formation (i.e., by deleting the and TCR domain genes TRAC and TRBC, respectively) and to limit the development of T cell exhaustion, which can be triggered by the checkpoint ligands PD-L1 and PD-L2 (i.e., by deleting PDCD1).

The phase 1 human trial (clinicaltrials.gov; trial NCT03399448) was designed to assess the safety and feasibility of infusing autologous NY-ESO-1 TCRengineered T cells in patients after CRISPR-Cas9 editing of the TRAC, TRBC, and PDCD1 loci. During the manufacturing process, cells were taken out of the cancer patient, engineered, and then infused back into the individual. The genetically engineered T cell product was termed NYCE (NY-ESO-1transduced CRISPR 3X edited cells) and is referred to as NYCE hereafter. During clinical development of the protocol, we elected to use a TCR rather than a CAR because the incidence of cytokine release syndrome is generally less prevalent using TCRs (11). In principle, this allowed a more discriminating assessment of whether gene editing with Cas9 was potentially immunogenic or toxic when compared with the baseline low level of adverse events observed in our previous clinical trial targeting NY-ESO-1 with transgenic TCRs (11). The autologous T cells were engineered by lentiviral transduction to express an HLA-A2*0201restricted TCR specific for the SLLMWITQC peptide in NY-ESO-1 and LAGE-1. The manufacturing process, vector design, and clinical protocol for NYCE T cells are described in the materials and methods and are depicted schematically (figs. S1 and S2). Of the six patients who were initially enrolled, four patients had successfully engineered T cells that were subjected to detailed release criteria testing as specified in the U.S. Food and Drug Administration (FDA)accepted Investigational New Drug application (table S1) (see fig. S3 for the consort diagram). Of the four patients with cell products available, one patient assigned unique patient number (UPN) 27 experienced rapid clinical progression and was no longer eligible for infusion owing to the inability to meet protocol-mandated safety criteria (see supplementary materials). Of the three patients who were infused with CRISPR-Cas9engineered T cells, two patients had refractory advanced myeloma and one patient had a refractory metastatic sarcoma not responding to multiple prior therapies (Table 1). The patients were given lymphodepleting chemotherapy with cyclophosphamide and fludarabine on days 5 to 3 (i.e., before administration with CRISPR-Cas9engineered T cells) and a single infusion of 1 108 manufactured CRISPR-Cas9engineered T cells per kilogram on day 0 of the protocol (fig. S2). No cytokines were administered to the patients.

MM, multiple myeloma; BM, bone marrow; XRT, radiation therapy; ASCT, autologous hematopoietic stem cell transplant; ND, not done.

The T cell product was manufactured by electroporation of ribonucleoprotein complexes (RNPs) comprising recombinant Cas9 loaded with equimolar mixtures of single guide RNA (sgRNA) for TRAC, TRBC, and PDCD1 followed by lentiviral transduction of the transgenic TCR (Fig. 1A). All products were expanded to >1 1010 T cells by the time of harvest (Fig. 1B). The transgenic TCR could be detected by flow cytometric staining for V8.1 or dextramer staining, ranging from 2 to 7% of T cells in the final product (Fig. 1C). The frequency of editing, as determined by digital polymerase chain reaction (PCR), varied according to the sgRNA and was about 45% for TRAC, 15% for TRBC, and 20% for PDCD1 (Fig. 1D). Final product transduction efficiency, CD4:CD8 ratio, and dosing are shown in table S2.

(A) Schematic representation of CRISPR-Cas9 NYCE T cells. (B) Large-scale expansion of NYCE T cells. Autologous T cells were transfected with Cas9 protein complexed with sgRNAs (RNP complex) against TRAC, TRBC (i.e., endogenous TCR deletion), and PDCD1 (i.e., PD-1 deletion) and subsequently transduced with a lentiviral vector to express a transgenic NY-ESO-1 cancer-specific TCR. Cells were expanded in dynamic culture for 8 to 12 days. On the final day of culture, NYCE T cells were harvested and cryopreserved in infusible medium. The total number of enriched T cells during culture is plotted for all four subjects (UPN07, UPN27, UPN35, and UPN39). (C) NY-ESO-1 TCR transduction efficiency was determined in harvested infusion products by flow cytometry. Data are gated on live CD3-expressing and V8.1- or dextramer-positive lymphocytes and further gated on CD4-positive and/or CD8-positive cells. (D) The frequencies of TRAC, TRBC, and PDCD1 gene-disrupted total cells in NYCE infusion products were measured using chip-based digital PCR. All data are representative of at least two independent experiments. Error bars represent mean SEM.

The potency of the final engineered T cells was assessed by coculture with HLA-A2+ tumor cells engineered to express NY-ESO-1 (Fig. 2A). The engineered T cells had potent antigen-specific cytotoxicity over a wide range of effector-totarget cell ratios. Interestingly, the cells treated with CRISPR-Cas9 were more cytotoxic than control cells transduced with the TCR but electroporated without CRISPR-Cas9 (i.e., cells that retained endogenous TCR). This is consistent with previous findings in mouse T cells, when a transgenic TCR was inserted into the endogenous locus, ablating expression of the endogenous TCR (15). Further studies will be required to determine if PD-1 knockout contributes to the increased potency afforded by knockout of the endogenous TCR.

(A) Cytotoxicity of NYCE T cells cocultured with HLA-A*0201positive Nalm-6 tumor cells engineered to express NY-ESO-1 and luciferase. Patient T cells transduced with the NY-ESO-1 TCR without CRISPR-Cas9 editing (NY-ESO-1 TCR) and untransduced T cells with CRISPR-Cas9 editing of TRAC, TRBC, and PDCD1 (labeled CRISPR) were included as controls (n = 4 patient T cell infusion products). Asterisks indicate statistical significance determined by paired Students t tests between groups (*P < 0.05). Error bars represent SEM. (B) Levels of soluble interferon- produced by patient NYCE T cell infusion products (labeled NYCE) after a 24-hour coculture with anti-CD3 and anti-CD28 antibody-coated beads or NY-ESO-1expressing Nalm-6 target cells. Patient NY-ESO-1 TCRtransduced T cells (NY-ESO-1 TCR) and untransduced, CRISPR-Cas9edited T cells (labeled CRISPR) served as controls. Error bars represent SEM. (C) Quantification of residual Cas9 protein in NYCE T cell infusion products in clinical-scale manufacturing is shown over time. Asterisks indicate statistical significance determined by paired Students t tests between time points (*P < 0.05). (D) Results from the fluorescence-based indirect ELISA screen performed to detect antibodies against Cas9 protein in the sera of three patients treated with NYCE T cells. Each dot represents the amount of anti-Cas9 signals detected in patient serum before T cell infusion (indicated by a vertical black arrow) and at various time points after NYCE T cell transfer. RFU, relative fluorescent units. (E) Immunoreactive Cas9-specific T cells in baseline patient leukapheresis samples were detected. Representative flow cytometry plots (left) from two patients whose T cells were positive for interferon- in response to Cas9 peptide stimulation. Unstimulated T cells treated with vehicle alone (dimethyl sulfoxide, DMSO) served as a negative control, whereas matched T cells stimulated with phorbol myristate acetate (PMA) and ionomycin served as a positive control. Bar graphs (right) show the frequency of ex vivo CD4+ and CD8+ T cells from patients or healthy donor controls (n = 6) that secrete interferon- in response to stimulation with three different Cas9 peptide pools. The background frequency of interferon-expressing T cells (unstimulated control group, DMSO alone) is subtracted from the values shown in the bar graph. Error bars represent SD.

We developed a sensitive immunoassay for detection of Streptococcus pyogenes Cas9 protein and quantified Cas9 early in the manufacturing process, showing declining levels that were <0.75 fg per cell in the harvested final product (Fig. 2C). Using a competitive fluorescence enzyme-linked immunosorbent assay (ELISA) screen, we found that healthy donors have humoral reactivity to Cas9 in serum (data not shown) and T cells (Fig. 2E), confirming previous reports (2830). Interestingly, we found that the three patients tested at a variety of time points after infusion of the engineered T cells did not develop humoral responses to Cas9. The lack of immunization to Cas9 is consistent with the extended persistence of the infused cells (Fig. 3) and could be a consequence of the low content of Cas9 in the infused product and/or to the immunodeficiency in the patients as a result of their extensive previous treatment histories (Table 1).

(A) The total number of vector copies per microgram of genomic DNA of the NY-ESO-1 TCR transgene in the peripheral blood (UPN07, UPN35, and UPN39), bone marrow (UPN07 and UPN35; multiple myeloma), and tumor (UPN39; sarcoma) is shown pre and postNYCE T cell infusion. (B) Calculated absolute numbers of NY-ESO-1 TCRexpressing T cells per microliter of whole blood from the time of infusion to various postinfusion time points in the study are shown. The limit of detection is about 2.5 cells per microliter of whole blood. (C) Frequencies of CRISPR-Cas9edited T cells (TRAC, TRBC, and PDCD1 knockout) before and after adoptive cell transfer are depicted. Error bars represent SD.

Three patients with advanced, refractory cancer were given infusions of the CRISPR-Cas9engineered T cells. The infusions were well tolerated, with no serious adverse events (Table 2); importantly, there were no cases of cytokine release syndrome, which is a potentially life-threatening systemic inflammatory response that has been associated with cancer immunotherapies (31). All three patients were infused with 1 108 cells/kg, and, owing to the considerable variation in TCR transduction efficiencies (table S2), the absolute number of infused engineered T cells ranged from 6.0 107 to 7.1 108 cells. Despite the variation in engineered cells, there were high peak levels and sustained persistence of the engineered cells in the blood of all three patients (Fig. 3A). The peak and steady-state levels of engineered cells were lowest in patient UPN35, who also had the lowest transduction efficiency (table S2). The persistence of the transduced cells is notably stable from 3 to 9 months after infusion, varying from 5 to 50 cells per microliter of blood (Fig. 3B). Using a subject-specific piecewise linear model, the decay half-lives of the transduced cells were 20.3, 121.8, and 293.5 days for UPN07, UPN35, and UPN39, respectively. The average decay half-life was 83.9 days (15 to 153 days, 95% confidence interval) for the three subjects, as estimated by a piecewise linear mixed-effects model that assumes cells decay linearly from day 14 postexpansion and random effects to allow varying level of expansion (or peak values) across subjects. The stable engraftment of our engineered T cells is notably different from previously reported trials with NY-ESO-1 TCRengineered T cells, in which the half-life of the cells in blood was ~1 week (11, 32, 33). Biopsy specimens of bone marrow in the myeloma patients and tumor in the sarcoma patient demonstrated trafficking of the engineered T cells to the tumor in all three patients at levels approaching those in the blood compartment (Fig. 3A).

indicates no adverse event.

