Archive for December, 2020

Approximately one in 11 persons in the United States has been affected by kidney stones; among those who have experienced a kidney stone, the likelihood of recurrence is high, with up to 50% developing a recurrent stone within 10 years of the first episode. Hyperparathyroidism (PHPT) is evident in approximately 3% to 5% of patients with kidney stones and screening for PHPT is a strategy aimed at reducing the recurrence rate. Patients with kidney stones and PHPT present with hypercalcemia and hypercalciuria, raising the risk for stones by increasing urine supersaturation for calcium oxalate or phosphate.

Guidelines from the American Urological Association and the European Association of Urology call for measurement of serum calcium in patients with kidney stones, followed by the serum parathyroid level (PTH) if there is clinical suspicion for PHPT. It is unknown whether patients with kidney stones receive those recommended screenings in clinical practice. Results of a previous study suggested that fewer than one in four veterans with persistent hypercalcemia treated in the Veterans Health Administration (VHA) were screened for PHPT.

Calyani Ganesan, MD, MS, and colleagues conducted a cohort study to examine the prevalence of PTH testing in veterans with kidney stones and hypercalcemia. The researchers also sought to identify the demographic, geographic, and clinical characteristics of veterans who were more or less likely to receive PTH testing. The study was designed to test the hypothesis that the frequency of PTH testing remains low despite current clinical practice guidelines and that a wide variation in screening practices is not adequately explained by patient-specific or facility-level factors. Results of the study were reported online in JAMA Surgery [doi:10.1001/jamasurg.2020.2423].

The study utilized VHA health records to identify patients with kidney stones and hypercalcemia who received care in one of the 130 VHA facilities across the United States from January 1, 2008, through December 31, 2013. Patients with kidney stones were those with one or more inpatient International Classification of Diseases, Ninth Revision (ICD-9) codes for kidney or ureteral stones, two or more outpatient ICD-9 codes for kidney or ureteral stones, or one or more Current Procedural Terminology codes for kidney or ureteral stone procedures within 1 year. Exclusion criteria included previous screening for PHPT, defined as those with a PTH level measurement between 6 and 30 months prior to the index stone diagnosis.

Data collection occurred from January 1, 2006, to December 31, 2014. Data analysis occurred from June 1, 2009, to January 31, 2020. The primary outcomes of interest were the proportion of patients with a serum PTH level measurement and the proportion of patients with biochemical evidence of PHPT who underwent parathyroidectomy.

A total of 157,539 unique veterans were diagnosed with kidney stones during the study period. Of those, 139,115 had a serum calcium determination within 6 months of their index stone diagnosis, and 7381 had been previously screened with a serum PTH level measurement and were excluded. Following application of exclusion criteria, the final cohort comprised 7561 patients with kidney stones and measured hypercalcemia (n=3938) or albumin-corrected hypercalcemia (n=3623). Mean age of the final cohort was 64.3 years, 94.4% (n=7139) were men, 5.6% (n=422) were women, and 75.0% (n=5673) were white. Patients with hypercalcemia compared with those with normocalcemia (n=124,173) were more likely to have diabetes (39.8% vs 29.5%), impaired kidney function, defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (36.1% vs 15.1%), osteoporosis (4.4% vs 2.1%), and fractures (7.1% vs 4.2%).

Of the 7561 patients with kidney stones and hypercalcemia, 24.8% (n=1873) completed a serum PTH level measurement around the time of the initial stone diagnosis. In the 3938 patients with measured hypercalcemia, 34.8% (n=1369) completed a serum PHT level measurement; only 13.09% (n=504/3623) of the patients with albumin-corrected hypercalcemia did so. Of the 1873 veterans with PTH testing, 38.3% (n=717) had an elevated PTH level consistent with biochemical PHPT.

Results of multivariable logistic regression models demonstrated that the odds of PTH testing in patients with kidney stones and hypercalcemia were lower with older age (odds ratio [OR], 0.95 per decade; 95% confidence interval [CI], 0.90-1.00) and among patients with a history of metastatic cancer (OR, 0.63; 95% CI, 0.49-0.81). Patients with albumin-corrected hypercalcemia were less likely to complete PTH testing compared with patients with measured hypercalcemia (OR, 0.32; 95% CI, 0.28-0.37).

The odds of PTH testing were higher for patients who visited either a nephrologist or a urologist (OR, 1.56; 95% CI, 1.35-1.81), and much higher for those who visited both a nephrologist and a urologist (OR, 6.57; 95% CI, 5.33-8.10) compared with patients who did not visit a stone specialty clinic during the observation period.

Across the 130 VHA facilities in the United States, the prevalence of PHT testing among the veterans with kidney stones varied between 4.0% and 57.0%. The study researchers examined the composite complexity score assigned to each facility and found no association with PTH testing rate for each facility. None of the individual facility-level variables of the complexity score were associated with PTH testing across the 130 facilities. In a comparison of facilities in the top quartile versus the bottom quartile of the PTH testing, there was an association between PTH testing and the presence of stone specialty care at each facility. There was no association between PTH testing and the mean number of parathyroidectomies performed at each facility.

Study limitations cited by the authors included the high proportion of male participants, using a single definition of PHPT, and the inability to capture medical care for veterans with kidney stones who received care outside the VHA system.

In conclusion, the researchers said, In this cohort study, a generally low rate of PTH testing was found in veterans with kidney stones and hypercalcemia, and extensive variation in PTH testing rates was found across VHA facilities in the United States. More awareness of the level or frequency of elevated serum calcium concentration may be associated with higher rates of PTH testing in patients with kidney stones. Improved screening for PHPT could increase the rates of detection and treatment of PHPT and decrease stone recurrence associated with missed or untreated PHPT.

Takeaway Points

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Parathyroid Hormone Testing in Veterans with Kidney Stones and Hypercalcemia - DocWire News

Roughly one in four women will have one. You probably know one of them, whether shes told you about it or not. As of 2017, theyre at a record low rate in America, thanks in part to the Affordable Care Acts requirement that birth control is covered by private insurance as out-of-pocket costs. Sixty-one percent of Americans say it should be legal in all cases, but a considerable subsection of them, especially in the South, dont have reliable access to it. Thats right: were talking about abortion and the musicians who are working to preserve access to it.

If youve seen some of your faves posting about the issue on Instagram (Kim Gordon and Karen O doing it caught my eye), youve probably been seeing the work of a New Mexico-based initiative called Noise For Now. They play matchmaker between musicians who want to support reproductive rights, including abortion and local funds. They aim to destigmatize the conversation around abortion. Hence, part of their plan is to ask artists to post about the organization and why access to healthcare for women is essential. Co-founder and President Amelia Bauer moved to the Southwest from New York after the 2016 election and, while trying to find a way to get involved with local reproductive rights organizations, ended up organizing a concert to benefit the National Organization For Women. It outraised all the big donor dinners and galas they had been putting on.

The idea to work as a connector between those with a large audience your favorite musician and small, local abortion funds hits at a targeted play to provide access to reproductive health care that includes abortion to women who are systematically cut off from it. Since 2011, Texas has lost 25 clinics. In the Midwest, 33 clinics have shut down. In the South, its 50. Even after the TRAP (targeted regulation of abortion providers) laws that closed them were largely overturned by the courts, most of those clinics have not reopened. Theres no doubt that in specific regions of America, the right to choose is under attack. Meanwhile, 59 new womens health clinics opened in the Northeast. More and more, having access to reproductive care and abortion is a matter of how much money you have and where you live.

When you have state legislators working against the will of the people, they create barriers to abortion for people without means, Bauer explains. Anyone with means can travel to another state to access abortion if they cant reach it near their home. That means people who work multiple jobs, who cant get time off, who cant afford a plane or bus ticket, who cant afford childcare are left out of access to safe abortion. She notes that in the U.S., where most abortions are performed in clinics, the procedure is extremely safe, while in countries where it has been outlawed and criminalized, it becomes dangerous for women. Thats why Noise For Now focuses on working with funds that support and are run by Black, brown, indigenous, and undocumented people.

For Bauer, her work in New Mexico started with an eye on preserving the access that women in nearby states traveled to get and in making that travel and all the things that go with it, from the time off work to childcare, possible. The current Supreme Court, which leans more conservative than it has in generations, has caused many to worry about stripping away the landmark Roe vs. Wade ruling. It is what guarantees women the right to have an abortion under the Fourteenth Amendment right to privacy, as explained in the majority opinion by Justice Harry Blackmun a lifelong Republican. With the current slate of justices, Bauer predicts the worst, saying, I dont have a crystal ball, but I dont think its very likely it will survive this court.

Amanda Shires is all too aware of the restrictions placed on womens access to reproductive rights. In Tennessee, 96% of the counties have no facilities that provide abortions. The issue is also bleak for women in neighboring Alabama, Kentucky, and Mississippi the latter has only one clinic and three facilities in total where women can obtain an abortion.

Part of the problem is if people are out protesting [clinics], theyre protesting contraceptive services, HIV testing, hormone therapy, treatment for erectile dysfunction, and all kinds of stuff they dont even think about. And cancer screenings. And LGBTQA+ hormone therapy, Shires points out. She later continues, saying, What I try to do is say, to the best I can, is that Im on your side, whatever side of this you choose, in hopes people dont have to walk around feeling alone.

For Shires, who performed at Noise For Nows Voices For Choice event and the Pro Roe Tee Campaign for Planned Parenthood, talking about things is the most effective way to destigmatize them and affect change. It sometimes feels hard to make a change on your own because you cant. If you can align and affiliate and help and take action, then I dont know about you, but it makes me feel like I can sleep a tiny bit better at night, Shires says.

Shires released The Problem near the end of 2020. This song imagines a conversation between a couple discussing abortion, with proceeds benefitting the Yellowhammer Fund. This Alabama-based fund offers financial and logistic support to those in need of abortion in the state. Yellowhammer is also a fund that Noise For Now has supported. Its Executive Director Laurie Bertram Roberts points out that having these conversations in spaces where its typically verboten, namely among the conservative audiences of country music, is part of removing the stigma.

We need to be talking about how we make sure were having these conversions in spaces we may not think are welcoming, but are maybe more welcoming than we think they are, Roberts says and notes that some of the most significant legacies in country music have been all about womens issues.

Amandas song is one is a long legacy of country women artists giving social critique. It goes back to the first women in country music. It goes to Kitty Wells. It goes to Loretta Lynn and The Pill. Even Tammy Wynette singing D-I-V-O-R-C-E. All those things were controversial at the time, but it tells womens stories. Even Martina McBride talking about Independence Day. Those are women telling their stories in a way that made it accessible and acceptable to talk about those subjects.

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Noise For Now Connects The Indie Scene To Support Women's Health Care - UPROXX

Medicine is ever-evolving on a daily basis. Keeping track of the changes can be an almost-full-time job.Stacker looked at a number of medical journals and media sources to discover the biggest breakthroughs the year you were born, from 1921 to the current day.

From diseases that have been around for decades, such as diabetes and the flu, to cutting-edge tools like artificial intelligence and 3D printing, explore how medical and scientific professionals continually conduct research and clinical trials to improve the lives of patients. Sometimes advances arent immediately adopted, as with the Pap smearthat wasnt integrated into womens health care for 16 years after it was invented. But other times the path from laboratory to everyday use is much more abbreviated, like with insulin, which was used to treat diabetes only a year after it was discovered.

Another recurring theme in medical history is the repurposing of medicines that have worked for one disease in the past, to see how theyll work with another. A number of drugs and vaccines are being re-explored to manage COVID-19. Not all the heroes of medical research come from a traditional backgroundone was an electric engineer who worked for a major record label. Some were recognized with the highest honors, but others still have little visibility decades after their death. Funding for the research behind the breakthroughs is always a considerationsometimes it comes from foundations and government entities, but other times via donations from individuals and enterprises.

The dark side of medical history shown here includes unethical behavior by researchers in the past, which explains why some in the Black community arent exactly early adopters when it comes to clinical trials and new treatment options.

Advances noted here focus not only on the body, but also the mind. Explore this slideshow to see all the ways that health care has changed over the past century.

You may also like: Countries with the best life expectancy

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Medical history from the year you were born - Bryan-College Station Eagle

DARE-BV1 met the primary endpoint of the study and all pre-specified secondary efficacy endpoints; demonstrated significantly greater clinical cure rates compared to placebo

DARE-BV1 has Fast Track and QIDP designations from FDA

New drug application (NDA) submission planned 1H of 2021

SAN DIEGO, Dec. 07, 2020 (GLOBE NEWSWIRE) -- Dar Bioscience, Inc. (NASDAQ: DARE), a leader in womens health innovation, today announced positive topline results from the DARE-BVFREE Phase 3 randomized, double-blinded, placebo-controlled clinical trial evaluating DARE-BV1 in 307 women diagnosed with bacterial vaginosis, a serious condition estimated to affect approximately 21 million women in the United States. DARE-BV1 is an investigational thermosetting bioadhesive hydrogel containing clindamycin phosphate 2% designed as a convenient, one-time vaginally-administered treatment for bacterial vaginosis. The trial met its primary endpoint demonstrating that a single administration of DARE-BV1 was superior to placebo as a primary therapeutic intervention for women diagnosed with bacterial vaginosis.

Based on these topline results, DARE-BV1 delivered clinical cure rate values greater than those of currently marketed FDA-approved products for the treatment of bacterial vaginosis. This successful Phase 3 clinical trial marks another important achievement for Dar. We began 2020 with the announcement of a commercial partnership for Ovaprene with Bayer, marketer of one of the most successful contraceptive products in womens health, and were concluding the year with another exciting milestone, the successful completion of our Phase 3 clinical trial of DARE-BV1 to support an NDA for the treatment of bacterial vaginosis, said Sabrina Martucci Johnson, President and CEO of Dar Bioscience. We believe there is a large unmet need for a more efficacious and convenient, single-dose vaginally-administered product to treat bacterial vaginosis, and we believe DARE-BV1 could become a new front-line treatment option. DARE-BV1 received Fast Track designation from the FDA earlier this year and, based on the topline results of this trial, we plan to file our NDA in the first half of 2021.

Topline Results of the Phase 3 Randomized Clinical TrialDARE-BVFREE randomized 307 women at 32 centers across the United States in a 2:1 ratio to receive a single vaginal dose of DARE-BV1 (N=204) or a single vaginal dose of placebo gel (N=103) to be applied intravaginally within one day of randomization.

The primary endpoint for the study was clinical cure of bacterial vaginosis determined at the final study visit which occurred 21 to 30 days after study drug administration, also referred to as the test-of-cure (TOC) visit, in the modified intent-to-treat (mITT) study population (N=180). In accordance with U.S. Food and Drug Administration (FDA) guidance, the mITT population excludes subjects from the intent-to-treat (ITT) population (N=307) who subsequently demonstrated a positive test result for other concomitant vaginal or cervical infections at baseline.

A single vaginal dose of DARE-BV1 proved statistically superior to placebo at p-value < 0.001 at the TOC visit that occurred 21 to 30 days after study drug administration (primary efficacy endpoint) and also at the assessment visit that occurred 7 to 14 days after study drug administration. DARE-BV1 also demonstrated statistically significant efficacy in all four additional pre-specified secondary efficacy assessments. The clinical cure endpoint results are shown in the following table:

Summary of Clinical Cure Results (mITT Population), p-value < 0.001:

The clinical cure rate at the Day 21-30 visit for the ITT population was similar to that for the mITT population (70.1% for the DARE-BV1 group (N=204) and 36.9% for the placebo group (N=103), p-value < 0.001), demonstrating effectiveness of DARE-BV1 in treating bacterial vaginosis even when other concomitant vaginal or cervical infections were present.

The DARE-BVFREE studys two treatment arms were well balanced in terms of age, race, ethnicity, bacterial vaginosis history, and body mass index (BMI). The ITT population comprised primarily patients aged 15 to 51 years, with a mean age of 34.8 (standard deviation 8.84) and median age of 35. Over 53% of the ITT population qualified as obese (BMI 30.0), with a mean BMI of 31.50 (standard deviation 8.499). In the ITT population, 56.0% of women identified as Black or African American, 41% identified as white and 25.5% identified as of Hispanic or Latino origin (compared to 74.5% as not of Hispanic or Latino origin). In addition, more than 75% of the women in the ITT population reported one or more episodes of bacterial vaginosis diagnosed in the 12 months before they were randomized into the study (76.9% in the DARE-BV1 group and 73.8% in the placebo group).

DARE-BV1 was well-tolerated in the study. There were no early discontinuations due to adverse events (AEs), and the only serious AE occurred in a woman in the placebo group. In the DARE-BV1 group, 15.3% of patients reported AEs that were considered to be possibly, probably or definitely related to study treatment compared to 9.7% of patients in the placebo group.

Only two AEs were reported by more than 2% of patients in the DARE-BV1 arm and at a rate higher than in patients in the placebo arm vulvovaginal candidiasis, commonly called a vaginal yeast infection (17.2% in the DARE-BV1 group and 3.9% in the placebo group), and vulvovaginal pruritus, commonly referred to as vaginal itching (4.4% in the DARE-BV1 group and 1.9% in the placebo group). Over half of the vaginal yeast infections reported in the DARE-BV1 group and exactly half of those reported in the placebo group occurred in patients who exhibited a positive yeast culture prior to dosing.

"We believe these data demonstrate that DARE-BV1 is significantly effective in a representative patient population, including a large proportion of patients who have been previously treated for this infection. Today, about half of the patients treated for bacterial vaginosis experience recurrence of the infection within 12 months of their treatment, and currently marketed FDA-approved products for the treatment of bacterial vaginosis have clinical cure rates in the mid-30% to the high-60% range, said David Friend, PhD, Chief Scientific Officer of Dar Bioscience. If approved, we believe DARE-BV1 will be an important new and convenient one-time vaginally-administered treatment option with the potential to improve clinical outcomes and overall quality of life for women suffering with bacterial vaginosis.

Based on the topline results from the study, Dar expects to have a pre-NDA meeting with the FDA in early 2021 and to submit an NDA during the first half of 2021. DARE-BV1 received both Fast Track and Qualified Infectious Disease Product (QIDP) designations from the FDA for the treatment of bacterial vaginosis. Given these designations, the NDA could be eligible for priority review, which, if granted, could allow for a 2021 PDUFA date, and, assuming approval, an early 2022 commercial launch in the U.S.

About the Phase 3 Study

DARE-BVFREE was a randomized, multicenter, double-blind, placebo-controlled study of a single administration of DARE-BV1 (clindamycin phosphate vaginal gel, 2%) compared to a single administration of placebo vaginal gel (HEC Universal Placebo Gel) for the treatment of bacterial vaginosis. Patients were evaluated during three clinic visits: Day 1 (screening and randomization visit), Day 7-14 (assessment visit), and Day 21-30 (TOC visit). Clinical cure was defined as resolution of the specific clinical signs that comprise the Amsel criteria; specifically, resolution of abnormal vaginal discharge associated with bacterial vaginosis, clue cells less than 20% of total epithelial cells on microscopy, and a negative 10% KOH whiff test. The total study duration was approximately one month for each individual patient.

About Bacterial Vaginosis

Bacterial vaginosis is the most common cause of vaginitis worldwide and is estimated to affect approximately 21 million women in the United States.1,2 Prevalence of bacterial vaginosis among non-white women in the U.S. is higher than among white women (African American 51%, Mexican American 32%, white 23%).2 While there are several therapeutic options for women in the U.S. diagnosed with bacterial vaginosis, currently approved options have relatively insufficient clinical cure rates, require sequential daily administrations or can be otherwise inconvenient for women to use. It is estimated that as many as 50% of women treated for bacterial vaginosis will experience a recurrence within 12 months of their treatment.3

About DARE-BV1

DARE-BV1 is an investigational thermosetting bioadhesive hydrogel containing clindamycin phosphate 2% being evaluated as a one-time, vaginally-administered treatment for bacterial vaginosis.

About Dar Bioscience

Dar Bioscience is a clinical-stage biopharmaceutical company committed to the advancement of innovative products for womens health. The companys mission is to identify, develop and bring to market a diverse portfolio of differentiated therapies that expand treatment options, improve outcomes and facilitate convenience for women, primarily in the areas of contraception, vaginal health, sexual health, and fertility.

Dars product portfolio includes potential first-in-category candidates in clinical development: Ovaprene, a hormone-free, monthly contraceptive intravaginal ring whose U.S. commercial rights are under a license agreement with Bayer; Sildenafil Cream, 3.6%, a novel cream formulation of sildenafil to treat female sexual arousal disorder utilizing the active ingredient in Viagra; DARE-BV1, a unique hydrogel formulation of clindamycin phosphate 2% to treat bacterial vaginosis via a single application; and DARE-HRT1, a combination bio-identical estradiol and progesterone intravaginal ring for hormone replacement therapy following menopause. To learn more about Dars full portfolio of womens health product candidates, and mission to deliver differentiated therapies for women, please visit http://www.darebioscience.com.

Dar may announce material information about its finances, product candidates, clinical trials and other matters using the Investors section of its website (http://ir.darebioscience.com), SEC filings, press releases, public conference calls and webcasts. Dar will use these channels to distribute material information about the company, and may also use social media to communicate important information about the company, its finances, product candidates, clinical trials and other matters. The information Dar posts on its investor relations website or through social media channels may be deemed to be material information. Dar encourages investors, the media, and others interested in the company to review the information Dar posts in the Investors section of its website and to follow these Twitter accounts: @SabrinaDareCEO and @DareBioscience. Any updates to the list of social media channels the company may use to communicate information will be posted on the investor relations page of Dars website mentioned above.

Forward-Looking Statements

Dar cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. In this press release, forward-looking statements include, but are not limited to, statements regarding Dars plans and strategies for regulatory approval and commercialization of DARE-BV1, including expected timing of Dars engagement with the FDA regarding an NDA for DARE-BV1, submission of an NDA for DARE-BV1, FDA review and approval of the NDA, and commercial launch of DARE-BV1 in the U.S. if approved; DARE-BV1s potential importance to and utilization by women with bacterial vaginosis, including its potential ability to improve clinical outcomes and overall quality of life compared to currently available therapeutic options for bacterial vaginosis if approved; and DARE-BV1s commercial potential. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Dars actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, without limitation, risk and uncertainties related to: the risk that topline results from a clinical trial, including the DARE-BVFREE study, are based on Dars preliminary analysis of key efficacy and safety data and, following a comprehensive review of study data, such results may change and topline results may not accurately reflect the complete results from the clinical trial; the risk that the FDA, other regulatory authorities or members of the scientific or medical communities may not accept or agree with Dars interpretation of or conclusions regarding the study data; Dars ability to raise additional capital when and as needed to advance its product candidates and continue as a going concern; the effects of the COVID-19 pandemic on Dars operations, financial results and condition, and ability to achieve current plans and objectives, including the potential impact of the pandemic on the ability of third parties on which Dar relies to assist in the conduct of its business, including its clinical trials, to fulfill their contractual obligations to Dar; Dars ability to develop, obtain regulatory approval for, and commercialize its product candidates; the failure or delay in starting, conducting and completing clinical trials or obtaining FDA or foreign regulatory approval for Dars product candidates in a timely manner; Dars ability to conduct and design successful clinical trials, to enroll a sufficient number of patients, to meet established clinical endpoints, to avoid undesirable side effects and other safety concerns, and to demonstrate sufficient safety and efficacy of its product candidates; the risk that positive findings in early clinical and/or nonclinical studies of a product candidate may not be predictive of success in subsequent clinical and/or nonclinical studies of that candidate; Dars ability to retain its licensed rights to develop and commercialize a product candidate; Dars ability to satisfy the monetary obligations and other requirements in connection with its exclusive, in-license agreements covering the critical patents and related intellectual property related to its product candidates; the risks that the license agreement with Bayer may not become effective and, if it becomes effective, that future payments to Dar under the agreement may be significantly less than anticipated or potential amounts; developments by Dars competitors that make its product candidates less competitive or obsolete; Dars dependence on third parties to conduct clinical trials and manufacture clinical trial material; Dars ability to adequately protect or enforce its, or its licensors, intellectual property rights; the lack of patent protection for the active ingredients in certain of Dars product candidates which could expose its products to competition from other formulations using the same active ingredients; the risk of failure associated with product candidates in preclinical stages of development that may lead investors to assign them little to no value and make these assets difficult to fund; cyber attacks, security breaches or similar events that compromise Dars technology systems or those of third parties on which it relies and/or significantly disrupt Dars business; and disputes or other developments concerning Dars intellectual property rights. Dars forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. For a detailed description of Dars risks and uncertainties, you are encouraged to review its documents filed with the SEC including Dars recent filings on Form 8-K, Form 10-K and Form 10-Q. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Dar undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

Investors on behalf of Dar Bioscience, Inc.:Lee RothBurns McClellanEmail: lroth@burnsmc.com+1 212-213-0006

Source: Dar Bioscience, Inc.

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Dar Bioscience Announces Positive Topline Results From DARE-BVFREE, a Phase 3 Trial of DARE-BV1 in Patients Diagnosed with Bacterial Vaginosis -...

Touro College of Osteopathic Medicine Middletown student Atif Towheed, Ph.D., is researching the health care provider's role in vaccination

Please can you share a couple of your top findings to date?

One of the most significant findings was the need for more education about vaccination. Respondents said this was a need they had for themselves as well as for their patients. We also confirmed the widespread belief that social media plays a critical role in patients decision-making when it comes to vaccines. Additionally, we learned that practitioners confidence levels in discussing vaccines with patients varied significantly between rural and urban areas, with more confidence in urban settings.

What are some of the key factors that pose barriers to vaccination?

Our research showed that key factors posing barriers to vaccination include lack of education on vaccines, fear of becoming sick after vaccination, parental or patient hesitancy, and safety concerns. There are ways to combat these barriers by increasing awareness through patient-provider interactions, including discussions about the risks and benefits of vaccines during patient interactions on routine visits. Based on these findings, we recommend an education program tiered to target health professionals at various levels of their education and careers.

How did you come to research this topic?

The study was initiated in summer 2019 after a noted outbreak of measles in and around our community. Our team of five includes faculty and students at TouroCOM, Middletown and a representative from the Orange County Department of Health. The work grew out of a discussion about the critical importance of vaccination for preventing illness. Under the supervision of Dr. Stephanie Zeszutek, clinical associate professor in the Department of Primary Care, we considered how vaccines also help lower health care costs, especially given the increasing number of vaccine-preventable diseases in the United States.

Others have looked into the relationship between vaccination rates and the education and views/beliefs of health care providers. How is your study different?

Most studies have focused specifically on patient populations. Although there are reports on health care providers views and beliefs, most of them are limited either to specific vaccines or to examining specific health care provider categories. Our study covers views and perspectives on most of the vaccines available in the U.S. We also have a very diverse survey population of health care workers and students.

Please share your background and how you became interested in science.

I was born and raised in India. My parents are both zoologists - my father is an endocrinologist, and I spent a lot of time in his lab learning from him. My mother is an assistant professor of sericulture (the study of silkworms). Their work made enough of an impression on me that I decided to pursue science; at the same time, I like to interact with people, so medical practice was always in the back of my mind.

After receiving my masters degree in biotechnology in India, I joined a U.N. research lab where I studied viruses, including the now-infamous SARS coronavirus. In 2009, I came to the U.S. to earn my Ph.D. at the University of Pittsburgh School of Medicine, after which I accepted a postdoctoral fellowship at The Childrens Hospital of Philadelphia (CHOP).During these years of research, I studied and evaluated gene therapy for mitochondrial diseases, including a potential treatment for Leber Hereditary Optic Neuropathy, an inherited form of vision loss.

How did you finally end up in medical school and at TouroCOM?

During my research and training, I was always associated with hospitals, collaborating with physicians, and talking about patients. I wanted to interact with patients directly, but the final decision to apply to medical school came when my son was born and suffered birth trauma. His doctor was a DO at CHOP, and her management of his care was holistic and inspiring, leading me to finally apply - and to DO schools. My wife often travels to New York City on business, so we wanted to find a school nearby. I attended an open house at TouroCOM and loved the school and the faculty. Im grateful to TouroCOM for giving me the chance to follow my passion.

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Vaccination in the Era of Covid - Touro College News

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that new data from the pivotal Phase III MURANO and CLL14 studies support the efficacy of fixed-duration, chemotherapy-free Venclexta (venetoclax)-based combinations in certain people with chronic lymphocytic leukemia (CLL) and provide more evidence on the potential value of minimal residual disease (MRD). Data were presented at the all-virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition on Saturday, December 5, 2020.

These results reinforce the long-term value of fixed-duration, chemotherapy-free Venclexta-based combinations in CLL, potentially offering patients a significant period of time without treatment following initial therapy, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. These data also reflect our ongoing commitment to accelerating clinical advancements for patients by exploring the novel endpoint minimal residual disease as a potential predictor of patient outcomes.

Five-year data from the pivotal Phase III MURANO trial continue to show sustained investigator-assessed progression-free survival (PFS) with Venclexta plus Rituxan (rituximab). Data, presented in an oral session, showed:

Data from the Phase III CLL14 study contributes to growing evidence regarding the potential of MRD measurements to predict future outcomes for certain people with previously untreated CLL who were treated with fixed-duration Venclexta plus Gazyva (obinutuzumab):

Exploring novel endpoints, such as MRD, is an important area of development for Genentech, which continues to investigate Venclexta in a robust clinical development program. This includes the Phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.

*Minimal residual disease (MRD) is a measure of the number of remaining cancer cells. Undetectable MRD (uMRD), sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes.

About the MURANO Study

MURANO [NCT02005471] is a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of fixed-duration Venclexta (venetoclax) in combination with Rituxan (rituximab) compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta, patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukemia, with or without 17p deletion, who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta plus Rituxan or BR. The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the CLL14 Study

CLL14 [NCT02242942] is a randomized Phase III study evaluating the combination of fixed-duration Venclexta (venetoclax) plus Gazyva (obinutuzumab) compared to Gazyva plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta alongside six-month duration of Gazyva (Arm A) or six-month duration of Gazyva alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva followed by a five-week Venclexta dose ramp-up to help reduce the risk of tumor burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee, minimal residual disease (MRD) status, overall response rate, complete response rate (with or without complete blood count recovery), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety. MRD-negativity, or undetectable MRD, means no cancer can be detected using a specific and highly sensitive test, and was defined as less than one cancer cell in 10,000 leukocytes. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About CLL

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. In the United States, it is estimated that more than 20,000 new cases of CLL will be diagnosed in 2020. Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of cancerous cells.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood and other cancers.

In the United States, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. Food and Drug Administration (FDA): one for previously untreated CLL, two for relapsed or refractory CLL and two for previously untreated acute myeloid leukemia.

Venclexta Indications

Venclexta is a prescription medicine used:

are 75 years of age or older, or have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Important Safety Information

What is the most important information patients should know about Venclexta?

Venclexta can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. The patients doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids into their vein.

The patients doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they have any symptoms of TLS during treatment with Venclexta, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Patients should drink plenty of water during treatment with Venclexta to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose on the day of the first dose of Venclexta, and each time a dose is increased.

The patients doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects. When restarting Venclexta after stopping for 1 week or longer, the patients doctor may again check for the risk of TLS and change the patients dose.

What patients should not take Venclexta?

Certain medicines must not be taken when the patient first starts taking Venclexta and while the dose is being slowly increased because of the risk of increased TLS.

Before taking Venclexta, patients must tell their doctor about all of their medical conditions, including if they:

What to avoid while taking Venclexta:

Patients should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patients blood.

What are the possible side effects of Venclexta?

Venclexta can cause serious side effects, including:

Patients should tell their doctor right away if they have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell count; low platelet count; low red blood cell count; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of arms, legs, hands, and feet.

The most common side effects of Venclexta in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

Venclexta may cause fertility problems in males. This may affect the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at 1-888-835-2555.

Please see the Venclexta full Prescribing Information, including the Medication Guide, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) is a prescription medicine used to treat adults with:

Important Safety Information:

Rituxan can cause serious side effects that can lead to death, including:

What should patients tell their doctor before receiving Rituxan?

Before receiving Rituxan, patients should tell their doctor if they:

What are the possible side effects of Rituxan?

Rituxan can cause serious side effects, including:

TLS can happen within 12 to 24 hours after an infusion of Rituxan. The patients doctor may do blood tests to check for TLS. The patients doctor may give medicine to help prevent TLS. Patients must tell their doctor right away if they have any of the following signs or symptoms of TLS:

The patients doctor will stop treatment with Rituxan if they have severe, serious, or life-threatening side effects.

What are the most common side effects during treatment with Rituxan?

Other side effects include:

These are not all of the possible side effects with Rituxan.

Please see the Rituxan full Prescribing Information, including the Medication Guide, for additional Important Safety Information at http://www.Rituxan.com.

Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Gazyva Indications

Gazyva (obinutuzumab) is a prescription medicine used:

Important Safety Information

The most important safety information patients should know about Gazyva

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that can become serious or life threatening, including:

Who should not receive Gazyva:

Patients should NOT receive Gazyva if they have had an allergic reaction (e.g., anaphylaxis or serum sickness) to Gazyva. Patients must tell their healthcare provider if they have had an allergic reaction to obinutuzumab or any other ingredients in Gazyva in the past.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effect they experience. Gazyva can cause side effects that may become severe or life threatening, including:

The most common side effects of Gazyva in CLL were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

The safety of Gazyva was evaluated based on 392 patients with relapsed or refractory NHL, including FL (81 percent), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which Gazyva is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of side effects that were seen were consistent with the overall population who had NHL. The most common side effects of Gazyva were infusion reactions, low white blood cell counts, nausea, fatigue, cough, diarrhea, constipation, fever, low platelet counts, vomiting, upper respiratory tract infection, decreased appetite, joint or muscle pain, sinusitis, low red blood cell counts, general weakness, and urinary tract infection.

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of Gazyva as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86 percent) or marginal zone lymphoma (14 percent). The most common side effects of Gazyva were infusion reactions, low white blood cell count, upper respiratory tract infection, cough, constipation and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Patients should tell their doctor about any side effects.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088, or http://www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please visit http://www.Gazyva.com for the Gazyva full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, were investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit http://www.gene.com/hematology.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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Genentech Announces New Data Reinforcing the Long-Term Benefit of Venclexta-Based Combination for People With Relapsed or Refractory Chronic...

Medicare provides coverage options for people with cystic fibrosis who are aged 65 years and older or receive Social Security disability insurance payments.

Cystic fibrosis (CF) is a severe and potentially life threatening disease. People with CF have abnormally thick and sticky mucus that can clog their lungs and make it difficult to breathe.

More than 30,000 people in the United States live with CF, and there is currently no cure.

This article explores Medicare coverage for CF medication and other treatments. It also looks at the costs and the financial assistance that may help.

We may use a few terms in this piece that can be helpful to understand when selecting the best insurance plan:

CF is a hereditary disease that occurs when a person inherits two defective genes one from each biological parent.

It primarily affects the lungs and pancreas, making the mucus in the lungs thicker and stickier than normal. The thick mucus can reduce the effectiveness of a persons airways, leading to infection and inflammation. Over time, CF can lead to respiratory failure.

The abnormal amount of thick mucus also prevents a persons pancreas from releasing digestive enzymes. Without these enzymes, a person cannot absorb nutrients and may become malnourished. The excess mucus can also cause liver disease by blocking the bile duct in the liver.

There are different tests to diagnose CF, and a doctor will screen newborn babies for the condition. The Cystic Fibrosis Foundation (CFF) note that most people receive a diagnosis of the condition by the age of 2 years. Other tests may include a genetic or carrier test, a sweat test, and an evaluation at a healthcare clinic that the CFF have accredited.

Federally funded Medicare is a health insurance program for older people in the U.S. Some people with disabilities also benefit from Medicare.

The program has four parts, each of which offers coverage for some CF-related services:

If someone with CF needs care in an inpatient facility, hospital, or clinic, Medicare Part A covers some of these costs.

For example, if a person needs CF-related treatment, such as a blood transfusion, or a surgical procedure, such as a lung transplant, Part A covers the services. If the person needs hospice or home healthcare, Part A is also the coverage provider.

Learn more about Part A coverage here.

Medicare Part B covers doctors visits, diagnostic and laboratory tests, and other outpatient procedures. If a doctor recommends that a person with CF receive physical therapy, such as pulmonary rehabilitation, Part B covers this service.

Another item that Part B covers is a nebulizer, as long as a doctor has prescribed the device for a medically approved reason, such as CF. Medicare considers a nebulizer to be durable medical equipment (DME). Therefore, it covers 80% of the cost of the equipment and the nebulized CF medications.

Learn more about Part B coverage here.

Private insurance companies provide Medicare Advantage plans as an alternative to original Medicare. Legally, these plans must have the same coverage as original Medicare, and they often also include other benefits, such as prescription drug coverage and dental, vision, and hearing care.

A person enrolled in a Medicare Advantage plan may have to use the plan providers specific network of doctors and hospitals for CF treatment.

Learn more about Medicare Advantage here.

Private insurance companies provide stand-alone Part D plans to people with original Medicare. The plans offer coverage for prescription drugs and cover the cost of regular medication, as long as a doctor has prescribed it.

Part D plans use a formulary that lists the covered drugs. A person can use this online tool to check whether their chosen Plan D plan formulary includes their medication.

Learn more about Part D plans here.

At this time, there is no cure for CF, and treatments aim to help people manage the symptoms and live a healthier life. According to the CFF, there are several options, including medication, nutritional therapies, and fitness routines.

Some of the available options include:

CF transmembrane conductance regulator (CFTR) modulator therapies are newer medications that target the faulty gene causing CF and encourage the correct balance of salt and fluids in the lungs, which thins the mucus.

A doctor may advise a person with CF to have a lung transplant. However, the process includes an evaluation and a significant amount of planning and preparation.

The Food and Drug Administration (FDA) have approved Kalydeco and Orkambi for children with CF who are 2 years of age and older. They have also approved Symdeko for those older than 5 years and Trikafta for those aged 12 years and older.

The cost of CF treatment varies considerably according to the individuals needs. Medicare costs may include premiums, deductibles, copays, and coinsurance.

Most people do not pay a premium for Part A, as long as they have paid Medicare taxes for 40 or more quarters. However, if a person has to pay the premium, the cost in 2021 ranges from $259 to $471.

If a person needs inpatient care in a hospital or clinic, Medicare Part A covers the cost. However, a person must meet the deductible of $1,484 (in 2021) before Medicare contributes. Medicare assesses the deductible per benefit period, which starts when someone enters the hospital and lasts for 60 days.

The Part B basic premium for 2021 is $148.50. A person with an annual income level above $88,000 may have a higher premium, ranging from $207.90 to $504.90.

Part B covers 80% of a persons outpatient healthcare costs.

Advantage plan costs vary depending on several factors, including location, coverage, and a persons age. However, in addition to the plans costs, a person will pay the basic Part B premium.

Learn more about Advantage plan costs here.

Part D costs vary among plans. Monthly premiums are based on income, and Medicare uses the adjusted gross income from a persons tax returns to assess the premium. A person may also pay an adjusted monthly fee.

Learn more about Part D costs here.

Some programs, including Medigap, Medicaid, and Extra Help, may help cover a persons out-of-pocket expenses.

This supplementary insurance helps people pay for some out-of-pocket Medicare expenses, such as copays, deductibles, and coinsurance. Private insurance companies provide 10 Medigap plans with different coverage levels. The costs depend on location and vary among plans.

Learn more about Medigap here.

Medicaid is a government program to assist people with a low income and few resources. The criteria to qualify for the program vary among states.

Learn more about Medicaid here.