To determine the engraftment frequency of the CRISPR-Cas9 gene-edited cells, we initially used chip-based digital PCR. With this assay, engraftment of cells with editing at the TRAC and PDCD1 loci was evident in all three patients (Fig. 3C). There was sustained persistence of TRAC and PDCD1 edits in patients UPN39 and UPN07 at frequencies of 5 to 10% of circulating peripheral blood mononuclear cells (PBMCs), whereas TRBC-edited cells were lowest in frequency and only transiently detected. The low-level engraftment of TRBC-edited cells is likely related to the observation that this locus had the lowest level of editing efficiency in our preclinical studies (25) and in the harvested products (Fig. 1D).

On- and off-target editing efficiency was assessed in the NYCE cells at the end of product manufacturing. Details of the analysis for UPN07 are shown as an example in Fig. 4, with detailed analysis of the other three manufactured products shown in table S3. The average on-target CRISPR-Cas9 editing efficiency for all engineered T cell products for each target is shown in Table 3. We used iGUIDE (34), a modification of the GUIDE sequencing (GUIDE-seq) method (35), to analyze the Cas9-mediated cleavage specificity. A complication of assays to assess repair by nonhomologous end joining (NHEJ) is that DNA double-strand breaks are formed spontaneously during cell division at high rates in the absence of added nucleases (36), which can increase the background in assays of off-target cleavage. The distribution of on- and off-target cleavage is expected to vary for the three sgRNAs that were used in the manufacturing process (fig. S1A). Of the three sgRNAs, there were more off-target mutations identified for TRBC than for the other loci (Fig. 4C and figs. S4 and S5). The sgRNA for PDCD1 was the most specific, because very few off-target edits were identified in more than 7000 sites of cleavage and there were very few off-target reads identified at the TRAC1 and TRAC2 loci (Fig. 4C).

(A) Genomic distribution of oligonucleotide (dsODN) incorporation sites, which mark locations of double-strand breaks. The ring indicates the human chromosomes aligned end to end, plus the mitochondrial chromosome (labeled M). The targeted cleavage sites are on chromosomes 2, 7, and 14. The frequency of cleavage and subsequent dsODN incorporation is shown on a log scale on each ring (pooled over 10-Mb windows). The purple innermost ring plots all alignments identified. The green ring shows pileups of three or more overlapping sequences, the blue ring shows alignments extending along either strand from a common dsODN incorporation site (flanking pairs), and the red ring shows reads with matches to the gRNA (allowing <6 mismatches) within 100 bp (target matched). (B) Distribution of inferred positions of cleavage and dsODN incorporation at an on-target locus. Incorporations in different strand orientations are shown on the positive (red) and negative (blue) y axis. The percentage in the bottom right corner is an estimate of the number of incorporations associated with the on-target site (based on pileups) captured within the allowed window of 100 bp. (C) Sequences of sites of cleavage and dsODN incorporation are shown, annotated by whether they are on target or off target (Target); the total number of unique alignments associated with the site (Abund.); and an identifier indicating the nearest gene (Gene ID). An asterisk after the gene name indicates that the site is within the transcription unit of the specific gene, whereas ~ indicates that the gene appears on the allOnco cancer-associated gene list.

The genomic localization of identified DNA cleavage sites was as expected, given the chromosomal location of the three targeted genes on chromosomes 2, 7, and 14 (Fig. 4A). The distribution of the incorporation of the double-stranded oligodeoxynucleotide (dsODN) label around on-target sites, based on pileups within a window of 100 base pairs (bp), is shown in Fig. 4B and fig. S4. Although most mutations were on target, there were off-target mutations identified (Fig. 4C and fig. S5). For the TRAC sgRNA, there were low-abundance mutations within the transcriptional unit of CLIC2 (chloride intracellular channel 2); however, disruption of CLIC2 in T cells is not expected to have negative consequences because it is not reported to be expressed in T cells. For the TRBC sgRNA, off-target edits were identified in genes encoding a transcriptional regulator (ZNF609) and a long intergenic nonprotein coding RNA (LINC00377) (table S3). In addition to the above post hoc investigations of multiplex editing specificity, all products were shown not to have cellular transformation by virtue of the absence of long-term growth before infusion (table S1).

In addition to the above detection of repair of double-strand DNA breaks by NHEJ, on-target mutagenesis by engineered nucleases can result in deletions, duplications, inversions, and translocations and can also lead to complex chromosomal rearrangements under some conditions (37). CRISPR-Cas9 has been used to intentionally create oncogenic chromosomal rearrangements (38). In preclinical studies with human T cells, simultaneous gene editing of TRAC and CD52 using TALENs led to translocations that were detected at frequencies of 104 to 102 (39). In a subsequent clinical report using dual-gene editing with TALENs, chromosomal rearrangements were observed in 4% of infused cells (40). To study the safety and genotoxicity of multiplex CRISPR-Cas9 genome editing on three chromosomes, we used stringent release criteria of the manufactured cells and assays to detect translocations (fig. S6). We developed and qualified quantitative PCR (qPCR) assays to quantify the 12 potential translocations that could occur with the simultaneous editing of four loci: TRAC, TRBC1, TRBC2, and PDCD1 (see materials and methods). We observed translocations in all manufactured products; however, the translocations were at the limit of detection for the assay in patient UPN39 (Fig. 5A). TRBC1:TRBC2 was the most abundant rearrangement (Fig. 5A), resulting in a 9.3-kb deletion (supplementary materials). The deletion and translocations peaked on days 5 to 7 of manufacturing and then declined in frequency until cell harvest. The translocations and the TRBC1:TRBC2 deletion were evident in the three patients between 10 days after infusion and 30 to 170 days after infusion (Fig. 5B). However, the rearrangements declined in frequency in vivo, suggesting that they conferred no evidence of a growth advantage over many generations of expansion in the patients on this trial (Fig. 3, A and B). At days 30, 150, and 170 in patients UPN07, UPN35, and UPN39, respectively, chromosomal translocations were at the limits of detection or not detected for all rearrangements except for the 9.3-kb deletion for TRBC1:TRBC2.

(A) Evaluation of chromosomal translocations in NYCE T cell infusion products during the course of large-scale culture is shown. For the 12 monocentromeric translocation assays conducted, a positive reference sample that contains 1 103 copies of the synthetic template plasmid was evaluated as a control, and the percent difference between expected and observed marking was calculated. The absence of amplification from the 12 reactions that correspond to the different chromosomal translocations indicates assay specificity (see methods). (B) Longitudinal analysis of chromosomal translocations in vivo in three patients pre and postNYCE T cell product infusion is displayed. In (A) and (B), error bars represent SD. For graphical purposes, the proportions of affected cells were plotted on a log scale; a value of 0.001% indicates that translocations were not detected.

We used single-cell RNA sequencing (scRNA-seq) to comprehensively characterize the transcriptomic phenotype of the NYCE T cells and their evolution over time in patient UPN39 (fig. S7). UPN39 was chosen because they had the highest level of cell engraftment and because this patient had evidence of tumor regression. CRISPR-Cas9engineered T cells were infused to patient UPN39 and recovered after infusion from the blood on day 10 and at ~4 months (day 113) and were analyzed by scRNA-seq, as described in the materials and methods. For each sample (infusion product, day 10 and day 113), T cells were sorted on the basis of expression of CD4 or CD8 and processed using droplet-based 5 scRNA-seq. From the gene expression libraries, PCR was used to further amplify cellular cDNA corresponding to the NY-ESO-1 TCR transgene, as well as TRAC, TRBC, and PDCD1 target sequences, allowing us to genotype single cells as wild type or mutant. In the infusion product, cells were identified that contained mutations in all three target sequences (Fig. 6, A and B). The most commonly mutated gene was TRAC. About 30% of cells had no mutations identified, whereas ~40% had one mutation, and ~20 and ~10% of the T cells in the manufactured product were double mutated and triple mutated, respectively, at the target sequences. Of the transgenic TCR+ cells in the infusion product, monogenic mutations were less frequent than digenic and trigenic mutations (Fig. 6A). Single-cell genotyping of UPN39 cells at 10 days and 4 months after infusion showed a decline in the frequency of gene-edited T cells from the levels in the infusion product, and this decline occurred regardless of whether the cells were transduced with the NY-ESO-1 TCR (Fig. 6C). The frequency of gene-edited cells was quite stable between day 10 and 4 months postinfusion, and notably, about 40% of the peripheral bloodcirculating T cells in this patient 4 months after infusion were mutated at any one of the targeted genes (Fig. 6, B and C, and table S4).

(A) Venn diagram showing relative numbers of NY-ESO-1 TCRpositive cells with TRAC, TRBC, and/or PDCD1 mutations in the NYCE T cell infusion product (IP) (day 0). (B) Proportions of preinfusion (IP, day 0) and postinfusion (days 10 and 113) wild-type T cells with TRAC, TRBC, or PDCD1 mutations or expressing the NY-ESO-1 TCR transgene. Numbers of cells belonging to each of these categories are listed below the graph. (C) Analysis of NY-ESO-1 TCRpositive (right) and NY-ESO-1 TCRnegative (left) cells without mutations (wild type) or with single, double, or triple mutations at day 0 (NYCE T cell infusion product) and day 113 postNYCE T cell infusion. Numbers of analyzed cells for each time point are listed above the bars. (D) Uniform manifold approximation and projection (UMAP) plots of gene expression data. Analysis was performed on all T cells integrated across time points, but only NY-ESO-1 TCRexpressing cells, split by time point, are shown (top). The increase in TCF7 expression is indicative of an acquired central memory phenotype (bottom, same cells). (E) Heatmap showing scaled expression of differentially expressed genes in NY-ESO-1 TCRpositive T cells across time points. Color scheme is based on scaled gene expression from 2 (purple) to 2 (yellow).

Of particular interest is the frequency and evolution of PD-1deficient T cells owing to the previous mention that genetic disruption of PDCD1 in CAR and TCR T cells enhances antitumor efficacy in preclinical models (19, 2124). We found that ~25% of the T cells expressing the NY-ESO-1 TCR in the infusion product had mutations in the PDCD1 locus (fig. S8). It is interesting that the frequency of cells with edits in the PDCD1 locus decreased to ~5% of the cells expressing the transgenic TCR at 4 months postinfusion. This would be consistent with mouse studies of chronic infection in which PD-1deficient T cells are less able to establish memory (18).

Figure 6D shows the distribution of engineered T cells expressing the NY-ESO-1 TCR transgene in the infusion product of patient UPN39, and again at 4 months in vivo as they evolve from the infused cells. In the heatmap (Fig. 6E), the most differentially expressed genes in the cells expressing the NY-ESO-1 transcript at the various time points are shown in table S5. Notably, UPN39 had increases in expression of genes associated with central memory (IL7R and TCF7) over time (Fig. 6, D and E, and table S4). This is in marked contrast to the recently published results with NY-ESO-1 T cells in the absence of genome editing, in which the infused transgenic T cells evolved to a terminally differentiated phenotype and displayed characteristics of T cell exhaustion in cancer patients (12).

The clinical course of the three infused cancer patients is shown in Fig. 7 (and described in the materials and methods). No patient experienced cytokine release syndrome or overt side effects attributed to the cell infusion (table S5). The best clinical responses were stable disease in two patients. UPN39 had a mixed response, with a ~50% decrease in a large abdominal mass that was sustained for 4 months (Fig. 7D), although other lesions progressed. As of December 2019, all patients have progressed: Two are receiving other therapies, and UPN07 died from progressive myeloma.

(A) Swimmers plot describing time on study for each patient, duration of follow-up off study (defined as survival beyond progression or initiation of other cancer therapy), and present status (differentially colored) is shown. Arrows indicate ongoing survival. SD, stable disease; PD, progressive disease. (B) Changes in kappa light chain levels (mg/liter 103) in patient UPN07 after NYCE T cell product infusion are depicted. Vertical black arrow indicates initiation of a D-ACE salvage chemotherapy regimen (defined as intravenous infusion of cisplatin, etoposide, cytarabine, and dexamethasone). (C) Longitudinal M-spike levels (g/dl) in patient UPN35 postNYCE T cell product administration are shown. Vertical black arrows indicate administration of combination therapy with elotuzumab, pomalidomide, and dexamethasone. (D) Computed tomography scans demonstrating tumor regression in patient UPN39 after administration of an autologous NYCE T cell infusion product. Radiologic studies were obtained before therapy and after adoptive transfer of NYCE T cells. Tumor is indicated by red X. (E) Cytolytic capacity of NY-ESO-1specific CD8+ T cells recovered at the indicated month after infusion and expanded from patients is shown. PBMC samples collected after NYCE T cell product infusion were expanded in vitro in the presence of NY-ESO-1 peptide and interleukin-2. The ability of expanded effector cells to recognize antigen and elicit cytotoxicity was tested in a 4-hour 51Cr release assay incorporating Nalm-6 NY-ESO-1+, parental Nalm-6 (NY-ESO-1), and A375 melanoma cells (NY-ESO-1+). All target cell lines were HLA-A*02 positive. Assays were performed in triplicate, and error bars represent SD.

Biopsies of bone marrow and tumor showed trafficking of the NYCE-engineered T cells to the sites of tumor in all three patients (Fig. 3A). It is interesting to note that even though the tumor biopsies revealed residual tumor, in both patients with myeloma, there was a reduction in the target antigens NY-ESO-1 and/or LAGE-1 (fig. S9). The reduction of target antigen was transient in patient UPN07 and persistent in patient UPN35. This result is consistent with an on-target effect of the infused cells, likely resulting in tumor editing (41).

To determine whether the NYCE cells retained antitumor activity after infusion, samples of blood obtained from patients 3 to 9 months after infusion were expanded in culture in the presence of NY-ESO-1 peptide and assessed for cytotoxicity against tumor cells (Fig. 7E and fig. S10). Antigen-specific cytotoxicity was observed in all three patients. It is interesting to note that the most potent antitumor cytotoxicity was observed in UPN39, because UPN39 was the only patient to have tumor regression after infusion of the CRISPR-Cas9engineered T cells (Fig. 7D).

Our phase 1 first-in-human pilot study demonstrates the initial safety and feasibility of multiplex CRISPR-Cas9 T cell human genome engineering in patients with advanced, refractory cancer. In one patient analyzed at depth, a frequency of 30% of digenic and trigenic editing was achieved in the infused cell population, and 20% of the TCR transgenic T cells in circulation 4 months later had persisting digenic and trigenic edits. We chose to redirect specificity of the T cells with a T cell receptor, rather than a CAR, to avoid the CAR-associated potential toxicities such as cytokine release syndrome (31). This provided a lower baseline toxicity profile, thus enhancing the ability to detect toxicity specifically associated with the CRISPR-Cas9engineering process. We observed mild toxicity, and most of the adverse events were attributed to the lymphodepleting chemotherapy. We note that although the initial clinical results have acceptable safety, experience with more patients given infusions of CRISPR-engineered T cells with higher editing efficiencies, and longer observation after infusion, will be required to fully assess the safety of this approach.

Our large-scale product manufacturing process resulted in gene-editing efficiencies similar to those in our preclinical studies (24). A surprising finding was the high-level engraftment and long-term persistence of the infused CRISPR-Cas9engineered T cells. In previous clinical studies testing adoptively transferred NY-ESO-1 transgenic T cells, the engrafted cells had an initial decay half-life of about 1 week (1012). The explanation for the extended survival that we observed remains to be determined and could include the editing of the endogenous TCR, PD-1, and/or the choice of the TCR and vector design.

The use of scRNA-seq technology permitted the analysis of the transcriptome of the infused NY-ESO-1specific T cells (i.e., CRISPR-Cas9engineered T cells) at baseline and for up to 4 months in vivo. The results shown for UPN39 revealed that the infused cells evolved to a state consistent with central memory. These results are in contrast to a recent study in which the infused NY-ESO-1 T cells evolved to a state consistent with T cell exhaustion (12). A limitation of our in vivo single-cell analysis is that for purposes of feasibility, it is limited to the one patient who had the highest level of engraftment. Another limitation is that we were not able to compare the transcriptional state of the modified cells in the tumor microenvironment with circulating NYCE T cells.

Analysis of the manufacturing process in vitro demonstrated monochromosomal translocations and rearrangements, and some of these persisted in vivo. The translocations were not random in occurrence and occurred most frequently between PDCD1:TRAC and TRBC1:TRBC2. The frequency of translocations that we observed with trigenic editing is similar to that reported for digenic editing using TALEN-mediated gene editing in preclinical and clinical studies, in which rearrangements were detected in about 4% of cells (39, 40). It is important to note that healthy individuals often harbor oncogenic translocations in B and T cells (4244). T cells bearing translocations can persist for months to years without evidence of pathogenicity (4547).

Antagonism of the PD-1:PD-L1 costimulatory pathway can result in organ-specific and systemic autoimmunity (17, 48). PD-1 has been reported to function as a haploinsufficient tumor suppressor in mouse T cells (49). Our patients have had engraftment with PD-1deficient T cells, and to date, there is no evidence of autoimmunity or T cell genotoxicity.

In conclusion, our phase 1 human pilot study has confirmed that multiplex CRISPR-Cas9 editing of the human genome is possible at clinical scale. We note that although the initial clinical results suggest that this treatment is safe, experience with more patients given infusions with higher editing efficiencies and longer observation after infusion will be required to fully assess the safety of this approach. The potential rejection of infused cells due to preexisting immune responses to Cas9 (28, 29) does not appear to be a barrier to the application of this promising technology. Finally, it is important to note that our manufacturing was based on the reagents available in 2016, when our protocol had been reviewed by the National Institutes of Health (NIH) Recombinant DNA Advisory Committee and received approval. Our Investigational New Drug application was subsequently reviewed and accepted by the FDA. There has been rapid progress in the field since that time, with the development of reagents that should increase efficiencies and decrease off-target editing using CRISPR-based technology (50).

The clinical protocol is listed at clinicaltrials.gov, trial NCT03399448. Protocol no. 1604-1524 Phase 1 trial of autologous T cells engineered to express NY-ESO-1 TCR and CRISPR gene edited to eliminate endogenous TCR and PD-1 (NYCE T Cells) was reviewed and approved by the U.S. National Institutes of Health Recombinant DNA Advisory Committee on 21 June 2016. See fig. S1B for clinical trial design. Patient demographics are shown in Table 1. A list of adverse events is depicted in Table 2.

The genomic gRNA target sequences with protospacer adjacent motif (PAM) underlined were: TRAC1 and TRAC2: 5-TGTGCTAGACATGAGGTCTATGG-3, TRBC: 5-GGAGAATGACGAGTGGACCCAGG-3, and PDCD1: 5-GGCGCCCTGGCCAGTCGTCTGGG-3. In vitro transcribed gRNA was prepared from linearized DNA (Aldevron) using Bulk T7 Megascript 5X (Ambion) and purified using RNeasy Maxi Kit (Qiagen).

Cas9 recombinant protein derived from S. pyogenes was TrueCut Cas9 v2 (catalogue no. A36499, ThermoFisher). Cas9 RNP was made by incubating protein with gRNA at a molar ratio of 1:1 at 25C for 10 min immediately before electroporation.

The 8F TCR recognizes the HLA-A*0201 SLLMWITQC epitope on NY-ESO-1 and LAGE-1. The 8F TCR was isolated from a T cell clone obtained from patient after vaccination with NY-ESO-1 peptide. The TCR sequences were cloned into a transfer plasmid that contains the EF-1 promoter, a cPPT sequence, a Rev response element and a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), as shown in fig. S1B. Plasmid DNA was manufactured at Puresyn, Inc. Lentiviral vector was produced at the University of Pennsylvania Center for Advanced Retinal and Ocular Therapeutics using transient transfection with four plasmids expressing the transfer vector, Rev, VSV-G, and gag-pol, in human embryonic kidney 293T cells.

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CRISPR-engineered T cells in patients with refractory cancer - Science Magazine

Recommendation and review posted by Bethany Smith

CRISPR Therapeutics (NASDAQ:CRSP) has done very well for itself, with the company's stock almost doubling in 2019 as optimism surrounding its gene-editing technology continues to grow. Considering how much of a game-changer gene-editing technology can be for patients with incurable conditions, it makes sense that people are excited.

While shares have tumbled over the past couple of months, this might be a good thing for investors looking to buy this promising stock at a cheaper price. If you're on the fence about CRISPR or are looking for a stock with great upside potential, here are a few reasons why CRISPR looks like a good pick in 2020.

Image source: Getty Images.

CRISPR is arguably the top name in the relatively young gene-editing market right now. The company currently has nine drug candidates, with four either having begun clinical testing or close to starting.

CRISPR's flagship candidate is CTX001, a drug that targets sickle cell disease and transfusion-dependent beta-thalassemia (TBT). Patients with either of these conditions have malformed red blood cells that struggle to deliver oxygen throughout the body. Approximately 300,000 infants are born with sickle cell disease each year, with another 60,000 born annually with TBT.At present, there are no treatments for either condition.