Federally funded Medicare Extra Help is sometimes known as Part D low income subsidy. It assists a person on a low income in meeting the costs of Medicare prescription drugs. The Social Security Administration (SSA) oversee the program.

Learn more about Extra Help here.

Cystic fibrosis is an inherited genetic condition that causes lung dysfunction and related issues.

Medicare covers most of the costs of inpatient and outpatient care for CF after a person has met the annual deductible. Medicare Part D and Advantage plans may also cover costs.

The information on this website may assist you in making personal decisions about insurance, but it is not intended to provide advice regarding the purchase or use of any insurance or insurance products. Healthline Media does not transact the business of insurance in any manner and is not licensed as an insurance company or producer in any U.S. jurisdiction. Healthline Media does not recommend or endorse any third parties that may transact the business of insurance.

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Medicare and cystic fibrosis: Coverage, options, treatments, and costs - Medical News Today

Medicine is ever-evolving on a daily basis. Keeping track of the changes can be an almost-full-time job.Stacker looked at a number of medical journals and media sources to discover the biggest breakthroughs the year you were born, from 1921 to the current day.

From diseases that have been around for decades, such as diabetes and the flu, to cutting-edge tools like artificial intelligence and 3D printing, explore how medical and scientific professionals continually conduct research and clinical trials to improve the lives of patients. Sometimes advances arent immediately adopted, as with the Pap smearthat wasnt integrated into womens health care for 16 years after it was invented. But other times the path from laboratory to everyday use is much more abbreviated, like with insulin, which was used to treat diabetes only a year after it was discovered.

Another recurring theme in medical history is the repurposing of medicines that have worked for one disease in the past, to see how theyll work with another. A number of drugs and vaccines are being re-explored to manage COVID-19. Not all the heroes of medical research come from a traditional backgroundone was an electric engineer who worked for a major record label. Some were recognized with the highest honors, but others still have little visibility decades after their death. Funding for the research behind the breakthroughs is always a considerationsometimes it comes from foundations and government entities, but other times via donations from individuals and enterprises.

The dark side of medical history shown here includes unethical behavior by researchers in the past, which explains why some in the Black community arent exactly early adopters when it comes to clinical trials and new treatment options.

Advances noted here focus not only on the body, but also the mind. Explore this slideshow to see all the ways that health care has changed over the past century.

You may also like: Countries with the best life expectancy

See the rest here:
Medical history from the year you were born - The Elkhart Truth

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About nine years ago, California-based longhaul truck driver Richard Hall was in for a big surprise when he got his first Department of Transportation medical exam.

You should be in a coma, the medical examiner said, looking at the results of Halls bloodwork. He told me my blood sugar level was 392, and that Im diabetic.

Needless to say Hall, 50, a former physically active construction worker before becoming a truck driver, was shocked. Like many truck drivers, Hall had no idea he was diabetic, or that his blood sugar levels were dangerously high.

Nine years ago, Richard Hall was suprised to learn he had Type 2 diabetes.(Courtesy Hall)

Doctors and diabetes experts say Hall is one of a growing number of truck drivers and Americans in general who either have no clue they have Type 2 diabetes by far the most common form of diabetes or might be ignoring some of the more common signs of the so-called lifestyledisease. Unfortunately, even some drivers who have been diagnosed with diabetes are taking chances by not watching their weight, not eating right and not exercising, according to experts.

Diabetes is a disease in which the bodys ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose-surge in the blood and urine. It can be detected in a urine or blood test, or at home by pricking a finger, putting a drop of blood onto a test strip, and inserting it into a glucose monitor.

Early on, youll feel fine, until one day, boom, your body is going to crash, said Kay Pfeiffer, senior vice president at TrueLifeCare of Brentwood, Tenn., a firm that helps employers and employees wrestle with the impact of diabetes.

Pfeiffer

Medications are a temporary solution, Pfeiffer told Transport Topics. Diabetes not managed, sooner or later, something is going to happen.

For instance, untreated diabetes is one of the leading causes of blindness.

If blood sugar is too high for too long, you run the risk of having damage to the eyes, the kidneys and the heart, said Natalie Hartenbaum, a medical doctor and recognized expert in occupational fitness and truck driver health. Those that cant control their blood sugar will generally end up on insulin.

Hall says diabetes has not interfered with his driving. But he only drives about nine hours a day to avoid getting fatigued.

RELATED: Options Abound for Elevating Drivers Health and Wellness

Because of his diagnosis, Hall was only given a one-year medical card, rather than the two-year card that a healthier diver is typically given after passing a medical exam administered by one of the more than 50,000 certified Federal Motor Carrier Safety Administration examiners. About 43% of drivers have a medical certification of one year or less, according to David Thorpe, a Fayetteville, N.Y., chiropractor who has trained more than 5,000 FMCSA certified medical examiners in his career. Thorpe has focused his medical practice on drivers and occupational medicine for over 30 years.

Thorpe

So why is diabetes such a prominent issue among drivers? The answer is its a stressful job, a lot of time away from home, poor eating habits, drivers are notoriously overweight, and in poor health in general. Plus it's an aging population, Thorpe told TT.

Thorpe said that diabetic drivers can sometimes be managed without drugs, but its not uncommon for them to receive oral medications. Oftentimes they work very well, other times they dont, he said. Even when taking drugs, Type 2 diabetics need to take care of their health, Thorpe said.

Really, we dont know that much about Type 2 diabetes, Pfeiffer said.

The medical experts do know this: There is no cure for Type 2 diabetes. Its a disease that requires those who have it to eat healthy, keep their weight in check, and exercise. You have to get in front of diabetes. You have to have the will to manage diabetes, Pfeiffer, a former hospital nurse, told Transport Topics.

Type 1 diabetics, believed to be only about 5% of the U.S. diabetic population, are dependent on insulin to stay healthy and risk almost certain death if not taking it.

But in a way, Type 2 diabetics have a tougher battle ahead of them because they must radically alter their daily lives.

While about 7% to 10% of the U.S. population is believed to diabetic, a 2014 FMCSA survey of longhaul drivers self-reported higher rates of diabetes for drivers 14.1%. The study also concluded that the prevalence of obesity is more than twice as high (69% vs. 31%) in longhaul drivers as the general population, and the prevalence of morbid obesity is more than twice as high as well (17% vs. 7%).

About 25% of truck drivers over the age of 54 are diabetic, according to numbers compiled by TrueLifeCare.

This past June, an FMCSA-sponsored Virginia Tech Transportation Institute study, Commercial Driver Safety Risk Factors, used data from more than 21,000 drivers to help understand the impact of health and other challenges for those sitting behind the wheel.

While the study concluded that treated diabetic truck drivers are at no greater risk of accidents, it noted that those same treated drivers were 38% more likely to be convicted of a moving violation compared to drivers who do not have diabetes or elevated blood sugar.

The study further concluded that diabetic drivers not being medicated for the disease had a threefold increased crash risk.

Larry Wolfe, retired medical doctor

While there are many good reasons for drivers such as Hall to keep their blood sugar in control, diabetes is an issue for the whole country, not just truck drivers, said Larry Wolfe, a retired medical doctor who specialized in endocrinology nearly his entire career. Wolfe was a staff doctor at the Vanderbilt University Diabetes Center for 10 years.

Its almost an epidemic, he told TT. Truck drivers tend to be obese, dont exercise, they eat wrong, so their diabetes is a real problem to manage, even under the best of circumstances. The major fear always was that they could experience hypoglycemia and lose consciousness while they are driving.

The common signs of Type 2 diabetes include profuse sweating, irritability, a lack of coordination, blurry vision and shaky hands. Ignoring the signs of Type 2 diabetes can lead to ulcers on the feet or legs that can ultimately result in amputations.

Pfeiffer said when some drivers feel symptoms of the disease, they sometimes stop at a convenience store and get a Coke.

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Theyll say to themselves, Ive gotten used to it, she said. But its very, very dangerous.

Thats why Hall, who spends three months at a time away from home hauling dry goods across much of the country in his tractor-trailer, says he tries to eat mostly chicken and fish and avoids sweets to do the best job he can to control his blood sugar. And when he gets home, he visits his doctor.

To get exercise, I even walk around the truck three times to do my pre-trip, Hall said. The last time he checked his blood sugar level, it was 182, a little high, but he has registered up to 249. The American Diabetes Association (ADA) says a normal blood sugar reading for an individual fasting is 100 or lower. If the level is 126 or higher after fasting for eight hours or more, a person could be diabetic.

There also is another problematic issue related to diabetes: It adds costs to an employers bottom line, according to the most recent diabetes report by the Health Care Cost Institute. The per capita annual spend in 2014 for people with diabetes enrolled in employer health plans was $16,021 (combined employer and employee). Thats nearly four times the $4,396 per capita spend for health plan members without diabetes.

How did turkey-to-table change this year? What obstacles were suppliers going through to get turkeys to grocery stores? Join us as we talk with J.J. Smith, President of Valley Proteins, about how staying open-minded and flexible helped his business of delivering turkeys persevere.Hear a snippet, above, and get the full program by going to RoadSigns.TTNews.com.

The ADA states that people with diabetes typically will experience three additional days of absenteeism and have 12 days of lost productivity each year associated with the disease.

Diabetes goes along with the epidemic of obesity, Wolfe said. And unfortunately, we wont be able to get a good handle on the treatment of Type 2 diabetes until we get a handle on how to treat obesity. Thats the real problem that we dont know how to get people to lose weight. If we could, there would be a whole lot less Type 2 diabetes.

Wolfe said a person can have Type 2 diabetes for 10 years and not know it. Since it is possible for drivers to not have symptoms, the easiest thing for some of them to do is deny having the disease. Its a very frustrating practice to take care of truck drivers, he said.

Wolfe added, Its a disease where the patient has to assume a lot of the responsibility for treatment. Its a complicated disease because it requires you to think about it every day of your life. If you dont take it seriously, no doctor in the world is going to help you.

What was really sad for me as a physician was when the poor patient was in the position of having to choose between his health and making a living, Wolfe said.

From a regulatory standpoint, FMCSA relies on a drivers treating physician and the medical examiners to ensure that drivers who take insulin and those who dont take it all have a stable medication and treatment regimen prior to medically qualifying them to get a medical card.

Federal regulations require that insulin-treated diabetics fill out an assessment form in which the drivers treating clinician must attest that the driver has a stable insulin regimen and well-controlled diabetes. The form poses a series of diabetes management-related questions that can aid the medical examiner in deciding if a driver is fit to get behind the wheel.

Hartenbaum

Hartenbaum said she believes that since there are no specific federal guidelines for medical examiners, the so-called best practices used by medical examiners to qualify a driver can vary.

Because of the lack of specific federal guidance, Hartenbaum said she is very concerned that there may be an increased crash risk for diabetics. But it hasnt shown up yet, she said.

FMCSA doesnt monitor medical conditions, Hartenbaum said. They dont monitor sleep apnea, they dont monitor blood pressure, they dont monitor heart disease. They have medical standards and medical guidelines. But its up to the medical examiner to evaluate whether the individual is at risk of sudden or gradual incapacitation due to a medical condition, and whether a study is needed to evaluate that.

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Diabetes: The Bump in the Road for the Longhaul Truck Driver - Transport Topics Online

In 1992 when investigators began testing trastuzumab (Herceptin) in women with HER2-positive breast cancer, many observers predicted failureand they kept on predicting failure throughout the trial process. Even after the FDA approved the drug in 1998, some observers scoffed at the modest survival benefit it had demonstrated to that point and predicted that targeted therapy would never be a major form of cancer treatment. There was a great deal of skepticism about targeted monoclonal antibodies back in the 1990s. People didnt believe that it would be possible to make antibodies that bound specifically to cancer cells or, if it was possible, that the antibodies would kill the cancer cells. Its hard to imagine now, but those first trastuzumab trials I did in the mid-90s were actually controversial, said Howard A. Skip Burris III, MD, president of clinical operations and chief medical officer at Sarah Cannon in Nashville, Tennessee.

It wasnt until the subsequent trials that used trastuzumab in women with early-stage breast cancers, trials that showed a much bigger survival benefit than the trials in metastatic cancers, that everyone saw trastuzumab as a major breakthrough, and many people realized that targeted therapies might proliferate quickly, he said.

There was, of course, reason for skepticism. A small number of successful targeted therapies existed longbefore trastuzumab, but none of them launched a new class of cancer treatments that successfully fought a wide range of tumor types.

Indeed, physicians have known since the 1940s that iodine-131 therapy can selectively target thyroid cancer and that androgen deprivation therapy can selectively target prostate cancer. Hormone deprivation did find one other major use in the 1970s, when tamoxifen (Soltamox) was approved for hormone receptorpositive breastncancer, but neither iodine-131 nor any other elemental radioisotopes have become major treatment types.

Thus, many people doubted that the approval of the first 2 monoclonal antibodies, trastuzumab and rituximab (Rituxan), signified an explosion in new targeted therapies, and if not for rapid advances in genetics, proteomics, and molecular synthesis, the doubters may have been right.

But the 2001 approval of a third novel targeted therapy, imatinib mesylate (Gleevec), turned many skeptics into believers. Unlike trastuzumab and rituximab, imatinib is a small molecule drug, but it is a highly specific inhibitor of tyrosine kinase enzymes that are overactive in a number of cancers that are Philadelphia chromosome positive. It was also obvious, from the very first trials, that imatinib was an incredibly effective treatment, particularly for chronic myelogenous leukemia (CML). A phase 1 trial launched in 1998 reported that the drug caused CML to quickly disappear in the vast majority of patients with early-stage disease, and a 5-year follow-up found that 98% of patients were still in remission.1

Within a decade of trastuzumabs initial approval, the FDA approved another 23 targeted cancer therapies. More than 80 targeted cancer therapies are now available to patients.2

Its been an amazingly rapid proliferation, and its happened because weve made huge technical advances on 2 distinct fronts, Burris said. When trastuzumab arrived, we were still working to sequence one human genome at a cost of many billions of dollars. Systematically analyzing tumors for druggable driver mutations seemed unrealistically expensive, but then, over the course of just a few years, the technology became so much faster and so much cheaper that it was entirely feasible. The other big advance has been on the chemistry side. Pharmaceutical and biotech companies have gotten much better at creating molecules that will bind to their intended targets. Better chemistry has allowed medications to bind to many targets like KRAS that were once considered undruggable.

Monoclonal Antibodies

The first attempt to develop a targeted monoclonal antibody treatment for cancer dates back to 1980, when a team led by Lee Marshall Nadler, MD, treated a patient affected by non-Hodgkin lymphoma with the murine monoclonal antibody AB 89. The treatment, however, did not produce a significant clinical response.3

Several other research groups tested monoclonal antibodies against hematological cancers over the next decade, but none of them worked well enough for FDA approval. In fact, many of these murine formulations induced immune reactions that both created adverse effects and reduced therapeutic half-life.4

The first monoclonal antibody to demonstrate itself safe and effective enough for FDA approval was rituximab, which kills B cells by targeting the surface antigen CD20. The drug, which was first approved in 1997 for B-cell lymphoproliferative disorders, is currently indicated, alone or in various combinations, to treat forms of non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Trastuzumab, which was approved a year later, is a genetically engineered, humanized monoclonal antibody that fights cancer 2 ways. First, it inhibits HER2, a glycoprotein receptor with tyrosine kinase activity that promotes breast cancer cell growth. Second, it induces cancer cell death via antibodydependent cell-mediated cytotoxicity.

Trastuzumab was developed at the University of California, Los Angeles (UCLA) by a team led by Dennis Slamon, MD, PhD. Slamon identified the HER2-positive subtype of breast cancer in the early 1980s, demonstrated that this subtype was particularly deadly and aggressive, and hypothesized that a HER2 inhibitor would extend life. The team spent several years developing drug candidates, and the very first human trials were conducted at UCLA in 1990.

Trastuzumab has since shown significantand often dramaticbenefit when used in a variety of ways against HER2-positive breast cancer. For example, a 2005 trial of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer found that after a median follow-up of one year, 1693 women assigned to the observation group had nearly twice as many events (recurrence, contralateral breast cancer, second nonbreast malignant disease, or death) as the 1694 women assigned to the trastuzumab group.5

In the early 1990s, women with the HER2-positive subtype had an average life expectancy after diagnosis of 3 to 5 years. Today, an estimated 3 million patients have an average life expectancy of 7 to 10 years, thanks largely to receiving trastuzumab.6

The next targeted therapy to reach patients was gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (TKI) approved in 2003 for the treatment of nonsmall cell lung cancer (NSCLC). Studies published the following year showed that a particular subset of patients with EGFR mutation positive NSCLC were far more likely than others to respond to gefitinib7 and a second EGFR TKI approved in 2004, erlotinib (Tarceva).8

The phase 3 trial that led to erlotinibs approval found that only 8.9% of patients responded to the drug and that it increased median overall survival (OS) by just 2 months to 6.7 months,9 but the subgroup analysis found traits ranging from female sex to never smoking to EGFR expression that predicted response.

Later research demonstrated that EGFR TKIs greatly increase survival in patients with EGFR-positive NSCLC. Combination chemotherapy in advanced NSCLC typically results in a median OS of 8 to 12 months and a median progression-free survival (PFS) of 5 to 6 months.10 Among 137 patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009, however, median PFS and OS were 12.1 months and 30.9 months, respectively. Twenty patients (14.6%) were 5-year survivors.11

Even though targeted therapies had already proven themselves effective against other tumor types, especially imatinib against CML, a lot of people were still skeptical that they would work against lung cancer, said Paul Bunn, MD, distinguished professor of medicine-medical oncology and the James Dudley Chair in Cancer Research at the University of Colorado School of Medicine in Aurora, Colorado. But the skeptics were quickly silenced. The trial results were pretty convincing.

Shortly after the FDA approved erlotinib, it also approved bevacizumab (Avastin), the first example of another novel form of targeted therapies called antiangiogenics, which are designed to deprive tumors of blood.

Many targeted therapies were conceived long before they were approved, including antiangiogenics. The idea of fighting cancer by starving tumors of blood first occurred to Judah Folkman, MD, in 1963, when he and Fred Becker, MD, were comparing possible substitutes for blood transfusions. During those experiments, the 2 young doctors injected adult mouse melanoma cells into isolated, perfused thyroid glands taken from dogs and noticed that while tumors did form, they never developed blood vessels or grew beyond 2 mm in diameter.12

Other investigators had already made similar observations, but Folkmans efforts to understand his findings led him to complete a few more experiments and then to hypothesize, via a 1971 piece in the New England Journal of Medicine, 13 several very new ideas:

The paper drew such negative response that it quickly made Folkman a pariah.

The approval of bevacizumab in 2004 was a triumph for Folkman, but because he died in 2008, he did not live long enough to see how broadly the use of antiangiogenics would expand. Bevacizumab alone is now approved as monotherapy or in combination with other medications to treat 7 different tumor types,14 and more than a dozen other angiogenesisinhibiting medications have subsequently been approved as cancer treatments.15

Many of them work by binding to VEGF, preventing it from activating the VEGF receptor, and blocking the formation of new blood vessels. The first 2 approved drugs that targeted this pathway were sorafenib (Nexavar), which was approved in 2005, and sunitinib malate (Sutent), which was approved in 2006.16,17

Oddly, an antiangiogenic drug had already been approved for use in most of the world (just not the United States) slightly before Folkman first devised the idea in 1963, but it was approved to treat sleeplessness and morning sickness rather than cancer. That drug, of course, was thalidomide (Synovir, Thalomid), which was later approved to treat multiple myeloma, many decades after the discovery that it causes birth defects.