The other three noteworthy candidates in CRISPR's pipeline are CTX110, CTX120, and CTX130. These drug candidates are a type of new cancer-immunology treatment known as a chimeric antigen receptor T cell (CAR-T) therapy. These types of treatments involve modifying a patient's immune cells in a lab to make them better at killing cancer cells. While it's traditionally quite expensive, CRISPR's technology could possibly make these new CAR-T therapies cheaper than the competition.

While the drug is still in early clinical testing, CRISPR reported some success with CTX001 back in November when it announced that two patients had been treated successfully with the drug. The two patients, one diagnosed with sickle cell disease and the other with TBT, managed to eliminate all of their symptoms following a single CTX001 infusion.

In the case of TBT, the number of required blood transfusions dropped to zero, while the sickle cell disease patient experienced zero occlusive crises (blood vessel blockages that occur due to the abnormal shape of the patient's blood vessels).

CRISPR has confirmed that it will be providing more data for both CTX001 and its cancer immunotherapies sometime this year. That means that investors can look forward to further potential catalysts in 2020, likely toward the latter half of the year.

In general, investors shouldn't take too much stock in the financial figures of early-stage biotechstocks unless there's something really alarming going on (like not having enough cash). Revenue figures change dramatically once a drug receives approval, and companies tend to report significant losses until drug candidates reach late clinical stages.

However, CRISPR's situation is different. In its recently released fourth-quarter financial results, the company reported an impressive $77 million in revenue, a substantial improvement from the mere $100,000 seen last year. Annual revenue for 2019 came in at $289.6 million in comparison to 2018's $3.1 million.

While this virtually all comes from CRISPR's collaboration agreement with Vertex Pharmaceuticals, the important point is that CRISPR is now reporting a profit. Net income for the fourth quarter came in at $30.5 million, whereas last year the company saw a net loss of $47.6 million.

Data source: YCharts, CRISPR Therapeutics.

No other notable gene-editing stock out there is reporting a profit right now. Even if CRISPR ends up dipping into a net loss again in subsequent quarters, the fact that the company managed to report a positive net income this early on in its drug development program is impressive.

Given how young the gene-editing industry is and how experimental this technology can be, positive clinical results in this field can have a positive effect on all stocks in the sector. When Intellia Therapeuticspresented new data regarding two of its drug-editing programs earlier in February, shares of all gene-editing stocks -- including CRISPR -- shot up, despite the fact that they are all competitors.

While this might seem strange at first, it makes sense given how young this industry is. Further clinical proof that gene-editing drugs work, no matter where it comes from, is good for the entire sector. A rising tide lifts all ships, and CRISPR investors also should look out for potential catalysts from other gene-editing companies, which could act as an indirect catalyst for CRISPR's stock.

Intellia, Editas Medicine, and Sangamo Therapeuticsare all working on sickle cell disease and transfusion-dependent beta-thalassemia treatments of their own. Positive developments from their treatments could have a spillover effect on CRISPR's stock. Editas stated recently that it expects to file an Investigational New Drug (IND) application for EDIT-301, its sickle cell drug, by the end of 2020.

The answer is yes, it definitely can. CRISPR Therapeutics has plenty of good things going for it, and there is a lot of long-term enthusiasm surrounding both the company and the industry. While shares of CRISPR have fallen a fair bit over the past couple of months -- down 14% since the start of 2020-- so have other gene-editing stocks. As such, it doesn't seem to be as much of a problem with CRISPR in particular as it is a sector-wide phenomenon. Since there's no real news that appears to be behind this decline, I wouldn't worry about it too much.

Instead, now looks like a good time to buy gene-editing stocks, because they're trading at a bit of a discount. Back in November, Oppenheimer analyst Silvan Turkcan issued a price target of $80 for CRISPR Therapeutics, suggesting at least a 57.1% upside to the stock based on current prices. That seems very reasonable, and I wouldn't be surprised if CRISPR does much better than that in 2020.

However, CRISPR still remains a high-risk investment given the fact it's an early-stage biotech stock. If you want to buy shares right now, keep your position on the smaller side. Never risk too much of your portfolio on a single stock, no matter how promising it might seem.

More:
Can CRISPR Therapeutics Double Your Money in 2020? - The Motley Fool

Recommendation and review posted by Bethany Smith

ZUG, Switzerland and CAMBRIDGE, Mass., Feb. 26, 2020 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced it proposes to elect Doug Treco, Ph.D. to its Board of Directors at the Companys upcoming annual general meeting to be held later this year. The Company also announced that Pablo Cagnoni, M.D., Chief Executive Officer of Rubius Therapeutics, will resign from the Board of Directors to focus on other commitments, effective immediately.

On behalf of our Board of Directors and management team, I would like to thank Pablo for his years of service and his many contributions to CRISPR Therapeutics, and I wish him the best in his future endeavors, said Rodger Novak, M.D., President and Chairman of the Board of CRISPR Therapeutics. We are grateful for his thoughtful guidance and support over the years.

Dr. Novak added: We are excited to invite Doug to our Board during an important time in CRISPR Therapeutics continued evolution. He has an impressive track record of success in advancing the development of numerous drug candidates, with a unique focus on rare disease, gene targeting, and gene therapy. His deep expertise and leadership experience will make him an outstanding addition to our Board, and we look forward to the valuable insights he will bring.

Doug co-founded Ra Pharmaceuticals, Inc. (RARX) in 2008 and has been Chief Executive Officer and a member of the Board of Directors since its inception. Ra Pharma is a leader in macrocyclic peptide and small molecule therapeutics targeting the complement pathway and has advanced its lead molecule, zilucoplan, into the clinic for multiple neuromuscular indications, including an ongoing pivotal Phase 3 study in myasthenia gravis. In October 2019, Ra Pharma entered into a merger agreement with UCB pursuant to which UCB will acquire Ra Pharma. He was an Entrepreneur-in-Residence at Morgenthaler Ventures from January 2008 to May 2014. In 1988, Doug co-founded Transkaryotic Therapies Inc. (TKT), a multi-platform biopharmaceutical company developing protein and gene therapy products, where he led the discovery of a number of approved biopharmaceuticals, including Dynepo, Replagal, Elaprase, and Vpriv. TKT (formerly Nasdaq: TKTX) was acquired by Shire Pharmaceuticals Group plc in 2005. He was a Visiting Scientist in the Department of Molecular Biology at Massachusetts General Hospital and a Lecturer in Genetics at Harvard Medical School from 2004 to 2007. Doug received his Ph.D. in Biochemistry and Molecular Biology from the State University of New York at Stony Brook and performed postdoctoral studies at the Salk Institute for Biological Studies and Massachusetts General Hospital.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

Important Additional Information and Where to Find ItCRISPR Therapeuticswill file a proxy statement with theUnited States Securities and Exchange Commission(SEC) in connection with the solicitation of proxies for its 2020 annual general meeting (2020 Annual Meeting). SHAREHOLDERS ARE STRONGLY ADVISED TO READ THE PROXY STATEMENT WHEN IT BECOMES AVAILABLE BECAUSE IT WILL CONTAIN IMPORTANT INFORMATION. Shareholders may obtain a free copy of the proxy statement, any amendments or supplements to the proxy statement and other documents thatCRISPR Therapeutics files with theSECfrom the SECs website atwww.sec.govor CRISPR Therapeutics website atwww.crisprtx.comas soon as reasonably practicable after such materials are electronically filed with, or furnished to, theSEC.

Story continues

Certain Information Regarding ParticipantsCRISPR Therapeutics, its directors, nominees for election as director, executive officers and other persons related toCRISPR Therapeutics may be deemed to be participants in the solicitation of proxies from CRISPR Therapeutics shareholders in connection with the matters to be considered at the 2020 Annual Meeting. Information concerning the interests of CRISPR Therapeutics participants in the solicitation is set forth in the materials filed byCRISPR Therapeutics with theSEC, including in its definitive proxy statement filed with theSEConApril 30, 2019, and will be set forth in the proxy statement relating to the 2020 Annual Meeting when it becomes available.

Investor Contact:Susan Kimsusan.kim@crisprtx.com

Media Contact:Rachel EidesWCG on behalf of CRISPR617-337-4167 reides@wcgworld.com

Read more:
CRISPR Therapeutics Proposes Changes to the Board of Directors - Yahoo Finance

Recommendation and review posted by Bethany Smith

The Global CRISPR And CRISPR-Associated (Cas) Genes Market report by Globalmarketers.Biz sets out the production, consumption, revenue, gross margin, cost, gross, market share, CAGR, and global market influencing factors of the market for 2020-2025. The segmentation of regional market included the historical and forecast mandates for North America, Europe, Asia-Pacific, Latin America, the Middle East and Africa. The CRISPR And CRISPR-Associated (Cas) Genes Market report provides a far-reaching industry analysis by types, applications, players and regions.

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Excerpt from:
Global CRISPR And CRISPR-Associated (Cas) Genes Market Is Set to Boom in 2020,Coming Years - News Times

Recommendation and review posted by Bethany Smith

SEATTLE Samira Ummat, MD of Longevity Medical Clinic says there is evidence that androgens (or hormones) like testosterone are breast protective in women.

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The rest is here:
Androgen therapy looks promising for high-risk breast cancer patients - KING5.com

Recommendation and review posted by Bethany Smith

click to enlarge

Daniel Walters photo

Ken Peters, pastor of the Church at Planned Parenthood.

But to local anti-abortion Pastor Ken Peters, Planned Parenthood also represents another setting: the "gates of hell." And it's the job of a Christian church, he argues, to prevail against the gates of hell.

In October 2018, inspired by a sermon from anti-abortion protest movement leader Rusty Thomas,Peters launched "the Church at Planned Parenthood," conducting worship, prayer and fiery anti-abortion preaching on the public lawn directly outside of the Planned Parenthood clinic on Indiana Avenue on Wednesday evenings. Peters didn't consider it a protest. He considered it church.

But Planned Parenthood considered it something else: harassment. The clinic reported that theamplified sermons and condemnations from the Church at Planned Parenthoodwould leak through their clinic walls, and that, according to their attorney, "patients and caregivers cannot hear each other speak even when sitting right across from each other."

Over the last year and a half, tensions between the church, Planned Parenthood and pro-choice counter-protesters have continued to ratchet up. Teams of armed police officers have attended some City Council meetings, responding to unspecified social media threats. And this Monday, the conflict will come to a head when the City Council will likely pass Councilwoman Lori Kinnear's resolution intended to strengthen the city's noise ordinance in response to the concerns.

But last Friday,Mayor Nadine Woodward took her own action: Her staff sent out an email to both Peters and Karl Eastlund, CEO of the Planned Parenthood of Greater Washington and North Idaho, with a message: Let's all sit down and talk.

"Mayor Woodward asked if we could arrange a meeting to discuss the current concerns about noise, assembly, ordinances, etc," the email reads."We are hopeful to have a small group that represents the voices of interested parties.This includes each of you, the Police Chief, Councilmember Kinnear, Council President Beggs, the Mayor and the City Administrator."

City spokesman Brian Coddington says the proposal to bring everyone together was Mayor Woodward's idea. The mayor, he says, was concerned about the sheer number of police officers and supervisors who were needed to keep the peace and handle existing noise ordinance complaints during services. According to an email from the Spokane Police Department to Councilman Michael Cathcart, the law enforcement response to the Jan. 29 Church at Planned Parenthood service required one police captain, one lieutenant, two sergeants, one detective and eight police officers, costing the taxpayer more than $5,450 in police overtime in a single night.

Woodward, Coddington says, was "looking for a chance to be an intermediary for the situation and seeing if there's another solution that doesnt involve a commitment of city resources." Local government might be one fo the last places we can get around everyone in the same table with common goals: Lets keep everyone safe, and protect everyones rights, City Administrator Wes Crago says. I think the mayor, to her credit, said, 'Lets reach out to both sides and lets set up a dialogue.'

"Mr. Peters continues to incite his followers with violent rhetoric and has vowed to continue to disrupt our health care services," Eastlund wrote in an email. "You would be better off meeting with him and police separately to discuss how enforcement will impact him and his followers."

Daniel Walters photo

Ken Peters greets Rep. Matt Shea at a December meeting of the Church at Planned Parenthood.

THE KEN PETERS MEETING

He says the mayor wasn't trying to take one side or the other, only looking for ways that everyone could accomplish what she wanted to accomplish.

"I think shes wanting to work this out so where it doesnt escalate," Peters says. "I think shes doing exactly what a mayor should do, trying to resolve problems at a table and bring all the parties together."

City Council President Breean Beggs says there was "no grand resolution" or possible third-way compromise floated at the meeting that would result in delaying or canceling Monday night's vote. Instead, he sees the possibility of addressing the conflict after the ordinance passes.

"The closer we can get to Planned Parenthood the better," Peters says.

"You cant stop sin with sin. You stop sin with holiness," Peters says. "Gods weaponry are prayer and worship and preaching. Its never any kind of sin or violence. ... We wouldnt harm a flea."

"For us, its our constitutional rights of freedom of worship and freedom of speech and freedom to peaceably assemble without a dark cloud held over our head," Peters says. "Thats what we want and thats what were fighting for."

The draft version of Kinnear's ordinance goes beyond the state standard barring "noise that unreasonably disturbs the peace within" a health facility. Instead, it bans intentionally making any noise outside a health care facility that is intended to cause or actually causes "interference with the safe and effective delivery of health services within the building" after a law enforcement officer has told them to cease. Not only that, but it allows individuals to sue violators directly in civil court.

"Im hoping that well find a resolution with all parties involved, so we dont have to go to court and use lawyers and all that stuff," Peters says.

"The First Amendment does not demand that patients at a medical facility undertake Herculean efforts to escape the cacophony of political protests," wrote Chief Justice William Renquist, a Reagan appointee.

"He didnt go run and hide, he kept praying," Peters says. "Theres law that is higher than mans law Gods law. The kingdom of heaven has laws that are higher than the United States of America."

In other words, even if the law passes, don't expect the Church at Planned Parenthood to go away quietly.

"Were going to show up until Jesus Christ comes to take us home or until abortion is abolished in America," Peters says.

Daniel Walters photo

Planned Parenthood has repeatedly asked counter-protesters like these to quit it. In recent months, the numbers of counter-protesters have dwindled as a result.

Paul Dillon, vice president of public affairs, says that Planned Parenthood met with city officials on Thursday. Woodward, he says, left the meeting early on, but other officials like Police Chief Craig Meidl and City Administrator Wes Crago stayed to listen.

"The meeting really started with us explaining how this has been escalating and the fears around that," Dillon says. "It seemed like at the end of the day they understood that and also had concerns."

Dillon sent the Inlander a slew of screenshots of comments from Peters on social media to bolster the argument that Peters is looking to interfere with the clinic, not just to sing worship songs and pray outside.

"The Planned Parenthood Staff fled the building in fear when we showed up and started our church service," Peters wrote on Facebook in October 2018.

To him, there's a distinction: Yelling at a woman that she's a "baby murderer" is harassment, but softly pleading with her not to kill her baby is advocacy.

Confrontations between anti-abortion activists and counter-protesters can become particularly disruptive, Dillon says.

"This guy just drove his car right up to the egress and just looked like he was going to ram [an anti-abortion activist] but stops his car, and just laid on the horn for 15-minutes," Dillon says. "That is really scary."

Dillon says that Planned Parenthood has repeatedly been explicit with counter-protesters: They're not helping.

Because ultimately, Planned Parenthood's complaint is about both the enforcement of the law and the alleged violators of it.

Planned Parenthood supporters were particularly horrified this month when a records request revealed a cop on a body camera assessing the comparative aesthetic merits of the women on each side of the abortion divide.

Daniel Walters photo

Nadine Woodward at her campaign kickoff breakfast last year.

Last year, when Woodward was introduced for her mayoral campaign kickoff breakfast, she was praised for her work with a variety of nonprofits, including Life Services' crisis pregnancy center, an anti-abortion group that aims to both help pregnant women and discourage them from having abortions, sometimes through controversial tactics. Pressed on her position on the issue by the Inlander last year, she said she was in favor of women having "choices," emphasizing the "S."

And at a Spokesman-Review hosted candidate forum last year, Woodward was asked by Planned Parenthood's Dillon what she would do to enforce existing noise ordinances at health care facilities like Planned Parenthood. She replied in generalities.

"Noise ordinances should be enforced everywhere. In neighborhoods, on business districts, I would say they should be enforced everywhere," Woodward said. "I would say everywhere, doesn't matter where it is."

But now, that she's mayor, the question has gone from theoretical to very real:To start with, she has to decide if she'll veto Kinnear's ordinance or sign it. On Thursday afternoon, Coddington said Woodward hadn't committed to either course yet, saying the language of the resolution could still be changed.

"There still needs to be legal review of the language to make sure its practical and implementable," Coddington says. Coddington says the mayor's primarily driven by the burden the conflict has put on the Police Department, and the interests of the surrounding neighborhood. Coddington says the mayor is still looking to broker an agreement between the two groups.

There is a hope that, at some point, we could get to a point where there is a mutually accepted solution, Coddington says. That typically happens better when you can have both parties at the table at the same time.

See the rest here:
Mayor Woodward to controversial anti-abortion church and Planned Parenthood: Let's sit down and talk - Pacific Northwest Inlander

Recommendation and review posted by Bethany Smith

You are infantilising women! I heard my mother yell one day when I was a teenager. Alarmed, I went into the kitchen to find her slamming the phone receiver down.

Have you seen this? she said, holding up a roll of paper towels printed with colourful images of teddy bears and blocks.

Mom, I said. Did you just call the Bounty paper-towel company to complain about these teddy bears?

Yes, she said, eyes flashing. They should be ashamed.

In retrospect, I think that my then middle-aged mother dealing with a grouchy teenage daughter, dying parents, marriage problems and an acting career ending because she was no longer young might have been finding a way to express her feelings without bothering anyone except a supervisor at that paper-towel company.

Twenty-five years later, struggling with a career that felt over, facing various physical problems and trying to get my child into a good school, I found myself paying a lot of attention to my sons pet turtle.

Jenny looks bored, I said, gazing into the tank. When was the last time Jenny had some fun?

Shes a turtle, my husband said. Turtles dont have hobbies.

Maybe they want more! I snapped.

And that was the moment I realised that Jenny the turtle had become my very own paper-towel teddy bear.

Menopause, defined as a full year with no period, hits women on average around the age of 51. But the years before that cessation called perimenopause can be more emotionally and physically fraught than we anticipate. We change a lot during these years. And, as we may remember from puberty, transitions can be awkward. Our bodies and our moods frequently betray us, but one of the worst parts of perimenopause and menopause is that no one talks about them.

Sometimes my own perimenopausal moods are more rage than anxiety. I woke up the other day and noticed that my husband had placed a couple of champagne corks on top of a picture frame. It made me want to start breaking things. What is this, a goddamned student house? In this state, I noticed things I had missed before: bags spilling out of cupboards, stacks of receipts and change on a table, my sons stuff everywhere. Its like living in Hoarders! I ranted. If Id had a pack of matches I could have burned the place down.

When I open the book How to Face the Change of Life with Confidence, published in 1955, I see a question from a woman, 37, who has wild mood swings before she gets her period. The expert male gynaecologist author tells her: Man reaches physical maturity at 25, and emotional maturity at 35. Unfortunately, you seem to have missed the boat somewhere along the line, and you are still in your childish stage of emotional reactions.

Decades of that sort of condescension have kept women from asking certain questions twice.

Almost every woman I know of my age is feeling confused and in a state of transition even as most of us are at the top of our game in our careers, financially stable and pretty comfortable with being parents, said Yvette, 43, a Californian who is the COO of a video game company. I spend a lot of time with other friends of my age. We talk about the fact that we are widening and softening where we dont want to and dont know if it makes us shallow or not feminists to do something about it; the fear that we dont know how to monitor our childrens screen time; the fact that we dont really like or need sex very often; our worry that we are losing time to try our dream job.

Experts in gynaecology maintain that hormone replacement therapy (HRT) remains the most effective scientifically proven treatment for the symptoms of menopause. And yet, fearing the increased risk of cancer, stroke and blood clots that weve long heard comes with a hormone therapy regimen, weve gone rogue. That, perhaps, is why Gwyneth Paltrows online community Goop can get away with selling us expensive jade eggs to stick up our yonis.

Gynaecologists I spoke to said they werent surprised that women were casting around for exotic fixes to their perimenopausal woes. Jacqueline Thielen, who works at the Womens Health Clinic at the Mayo Clinic in Minnesota, said she sees many women in their 40s and 50s who tell her theyre scared of hormone therapy, but made miserable by symptoms and being swamped with responsibilities.

This makes them vulnerable, Dr Thielen said, to controversial things like subcutaneous hormone pellet therapy, inappropriate ovary removal, or pricey vaginal rejuvenation, which can cost a fortune and may involve shooting lasers into your vagina one more thing I guarantee you our mothers did not have on their to-do lists.