Molecules that inhibit PARPs, which play a major role in DNA damage repair, were another form of targeted therapy that existed long before FDA approval to treat cancer. PARP-inhibiting substances, such as nicotinamide, have been used for various indications over the decades. In the 1970s, some thought these substances might prime patients for better response to chemotherapy or radiation.18

The FDA, however, did not support a PARP inhibitor for cancer treatment until 2014, when it approved olaparib (Lynparza) for advanced ovarian cancer with a deleterious or suspected deleterious germline BRCA mutation.19 It has since approved more PARP inhibitors, including rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) across a wide variety of tumors, including metastatic prostate cancer and certain subtypes of breast cancer (TABLE19-22).20-22

Immunotherapies are another type of targeted cancer treatment that were hypothesized many decades before they were realized. A German physician working in the mid-19th century noticed that tumors tended to regress when cancer patients were infected by erysipelas, so in 1868, he intentionally infected a patient with erysipelas to treat their cancer.23

In the 19th century, the American doctor William Coley began directly injecting tumors with mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens. He reported more than 1000 regressions or cures over the course of his career, but he was poorly esteemed among researchers of the day and his findings were largely ignored.24

The work that laid the foundation for todays immunotherapies took place in 1982, nearly a century after Coleys first efforts at immunotherapy, when James Allison, PhD, and colleagues identified and described tumor-specific antigens in a mouse model of T-cell lymphoma. 25 A year later, they described the first T-cell antigen receptor.

The first immune checkpoint molecule was discovered in 1987 and named CTLA-4. Just one year later, the first CTLA-4blocking antibody was discovered, and in 2011, the first CTLA-4blocking drug, ipilimumab (Yervoy), was approved by the FDA.26

The sheer number of targeted therapies that have been approved in the [past] 20 years is amazing, even if youre just looking at my specialty of lung cancer, said Bunn, who is a past president of the American Society of Clinical Oncology. And thanks to those treatments, along with earlier diagnosis, survival rates have improved considerably, from roughly 4 to 6 months untreated to a year with chemotherapy to 5 years or more with TKIs. But theres still work to be done because neither the TKIs nor the immunotherapies, or anything else, tends to produce complete responses or absolute cures. We need to find things we can pair with TKIs to kill the cancer cells they dont, and there are a large number of combinations that are currently being investigated.

Burris is also excited to see so many new targeted treatmentsand combinations of targeted treatmentsin trials right now. He is particularly optimistic about antibody-drug conjugates, therapies that combine antibodies that bind to tumors with a second agent that attacks the tumor. The most successful such product may be ado-trastuzumab emtansine (Kadcyla), which combines trastuzumab with a cytotoxic drug thats released after the molecule binds to the cancer.

When you see what big pharmaceutical companies are paying to acquire the makers of antibody- drug conjugates, you get a good sense of how promising the technology is, Burris said. The technology for binding the antibody and the cytotoxic agent, for getting the antibody to bind with the tumor, and for releasing the cytotoxic agent at the right time all keep improving. This is a promising strategy for attacking a wide range of tumors that dont have a druggable driver mutation.

References:

1. Druker BJ, Guilhot F, OBrien SG, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J. Med. 2006;355(23):2408-2417. doi: 10.1056/NEJMoa063867

2. Targeted therapies: overview of targeted therapies for cancer. My Cancer Genome. Updated May 27, 2019. Accessed November 2, 2020. https://bit.ly/385txmr

3. Nadler LM, Stashenko P, Hardy R, et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 1980;40(9):3147-3154.

4. Dillman RO, Beauregard JC, Halpern SE, Clutter M. Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies antibodies. J Biol Response Mod. 1986;5(1):73-84.

5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. doi:10.1056/NEJMoa052306

6. UCLA oncologist Dennis Slamon wins 2019 Lasker Award for clinical medical research. UCLA newsroom. September 9, 2019. Accessed November 2, 2020. https://bit.ly/2TKzvkt

7. Paez JG, Jnne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314

8. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144. doi:10.1056/NEJMoa050736

9. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med. 2005;353(2):123-132. doi:10.1056/NEJMoa050753

10. Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced nonsmall- cell lung cancer. N Engl J Med. 2002;346(2):92-98. doi:10.1056/NEJMoa011954

11. Lin JJ, Cardarella S, Lydon CA, et al. Five-Year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol. 2016;11(4):556-565. doi:10.1016/j.jtho.2015.12.103

12. Folkman J, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453-467. doi:10.1002/1097-0142(196304)16:4<453::aid-cncr2820160407>3.0.co;2-y

13. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186. doi:10.1056/NEJM197111182852108

14. Bevacizumab. National Cancer Institute. October 5, 2006. Updated September 10, 2020. Accessed November 2, 2020. https://bit.ly/2TKcNcn

15. Angiogenesis inhibitors. National Cancer Institute. Updated April 2, 2018. Accessed November 2, 2020. https://bit.ly/325ldQ0

16. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2010. Accessed November 2, 2020. https://bit.ly/360eQid

17. Sutent. Prescribing information. Pfizer Inc; 2011. Accessed November 2, 2020. https://bit.ly/2I0jzbr

18. Clark JB, Ferris GM, Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5-methyl nicotinamide. Biochim Biophys Acta. 1971;238(1):82-85. doi:10.1016/0005-2787(71)90012-8

19. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA. Updated August 17, 2017. Accessed November 3, 2020. https://bit.ly/324l5Ah

20. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed November 3, 2020. https://bit.ly/34Pzsu7

21. Niraparib (Zejula). FDA. Updated May 30, 2017. Accessed November 2, 2020. https://bit.ly/36bQT7J

22. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Updated December 14, 2018. Accessed November 2, 2020. https://bit.ly/3jUsp7r

23. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger).

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A Look Back Prompts Memories of Initial Skepticism for Targeted Agents Shattered by Positive Efficacy Trials - Targeted Oncology

Abstract

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cellderived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.

Remyelination occurs in multiple sclerosis (MS) lesions but its capacity decreases over time (13). Failed remyelination in MS leads to altered conduction followed by axon degeneration, which, in the long run, results in severe and permanent neurological deficits (4). MS lesions may or may not harbor immature oligodendroglia (oligodendrocyte progenitors and pre-oligodendrocytes), with these cells failing to differentiate into myelin-forming cells, suggesting that oligodendrocyte differentiation is blocked (57). So far, the mechanism underlying this block is poorly understood. It may result from adverse environmental conditions or the failed capacity of oligodendrocyte progenitors/pre-oligodendrocytes to migrate or mature efficiently into myelin-forming cells or even a combination of these conditions, all of which may worsen with aging. It has been shown that increasing remyelination either through manipulating the endogenous pool (8, 9) or by grafting competent myelin forming oligodendroglia (10, 11) or both (12) can restore the lost axonal functions, improve the clinical scores, and protect from subsequent axonal degeneration in experimental (13, 14) or clinical (3) settings.

There are multiple ways to investigate the oligodendroglial lineage in disease. Cells can be studied in postmortem tissue sections or purified from postmortem adult human brain for in vitro and transcriptomic/proteomic analysis. In this respect, in vitro experiments highlighted the heterogeneity of the adult human oligodendrocyte progenitor population in terms of antigen and microRNA expression, suggesting that remyelination in the adult human brain involves multiple progenitor populations (15). Moreover, single-cell transcriptomics characterized in detail the heterogeneity of human oligodendroglial cells, emphasizing changes in MS, with some subpopulations expressing disease-specific markers that could play a role in disease onset and/or aggravation (16, 17).

Yet, this MS signature could preexist or be acquired early at disease onset. Moreover, most of these MS postmortem analyses or experimental models cannot overlook the involvement of extrinsic factors such as immune factors that might add more complexity toward understanding the behavior of MS oligodenroglial cells.

Little is known about the biology of the MS oligodendroglial lineage, primarily due to the impossibility, for ethical reasons, to harvest oligodendroglial populations from patients and study the diseased cells and their matching controls in vitro or in vivo after cell transplantation. While cell-cell interactions and cell heterogeneity in diseased conditions generate more complexity when comparing control and pathological samples, the induced pluripotent stem cell (iPSC) technology provides a unique opportunity to study homogeneous populations of human oligodendroglial cells and gain further insights into monogenetic diseases and multifactorial diseases, such as MS. The iPSC technology has unraveled differences in oligodendroglia biology, in Huntingtons disease (18), and schizophrenia (19, 20), indicating that these cells can contribute autonomously to multifactorial diseases outcome. However, so far, little is known about the potential contribution of MS oligodendroglia to failed remyelination. While senescence affects iPSCneural precursor cells (NPCs) derived from patients with primary progressive MS (PPMS) (21), only few preliminary reports alluded to the fate of PPMS (22, 23) or relapsing-remitting (RRMS) (24) iPSC-derived oligodendroglia after experimental transplantation and did not study per se their capacity to differentiate into functional myelin-forming cells. We exploited a robust approach (25) to generate large quantities of iPSCs-derived O4+ oligodendroglial cells from skin fibroblasts (hiOLs) of three RRMS and three healthy subjects, including two monozygous twin pairs discordant for the disease. As a critical feature of the pluripotent-derived cells should be their ability to fully integrate and function in vivo, we compared the capacity of healthy and MS-hiOL derivatives to integrate and restore axo-glial and glial-glial functional interactions after engraftment in the developing dysmyelinated murine central nervous system (CNS). Our data show that in noninflammatory conditions, the intrinsic properties of iPSC-oligodendroglial cells to differentiate, myelinate, and establish functional cell-cell interactions in vivo are not altered in MS, making them candidates of interest for personalized drug/cell therapies as pluripotency maintains MS oligodendroglial cells in a genuine nonpathological state.

Fibroblasts were isolated from three control and three patients with MS and reprogrammed into iPSC. Pluripotent cells were differentiated into NPCs and further into O4+ hiOLs for 12 days in vitro under glial differentiation medium (GDM) conditions as previously described (25). hiOL cells were selected using flow cytometry for O4 before transplantation. Because our aim was to study the intrinsic properties of MS cells, we chose to engraft O4+ hiOLs in the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects.

We first questioned whether MS-hiOLs differed from control-hiOLs wild type (WT) in their capacity to survive and proliferate in vivo. To this aim, we grafted MS- and control-hiOLs in the forebrain of neonatal Shi/Shi:Rag2/ mice. MS cells engrafted (one injection per hemisphere) in the rostral forebrain, spread primarily through white matter, including the corpus callosum and fimbria, as previously observed using control human fetal (11, 26, 27) and iPSC (25, 28) progenitors. With time, cells also spread rostrally to the olfactory bulb and caudally to the brain stem and cerebellum (fig. S1). Examining engrafted brains at 8, 12, and 16 weeks postgraft (wpg), we found that MS-hiOLs expressing the human nuclear marker STEM101 and the oligodendroglial-specific transcription factor OLIG2 maintained a slow proliferation rate at all times (5 to 19% of STEM+ cells), with no difference in Ki67+ MS-hiOLs compared to control (Fig. 1, A and C). Moreover, immunostaining for cleaved Caspase3 at 8 wpg indicated that MS cells survived as well as control-hiOLs (Fig. 1, B and D). Evaluation of the cell density of human cells based on STEM positivity at each stage revealed no significant difference between grafted MS-hiOLs and control cells (fig. S2).

(A and C) Immunodetection of the human nuclei marker STEM101 (red) combined with OLIG2 (green) and the proliferation marker Ki67 (white) shows that a moderate proportion of MS-hiOLs sustains proliferation (empty arrowheads in the insets) following transplantation in their host developing brain, with no significant difference in the rate of proliferation between MS- and control-hiOLs over time. (B and D) Immunodetection of the apoptotic marker Caspase3 (green) indicates that MS-hiOLs survive as well as control-hiOLs 8 wpg. Two-way analysis of variance (ANOVA) followed by Tukeys multiple comparison or Mann-Whitney t tests were used for the statistical analysis (n = 3 to 4 mice per group). Error bars represent SEMs. H, Hoechst dye. Scale bars, 100 m.

Because MS-hiOLs and control cells proliferated and survived to the same extent, we next questioned whether their differentiation potential into mature oligodendrocytes could be affected. We used the human nuclei marker STEM101 to detect all human cells in combination with SOX10, a general marker for the oligodendroglial lineage, and CC1 as a marker of differentiated oligodendrocytes. We found that the number of MS oligodendroglial cells (SOX10+) increased slightly but significantly with time, most likely resulting from sustained proliferation (Fig. 2, A and B). Moreover, they timely differentiated into mature CC1+ oligodendrocytes with a fourfold increase at 12 wpg and a fivefold increase at 16 wpg when compared to 8 wpg and with no difference with control-hiOLs (Fig. 2, B and C).

(A) Combined immunodetection of human nuclei marker STEM101 (red) with CC1 (green) and SOX10 (white) for control (top) and MS-hiOLs (bottom) at 8, 12, and 16 wpg. (B and C) Quantification of SOX10+/STEM+ cells (B) and CC1+ SOX10+ over STEM+ cells (C). While the percentage of human oligodendroglial cells increased only slightly with time, the percentage of mature oligodendrocytes was significantly time regulated for both MS- and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 3 to 4 mice per group). Error bars represent SEMs. *P < 0.05 and ****P < 0.0001. Scale bar, 100 m.

The absence of abnormal MS-hiOL differentiation did not exclude a potential defect in myelination potential. We further investigated the capacity of MS-hiOLs to differentiate into myelin-forming cells. We focused our analysis on the core of the corpus callosum and fimbria. MS-hiOLs, identified by the human nuclear and cytoplasmic markers (STEM101 and STEM121), evolved from a bipolar to multibranched phenotype (Fig. 3A and fig. S3: compare 4 wpg to 8 and 12 wpg) and differentiated progressively into myelin basic proteinpositive (MBP+) cells associated, or not, with T-shaped MBP+ myelin-like profiles of increasing complexity (Fig. 3A and figs. S3 and S4B). Myelin-like profiles clearly overlapped with NF200+ axons (fig. S4A) and formed functional nodes of Ranvier expressing ankyrin G and flanked by paranodes enriched for CASPR (fig. S4B) or neurofascin (fig. S4C), as previously observed with control-hiOLs (25).

(A) Combined detection of human nuclei (STEM101) and human cytoplasm (STEM 121) (red) with MBP (green) in the Shi/Shi Rag2/ corpus callosum at 8, 12, and 16 wpg. General views of horizontal sections at the level of the corpus callosum showing the progressive increase of donor-derived myelin for control- (top) and MS- (bottom) hiOLs. (B) Evaluation of the MBP+ area over STEM+ cells. (C and D) Quantification of the percentage of (C) MBP+ cells and (D) MBP+ ensheathed cells. (E) Evaluation of the average sheath length (m) per MBP+ cells. No obvious difference was observed between MS and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 6 to 14 mice per group). Error bars represent SEMs. *P < 0.05, **P < 0.01, and ***P < 0.001. Scale bar, 200 m. See also figs. S3 and S5.

We further analyzed, in depth, the myelinating potential of MS-hiOLs, applying automated imaging and analysis, which provided multiparametric quantification of MBP as established in vitro (29) for each donor hiOL (three controls and three RRMS) at 4, 8, 12, 16, and 20 wpg in vivo (Fig. 3, B to D). We first examined the MBP+ surface area generated by the STEM+ cell population (Fig. 3B). While MS-hiOLs generated very low amount of myelin at 4 wpg, they generated significantly more myelin at 12, 16, and 20 wpg, with similar findings for control-hiOLs, highlighting the rapid progress in the percentage of myelin producing STEM+ cells in MS group over time. Detailed MBP+ surface area generated by the STEM+ cell population per donor is presented in fig. S5 and shows differences among hiOLs in the control and MS groups, respectively.

We also quantified the percentage of STEM+ cells expressing MBP and the percentage of MBP+ with processes associated with linear myelin-like features, which we called MBP+ ensheathed cells. Both parameters increased significantly with time for control-hiOLs, reaching a plateau at 16 wpg. The same tendency was achieved for MS-hiOLs with no significant differences between the control- and MS-hiOL groups (Fig. 3, C and D).

Myelin sheath length is considered to be an intrinsic property of oligodendrocytes (30). We analyzed this paradigm in our MS cohort at 12 and 16 wpg, time points at which sheaths were present at a density compatible with quantification. For those time points, we found that the average MS MBP+ sheath length was equivalent to that of control with 25.86 0.98 and 27.74 1.52 m for MS-hiOLs and 24.52 1.48 and 27.65 0.96 m for control-hiOLs at 12 and 16 wpg, respectively (Fig. 3F). In summary, our detailed analysis of immunohistochemically labeled sections indicates that MS-hiOLs did not generate abnormal amounts of myelin in vivo when compared to control-hiOLs.

Moreover, the myelinating potential of MS-hiOLs was further validated after engraftment in the developing spinal cord (4 weeks of age). Immunohistological analysis 12 wpg revealed that STEM+ cells not only populated the whole dorsal and ventral columns of the spinal cord with preferential colonization of white matter but also generated remarkable amounts of MBP+ myelin-like internodes that were found on multiple spinal cord coronal sections (fig. S6), thus indicating that their myelination potential was not restricted to only one CNS structure.

The presence of normal amounts of donor MBP+ myelin-like structures in the shiverer forebrain does not exclude potential structural anomalies. Therefore, we examined the quality of MS derived myelin at the ultrastructural level at 16 wpg in the Shi/Shi:Rag2/ forebrain. In the corpus callosum of both MS and control-hiOLs grafted mice, we detected numerous axons surrounded by electron dense myelin, which at higher magnification was fully compacted compared to the uncompacted shiverer myelin (Fig. 4, A to F) (25, 31). Moreover, MS myelin reached a mean g ratio of 0.76 1.15 comparable to that of control myelin (0.75 1.56) (Fig. 4G) and thus a similar myelin thickness. This argues in favor of (i) MS-hiOLs having the ability to produce normal compact myelin and thus its functional normality and (ii) a similar rate of myelination between the two groups and, consequently, an absence of delay in myelination for MS-hiOLs.

(A to F) Ultrastructure of myelin in sagittal sections of the core of the corpus callosum 16 wpg with control-hiOLs (A to C) and MS-hiOLs (D to F). (A and D) General views illustrating the presence of some electron dense myelin, which could be donor derived. (B, C, E, and F) Higher magnifications of control (B and C) and MS (E and F) grafted corpus callosum validate that host axons are surrounded by thick and compact donor derived myelin. Insets in (C) and (F) are enlargements of myelin and show the presence of the major dense line. No difference in compaction and structure is observed between the MS and control myelin. (G) Quantification of g-ratio revealed no significant difference between myelin thickness of axons myelinated by control- and MS-hiOLs. Mann-Whitney t tests were used for the statistical analysis of this experiment (n = 4 mice per group). Error bars represent SEMs. Scale bars, (A and D) 5 m , (B and E) 2 m, and (C and F) 500 nm [with 200 and 100 nm, respectively in (C) and (F) insets].

Myelin compaction has a direct impact on axonal conduction with slower conduction in shiverer mice compared to WT mice (10, 32). We therefore questioned whether newly formed MS-hiOLderived myelin has the ability to rescue the slow axon conduction velocity of shiverer mice in vivo (Fig. 5). As previously performed with fetal glial-restricted progenitors (11), transcallosal conduction was recorded in vivo at 16 wpg in mice grafted with MS- and control-hiOLs and compared with nongrafted shiverer and WT mice. As expected, conduction in nongrafted shiverer mice was significantly slower compared to WT mice. However, axon conduction velocity was rescued by MS-hiOLs and, to the same extent, by control-hiOLs.

(A) Scheme illustrating that intracallosal stimulation and recording are performed in the ipsi- and contralateral hemisphere, respectively. (B) N1 latency was measured following stimulation in different groups of Shi/Shi:Rag2/: intact or grafted with control or MS-hiOLs and WT mice at 16 wpg. MS-hiOLderived myelin significantly restored transcallosal conduction latency in Shi/Shi:Rag2/ mice to the same extent than control-derived myelin (P = 0.01) and close to that of WT levels. One-way ANOVA with Dunnetts multiple comparison test for each group against the group of intact Shi/Shi:Rag2/ was used. Error bars represent SEMs. *P < 0.05. (C) Representative response profiles for each group. Scales in Y axis is equal to 10 V and in the X axis is 0.4 ms.