For some women, its not a big deal. For others, it can be crushing. In a survey by the American Association of Retired Persons, 84% of participating women said that menopausal symptoms interfered with their lives.

You know, said JoAnn Pinkerton, executive director of the North American Menopause Society (Nams), we tell people who are grieving not to make major changes for a year. I dont think anybodys ever said: Dont make a major decision when youre perimenopausal.

Good idea, I think. We can just take it easy until perimenopause ends. How long is that, anyway? I asked.

Anywhere from a few months to 10 to 13 years.

Oh my goodness, I said.

On average, they call it four years, she said. But she added that menopause is actually a lot easier than the perimenopausal transition which is unpredictable. Its based on ovarian fluctuations. You might have six months of severe hot flashes, skipping periods and then your cycles come back for three to five years before it happens again.

Women need to recognise that its a time of vulnerability, and there are some things that they can do to help.

Dr Pinkerton gave me an example: A woman came into my office and said, I hate my husband. I hate my marriage. I need to get out of this. The husband had called me earlier and said, Ive noticed that my wife is really having exaggerated responses to things around the time of her periods.

We ended up getting her into counselling as well as on to oral contraceptives. The contraceptives calmed the hormones down and then doing some counselling let her start to see some of the stressors that were hidden.

I saw her recently, Dr Pinkerton continued, and she said her marriage could not be better. She recognised that the perimenopausal hormonal fluctuations were making the problems seem incapable of being solved. I guess what I would just say is if youre in perimenopause, recognise that hormonal fluctuations may make the problems at work or at home seem larger.

Women also benefit exponentially from sleeping more, Dr Pinkerton added. Its often the first thing to go, but its absolutely one of the things that can help you navigate this time. Then, stress reduction.

But heres what I want to know: why are Generation X women arriving in their 40s knowing something is going to happen, but without a clear idea of exactly what that is?

One answer is: denial. We have had incentives for a long time to pretend we are the same as men in every way. For decades, women have had to argue that they could still work and function through those messy period, pregnancy and menopause-related symptoms, and as a result weve minimised them, both to others and to ourselves. So as not to call attention to ourselves as women, we pretend its not happening. Boomer women arguably started this, entering the work world in shoulder-pad armour. It makes sense that they felt they had to hide the inconvenient fact of their womanhood, particularly in middle age.

After taking our children to see the latest Star Wars, a friend and I sat at her dining table while the kids ran around. Its just too hard, she said. This has ruined my life! Two years without sleeping through the night! Two years with hot flashes! Two years with no energy.

Id had no idea. I asked why she hadnt told me before.

I hate talking about menopause, she said. Its like saying youve closed up shop as a sexual being. Its embarrassing.

Aside from the embarrassment, we are getting less help than we should from our doctors. A 2013 Johns Hopkins survey found that only one in five American obstetrics and gynaecology residents had received formal training in menopause medicine. Thats 20% of gynaecologists. Forget about general practitioners.

As it turns out, the reason Gen X women have grown up believing that hormone replacement therapy again, one of the only proven treatments for menopausal symptoms is dangerous is something that happened in the medical community in 2002.

Its like saying that youve closed up shop as a sexual being

In 1993, as the menopause was becoming a hot topic, the Womens Health Initiative (WHI), a national, long-term study on the possible benefits of hormone treatment for postmenopausal women, was launched in the US. But, in July 2002, the premature termination of the oestrogen-progesterone part of the study was announced. The reason given was an apparent rise in the risk of coronary heart disease, stroke, blood clots and breast cancer.

There was a hitch in this: WHI had been looking at what the hormones did in women aged 50 to 79. The aim was to figure out if this type of hormone treatment could help protect these women from heart disease and other illnesses. It was not about short-term hormone therapy for treatment of symptoms in women in their 40s and 50s. But many midlife women heard only cancer and went off HRT immediately.

Dr Wulf Utian, founder of the Nams, wrote an editorial calling the manner in which the study was ended poorly planned, abrupt and inhumane. In 2017, Professor Robert D Langer, one of the original WHI investigators, said that errors in the 2002 report led to a lot of unnecessary suffering for women.

However, this has done little to calm the fears of hormone therapy among women, and even doctors. 9 July 2002 was the day the music died for menopausal women, said Dr Mary Jane Minkin of Yale, one of the nations leading experts on gynaecological health. One of the things that was very bad about it was that no one was given advance notice this report was coming out. There was also a journalistic cock-up. A WHI investigator gave the story to the Detroit Free Press on the grounds that it was an embargoed study due to appear the following week in the Journal of the American Medical Association. The Detroit Free Press broke the embargo.

Thats how Good Morning America got the story. Everybody went insane, she continued. In that week, every American woman went to her cabinet and took out her hormone prescription and flushed it down the toilet. Which, of course, was ridiculous, because the WHI Part One was the only study that was stopped at that point. That was the oestrogen plus progesterone. The oestrogen-only went on for another two years. It eventually showed a decreased risk of breast cancer, not an increased risk of breast cancer.

People of Generation X tend to be demanding, and theyre having all these things happen to them. Why? asked Dr Minkin. Whats going on? Theyre being told: Just ignore it; its going to get better, or You can take an SSRI [antidepressant], which will help your hot flashes though, yeah, its going to make you love sex less and get fat. Your options are not too fabulous, but they dont know how to handle hormonal therapy, because they think its going to give you breast cancer. The other part of the problem is that you have such authoritative spokespeople as Dr Kim Kardashian, Dr Suzanne Somers, Dr Oprah Winfrey, Dr Gwyneth Paltrow

Dr Minkin does not believe women should grin and bear it. Here is some of her advice for us: get daily exercise, especially weight-bearing exercise; a good diet; plenty of sleep. For hot flashes, she advises layering clothes and keeping a dry set of nightclothes next to the bed so you can change quickly if you wake up in the night. She recommends keeping the bedroom cool and getting your partner an electric blanket if he or she complains.

Other non-pill things can make life easier, too, like absorbent period-proof underwear and period tracker apps. She advises many women to consider oestrogen and progesterone hormone therapy (or just oestrogen, if youve had a hysterectomy), in the form of pills, patches, gels, or sprays, though its important to do so only under the direction of a doctor, because there are risks.

Low doses of an SSRI or SNRI antidepressant can combat hot flashes, as can gabapentin (Neurontin). For heavy or irregular periods, Dr Minkin says you can take a birth control pill or get a progesterone IUD called Mirena. When it comes to herbs and supplements like evening primrose oil or bee pollen, theres no proven benefit, though some women say that those things make them feel better.

Sifting through all the advice is hard, especially because it can seem to change with every new headline. In her history of hormones, Aroused, Randi Hutter Epstein writes: Those of us old enough to be in menopause cant help but wonder if the experts are going to change their minds again.

In her 2019 memoir, Deep Creek, Pam Houston gives a younger woman this advice: Im just saying, I guess, theres another version, after this version, to look forward to. Because of wisdom or hormones or just enough years going by. If you live long enough you quit chasing the things that hurt you; you eventually learn to hear the sound of your own voice.

Perimenopause may last months or years; it may be more or less drastic; but one day it will be over. On the other side, well be different perhaps more focused on whats most important to us and almost certainly calmer. Psychotherapist Amy Jordan Jones told me: This is the time of life when we learn we dont have to be pleasing; the work now is just to become more ourselves.

This is an extract from Why We Cant Sleep: Womens New Midlife Crisis by Ada Calhoun, published by Grove Press UK on 5 March. Order it for 12.59 at guardianbookshop.com

Originally posted here:
Surviving perimenopause: I was overwhelmed and full of rage. Why was I so badly prepared? - The Guardian

Recommendation and review posted by Bethany Smith

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

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

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

Canton - Clinic - Monday, March 2 - 8-4 - Appt needed

Canton - WIC Nutrition Education - Tuesday, March 3 - 8-4 - Appt needed

Canton - Clinic/Immunizations - Tuesday, March 3 - 4-7 - Appt needed

Canton - Clinic/Immunizations - Wednesday, March 4 - 8-4 - Appt needed

Astoria - Clinic, WIC Nutrition Educ. - Wednesday, March 4 - 9-3 - Appt needed

Canton - Clinic - Thursday, March 5 - 8-4 - Appt needed

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

Canton - Immunizations - Tuesday, March 3 - 4-7 - Appt needed

Canton - Immunizations - Wednesday, March 4 - 8-4 - Appt needed

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

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

Canton - Clinic - Wednesday, March 4 - 8-4 - Appt needed

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

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

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

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

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

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

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

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

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

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

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

Astoria - Screening - Wednesday, March 4 - 9-12 - Walk in

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

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

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Health Department announces services for the week of March 2 - Canton Daily Ledger

Recommendation and review posted by Bethany Smith

February 2020

Are you looking for a health care provider who offers innovative alternatives and a customized approach to your health issues? Indiana Regenerative Medicine Institute (IRMI) believes in offering specialized alternatives to health care. Its medical team, headed by Doctor of Chiropractic Preston Peachee, utilizes the latest developments in regenerative medicine, hormone replacement and pain management.

Dr. Peachee is a native of Jasper, Indiana. He graduatedfrom Logan College of Chiropractic and has been in practice since 2003. Hisareas of specialty include patients with chronic and severe back, neck andjoint pain as well as other complex neurological conditions.

Dr. Peachee has earned a reputation as an innovative thinkeras well as a compassionate practitioner who brings his wide expertise andexperience to the Greater Indianapolis area. His ability to help those in needof regenerative medicine, neuropathy pain relief, low testosterone or otherphysical ailments, such as back pain or fibromyalgia, makes him not only uniquebut highly sought-after.

A key member of the IRMI team is Leann Emery, FNP. Emery isa family nurse practitioner with more than 20 years of experience in hormonereplacement and alternative pain management. Emery provides optimal patientcare through personal consultations and assessments to identify her patientsspecific health needs. She was rated in the top 10% of providers in the U.S.with patient satisfaction.

Regenerative medicine is making huge leaps in our understanding of the human body, and it is offering real, possible treatments that would have seemed like science fiction a few short years ago, according to IRMI. Most patients we see have tried other more traditional treatments and have either not gotten any better or have gotten even worse. Unfortunately, a lot of people we see depend on multiple medications per day to try and function but still are not happy with how they feel or how they live their lives. It is unfortunately the nature of deteriorating and degenerative joints, they will get worse with time, and generally the pain increases as well.

Depending on the injury, Dr. Peachee will often combinelaser therapy with the regenerative medicine protocols to improve the outcomesand try and speed the recovery process.