Rodent oligodendrocyte progenitors and oligodendrocytes can be distinguished by cell stagespecific electrophysiological properties (33, 34). To assess the electrophysiological properties of oligodendroglial lineage cells derived from human grafted control- and MS-hiOLs, red fluorescent protein (RFP)hiOLs were engrafted in the Shi/Shi:Rag2/ forebrain and recorded with a K-gluconatebased intracellular solution in acute corpus callosum slices at 12 to 15 wpg (Fig. 6A). As previously described for rodent cells, hiOLs in both groups were identified by their characteristic voltage-dependent current profile recognized by the presence of inward Na+ currents and outwardly rectifying steady-state currents (Fig. 6B). We found that ~60 and ~44% of recorded cells were oligodendrocyte progenitors derived from MS and control progenies, respectively. No significant differences were observed in the amplitude of Na+ currents measured at 20 mV (Fig. 6D) or steady-state currents measured at +20 mV between MS- and control-derived oligodendrocyte progenitors (Isteady = 236.70 19.45 pA and 262.10 31.14 pA, respectively; P = 0.8148, Mann Whitney U test). We further confirmed the identity of these cells by the combined expression of SOX10 or OLIG2 with STEM101/121 and the absence of CC1 in biocytin-loaded cells (Fig. 6F, top). The remaining recorded cells (MS and control) did not show detectable Na+ currents after leak subtraction and were considered to be differentiated oligodendrocytes by their combined expression of SOX10, STEM101/121, and CC1 in biocytin-loaded cells (Fig. 6F, bottom). The I-V curve of these differentiated oligodendrocytes displayed a variable profile that gradually changed from voltage dependent to linear as described for young and mature oligodendroglial cells in the mouse (33). Figure 6C illustrates a typical linear I-V curve of fully mature MS-derived oligodendrocytes. No significant differences were observed in the amplitude of steady-state currents measured at +20 mV between MS- and control-derived oligodendrocytes (Fig. 6E). Overall, the electrophysiological profile of oligodendrocyte progenitors and oligodendrocytes derived from control and MS was equivalent and showed similar characteristics to murine cells (33, 34).

(A) Schematic representation of the concomitant Biocytin loading and recording of single RFP+ hiOL derivative in an acute coronal brain slice prepared from mice engrafted with hiOLs (control or MS) and analyzed at 12 to 14 wpg. (B and C) Currents elicited by voltage steps from 100 to +60 mV in a control-oligodendrocyte progenitor (B, left) and a MS-oligodendrocyte (C, left). Note that the presence of an inward Na+ current obtained after leak subtraction in the oligodendrocyte progenitor, but not in the oligodendrocyte (insets). The steady-state I-V curve of the oligodendrocyte progenitor displays an outward rectification (B, right) while the curve of the oligodendrocyte has a linear shape (C, right). (D) Mean amplitudes of Na+ currents measured at 20 mV in control and MS iPSCs-derived oligodendrocyte progenitors (n = 8 and n = 9, respectively, for four mice per condition; P = 0.743, Mann-Whitney U test). (E). Mean amplitudes of steady-state currents measured at +20 mV in control and patient differentiated iPSC-derived oligodendrocytes (n = 10 and n = 6 for 3 and four mice, respectively; P = 0.6058, Mann-Whitney U test). (F) A control iPSC-derived oligodendrocyte progenitor loaded with biocytin and expressing OLIG2, STEM101/121, and lacking CC1 (top) and an MS iPSCderived oligodendrocyte loaded with biocytin and expressing SOX10, CC1, and STEM101/121 (bottom). Scale bar, 20 m.

(A) Z-stack identifying a target and connected cell. One single grafted human RFP+ cell (per acute slice) was loaded with biocytin by a patch pipette and allowed to rest for 30 min. The white arrowheads and insets in (A) illustrate biocytin diffusion up to the donut-shaped tip of the human oligodendrocyte processes. Another biocytin-labeled cell (empty yellow arrowhead) was revealed at different morphological level indicating diffusion to a neighboring cell and communication between the two cells via gap junctions. (B and C) Split images of (A) showing the target (B) and connected (C) cell separately at different levels. Immunolabeling for the combined detection of the human markers STEM101/121 (red), OLIG2 (blue), and CC1 (white) indicated that the target cell is of human origin (STEM+) and strongly positive for OLIG2 and CC1, a mature oligodendrocyte, and that the connected cell is of murine origin (STEM-) and weakly positive for OLIG2 and CC1, most likely an immature oligodendrocyte. Scale bars, 30 m. See also fig. S7.

Studies with rodents have reported that oligodendrocytes exhibit extensive gap-junctional intercellular coupling between other oligodendrocytes and astrocytes (35). Whether oligodendrocytes derived from grafted human cells can be interconnected with cells in the adult host mouse brain was not known, and whether MS-hiOLs maintain this intrinsic property was also not addressed. Because biocytin can pass through gap junctions, we inspected biocytin-labeled cells for dye coupling (Figs. 6A and 7, A and B).

We found that two of seven MS-derived oligodendrocytes (~29%) and 5 of 21 control-derived oligodendrocytes (~24%) were connected with a single neighboring cell, which was either human or murine (Fig. 7), except in one case where three mouse cells were connected to the biocytin-loaded human cell. These findings reveal that gap junctional coupling can occur between cells from the same or different species, and MS-hiOLs can functionally connect to other glial cells to the same extent as their control counterparts.

To validate the presence of glial-glial interactions, we investigated whether the grafted hiOL-derived progeny had the machinery to be connected to one another via gap junctions. To this end, we focused on oligodendrocyte-specific Cx47 and astrocyte-specific Cx43 as Cx43/47 channels, which are important for astrocyte/oligodendrocyte cross talk during myelination and demyelination (36, 37). Combined immunolabeling for hNOGOA, CC1, OLIG2, and Cx47 revealed that MS-derived oligodendrocyte cell bodies and processes were decorated by Cx47+ gap junction plaques, which were often shared by exogenous MS-derived oligodendrocytes or by MS and endogenous murine oligodendrocytes (fig. S7A). In addition, colabeling exogenous myelin for MBP and Cx43 identified the presence of several astrocyte-specific Cx43 gap junction plaques between human myelin internodes, highlighting contact points between astrocyte processes and axons at the human-murine chimeric nodes of Ranvier (fig. S7B).

Last, colabeling of hNOGOA, with Cx47 and the astrocyte-specific Cx43, revealed coexpression of oligodendrocyte- and astrocyte-specific connexins at the surface of MS-derived oligodendrocyte cell bodies and at the level of T-shaped myelin-like structures (fig. S7C), thus implying connections between human oligodendrocytes and murine and/or human astrocytes, as a small proportion of the grafted hiOLs differentiated into astrocytes. Immunolabeling for human glial fibrillary acidic protein (GFAP), and Cx43 showed that these human astrocytes were decorated by Cx43+ aggregates, as observed in the host subventricular zone (fig. S8A).

Furthermore, immunolabeling for human GFAP, mouse GFAP, and Cx43 indicated that Cx43+ gap junctions were shared between human and mouse astrocytes as observed at the level of blood vessels (fig. S8B). These data validate interconnections between the grafted-derived human glia (MS and controls) with murine host glial cells and confirm their interconnection with the pan-glial network.

Two main hypotheses have been considered in understanding MS pathology and etiology: the outside-in hypothesis highlighting the role of immune regulators and environmental inhibitors as extrinsic key players in MS pathology and possibly its repair failure or the inside-out hypothesis pointing to the intrinsic characteristics of neuroglia including oligodendroglial cells as the main contributors in the MS scenario. Single-cell transcriptomic analysis revealed the presence of disease-specific oligodendroglia expressing susceptibility genes in MS brains (16) and altered oligodendroglia heterogeneity in MS (17). The question remains open as to whether these altered oligodendroglial phenotypes are acquired in response to the disease environment or whether they reflect intrinsic traits of the MS oligodendroglial population. On the other hand, the whole exome sequencing analysis in 132 patients from 34 multi-incident families identified 12 candidate genes of the innate immune system and provided the molecular and biological rational for the chronic inflammation, demyelination, and neurodegeneration observed in patients with MS (38) and revealed the presence of epigenetic variants in immune cells and in a subset of oligodendrocytes contributing to risk for MS (39).

While none of these hypotheses have been fully proven or rejected, research efforts for a better understanding of this multifactorial disease have continued. Impaired remyelination or oligodendrocyte differentiation block in MS is still considered a potentially disease-relevant phenotype (40, 41). Many histological and experimental studies suggest that impaired oligodendrocyte progenitor to oligodendrocyte differentiation may contribute to limited remyelination in MS, although some reports question the contribution of newly generated oligodendrocytes to remyelination (17, 42, 43). Understanding MS oligodendrocyte biology has been challenging mainly due to the following reasons: (i) oligodendroglial cells are not easily accessible to be studied in vivo; (ii) dynamic remyelination observed in patients with MS, which points to their individual remyelination potential, is inversely correlated with their clinical disability (3), highlighting even more complexity in oligodendrocyte heterogeneity between patients with MS; and (iii) exclusion of the role of immune system players in understanding MS oligodendrocyte biology being inevitable in most of clinical or experimental studies.

In such a complex multifactorial disease, one of the most accessible and applicable approaches to overcome these problems is the generation of large quantities of disease and control oligodendroglia using the iPSC technology, and to investigate their genuine behavior in vivo after engraftment in a B and T cellfree system. Using a very efficient reprogramming method (25), and the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects, we show that MS-hiOLs derivatives survive, proliferate, migrate, and timely differentiate into bona fide myelinating oligodendrocytes in vivo as efficiently as their control counterparts. Nicaise and colleagues reported that iPSC-NPCs from PPMS cases did not provide neuroprotection against active CNS demyelination compared to control iPSC-NPCs (44) and failed to promote oligodendrocyte progenitor genesis due to senescence without affecting their endogenous capacity to generate myelin-forming oligodendrocytes (21, 22). However, their myelinating potential was not evaluated against control cells. Generation of iPSC-oligodendrocyte progenitors from patients with PPMS or RRMS has also been reported by other groups, yet with no evidence for their capacity to become functional oligodendrocytes in vivo (23, 24). Thus, so far, no conclusion could be made regarding the potential impact of disease severity (PPMS verses RRMS) on the functionality of the iPSC-derived progeny.

We compared side by side, and at different time points after engraftment, hiOLs from patients with RRMS and controls including two pairs of homozygous twins discordant for disease. We found no significant difference in their capacity to timely differentiate (according to the human tempo of differentiation) and efficiently myelinate axons in the shiverer mouse in terms of the percentage of MBP+ cells generated, amount of myelin produced, length of MBP+ sheaths, and the ultrastructure and thickness of myelin sheaths. MS-hiOLs also reconstructed nodes of Ranvier expressing nodal components key to their function. We not only verified that the grafted MS-hiOLs derivatives were anatomically competent but also established their functionality at the electrophysiological level using (i) in vivo recordings of transcallosal evoked potentials and (ii) ex vivo recordings of the elicited current-voltage curves of the grafted MS-hiOLs verses controls. Our data show that the grafted MS-hiOLs were able to rescue the established delayed latency of shiverer mice to the same extent as control cells, as previously reported for human fetal glial progenitors grafted in the same model (11). Moreover, at the single-cell level, MS-hiOLderived oligodendrocyte progenitors and oligodendrocytes did not harbor aberrant characteristics in membrane currents compared to control cells ex vivo. Thus, iPSC-derived human oligodendroglial cells shift their membrane properties with maturation as previously observed in vitro (45) and these properties are not impaired in MS.

The absence of differences among control and MS-derivatives might be due to different causes. One might consider that pluripotency induction could by in vitro manipulation, erase cell epigenetic traits and/or reverse cells to an embryonic state, and as a result, modulate their intrinsic characteristics. Yet, several reports have highlighted differences in the behavior of diseased iPSC-derived oligodendrocytes in comparison to those from healthy controls using the same technology in multifactorial diseases such as schizophrenia (19, 20), Huntingtons disease (18), and others (46). In this regard, direct reprogramming of somatic cells into the desired cell type, bypassing the pluripotent stage, could be an attractive alternative. However, so far only mouse fibroblasts have been successfully directly converted into oligodendroglial cells, and with relatively low efficiency (47, 48).

iPSCs were transduced with three transcription factors to generate hiOLs in a fast and efficient way (25). While we cannot rule out that the use of these three transcription factors may have obscured differences between MS and controls, results for controls are quite comparable to our previously published data based on human fetal oligodendrocyte progenitor engraftment in the Shi/Shi:Rag2/ developing forebrain (49) or fetal NPC engrafted in the Shi/Shi:Rag2/ demyelinated spinal cord (50), suggesting that transduction with the three transcription factors does not overly modify the behavior of the grafted human cells. It could also be argued that the absence of differences between control and MS monozygous twins is not surprising given their equal genetic background. Yet, comparing controls with nonsibling MS hiOLS (compare C1 with RRMS2 and RRMS3; C2 with RRMS1, RRMS2, and RRMS3; and C3 with RRMS1 and RRMS2) revealed no defect in myelination for MS cells as well.

Analysis of hiOLs from each donor showed differences within each group. This could result from phenotypic instability, heterogeneity among donors, or disease subtype. Yet, the clinical history of each patient suggests a certain homogeneity among the MS disease phenotype, all being RRMS. In addition, the equal survival and proliferation rates between both groups argue in favor of cell stability. These confounding observations sustain that differences in terms of myelination are most likely due to heterogeneity among individuals rather than phenotypic instability or disease subtype.

While most preclinical transplantation studies have focused on myelination potential as the successful outcome of axo-glia interactions, less is known about the capacity of the grafted cells to fulfill glial-glial interactions in the pan-glial syncytium, which could ensure maintenance of newly generated myelin (51) and cell homeostasis (52). Oligodendrocytes are extensively coupled to other oligodendrocytes and oligodendrocyte progenitors through the homologous gap junctions Cx47 (35). These intercellular interactions between competing oligodendroglial cells influence the number and length of myelin internodes and the initiation of differentiation (53, 54). Oligodendrocytes are also coupled to astrocytes through heterologous gap junctions such as Cx32/Cx30 and Cx47/Cx43 (55). Disruption of oligodendrocytes from each other and from astrocytes, i.e., deconstruction of pan-glial network, has been observed in experimental models of demyelination (unpublished data) and frequently reported in MS and neuromyelitis optica (37, 56, 57). Mutations in Cx47 and Cx32 result in developmental CNS and PNS abnormalities in leukodystrophies (58, 59). Moreover, experimental ablation of Cx47 results in aberrant myelination (60) and significantly abolished coupling of oligodendrocytes to astrocytes (35).

In view of the major role of Cx-mediated gap junctions among oligodendrocytes and between oligodendrocytes and astrocytes during myelin formation (55), we asked whether the MS-hiOL progeny was capable of making functional gap junctions with other glial cells, and integrating into the host panglial network. We show that grafted MS-hiOLs, in common with rodent oligodendrocytes, express Cx47 that was frequently shared not only between the human and murine oligodendrocytes (through Cx47-Cx47) but also in conjunction with the astrocyte Cx43 (via Cx47/Cx43). The dye-coupling study highlighted that MS-hiOLs, similar to control cells, were capable of forming functional gap junctions with neighbor murine or human glial cells, indicating that MS-hiOLs retained the intrinsic property, not only to myelinate host axons but also to functionally integrate into the host pan-glial network. While our study focused mainly on oligodendroglial cells, a small proportion of the grafted hiOLs differentiated into astrocytes expressing Cx43. These human astrocytes were detected associated with blood vessels or the subventricular zone, where they were structurally gap-junction coupled to mouse astrocytes as observed after engraftment of human fetal glial restricted progenitors (61).

Together, our data highlight that human skinderived glia retain characteristics of embryonic/fetal brainderived glia as observed for rodent cells (10). In particular, we show that MS-hiOLs timely differentiate into mature oligodendrocytes, functionally myelinate host axons and contribute to the human-mouse chimeric pan-glial network as efficiently as control-hiOLs. These observations favor a role for extrinsic rather than intrinsic oligodendroglial factors in the failed remyelination of MS. The International Multiple Sclerosis Genetics Consortium after analyzing the genomic map of more than 47,000 MS cases and 63,000 control subjects, implicated microglia, and multiple different peripheral immune cell populations in disease onset (62). Moreover, neuroinflammation appears to block oligodendrocyte differentiation and to alter their properties and thereby aggravate the autoimmune process (63). Furthermore, MS lymphocytes are reported to exhibit intrinsic capacities that drive myelin repair in a mouse model of demyelination (64). On the other hand, a recent study highlighted the presence of disease-specific oligodendroglia in MS (16, 17). However, it should be considered that most of the data in the later were collected using single nuclei RNA sequencing of postmortem tissues from MS or control subjects of different ages that were suffering from other disorders ranging from cancer to sepsis and undergoing various treatment, and so died for different reasons, that may have influenced the type or level of RNA expression by the cells. In addition, the presence of genetic variants that alter oligodendrocyte function in addition to that of immune cells was also found (39). While this oligodendrocyte dysfunction contributes to MS risk factor, whether it is involved in other aspects of MS such as severity, relapse rate, and rate of progression is not yet known.

Numerous factors may cause the failure of oligodendrocyte progenitor maturation comprising factors such as axonal damage and/or altered cellular and extracellular signaling within the lesion environment (65) without neglecting aged-related environmental and cellular changes (40). Although the cells generated in this study are more of an embryonic nature, and did not experienced the kind of inhibitory environment that is present in MS, our data provide valuable findings in the scenario of MS pathology highlighting that RRMS-hiOLs, regardless of major manipulators of the immune system, do not lose their intrinsic capacity to functionally myelinate and interact with other neuroglial cells in the CNS under nonpathological conditions. Whether RRMS-hiOLs or oligodendroglial cells directly reprogrammed from MS fibroblasts would behave similarly well, if challenged with neuropathological inflammatory conditions as opposed to conditions wherein the immune system is intact (presence of T and B cells), or whether they would reflect intrinsic aging properties will require further investigation.

In summary, our findings provide valuable insights not only into the biology of MS oligodendroglia but also their application for cell-based therapy and should contribute to the establishment of improved preclinical models for in vivo drug screening of pharmacological compounds targeting the oligodendrocyte progenitors, oligodendrocytes, and their interactions with the neuronal and pan-glial networks.

We examined side by side the molecular, cellular, and functional behavior of MS hiOLs with their control counterparts after their engraftment in a dysmyelinating animal model to avoid the effect of major immune modulators. We used three MS and three control hiOLs including two monozygous twin pairs discordant for the disease. We performed in vivo studies in mouse with sample size between three to six animals per donor/time point/assay required to achieve significant differences. Numbers of replicates are listed in each figure legend. Animals were monitored carefully during all the study time, and animal welfare criteria for experimentation were fully respected. All experiments were randomized with regard to animal enrollment into treatment groups. The same experimenter handled the animals and performed the engraftment experiments to avoid errors. The data were analyzed by a group of authors.

Shiverer mice were crossed to Rag2 null immunodeficient mice to generate a line of Shi/Shi:Rag2/ dysmyelinating-immunodeficient mice to (i) prevent rejection of the grafted human cells and allow detection of donor-derived WT myelin and (ii) investigate the original behavior of MS-derived oligodendrocytes in a B cell/T cellfree environment. Mice were housed under standard conditions of 12-hour light/12-hour dark cycles with ad libitum access to dry food and water at the ICM animal facility. Experiments were performed according to European Community regulations and INSERM ethical committee (authorization 75-348; 20/04/2005) and were approved by the local Darwin ethical committee.

Fibroblasts were obtained under informed consent from three control and three RRMS subjects including two monozygous twin pairs discordant for the disease. They were reprogrammed into iPSCs using the replication incompetent Senda virus kit (Invitrogen) according to manufacturers instructions. Table S1 summarizes information about the human cell lines used in this study. The study was approved by the local ethical committees of Mnster and Milan (AZ 2018-040-f-S, and Banca INSpe).