We offer mesenchymal stem cell therapy, Dr. Peachee said. With the combination of laser therapy, mesenchymal stem cell therapy is incredibly effective for rotator cuff problems and treating knee pain. Eighty percent of our stem patients are dealing with knee pain or Osteoarthritis. Osteoarthritis-or O.A. of the knee- is a huge problem for a lot of people, and we get great results from these therapies. Most people can even avoidknee surgery.

Dr. Peachee recently introduced hormone treatments for low testosterone. Family Nurse Practitioner Leann Emery has been doing [hormone] treatments for 20 years, and that area of medicine became a natural fit for IRMI.

I have several patients who were seeking this type ofcaremany who are police officers and firefighterswho couldnt find thetherapy and individualized care and attention that they needed.

Dr. Peachee explained that low T treatments help patients with unique and even complicated cases of Erectile Dysfunction (E.D.). Most people seek us out for treatment because they are tired, worn out, stressed out and just simply lack the energy they used to have.

We are able to fill a niche with patients who hadcomplicated cases that were not responding well with their primary careproviders or other places, Dr. Peachee shared. We have a patient who hasstruggled for a long time with fertility issues but has done very well [withtreatments], and we just got good news that he and his wife are expecting aftertrying for a really long time. So, he is really enthused about that.

The typical candidates for low T treatments, according toDr. Peachee, are men who feel worn out, are lethargic and have lost theirzest for life.

Our patients dont have the same pep that they had 10 or20 years ago, Dr. Peachee stated. They struggle getting up in the morning andmight be struggling in the afternoon after having six cups of coffee or threeRed Bulls just to get through the day. We have a lot of people that want to getback into the gym and get the maximum benefit of their workouts. We can helpthem improve their overall health and energy so that they can enjoyrecreational activities like working out or practice with the Little Leaguewith their kids. Many times we hear from spouses, friends and family how muchbetter they feel and that they seem happier and get more out of life again.

It goes without saying that proper hormonal balance canimprove a patients personal relationships as well and improve the overallmental health of a patient by reducing stress, anxiety and depression oftencaused by symptoms related to low testosterone levels.

We focus on injectable [low T] treatments because we canmodify the dosage and give more frequent doses to keep our patients at a levelthats going to give them the maximum benefit and improvement for theirconditions, Dr. Peachee explained.

With the modern changes in medicine over the last 20 and 50years, were helping people to live a lot longer and adding 20 to 30 years totheir lives, but we have not given them an improved quality of life as theyage. By working with their hormones and getting them in balance, their qualityof life becomes way better, and were seeing a positive improvement for manypeople with these treatments.

Patients suffering from severe disc injuries, such a bulgingor herniated disc or discs, or who suffer from degenerative disc disease mayhave undergone treatment from chiropractors or have seen physical therapistsbefore coming to Indiana Regenerative Medicine Institute.

Our typical patient who comes in for this type of treatmenthas seen other therapists or chiropractors but hasnt found lasting relief,Dr. Peachee said. Many of our patients want to get off the rollercoaster ofopioids and pain medications. They are looking for a solution without narcoticsand risk of addiction or other possible negative side effects of narcoticsand/or surgery. We are generally able to alleviate the pain in 90% of patientsand are able to keep them from having surgery or from taking addictivemedications.

Laser therapy allows Dr. Peachee to work on the damaged tissue so that it can heal, and the method reduces inflammation and swelling in a way that traditional treatments cannot.

Its an innovative new therapy within the last decade thatallows us to do some amazing things, Dr. Peachee stated. We perform ourprocedures in our office and have several different devices for the specificneeds and issues of our patients. For instance, we have a unique device forpeople with knee pain that can help the majority of our patients walk betterand live more pain-free. We get a phenomenal outcome with this procedure.

One of the other major differentiators that sets IndianaRegenerative Medicine Institute apart from other offices and clinics is thatthey are advocates for their patients, especially when it comes to dealing withtheir patients insurance providers.

A lot of our low T patients are able to get their insurancecarriers to cover the services so that it doesnt cost them as much out ofpocket for the care they seek, Dr. Peachee said. Weve partnered with abilling company that has helped us to be able to navigate the craziness of ourmodern insurance companies, and by doing so, were able to keep the cost downfor a lot of patients. Not every insurance plan will cover this type of care,but a lot of them will. When its possible and ethical, we do whatever we canto benefit our patients to help keep the cost low. I have spent a lot of freetime writing letters on behalf of our patients. We go above and beyond with ourservice and care of our patients.

The Indiana Regenerative Medicine Institute team will make housecalls or come to a patients place of work when the situation calls for thatlevel of care.

We will go and draw blood for blood work, bring medications and even do exams in some situations, Dr. Peachee said. As I mentioned before, we see a lot of police officers and firemen all over the statefrom Mishawaka to South Bend and all over Indiana. We go once a month to see these patients at their departments and stations so that we see them all in one day versus making 10 to 15 guys drive hours to come in to see us. Its a service we can offer because we are a small clinic and we are focused on that one-on-one patient attention and relationship building. We have great relationships with our patients, and thats something that we work very hard at.

Building trust and transparency is crucial to the success ofhis practice, Dr. Peachee emphasized. The trust that we build with ourpatients is crucial to not only the success of the practice but to thepatients outcomes. And not just with hormone therapy but also with ournonsurgical spinal decompression patients. These are patients with significant discinjuries, and we need them to tell us everything we need to know so we can givemore accurate and complete care for a better outcome.

I would say to anybody if you have any doubts or reservations to take some of the burden and some of the anxiety out of the equation and schedule an initial consultationabsolutely free of charge, Dr. Peachee encouraged.

Dont put off living your best life any longer. Visit Indiana Regenerative Medicine Institutes website at indianaregen.com or call (317) 653-4503 for more information about its services and specialized treatments and schedule your free consultationtoday!

Writer:

Janelle Morrison

Photography:

Laura Arick and submitted

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Indiana Regenerative Medicine Institute Offers Innovative Approaches in Regenerative Medicine, Hormone Replacement and Pain Management - Zionsville...

Recommendation and review posted by Bethany Smith

WEST PALM BEACH, Florida Women who have no history of a full-term pregnancy show an earlier onset of progressive multiple sclerosis (MS) compared with those who have had pregnancies, and the apparent onset-delaying effect appears to increase with the number of pregnancies, new research suggests.

The results add to speculation on the effects of pregnancy in MS.

"Our results suggest that a higher number of full-term pregnancies than average is associated with later onset of progressive MS, while having no full-term pregnancies is associated with significantly younger age at progressive MS onset," first author Burcu Zeydan, MD, an assistant professor of radiology in the Center for MS and Autoimmune Neurology at the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

The study was presented here at the 5th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020.

The findings, which also link early menopause with faster disease progression, offer important insights into the broader effects of pregnancy on MS, commented ACTRIMS president Jeffrey A. Cohen, MD, who is the director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research, Cleveland Clinic, Ohio.

"We know pregnancy affects the short term disease activity relapses tend to quiet down during pregnancy but what has been somewhat conflicting is whether it affects the long-term prognosis or is just a temporary effect," he told Medscape Medical News.

"So that is the main interest in this study, and it does indicate that pregnancy affects the long-term prognosis and provides some insight into the mechanism by which it might do that."

While being female is in fact considered the most important risk factor for MS susceptibility, pregnancy has been suggested to have a protective role in disease progression. However, more research is needed on the nature of the effect and its mechanisms.

For this study, Zeydan and colleagues evaluated data on 202 patients (134 women, 68 men) with MS who were part of a Mayo Clinic survey.

They found that women who had no full-term pregnancies (n = 32), had an earlier onset of progressive MS (mean age 41.4 12.6 years) compared with women giving birth to one or more children (n = 95; 47.1 9.7 years; P = .012).

In addition, the mean age of progressive MS onset increased with a dose-effect trend according to the number of full pregnancies (no children, 41.4 12.6 years; 1-3 children: 46.4 9.2 years; 4 or more children: 52.6 12.9 years; P = .002).

A look at a subgroup of patients with secondary progressive MS also showed an earlier mean age of onset among women who had no full pregnancies(n = 19; 41.5 9.2 years) compared with women who had one or more full pregnancies (n = 57; 47.3 10.6 years; P = .049).

The later disease onset associated with pregnancy was also seen in relapsing-remitting MS: Mean age of onset was earlier women with no pregnancies (27.5 7.0 years) compared with those with one or more children (33.0 9.4 years;P = .021).

The mean duration of time from relapsing-remitting MS to secondary progressive MS was also shorter among women with premature or early menopause (n = 26; 12.9 9.0 years) compared with those who had menopause at a normal age (n = 39; 17.8 10.3 years).

The pattern was similar for women experiencing the onset of secondary progressive MS after menopause, with a shorter progression among those with early menopause (P = .012).

The trends of later onset with more pregnancies was also observed with the mean age of onset of secondary progressive MS (no full pregnancies: onset at 41.5 9.2 years; 1-3 pregnancies: onset 46.2 9.9 years; 4 or more pregnancies: onset 52.6 12.9 years; P = .010).

And likewise, the later mean age of onset of relapsing-remitting MS was seen with additional pregnancies (no full pregnancies: 27.5 7.0 years; 1-3 pregnancies: 32.4 9.3 years; 4 or more pregnancies: 35.8 9.8 years;P = .012).

"The dose effect was clearly a surprise (having no full-term pregnancies vs 1-3 vs 4 or more)," Zeydan said.

"In addition to the significant difference between having no vs 1 or more full-term pregnancies, the clear dose-effect consolidates our results related to the association between the number of pregnancies and age at progressive MS onset."

The study also showed that women with premature or early menopause had a shorter duration of progression from relapsing-remitting MS to secondary progressive MS (n = 26; 12.9 9.0 years) compared with women who experienced menopause at a normal age (n = 39; 17.8 10.3 years).

The patterns in early menopause are consistent with previous observations regarding menopause and MS progression, Cohen said.

"When women go through menopause, estradiol and pregnancy-related factors further decline and we know this coincides temporally with the development of progressive MS in women," he noted.

Compared with men, women with premature or early menopause furthermore had a longer duration from relapsing-remitting MS to secondary progressive MS (P = .008), and women with secondary progressive MS also had also had an earlier age of relapsing-remitting MS onset than men (P = .018).

The mechanisms of pregnancy could include a complex interaction between estrogen and factors such as astrocyte and microglia function, Zeydan explained.

"Estrogen, through various mechanisms of eliminating toxicity of highly activated neurons including preventing pro-inflammatory molecule release, supporting mitochondria function thereby eliminating energy failure, and promoting remyelination helps neuronal plasticity and delays neurodegeneration, which is closely related to the progressive phase of MS," she said.

"One could easily make the probable association, while yet to be proven, that our findings may relate to these mechanisms," Zeydan said.

The logical question of whether hormone replacement or some type of therapy that could mimic the effects of pregnancy could also benefit in delaying MS onset remain to be seen, Zeydan said.

"While we believe that is possible, particularly for delaying the onset of progressive phase, definitive evidence is lacking at this time," Zeydan said. "However, our study ultimately may lead to such a trial."

In the meantime, the findings provide additional insights that may be beneficial in sharing with patients regarding pregnancy, she said.

"As the contemporary problem in MS care is to delay or prevent progressive MS onset, our findings may suggest that how we counsel women with MS who are planning to get pregnant, or contemplating surgically induced menopause, or how we consider hormone therapies during perimenopause, may impact the course of their disease."

Zeydan cautions, however, that "our findings do not confirm causality beyond an association."

"More studies are needed in this important issue in a disease that affects women three times more than men," she stressed.

Zeydan has disclosed no relevant financial relationships. Cohen reports personal compensation for consulting for Adamas, Convelo, MedDay, Mylan, and Population Council; and serving as an editor of Multiple Sclerosis Journal.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020: Abstract P135. Presented February 27, 2020.

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Pregnancy Linked to Later Onset of Progressive MS - Medscape

Recommendation and review posted by Bethany Smith

In the predawn darkness, you can see an eerie red glow shining from the windows of the Hudson, Wisconsin, home of Thaddeus Owen and his fiance, Heidi Sime.

The couple are awake, having slept in their Faraday cage a canopy over their bed that blocks electromagnetic fields like the Wi-Fi signals or radiation from cellphone towers, which they believe are harmful.

Their primal sleeping environment also has special pads under the bed that are supposed to mimic the effect of sleeping on the ground under the influence of the Earths magnetic field, thus combating Magnetic Field Deficiency Syndrome.

Their house is bathed in red light because they think white incandescent, LED and fluorescent lighting robs them of sleep-regulating melatonin hormones. They wear special sunglasses indoors for the same reason, blocking the blue light from computers, cellphones or televisions when its dark outside.

Their morning routine includes yoga in a shielded, infrared sauna designed to create an EMF-free ancestral space, and putting tiny spoonfuls of bitter white powders under their tongues. These are nootropics, so-called smart drugs, which are supposed to improve focus, mood or memory.

When day breaks, they go out in their yard and face the rising sun Thaddeus in shorts and no shirt, Heidi in a sports bra and yoga pants doing Qigong in the snow and 25-degree air.

Getting early-morning sunlight, they believe, will correctly set the circadian rhythm of their bodies. Exposing their skin to the freezing temperatures, they hope, will help release human growth hormone, stimulate their immune system and trigger the body to burn fat to heat itself.

Forget Blue Zones. This is what your morning looks like if youre biohacking your way to an optimal you.

DIY HUMAN ENGINEERING

Biohacking is a DIY biology movement that started in Silicon Valley by people who want to boost productivity and human performance and engineer away aging and ordinary life spans. Think of it as high-tech tinkering, but instead of trying to create a better phone, biohackers are trying to upgrade to a faster, smarter, longer lasting, enhanced version of themselves.

Owen, 44, describes it as a journey of self-experimentation, using practices that are not talked about by mainstream media and your family doctor. His aim is to combine the latest technology and science with ancient knowledge to modify his environment, inside and out.

My entire goal is to basically age in reverse, he said.

Owen, who is from New York, studied chemical engineering in college. He worked for Procter & Gamble, helping to create beauty care products, and for pharmaceutical firms, developing manufacturing processes.

Now he works from home, managing worldwide product regulations in the sustainability department for office furniture company Herman Miller. But he moonlights as a biohacking guru.

He started a Twin Cities biohacking Meetup group that organizes weekly cold-water immersions at Cedar Lake in Minneapolis. Hes given a TEDx talk urging audience members to wear blue-light-blocking glasses indoors at night.

He founded the website primalhacker.com and he and the 45-year-old Sime (who also goes by the name Tomorrow) run a website called thaddeustomorrow.com, where they market biohacking products like red light panels, a baby blanket that blocks EMF radiation and a $5,499 Faraday cage sauna thats the same type used by Twitter founder Jack Dorsey.

Owen said he relies on tons of research to support avoiding blue light at night and the healing properties of the early morning sun.

WHATS THE DEAL WITH BLUE LIGHT?

The Harvard Health Letter, for example, said that blue light from devices, LED and compact fluorescent bulbs can throw off the bodys circadian rhythm, affect sleep and might contribute to cancer, diabetes, heart disease and obesity. Some studies have shown that exposing people to cold temperatures burns calories and repeated cold-water immersions might stimulate the immune system.

And those infrared saunas? They dont appear to be harmful and maybe they do some good, according to Dr. Brent Bauer, an internal medicine expert at the Mayo Clinic.

But being healthy really doesnt need to be that complicated, according to Dr. Michael Joyner, a human performance specialist at the Mayo Clinic.

All these things sound great, Joyner said of the biohacks. Theres a ring of what I call bioplausibility to them.

But Joyner said its often hard to find evidence that biohacking practices actually work and that most Americans would be healthier if they just followed basic advice: go for a walk, dont smoke, dont drink too much and dont eat too much.

But Owens goal is not to be merely healthy.

I want my biology to be shifted to that supernormal range, where Im optimally healthy, he said.

When he started biohacking about 12 years ago, Owens goal was to improve his sleep. As a competitive athlete, he was fit, but he had problems with anxiety and insomnia.

So he started wearing special glasses to block blue light. His co-workers used to think he was odd. Now Owens company is asking him for advice on what kind of lighting should be used in work settings to keep employees healthy. And his sleep and anxiety problems have gone away.

I went from being the weird guy to being consulted, he said.

We all sort of watch what he does, said Gabe Wing, director of sustainability at Herman Miller and Owens boss. Wing said Owen has influenced some co-workers to try blue-light-blocking tools.

When Owen first got into it, he didnt know of any other biohackers in the Twin Cities. Now there are more than 500 people in the Biohackers Twin Cities Meetup group.

Although many biohacks seem odd now, Owen is convinced that some of them will become common practices.

This whole blue light thing, its not going away, he said. More research comes out every day and its becoming more mainstream.

Owen and Sime have five of their children, ages 8 to 17, living with them. The kids wear blue-light-blocking glasses when they watch TV, but theyre OK with it, the couple said.

I think cellphone radiation is going to be the new lead, asbestos and smoking, said Owen, who turns his Wi-Fi off at night, keeps his cellphone in a special Faraday pouch when he sleeps and sometimes wears radiation-proof underwear.

(The National Institute of Environmental Health Sciences says scientific evidence has not conclusively linked cellphone use with any adverse human health problems, although scientists admit more research is needed.)

Owen eats what he describes as a local, seasonal diet: local vegetables, fruits, nuts and honey during the growing season. Thats followed by a high-fat, low-carb ketogenic diet in late fall and early winter. Then an all-carnivore diet in late winter, including animals hes raised at a friends farm.

Owen doesnt have a particular longevity goal, unlike biohacker and Bulletproof Coffee founder Dave Asprey, who has said he wants to live to at least 180.

Owen just wants to be healthy and independent for as long as he lives.

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Can red lights, sleep cages and ice baths really extend life spans? - yoursun.com

Recommendation and review posted by Bethany Smith

Annual Health Fair to be held March 5 from 8 a.m. to 6 p.m. in the Pond Student Union Ballroom

POCATELLO Continuing a 30-year tradition, the Idaho State University Health Fair will provide education and activities designed to help anyone with the goal of improving their health and quality of life. Among the highlights for 2020 are live food demonstrations, educational health and wellness information booths staffed by ISU students and staff, and free or reduced-cost health screenings.

The 2020 ISU Health Fair will take place from 8 a.m. to 6 p.m. March 5 at the ISU Pond Student Union and will showcase Kasiska Division of Health Sciences (KDHS) clinics. KDHS faculty and students will offerfree health screening services, including blood pressure screenings, point-of-service diabetes screening tests (blood glucose [sugar] and A1c), foot exams, dental screenings, hearing screenings and medication reviews.

Services available at the KDHS Clinics health-screening event are as follows:

After visiting the screening stations, attendees can talk with a health action plan team that includes ISU dietetic faculty and students to answer nutrition and lifestyle questions. ISU clinic personnel, KDHS faculty and students, and Health West ISU care coordinators can review screening results and provide recommendations for follow-up appointments.

As always, the 2020 ISU Health Fair will offer learning centers, educational booths, and displays from ISU programs and community businesses.

Food demonstrations will be offered throughout the day by ISU nutrition and dietetic students:

9 a.m.: Smoothies

10:30 a.m.: Energy bites

Noon: Heart-healthy and diabetes-friendly lunch sampler

1:30 p.m.: Easy salsa with tortilla chips

3 p.m.: Veggies with hummus or Greek yogurt dip

As in previous years, discounted laboratory services will also be available throughout the month of February and at the Health Fair, this year offered by Portneuf Medical Center. Blood screenings at the ISU Health Fair are always offered at reduced rates. Attendees can have all of the following tests performed:

Other blood screening tests are available. Individuals interested in having screening tests done can either have their blood drawn during the month of February at Portneuf Medical Center or the day of ISU Health Fair. Participants do not need to be fasting to have their blood drawn. Blood draws are available all day from 8 a.m. -to 6 p.m. during the ISU Health Fair.

Pre-Health Fair blood draws are available Feb. 1 through March 4 at the Portneuf Medical Center Laboratory Services, Monday through Friday from 7 a.m. to 6 p.m. and Saturday and Sunday from 7 a.m. to 1 p.m.

Results for blood work drawn at Portneuf Medical Center Laboratory Services by March 1 will be available for pick-up and review at the ISU Health Fair and can be reviewed by a KDHS faculty or Health West Health Action Plan team member.

Post-Health Fair blood draws are available March 6 through March 15 at the Portneuf Medical Center Laboratory Services, Monday through Friday from 7 a.m. to 6 p.m. and Saturday and Sunday from 7 a.m. to 1 p.m.

Event parking is free in the Pond Student Union parking lot during the time of the ISU Health Fair. Additionally, a free shuttle service will be available from the Holt Arena to the Pond Student Union to allow for additional parking. The last shuttle leaves the Pond Student Union at 5:40 p.m.

For more information, visitISU Health Fair.

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Health screenings, individualized health plans, education, food and demonstrations to highlight 2020 Idaho State University Health Fair - Idaho State...

Recommendation and review posted by Bethany Smith