Human iPSCs were differentiated into NPC by treatment with small molecules as described (66, 67). Differentiation of NPCs into O4+ oligodendroglial cells used a poly-cistronic lentiviral vector containing the coding regions of the human transcription factors Sox10, Olig2, and Nkx6.2 (SON) followed by an IRES-pac cassette, allowing puromycin selection for 16 hours (25). For single-cell electrophysiological recordings, the IRES-pac cassette was replaced by a sequence encoding RFP. Briefly, human NPCs were seeded at 1.5 105 cells per well in 12-well plates, allowed to attach overnight and transduced with SON lentiviral particles and protamine sulfate (5 g/ml) in fresh NPC medium. After extensive washing, viral medium was replaced with glial induction medium (GIM). After 4 days, GIM was replaced by differentiation medium (DM). After 12 days of differentiation, cells were dissociated by accutase treatment for 10 min at 37C, washed with phosphate-buffered saline (PBS) and resuspended in PBS/0.5% bovine serum albumin (BSA) buffer, and singularized cells were filtered through a 70-m cell strainer (BD Falcon). Cells were incubated with mouse immunoglobulin M (IgM) antiO4-APC antibody (Miltenyi Biotech) following the manufacturers protocol, washed, resuspended in PBS/0.5% BSA buffer (5 106 cells/ml), and immediately sorted using a FACS Aria cell sorter (BD Biosciences). Subsequently, human O4+ hiOLs were frozen and stored in liquid nitrogen. Media details were provided in (25). hiOLS from each donor was assayed individually (no cell mix) and studied as follows for forebrain engraftment: immunohistochemistry (all donors, three to seven mice per time point), electron microscopy (C1 and RRMS1, four mice per donor at 16 wpg), in vivo electrophysiology (C1 and RRMS1, six mice per donor and eight mice per medium at 16 wpg), dye coupling, and ex-vivo electrophysiology (C1-RFP and RRMS3-RFP, six to seven mice per donor at 16 wpg). For spinal cord engraftment: immuno-histochemistry (C1 and RRMS3, 3 and 4 mice respectively at 12 wpg).

RRMS1: Disease duration at biopsy was 11 years. Started on Rebif 22 and switched to Rebif 44 because of relapses. Relapse was treated with bolus of cortisone 20 to 30 days before biopsy and then switched to natalizumab.

RRMS2: Disease duration at biopsy was 16 months. Relapse at disease onset. On Rebif 22 from disease onset until biopsy with no episodes. A new lesion was identified 3 months after biopsy. At the time of biopsy, the patient reported cognitive difficulties, no motor dysfunctions.

RRMS3: Disease duration at biopsy was 15 months. Relapse 6 months before biopsy with dysesthesias and hypoesthesia right thigh and buttock. Active lesion identified by magnetic resonance imaging at day 10. On Rebif smart 44 mcg, 50 days later, and skin biopsy 4 months later. A new gadolinium negative temporal lesion identified 2 months after biopsy and the patient switched to Tecfidera.

To assay hiOL contribution to forebrain developmental myelination, newborn Shi/Shi:Rag2/ pups (n = 148) were cryo-anesthetized, and control and RRMS hiOLs were transplanted bilaterally, rostral to the corpus callosum. Injections (1 l in each hemisphere and 105 cells/l) were performed 1 mm caudally, 1 mm laterally from the bregma, and to a depth of 1 mm as previously described (49, 68). Animals were sacrificed at 4, 8, 12, 16, and, when indicated, 20 wpg for immunohistological studies and at one time point for electron microscopy (16 wpg), ex vivo (12 to 15 wpg), and in vivo (16 wpg) electrophysiology.

To assay the fate of hiOLs in the developing spinal cord, 4-week-old mice (n = 4) were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) (Alcyon) and xylazine (10 mg/kg) (Alcyon) and received a single injection at low speed (1 l/2 min) of hiOLs (1 l, 105 cells/l) at the spinal cord thoracic level using a stereotaxic frame equipped with a micromanipulator and a Hamilton syringe. Animals were sacrificed at 12 wpg for immunohistological studies.

Immunohistochemistry. Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 3 to 6 per group, donor and time point) were sacrificed by transcardiac perfusion-fixation with 4% paraformaldehyde in PBS. Tissues were postfixed in the same fixative for 1 hour and incubated in 20% sucrose in 1 PBS overnight before freezing at 80C. Serial horizontal brain and spinal cord cross sections of 12 m thickness were performed with a cryostat (CM3050S, Leica). Transplanted hiOLs were identified using anti-human cytoplasm [1:100; STEM121; Takara, Y40410, IgG1], anti-human nuclei (1:100; STEM101; Takara, Y40400, IgG1), and anti-human NOGOA (1:50; Santa Cruz Biotechnology, sc-11030, goat) antibodies. In vivo characterization was performed using a series of primary antibodies listed in tableS2. For MBP staining, sections were pretreated with ethanol (10 min, room temperature). For glial-glial interactions, oligodendrocyte-specific connexin was detected with anti-connexin 47 (1:200; Cx47; Invitrogen, 4A11A2, IgG1) and astrocyte-specific connexin, with anti-connexin 43 (1:50; Cx43; Sigma-Aldrich, C6219, rabbit), and sections were pretreated with methanol (10 min, 20C). Secondary antibodies conjugated with fluorescein isothiocyanate, tetramethyl rhodamine isothiocyanate (SouthernBiotech), or Alexa Fluor 647 (Life Technologies) were used, respectively, at 1:100 and 1:1000. Biotin-conjugated antibodies followed by AMCA AVIDIN D (1:20; Vector, A2006). Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (1 g/ml; Sigma-Aldrich) (1:1000). Tissue scanning, cell visualization, and imaging were performed with a Carl Zeiss microscope equipped with ApoTome 2.

Electron microscopy. For electron microscopy, Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 4 per group) were perfused with 1% PBS followed by a mixture of 4% paraformaldehyde/5% glutaraldehyde (Electron Microscopy Sciences) in 1% PBS. After 2-hour postfixation in the same solution, 100-m-thick sagittal sections were cut and fixed in 2% osmium tetroxide (Sigma-Aldrich) overnight. After dehydration, samples were flat-embedded in Epon. Ultra-thin sections (80 nm) of the median corpus callosum were examined and imaged with a HITACHI 120 kV HT-7700 electron microscope.

Electrophysiological recordings were performed in mice grafted with MS- and control-hiOLs, and compared with nongrafted intact or medium injected Shi/Shi:Rag2/ mice and WT mice 16 weeks after injection (n = 4 to 6 per group) as described (11). Briefly mice were anesthetized with 2 to 4% isoflurane performed under analgesia (0.1 mg/kg buprecare) and placed in a stereotaxic frame (D. Kopf, Tujunga, CA, USA). Body temperature was maintained at 37C by a feedback-controlled heating blanket (CMA Microdialysis). Electrical stimulation (0.1 ms at 0 to 0.1 mA) was applied using a bipolar electrode (FHC- CBBSE75) inserted to a depth of 200 m into the left cortex at 2 mm posterior to bregma and 3 mm from the midline. At the same coordinates in the contralateral hemisphere, homemade electrodes were positioned for recording local field potentials (LFPs) generated by transcallosal electric stimulation. Electrical stimulation and evoked LFPs were performed by the data acquisition system apparatus (Neurosoft, Russia), and signals were filtered at 0.01 to 1 000 Hz. Each response latency (in ms) was measured as the time between the onset of stimulus artifact to the first peak for each animal. A ground electrode was placed subcutaneously over the neck.

Slice preparation and recordings. Acute coronal slices (300 m) containing corpus callosum were made from Shi/Shi:Rag2/ mice grafted with control (n = 7) and RRMS (n = 6) RFP+ hiOLs. They were prepared from grafted mice between 12 and 15 wpg as previously described (69). Briefly, slices were performed in a chilled cutting solution containing 93 mM N-methyl-d-glucamine, 2.5 mM KCl, 1.2 mM NaH2PO4, 30 mM NaHCO3, 20 mM Hepes, 25 mM glucose, 2 mM urea, 5 mM Na-ascorbate, 3 mM Na-pyruvate, 0.5 mM CaCl2, and 10 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2) and kept in the same solution for 8 min at 34C. Then, they were transferred for 20 min to solution at 34C containing 126 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 20 mM glucose, 5 mM Na-pyruvate, 2 mM CaCl2, and 1 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2). Transplanted RFP+ hiOLs were visualized with a 40 fluorescent water-immersion objective on an Olympus BX51 microscope coupled to a CMOS digital camera (TH4-200 OptiMOS) and an light-emitting diode light source (CoolLed p-E2, Scientifica, UK) and recorded in voltage-clamp mode with an intracellular solution containing 130 mM K-gluconate, 0.1 mM EGTA, 2 mM MgCl2, 10 mM Hepes, 10 mM -aminobutyric acid, 2 mM Na2-adenosine 5-triphosphate, 0.5 mM Na-guanosine 5-triphosphate, 10 mM Na2-phosphocreatine, and 5.4 mM biocytin (pH 7.23). Holding potentials were corrected by a junction potential of 10 mV. Electrophysiological recordings were performed with Multiclamp 700B and Pclamp10.6 software (Molecular Devices). Signals were filtered at 3 kHz, digitized at 10 kHz, and analyzed off-line.

Immunostainings and imaging of recorded slices. For analysis of recorded cells, one single RFP+ cell per hemisphere was recorded in a slice and loaded with biocytin for 25 min in whole-cell configuration. After gently removing the patch pipette, biocytin was allowed to diffuse for at least 10 min before the slice was fixed 2 hours in 4% paraformaldehyde at 4C. Then, the slice was rinsed three times in PBS for 10 min and incubated with 1% Triton X-100 and 10% normal goat serum (NGS) for 2 hours. After washing in PBS, slices were immunostained for SOX10, CC1, and STEM101/121. Tissues were incubated with primary antibodies for 3 days at 4C. Secondary antibodies were diluted in 2% NGS and 0.2% Triton X-100. Tissues were incubated with secondary antibodies for 2 hours at room temperature. Biocytin was revealed with secondary antibodies using DyLight-488 streptavidin (Vector Laboratories, Burlingame, USA, 1:200). Images of biocytin-loaded cells were acquired either with a Carl Zeiss microscope equipped with ApoTome 2 or a LEICA SP8 confocal microscope (63 oil objective; numerical aperture, 1.4; 0.75-m Z-step) and processed with National Institutes of Health ImageJ software (70).

We adapted the heuristic algorithm from (29) to identify STEM+ MBP+ OLs in tissue sections. The foundations of the quantitative method remained the same. A ridge-filter extracted sheath-like objects based on intensity and segments associated to cell bodies using watershed segmentation. Two additional features adapted the workflow beyond its original in vitro application. First, we added functionality to allow colocalization of multiple fluorescent stains, as we needed to quantify triple positive STEM+/MBP+/DAPI+ cell objects. Second, because oligodendrocyte sheaths are not parallel and aligned in situ as they are in dissociated nanofiber cell cultures, we adapted the algorithm to report additional metrics about MBP production locally and globally that do not rely on the dissociation of sheaths in dense regions.

Cell nuclei were identified using watershed segmentation of DAPI+ regions and then colocalized pixel-wise with STEM+ objects. The DAPI+ nuclei were then used as local minima to seed a watershed segmentation of the STEM+ stain to separate nearby cell bodies. Last, the identified STEM+ cell bodies were colocalized with overlapping MBP+ sheath-like ridges to define ensheathed cells. We reported the area of MBP overlapping with STEM fluorescence in colocalized regions associated with individual cells, as well as the number of single, double, and triple fluorescently labeled cells. In addition, different cellular phenotypes were noted in situ that were then captured with the adapted algorithm. Qualitatively, we observed cells with expansive MBP production without extended linear sheath-like segments that were not observed in previous applications of the algorithm. These cells were denoted as tuft cells, and were quantitatively defined as STEM+/MBP+/DAPI+ cells without fluorescent ridges that could be identified as extended sheath-like objects.

The myelination potential of three control and 3 MS hiOLs was evaluated at 4, 8, 12, 16, and 20 wpg (n = 2 to 7 per line and per time point; n = 6 to 14 per time point). For each animal, six serial sections at 180-m intervals were analyzed. The percentage of MBP+ cells (composed of ensheathed or tuft cells) was evaluated. Total MBP+ area per STEM+ cells and the average length of MBP+ sheaths per MBP+ cells were analyzed.

Cell survival, proliferation, and differentiation in vivo. The number of STEM101+ grafted cells expressing Caspase3, or Ki67, or SOX10 and CC1 was quantified in the core of the corpus callosum at 8, 12, and 16 wpg. For each animal (n = 3 per group), six serial sections at 180-m intervals were analyzed. Cell counts were expressed as the percentage of total STEM101+ cells.

Myelination by electron microscopy. G ratio (diameter of axon/diameter of axon and myelin sheath) of donor-derived compact myelin was measured as previously described (10). Briefly, the maximum and minimum diameters of a given axon and the maximum and minimum axon plus myelin sheath diameter were measured with the ImageJ software at a magnification of 62,000 for a minimum of 70 myelinated axons per animal. Data were expressed as the mean of the maximal and minimal values for each axon for mice from each group (n = 4 mice per group). Myelin compaction was confirmed at a magnification of 220,000.

Data are presented as means + SEM. Statistical significance was determined by two-tailed Mann Whitney U test when comparing two statistical groups, and with one-way or two-way analysis of variance (ANOVA) followed by Tukeys or Dunnetts (in vivo electrophysiology) multiple comparison tests for multiple groups. Because electrophysiological data in brain slices do not follow a normal distribution after a DAgostino-Pearson normality test, we also performed two-tailed Mann-Whitney U test for comparison between groups. Statistics were done in GraphPad Prism 5.00 and GraphPad Prism 8.2.1 (GraphPad Software Inc., USA). See the figure captions for the test used in each experiment.

Acknowledgments: Funding: This work was supported by the Progressive MS Alliance [PMSA; collaborative research network PA-1604-08492 (BRAVEinMS)] to G.M., J.P.A., A.B.-V.E., and T.K., the National MS Society (NMSS RG-1801-30020 to T.K. and A.B.-V.E.), INSERM and ICM grants to A.B.-V.E., the German Research Foundation (DFG CRC-TR-128B07 to T.K.), and the Italian Multiple Sclerosis Foundation (FISM) (project no. Neural Stem Cells in MS to G.M.). M.C.A. was supported by grants from Fondation pour laide la recherche sur la Sclrose en Plaques (ARSEP) and a sub-award agreement from the University of Connecticut with funds provided by grant no. RG-1612-26501 from National Multiple Sclerosis Society. During this work, S.M. was funded by European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). B.G.-D. and M.J.F.L. were supported by the PMSA, PA-1604-08492 and the National MS Society (RG-1801-30020), respectively. B.M.-S. was supported by a Ph.D. fellowship from the French Ministry of Research (ED BioSPC). A.B. and M.C.A. thank respective imaging facilities, ICM Quant and IPNP NeurImag and their respective funding sources Institut des Neurosciences Translationnelles ANR-10-IAIHU-06 Fondation Leducq. Author contributions: Conceptualization: S.M. and A.B.-V.E. Methodology: S.M., L.S., B.M.-S., Y.K.T.X., B.G.-D., M.J.F.L., D.R., L.O., K.-P.K., H.R.S., J.P.A., T.K., G.M., T.E.K., M.C.A., and A.B.V.-E. Formal analysis: S.M., B.M-S., Y.K.T.X., M.C.A., and A.B.-V.E. Writing: S.M. and A.B.V.-E, with editing and discussion from all coauthors Funding acquisition: S.M. and A.B.V.-E. Supervision: A.B.V.-E. Competing interests: T.K. has a pending patent application for the generation of human oligodendrocytes. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

Link:
Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo - Science Advances

The Male Hypogonadism Therapy market report provides a detailed analysis of the emerging trends, opportunities, and as well as the challenges in the market. This extensive report sheds light on the latest developments, market drivers, and competitive analysis to help the new entrants and emerging players to make crucial decisions.

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Detailed overview of Male Hypogonadism Therapy

Changing market dynamics of the industry

In-depth market segmentation by Type, Application, etc.

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Research Objectives

To analyze and forecast the Worldwide Male Hypogonadism Therapy, in terms of value and volume.

Which segment has the potential to gain the highest market share?

To help decision-makers from a new offer perspective and benchmark existing marketing strategy.

Correlate cost structure historical data with key business segments.

Analyze marketing contribution and customer acquisition by up-selling and cross-selling.

Identifying Influencing factors keeping Worldwide Male Hypogonadism Therapy Intense, factored with periodic analysis of CR4 & CR8 concentration ratio & HHI Index.

Important Features that are under offering & key highlights of the report:

1) Does the study cover COVID-19 Impact Analysis and its effect on Growth %?

Yes, the overall industry has seen quite a big impact due to slowdown and shutdown in the production line & supply chain. The study covers a separate qualitative chapter on COVID-19 Impact analysis. Additionally, it also provides before and after the scenario of COVID-19 on sales growth & market size estimation to better analyze the exact scenario of the industry.

2) How companies are selected or profiled in the report?

List of some players that are profiled in the report include:

Eli LillyPfizerAbbVieNovo NordiskMerck KGaAMylanBayerTevaNovartisAbbottRocheEndo InternationalIpsenANI PharmaceuticalsTherapeuticsMDMale Hypogonadism Therap

Usually, we follow NAICS Industry standards and validate company profile with product mapping to filter relevant Industry players, furthermore the list is sorted to come up with a sample size of at least 50 to 100 companies having greater topline value to get their segment revenue for market estimation.

** List of companies mentioned may vary in the final report subject to Name Change / Merger etc.

3) Can we add or profiled a new company as per our needs?

Yes, we can add or profile a new company as per client need in the report, provided it is available in our coverage list as mentioned in answer to Question 1 and after feasibility run, final confirmation will be provided by the research team checking the constraints related to the difficulty of survey.

4) Can we narrow the available business segments?

Yes, depending upon the data availability and feasibility check by our Research Analyst, a further breakdown in business segments by end-use application or product type can be provided (If applicable) by Revenue Size or Volume*.

Male Hypogonadism Therapy market segmentation

The Study is segmented by following Product Type:

ParenteralTransdermalOralOthersMale Hypogonadism Therap

Major applications/end-users industry are as follows:

HospitalsDrugstoresOthers

5) Can a specific country of interest be added? What all regional segmentation covered?

Yes, Country-level splits can be modified in the study as per objectives. Currently, the research report gives special attention and focus on the following regions:

North America [United States, Canada, Mexico], Asia-Pacific [China, India, Japan, South Korea, Australia, Indonesia, Malaysia, Philippines, Thailand, Vietnam], Europe [Germany, France, UK, Italy, Russia, Rest of Europe], South America [Brazil, Argentina, Rest of South America], Middle East & Africa [GCC Countries, Turkey, Egypt, South Africa, Rest of the Middle East & Africa]

** One country of specific interest can be included at no added cost. For inclusion of more regional segment quotes will vary.

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Male Hypogonadism Therapy Market Detailed Analysis Of Current Industry Figures With Forecasts Growth By 2026 - Cheshire Media

Dataintelo, one of the worlds leading market research firms has rolled out a new report on Male Hypogonadism market. The report is integrated with crucial insights on the market which will support the clients to make the right business decisions. This research will help both existing and new aspirants for Global Male Hypogonadism Market to figure out and study market needs, market size, and competition. The report provides information about the supply and demand situation, the competitive scenario, and the challenges for market growth, market opportunities, and the threats faced by key players.

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The report is fabricated by tracking the market performance since 2015 and is one of the most detailed reports. It also covers data varying according to region and country. The insights in the report are easy to understand and include pictorial representations. These insights are also applicable in real-time scenarios. Components such as market drivers, restraints, challenges, and opportunities for Male Hypogonadism are explained in detail. Since the research team is tracking the data for the market from 2015, therefore any additional data requirement can be easily fulfilled.

The scope of the report has a wide spectrum extending from market scenarios to comparative pricing between major players, cost, and profit of the specified market regions. The numerical data is supported by statistical tools such as SWOT analysis, BCG matrix, SCOT analysis, and PESTLE analysis. The statistics are depicted in a graphical format for a clear picture of facts and figures.

The generated report is strongly based on primary research, interviews with top executives, news sources, and information insiders. Secondary research techniques are utilized for better understanding and clarity for data analysis.

The Male Hypogonadism Market is divided into the following segments to have a better understanding:

By Application:

Kallmann SyndromeKlinefelters SyndromePituitary DisordersOthers

By Type:

Testosterone Replacement TherapyGonadotropin-Releasing Hormones Therapy

By Geographical Regions:

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Some of the prominent companies that are covered in this report:

Key players, major collaborations, merger & acquisitions along with trending innovation and business policies are reviewed in the report. Following is the list of key players:

Astrazeneca Plc.Merck& Co. Inc.Laboratories GenevrierAllergan Plc.Endo International Plc.Ferring

*Note: Additional companies can be included on request

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Male Hypogonadism Market is Expected to Thrive at Impressive CAGR by 2026 & Top Key Players are Astrazeneca Plc., Merck& Co. Inc.,...

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiotherapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control.

This prospective phase 2 single arm trial enrolled men with low volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone once daily (AAP) and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable PSA at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual/ hormonal quality-of-life.

We enrolled 37 men between January 2014 and August 2016, 45% of whom were high-risk .All patients had T1-2 disease and PSAs <20 ng/ml. Median follow-up is 37 months (95% CI: 35.7, 39.1).Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no >G4 toxicities. The rate of undetectable PSA at 12-months was 55% (95% CI 36-72%). With 46 months median follow-up, two of 37 patients developed PSA progression (36-month PFS 96%; 95% CI: 76%, 99%), and 81% of patients recovered testosterone with median time to recovery 9.2 months. Hormonal/sexual function declined at six months with subsequent improvement by 24 months.

The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of QOL and excellent disease control in men with low volume intermediate or high-risk localized prostate cancer. Prospective comparative studies are justified.

International journal of radiation oncology, biology, physics. 2020 Nov 28 [Epub ahead of print]

Bridget F Koontz, Karen E Hoffman, Susan Halabi, Patrick Healy, Monika Anand, Daniel J George, Michael R Harrison, Tian Zhang, William R Berry, Paul G Corn, W Robert Lee, Andrew J Armstrong

Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Radiation Oncology, Duke University, Durham NC USA. Electronic address: ., Department of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston TX USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Biostatistics and Bioinformatics, Duke University, Durham NC USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Medicine, Division of Medical Oncology, Duke University, Durham NC USA; Department of Surgery, Division of Urology, Duke University, Durham NC USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Medicine, Division of Medical Oncology, Duke University, Durham NC USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Radiation Oncology, Duke University, Durham NC USA., Duke Cancer Institute Center for Prostate and Urologic Cancers Durham NC USA; Department of Medicine, Division of Medical Oncology, Duke University, Durham NC USA; Department of Surgery, Division of Urology, Duke University, Durham NC USA; Department of Pharmacology and Cancer Biology, Duke University, Durham NC USA.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33259932

Read more here:
Combination of Radiotherapy and Short-Term Androgen Blockade with Abiraterone Acetate plus Prednisone for M... - UroToday

What is Prader-Willi Syndrome?

Prader-Willi syndrome is a rare genetic disorder caused by a defect of genes in the proximal arm of chromosome-15 which leads to life-threatening childhood obesity. It is associated with obesity, hypogonadism, intellectual deficits, small stature along with small hands, and feet.

A child with PraderWilli Syndrome

The first case of Prader-Willi syndrome was first described in a mentally impaired adolescent girl in 1887 by Langdon Down and was later described in medical literature in 1956 by Swiss doctors Andrea Prader, Alexis Labhart, and Heinrich Willi.

Presence of characteristic facial features like almond-shaped eyes, narrow bifrontal diameter, and the nasal bridge thin upper lip and downturned mouth. These features are noticed soon after birth.

Prader-Willi syndrome has been described worldwide and is a genetic disorder occurring in approximately 1 in every 15,000 live birth. It affects males and females equally, all races and ethnicities are equally susceptible.It is highly unlikely for parents to have more than one child with Prader-Willi syndrome.

PWS is caused due to abnormality in the expression of genes on Chromosome 15 specifically on the long arm of chromosome 15. This abnormality can be attributed to the following :

The defects seen in Prader-Willi syndrome is mostly attributed to hypothalamic disorder, which may explain some typical features of the syndrome like delayed growth and hyperphagia as the hypothalamus is the center for hormone production, growth, and hunger regulation.

Various studies have implied the role of Ghrelin in satiety defect and have found Ghrelin to be about 4-5 folds higher in people with PWS. (Ghrelin is a hormone produced by enteroendocrine cells and is also known as the Hunger Hormone)

Three sets of diagnostic criteria have been established for the diagnosis of Prader-Willi Syndrome. These are major, minor, and supportive.

These criteria though they dont have points, aid in the diagnosis of the disease.

Based on the guidelines established by Holmes et.al the diagnosis of Prader-Willi syndrome is highly likely in children younger than 3 years if they score 5 points with 3 of those coming from the major criteria.

In the case of children older than 3 years with Prader Willi syndrome is highly likely if they score 8 points with 4 from major criteria.

Magnetic Resource Imaging (MRI) of the head to assess hypopituitarism. The individuals with Prader-Willi syndrome are at risk of pathological fractures, however high degrees of pain tolerance in these patients make it necessary to diagnose fractures to prevent stiffness and malunion of fractures. DEXA Scan: To detect complications of osteoporosis. Scoliosis Film of the vertebra.

To reach the diagnosis of PWS we need to differentiate it from other diseases which may be causing similar features:

These conditions can be differentiated from PWS with the help of the DNA Methylation technique.

Apart from these, other genetic conditions are causing short stature and obesity which need to be ruled out:

There is no permanent cure for Prader-Willi syndrome currently, and the treatment of the syndrome requires a multidisciplinary approach from geneticists, endocrinologists, nutritionists, pulmonologists, neurologists to prevent complications from PWS.

The treatment is generally directed towards symptomatic relief and problem management.

The treatment plan needs to be continuously reassessed as the child grows older as it needs changes.

Early diagnosis and treatment of PWS can go a long way in improving their quality of life and help them reach their full potential.

Children with PWS require proper care apart from specific symptomatic treatments. Most children can benefit from the following:

Infants with PWS have low muscle tone consequentially they are unable to breastfeed properly. A pediatrician can help by recommending special feeding methods and prescribing high-calorie diets. Use of a Nasogastric tube may be required.

A proper diet low on calories but providing necessary nutrition is key in managing the weight of PWS in children. Supplemental vitamins and minerals are required for balanced growth. Proper diet complemented with increased physical activity help in weight management. The child should exercise for at least 60 minutes. The exercise routine should be broken down into multiple 5- 10 minute sessions in children having decreased energy levels.

As the desire for appetite in children with PWS is high, parents need to keep strict vigilance on their eating habits, there should be proper meal times, food should be kept out of their view and no extra feeding should be done.

Human growth hormone (HGH) treatment. An endocrinologist can help decide if the baby will benefit from HGH injections. In children with Prader-Willi syndrome, it helps in facilitating growth, decreasing body fat content, increasing muscle size, and muscle tone.

Sex hormone treatment. Children with PWS have a very low sex hormone level, requiring hormone replacement therapy (Testosterone for males; estrogen and progesterone for females). HRT begins as the child approaches puberty. Apart from raising hormonal levels, it helps also in preventing bone thinning. Orchidopexy may be required for Cryptorchidism (Undescended testis).

Treating sleep disturbances related to PWS can improve daytime sleepiness and behavioral issues in children.

Strict parenting is required to keep the behavior in check, especially concerning food, to prevent over-eating; a proper diet plan needs to be formulated. Calmness is required while dealing with children showing temper tantrums- the situation should be deflated as soon as possible by engaging the child in another topic. Medication may be required in some cases.

A psychologist or a psychiatric consultation may be required to address obsessive-compulsive disorders, skin picking, or mood disorders in children with PWS. The childs nails should be trimmed so that they do not develop cellulitis or other skin infections as a result of constant skin picking; any cases of skin infection should be treated immediately using antibiotics.

Most people with Prader-Willi syndrome will need specialized care and supervision throughout their lives for continuous consultation with the doctor is required to transition medical care to adulthood.

In cases of severe skin and pinching and psychoses, Anti-depressant or anti-psychotics can be helpful. SSRIs are the antidepressants of choice. These drugs however come with associated risks, so they are generally avoided below the age of 18. Cognitive-behavioral therapy may be required in some cases. It is a talking therapy that helps to change the way the patient thinks and behaves to modify unhealthy behavioral patterns.

Patients with Prader-Willi syndrome are at risk of developing the following complications:

People with PWS, who receive early treatment usually have a normal lifespan and can function in a group home setting, perform vocational work.

People with PWS, having normal IQ can expect to accomplish many of the things their peers do. However, each person requires lifelong support from the people involved to lead an independent life.

Complications due to morbid obesity and psychological issues can affect the quality of life and sometimes shorten life expectancy in patients with PWS.

Scientists worldwide have been working on finding a permanent cure and improving the quality of life by reducing complications for PWS by carrying out various researches worldwide.

Livoletide is being monitored as a drug to reduce ghrelin and consequently hyperphagia and obesity.

A randomized, double-blind placebo-controlled study conducted in 2019 in 47 adults who took 3-4 mg of Livoletide once a day for two weeks, reported a significant decrease in food-related behaviors as compared to people who were given a placebo.

https://www.nhs.uk/conditions/prader-willi-syndrome/

Read more from the original source:
Prader-Willi Syndrome Facts: Causes, Diagnosis, Treatments and Prognosis - Gilmore Health News

Male hypogonadism usually is treated with testosterone replacement to return testosterone levels to normal. Testosterone can help counter the signs and symptoms of male Hypogonadism, such as decreased sexual desire, decreased energy, decreased facial and body hair, and loss of muscle mass and bone density.

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Male Hypogonadism HRT Treatment Market 2020-28 booming segments, latest trends and analysis with Merck & Co, Allergan, Endo International,...

Eduardo Rodriguez and the Boston Red Sox agreed to a one-year, $8.3-million contract for 2021, according to multiple reports on Tuesday.

The $8.3 million salary is the same the left-handed starter earned in 2020. The Red Sox beat Rodriguez at a salary arbitration hearing before the 2020 season when they filed at $8.3 million and Rodriguez filed for $8.675 million. The two sides avoided salary arbitration this offseason.

Rodriguez who is eligible for free agency after the 2021 season didnt pitch in 2020 because of myocarditis (inflammation of the heart), an after-effect of COVID-19. Rodriguez tested positive for COVID-19 before flying to Boston for summer training camp in early July. Tests in Boston revealed myocarditis. Rodriguez said he experienced every symptom of COVID.

I feel like I was 100 years old, Rodriguez said in July. My body was tired all the time. Throwing up. Headaches. Like I said, all the symptoms.

Rodriguez began throwing again in November after a lengthy recovery. He was Bostons top starter in 2019 and finished sixth in the American League Cy Young voting, going 19-6 with a 3.81 ERA and 1.33 WHIP in 34 starts.

The deadline for MLB teams to tender 2021 contracts to their pre-arbitration and arbitration-eligible players is Wednesday at 8 p.m. Boston has five other arbitration-eligible players Rafael Devers, Matt Barnes, Ryan Brasier, Kevin Plawecki and Austin Brice on its 40-man roster.

INDIANS-MARLINS: Cleveland sold side-arm reliever Adam Cimber to the Marlins for $100,000, and Miami designated right-hander Jos Urea for assignment.

Urea, the Marlins Opening Day starter in 2018 and 2019, spent six seasons with the Marlins and had been with them longer than any other active player. He went 0-3 with a 5.40 ERA in five starts last season, when he had a $3.75 million salary and earned $1,388,889 in prorated pay. He had been projected for a salary of about $4 million for 2021.

Cimber went 0-1 with a 3.97 ERA in 14 games this past season for Cleveland, which acquired the right-hander in 2018 from the San Diego Padres in the deal that brought All-Star closer Brad Hand to the Indians. The 30-year-old Cimber went 6-7 with a 4.30 ERA in 110 appearances with the Indians over 2 1/2 seasons. He was 6-3 in 2019, when he pitched in 68 games.

INDIANS: Rookie reliever Cam Hill underwent surgery on his right wrist after being involved in a car accident in Tulsa, Oklahoma.

Hill shared details of the incident on his Instagram account, saying he was very blessed to only bang up my wrist. Surgery went really well, most importantly the others involved in the accident were all okay.

Hill also posted a photo of him recovering in his hospital bed with his right arm heavily bandaged. He gave a thumbs up with his left hand.

Cleveland said Dr. Brian Chalkin, a hand specialist, operated Monday night on the right-handers lunate bone, located in the mid-carpal joint. The team said surgery went as expected and that it does not have any details yet on Hills rehab or when he might be able to pitch.

Hill made his major league debut with the Indians on July 26 and got his first save two days later against the Chicago White Sox. The 26-year-old went 2-0 with a 4.91 ERA in 18 games with Cleveland.

He made one postseason appearance, allowing three runs in Game 1 of the wild-card series against the New York Yankees.

HALL OF FAME Manager Tom Lasorda has been moved out of intensive care, although he remains hospitalized in Southern California.

Los Angeles Dodgers spokesman Steve Brener said that the teams 93-year-old former manager is doing rehab at the hospital in Orange County. Lasorda has been hospitalized since Nov. 8, although the team didnt make it public until a week later.

Lasorda attended the teams Game 6 victory over the Tampa Bay Rays on Oct. 27 in Texas that clinched the Dodgers first World Series title since 1988.

Lasorda had a record of 1,599-1,439 while managing the Dodgers from 1976-96, guiding them to World Series championships in 1981 and 88. The franchise won four National League pennants and eight division titles under Lasorda. He had a heart attack in June 1996 and retired from managing the Dodgers the following month.

ATHLETICS: Right-hander Burch Smith agreed to a $705,000, one-year contract a day before Wednesdays deadline for teams to offer deals to unsigned players on their rosters.

Smith went 2-0 with a 2.25 ERA and a save in six outings spanning 12 innings for Oakland but was lost for the season in mid-August because of a strained forearm on his pitching side. The As missed his presence in the bullpen as they won the AL West and the wild-card round against the Chicago White Sox before losing to the rival Astros in the AL Division Series.

Also Tuesday, catcher Francisco Pena received a minor league contract. He would earn $600,000 while in the majors if added to the 40-man roster.

METS: New York reached its first agreement with a free agent since Steven Cohen bought the team, a deal with 31-year-old right-hander Trevor May, a person familiar with the negotiations told The Associated Press.

May had a 3.86 ERA in 24 relief appearances for the Minnesota Twins last season, striking out 38 and walking seven in 23 1/3 innings while allowing 20 hits with a career-high fastball velocity averaging 96.66 mph. He earned $816,667 in prorated pay from a salary of $2,205,000.

May had spent all six big league seasons with the Twins, going 23-21 with a 4.44 ERA in 26 starts and 189 relief appearances.

He made 16 starts in 2015, going 8-9 with a 4.00 ERA over 48 appearances. May had Tommy John surgery on March 22, 2017, and returned to the major leagues on July 31, 2018.

May figures to join a bullpen that includes Edwin Diaz, Dellin Betances, Jeurys Familia, Brad Brach and Jacob Barnes.

New Yorks front office is being run by Sandy Alderson, who returned to the Mets as team president on the day that Cohen completed his $2.42 billion purchase from the Wilpon and Katz families.

DRUG TESTS: Major League Baseballs number of drug tests dropped sharply during the novel coronavirus pandemic.

There were 3,733 urine samples and 412 blood samples for human growth hormone testing collected during the year ending with the World Series, independent program administrator Thomas M. Martin said in his annual report. That was down from 9,332 urine samples and 2,287 blood samples in the year ending with the 2019 World Series.

The lower testing numbers were a result of the COVID-19 pandemic as well as the extended closure of the WADA-accredited anti-doping laboratory in Montreal, Martin wrote.

Spring training was interrupted in mid-March and the start of the regular season was delayed from late March until late July. Each teams schedule was cut from 162 games to 60.

There were 10 positive tests for performance-enhancing substances: two for Stanozolol (New York Mets second baseman Robinson Cano and free agent pitcher Victor Alcantara), five for Boldenone (Houston pitcher Francis Martes, Pittsburgh utilityman Pablo Reyes, Arizona infielder Domingo Leyba, Cleveland pitcher Emmanuel Clase and Pittsburgh pitcher Edgar Santana) and three for Dehydrochlormethyltestosterone (DHCMT) (Colorado pitcher Justin Lawrence, Washington catcher Tres Barrera and Houston pitcher Kent Emanuel).

Ninety-one therapeutic use exemptions were granted, 90 for Attention Deficit Hyperactivity Disorder and one for Hypersomnia. That was down from 94 for the previous year, which included 90 for ADHD and one each for Hypersomnia, Hypogonadism and kidney disease.

Exemptions for hyperactivity disorder had ranged from 105-119 annually from 2008-16, prompting some to criticize their issuance as too lenient.

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MLB notebook: Red Sox, Rodriguez agree to one-year, $8.3 million deal to avoid arbitration - pressherald.com

In its latest research titled, FSS Capacity Pricing Trends, Euroconsult, the leading global consulting firm focused on space and satellite-enabled markets, reported that the dramatic pricing declines of the past five years have slowed as a result of notable slowdowns in new capacity supply additions. However, intense pricing pressure is expected to return in advance of new capacity coming online in the 2022-23 timeframe.

Over the past five years, average capacity pricing levels in video markets have dropped 30 percent in aggregate, while data markets have experienced 60 percent declines. While pricing is beginning to stabilize, the previously strong mobility market is now seeing pricing erosion in the short term, due to the COVID-19 pandemic and its impact on global travel.

We are seeing a mixed landscape in current pricing trends, said Brent Prokosh, Senior Affiliate Consultant at Euroconsult and author of the report. Despite the generalized pricing declines globally, , strong demand for HTS capacity in places such as North America and Southeast Asia has led to regional shortages, alleviating pressure in the short-term. While fewer regions have reported sharply declining capacity pricing levels, more challenging competitive environments are reported for Latin America and the Russia & CIS regions. Further, at key orbital hotspots, Direct to Home (DTH) television platform pricing has also been notably resilient.

While DTH pricing of up to $8,000/MHz/month is still in effect in some locations, many platforms have sought to reduce their commitments through lower volume and/or shorter-term renewals. On the lower end, capacity pricing ranges have remained relatively stable over the past year, with $600/MHz/month for regular and less than $100/Mbps/month for large-volume long-term HTS capacity leases still prevailing.

In its 3rd annual edition of the report on satellite capacity pricing trends, Euroconsult provides an analysis of the structural trends impacting the industry and delves into regional pricing for nine different parts of the world. The analysis is based on an expansive database of more than 2,000 capacity pricing contracts and includes roughly 100 new price points derived from more than a dozen interviews and continuous desk research conducted over the past 12 months.

It includes capacity supply fill rates and case studies on the cost base of satellite capacity. It also breaks out pricing trends by spectrum and type of service and includes an overview of milsatcom and mobility pricing. Additionally, for the first time, this years edition of FSS Capacity Pricing Trends includes a section on in-orbit life extension services. It also provides an analysis of the cost base of capacity for nearly 40 HTS systems, including all major Very High Throughput Satellite (VHTS) systems and Non-Geostationary Orbit (NGSO) broadband constellations.

The research projects that HTS fill rates, which are comparatively lower than regular capacity, are expected to drop from 50 percent as of 2020, to below 20 percent by 2023 with new capacity expected to come on line in that time frame. This oversupply will put further pressure on capacity pricing. As a result, Euroconsult projects that operators will seek to drive utilization of new capacity by testing the price elasticity of demand.

Another way that operators are responding to oversupply and pricing erosion is by adopting vertical integration strategies, said Prokosh. This has the potential to provide them with a higher degree of control over pricing conditions. It is an especially relevant trend, given expectations that competition will continue driving the benefits of lower cost base of capacity towards end user services as opposed to the tradition FSS operator wholesale lease model.

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Satellite capacity pricing declines slow, but price pressure expected to increase with new supply entering service in 2023 - Geospatial World

The lame-duck Trump administration is defying precedent by pressing ahead with a fiscal 2022 defense budget request, and could release it before President-elect Joe Biden is sworn in.

The White House Office of Management and Budget and the Pentagon are going back and forth over various items. While the incoming Biden team will likely redo parts of the budget to reflect its own priorities, large portions developed by Trumps Pentagon team are sure to make it into Bidens proposal, which we probably wont see until the spring.

So lets go through whats inside Trumps fiscal 2022 request. My colleague Katie Bo Williams got a copy of the passback a document sent from the White House Office of Management and Budget ordering Pentagon planners to modify their proposal. Defense officials are due to respond with objections or changes this week. A few caveats: this is just a draft, as of earlier this week, and not a finished product. Also, the draft passback document rarely says what the original proposed amounts were, just the changes OMB wants made.

The Topline

The proposed $722 billion spending plan is exactly in line with the five-year budget projections included in Trumps 2021 proposal. Its a 2.3 percent increase over the $705 billion requested for 2021. Top Pentagon leaders have frequently lobbied for 3 percent to 5 percent annual growth. Something else worth noting is that the Trump administration has reduced the Overseas Contingency Operations, or war, portion of the budget from $69 billion in 2021 to roughly $16 billion in 2022. The remaining $706 billion is in the base budget. As usual, the topline figure does not include the Energy Department nuclear weapons spending or various pots of national security spending in other agencies budgets.

Missile Defense

The suggested Missile Defense Agency budget for 2022 is $9.3 billion (about $241 million more than planned), and $52.3 billion over five years (a plus-up of about $4.8 billion). OMB asked MDA to consider putting more money toward a proposed homeland-defense anti-missile layer based on the Aegis system. It also suggests a $1.8 billion plus-up over five years to the Next Generation Interceptor program. That money would fund two contractors through Critical Design Review (CDR) in early FY 2026 rather than just through [preliminary design review], the draft passback memo said. The NGI program is already high-risk, and the best mitigation is keeping two contractors through CDR. Theres also a recommendation for $203 million in fiscal 2022 (and $1.5 billion over five years) for countering hypersonic weapons. The 2022 money would be used to accelerate development and testing of a hypersonic glide phase defeat weapon, associated systems engineering, and integration into Aegis ballistic missile defense weapon systems to defeat adversarial hypersonic threats.

Missiles

OMB wants the Pentagon to spend at least $150 million in 2022 to demonstrate the Mobile Intermediate Range Missile (MIRM) variant to maintain development and testing of a viable ballistic option for future consideration.

Research and Development Priorities

OMB called for increases in Pentagons artificial intelligence and biotechnology research funding, as well as quantum information science.

F-35

The passback reveals a Pentagon proposal to reduce the planned purchase of F-35 Lightning II fighters over the next five years by 40, and use the funds to pay for other items related to the program. The Department should fund all F-35 program cost increases from within the program by reducing the corresponding number of F-35 aircraft to be procured in the FY 2022-26 [future years defense program] to offset those program cost increases, the memo says. The Pentagon is also proposing to cap annual F-35 purchases at 85 jets. Air Force and Navy 2021 budget documents show the Pentagon had planned to buy 85 F-35s, but then increase production to 94 jets in 2023 and 2024 and 96 jets in 2025. OMB directs that reductions to the planned fleet must be based on a strategic risk and capability analysis of the need for the F-35 in the most stressing contingency and that such an analysis is vital to obtain support for any proposed reductions to the fleet. The Department, therefore, shall provide to OMB a dynamic analysis of the ability and risks associated with the planned TACAIR fleet to prevail against expected threats in the Pacific theater in 2030 and 2040 with moderate risk.

Operation & Maintenance Cuts

The White House also asked individual services to trim their proposed operation and maintenance budget: the Army by $2.3 billion to $56.4 billion; the Air Force, $2.5 billion to $52.5 billion; and the Marine Corps, $457 million to $8.8 billion.

Navy

OMB forbids the Navy to go through with its plans to decommission five cruisers over the next five years, a measure that was meant to save some $1.9 billion. It also says the Navy must keep around two fast-attack submarines it planned to decommission in fiscal 2027. The bill for that is $710 million. OMB also orders the Navy to assess all Large Surface Combatants for maximum life extension opportunities after 2026.

Air Force Advanced Battle Management

OMB calls for a $137 million cut from an undisclosed amount in 2022 to the high-profile project known as ABMS. It also recommends a $200 million cut in 2023 and 2024. It was critical of the Air Force, citing a critical Government Accountability Office report released earlier this year.

Space

OMB says its concerned about FY 2020 and FY 2021 congressional marks against the Space Development Agency, the fast-buying satellite shop created by defense leaders less than two years ago. The Pentagon had proposed a precipitous increase in the organizations funding in 2022, which OMB recommends cutting by $200 million (the document does not say how much money SDA is asking for total). It also recommended $200 million in cuts in both 2023 and 2024.

Personnel

OMB directed the Pentagon to include a 2.7 percent pay raise for the military. Thats down from the 3 percent annual increase that the Trump administration requested for fiscal 2021.

Youve reached the Defense One Global Business Brief by Marcus Weisgerber. Send along your tips and feedback to mweisgerber@defenseone.com or @MarcusReports. Check out the Global Business Brief archive here, and tell your friends to subscribe!

Some of the numbers are "fabricated," says one official. But they shed light on GOP lines of attack awaiting Biden.

A Trump appointee wants Air National Guard planes sent to the state that holds the key to Senate control.

Defense Department-led pursuits of next-generation connectivity will hone in on survivability, security, and innovation.

The good news:it appears people should start getting coronavirus vaccines later this month. The bad news: itll take awhile to inoculate enough people to reduce the risk of transmission. This week, the Association of the U.S. Army canceled its annual Global Force Symposium in Huntsville, Alabama, scheduled for March. It will instead host a virtual event similar to what it did for its typically massive in-person October event. The Air Force Association is still scheduled to host an annual in-person conference in Orlando, Florida, in February.

Related: The pandemic could cut business travel 36 percent permanently, the Wall Street Journal reports. You can thank the technology that weve all become more accustomed to using over the past nine months for that.

Now the question remains whether President Trump will veto the bipartisan fiscal 2021 National Defense Authorization Act. The President wants the bill to repeal a law that protects social media companies, whichas Senate Armed Services Committee Jim Inhofe, R-Okla., said has nothing to do with the military.

The U.K.-based defense and security intelligence organization that owns the storied defense journal has purchased the defense market analysis business of D.C.-based consulting firm Avascent. The deal between Janes and Avascent also includes a collaboration agreement through which the two firms can pursue opportunities where their joint capabilities will provide clients with unparalleled insights and advice on critical defence and security issues, Janes said in a statement.

Lockheed Martin has completed its acquisition of Integration Innovation Inc.s (i3) hypersonics business. This acquisition expands Lockheed Martin's capabilities to design, develop and produce integrated hypersonic weapon systems for its customers, Lockheed said. Former i3 CEO Mike Wicks has been named vice president of the Hypersonic Engineering & Accelerated Technologies program within the Hypersonic Strike Portfolio for Lockheed Martin Space.

Speaking of hypersonics: the U.S. and Australian militaries have announced a bilateral effort to advance the development of air-breathing hypersonic technologies, the Pentagon said. The SCIFiRE effort aims to cooperatively advance air-breathing hypersonic technologies into full-size prototypes that are affordable and provide a flexible, long range capability, culminating in flight demonstrations in operationally relevant conditions. The effort will also pursue potential co-production opportunities between the two countries, and leverages U.S. and Australian collaborative hypersonic activities over the last 15 years, namely the Hypersonic International Flight Research Experimentation (HIFiRE) program.

The defense giant and Silicon Valley firm have formed an alliance to develop artificial intelligence solutions for aerospace and defense missions for government customers, including the U.S. Air Force and intelligence community.

Expect to hear lots of calls opposing the proposed F-35 fighter, MQ-9 drone and missile sale to UAE in advance of an expected U.S. Congress vote on the arms deal. Heres a list of some of the groups opposing the sale.

The U.S. Navy awarded BAE Systems a $197 million deal to drydock and modernize the amphibious assault ship. Hull, tank and mechanical work at BAEs Norfolk, Virginia, shipyards is expected to begin in February. If the Navy exercises additional options, the upgrade contract could increase to $237.7 million, according to the company.

Meanwhile, the Navy will decommission the USS Bonhomme Richard, the amphibious assault ship heavily damaged in a fire earlier this year.

The German military placed a $3.2 billion order for 31 NH90 helicopters. The helicopters jointly built by Airbus, Leonardo and Fokker will be used for shipborne operations with the German navy. They will replace Sea the Lynx Mk88A fleet, which entered into service in 1981.

Germanys Rheinmetall and the Czechoslovak Group signed a pact to collaborate on military vehicles. Under this new strategic partnership, both companies want to enable the transfer of defence technology between Germany and the Czech Republic in order to implement projects in the Visegrad states as well as other countries, Rheinmetall said.

President Trump on Monday nominated Scott OGrady, a former F-16 pilot shot down over Bosnia in 1995, to be the assistant secretary of defense for international security affairs.

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Team Trump's 2022 budget plan; COVID canks conference; Raytheon, C3.ai team up; and more. - Defense One

When you hear the word "conservation" you might think about newt-counting or anti-fracking actions. What you probably dont think about is blowing up Jupiter and using its raw materials to build a megastructure enveloping the Sun.

But this is exactly the idea suggested by the ingenious astrophysicist Freeman Dyson back in 1960. He suggested that we could construct a swarm of solar panels enclosing our sun, capturing all its energy. Dyson reasoned that as humans use more and more energy, eventually we are going to outrun what can be captured on Earth alone. Only by expanding the energy metabolism of our civilization beyond our planet could we avoid catastrophic resource exhaustion.

Nowadays, scientists dont think this would require demolishing Jupiter. Anders Sandberg, senior researcher at Oxford Universitys Future of Humanity Institute, explains that it turns out making a sphere from thin metal foil made out of asteroids is way easier. One benefit is that we dont need to disassemble planets, he explains over Skype.

Fortunately, it also turns out that there are more than enough asteroids in the Solar System to make that much foil.

Sandberg explains that such ambitious projects would ultimately provide ways to maintain things we value. If we value biology and biodiversity, then we should preserve it from losses, whether caused by mass extinctions or human stupidity," Sandberg said. But this also means encouraging growth. If biodiversity is good, then we want more of it, and for ecosystems to stick around longer. To this end, Sandberg refers to ideas like Dysons as space gardening. Because, in short, they would grant the ability to cultivate life beyond Earth and spread it throughout the Solar System.

Sandbergs plan for gardening space is new, but the idea that humanity should harness more of the sun to increase the amount of living things is an old one. In 1900, the Serbian inventor Nikola Tesla decided that the greatest problem of science is increasing the total energy flowing through human civilization. Because, he thought, with more energy, we could banish scarcity and live fuller lives.

Tesla didnt propose exactly how to solve this, but he knew what the solution would roughly look like. It will, he said, ultimately involve increasing the amount of the suns energy we can put to use. Because, he figured, almost all complex and valuable thingsfrom ecosystems to sentient brainsrun on solar power. Civilization is just like a big plant: consuming sunlight in the indirect form of crops or coal.

A few years before Tesla, a self-taught genius living in a modest shack in rural Russia had already considered the same problem. Konstantin Tsiolkovsky, who helped invent the rocket, did the math and estimated that our biosphere intercepts only about 4x10-10 of the suns total output. All the rest is squandered, pumped into frozen space. Thats a lot of waste.

Tsiolkovsky proposed a bold solution. He suggested that, in the far future, humans might rearrange the entire Solar System. At first, we could string together "necklaces of asteroids" into sun-girdling halos that could harvest more outgoing light. Later, we could reshape the mass of the planetsinto "cubes, discs, rings"for the same purpose. Then we could harness almost all the Sun.

Tsiolkovsky wanted to do this primarily because he wanted to spread life through the Solar System. At the moment, biology is stuck on one fragile planet. His motivations were, at heart, green: he thought a Solar System with more ecology was better than the current one which is almost entirely barren. Why not turn void and desert into a garden?

In ensuing decades, other scientistslike Vladimir Vernadskywarned that the only way for humanity to ultimately avoid resource depletion would be to wean ourselves off meat and oil and somehow come to feed off the sun directly. This would phase out the inefficiency and immorality of more indirect methods, such as fossil fuels or food chains, they insisted.

Dyson, writing during the 1960s, was driven by similar motivations. Of course, some people didnt like his suggestion of urbanizing a star. One suspicious journalist at the time complained that Dysons spheres would turn stars into traffic lights. But Dyson himself conceived of them as living systems, or artificial biospheres," not industrial disruptions. He said that bringing the Solar System to life in this way would be the stepping stone towards spreading biology to other stars and ultimately greening the galaxy.

But what about plans for space gardening today? Going through a menu of plausible options, Sandberg points first to what he calls biosphere life extension. Our planets biosphere is resilient, but not immortal: in around a billion years our planet will become uninhabitable by natural causes like the expansion of our sun. However, Sandberg and his colleague Karim Jebari, of Swedens Institute for Future Studies, argue that putting solar shields into orbit could protect the biosphere from being scorched as the sun ages. This could prolong the existence of life on our planet for at least another billion years, Sandberg tells me.

Of course, many people in environmental ethics would say, Wait a minute, this stuff is very extreme: theres a lot of hubris involved in trying to control the climate. But we are already messing with the climate of the planet, so we are already altering it regardless," he said.

Say you are an ecocentrist, or someone who cares about ecosystems (including Earth as a whole) beyond any use or value for humans. Even for the staunchest ecocentrist, the potential for using technology to extend the entire biospheres lifespan provides a great reason to keep humans around rather than hoping they go extinct, because they actually are the only species around that can handle the solar radiation and keep ecosystems alive longer term," says Sandberg.

So "gardening" could involve extending the lifespan of Earth. But what about extending life beyond Earth? A first step would be creating conditions for life to persist in space environments on its own, Sandberg explains. He imagines space stations with hydroponic gardens mining asteroids to build more space stations with hydroponic gardens, and this form of habitat filling up the Solar System.

This would be a revolution in the history of life. Life would now actually have the vacuum of space as an ecological niche. Someone could object that there is an awful lot of steel and plastic, compared to flowers, in that vision, he admits. But it is really just some asteroid material getting turned into protective habitats for life. Thats a form of space gardening.

We can think of grander visions. Since Gerard ONeil, scientists have imagined larger space habitats, housing whole ecosystems. Not just trays of hydroponic plants, but actual functioning forests," says Sandberg.

Fully engineered environments like these would allow not just for copies of ecosystems on Earth but experimenting with alternate ones. Indeed, rather than focusing on making other planets Earth-likeor terraforming themSandberg suggests it might make more sense to simply make other planets amenable to biology without necessarily having humans deciding whats there.

Finally, theres the really radical proposals. How about life that thrives within the vacuum of space?

Dyson once spoke about genetically engineering plants capable of living on comets, without atmosphere. Sandberg said that he is skeptical of this idea, but if anyone did manage it, there might be no stopping it.

They would be bound to spread to other Solar Systems in the really long run. And, at that point, theres of course going to be a greening of the galaxyregardless of whether we are planning it or not," he said.

How long might greening the entire galaxy take? If the spores are left to drift and spread passively by their own accord, this could take around two billion years, which is a bit slow by human standards. But, on the standard of the galaxy itself, thats only around about 8 galactic rotations; thats not an enormous amount of time to go from a galaxy that doesnt have life in lots of corners to one that does," he added.

But it's also possible that intelligent life might intervene and help speed up this greening process. This could take as little as 100,000 years. If that happens, then we could be poised for a "phase transition" between a mostly dead and a mostly living Milky Way. Indeed, Sandberg and others are skeptical that our galaxy is already green or has been greened by anyone else.

Given that we may potentially have the technology to send out spores in a few decades, we had better decide on the ethics of doing so soon, because people may try regardless of if a framework exists or not. We might, say, want to throw in a bit of intelligence and designso its more of a garden than a wilderness red in tooth and clawor it might be that we decide to let evolution take its course, Sandberg muses.

Of course, building sun-sapping spheres and seeding the galactic volume might seem ambitious. But, ultimately, if we want to safeguard a future for ecosystems within the universe in the longer term, then it might just be that gardening space and farming the stars is the only genuinely conservationist route.

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Researchers Think Megastructures Can Help Seed Life Throughout the Galaxy - VICE

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The report begin with a scope of the global Dehydroepiandrosterone(DHEA) Market that includes the key findings and essential statistics of the market. This market research report also consists of the market value of the major segments of the global Dehydroepiandrosterone(DHEA) Market. Reports Monitor has found a detailed classification and the definition of the global market that helps the readers to better understand the basic information of the Dehydroepiandrosterone(DHEA) Market. It also highlights the exclusions and inclusions that help the client to understand the scope of the Dehydroepiandrosterone(DHEA) Market.

In Chapter 4 and 14.1, on the basis of types, the Dehydroepiandrosterone(DHEA) market from 2015 to 2025 is primarily split into:PowderTabletsOthers

In Chapter 5 and 14.2, on the basis of applications, the Dehydroepiandrosterone(DHEA) market from 2015 to 2025 covers:Food IndustryPharmaceuticals IndustryOther

The report consists of key market trends, which are possible to impact the growth of the market over the forecast period 2020- 2025. Evaluation of in-depth industry trends is included in the report, along with their product innovations and key market growth.

Competitive Landscape:The report provides a list of all the key players in the Dehydroepiandrosterone(DHEA) Market along with a detailed analysis of the strategies, which the companies are adopting. The strategies mainly include new product development, research, and development, and also provides revenue shares, company overview, and recent company developments to remain competitive in the market.

Regional Analysis For Dehydroepiandrosterone(DHEA) Market:

North America(United States, Canada, and Mexico)Europe(Germany, France, UK, Russia, and Italy)Asia-Pacific(China, Japan, Korea, India, and Southeast Asia)South America (Brazil, Argentina, Colombia, etc.)Middle East and Africa(Saudi Arabia, UAE, Egypt, Nigeria, and South Africa)

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In this study, the years considered to estimate the market size of the Dehydroepiandrosterone(DHEA) are as follows:

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Dehydroepiandrosterone(DHEA) Market 2020-2025 with Growth Factors and Trends with Focusing Key players like BulkSupplements, Natrol, Jarrow Formulas,...

HealthA new stem cell treatment could restore eyesight in some people

Friday, 4th December 2020, 3:18 pm

Researchers discovered that the cells of damaged retinas could be repaired by injecting genetically modified stem cells into the eye.

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The news comes as comedian Al Murray pushed for stem cell donors to come forward, ahead of a charity gig for blood cancer organisation DKMS.

Heres everything you need to know about the scientific discovery - and how you can donate your own stem cells to save the lives of people with blood cell diseases.

Stem cells are produced by bone marrow, and they have the ability to grow into different types of blood cells such as red and white blood cells and platelets.

A stem cell or bone marrow transplant replaces damaged blood cells with healthy ones and can be used to treat conditions affecting the blood cells, like leukaemia and lymphoma.

The transplant involves destroying the unhealthy blood cells and replacing them with the stem cells removed from the blood or bone marrow.

Often, stem cells are taken from one person - usually a close family member or a match with the same or similar tissue type - and they are transferred to the person that needs them.

How could they be used to treat vision damage?

Researchers in Barcelona recently discovered that modified stem cells could potentially help to cure problems with vision.

They found that the cells of damaged eye retinas send out a rescue signal to attract the stem cells that can repair damage.

Stem cells were genetically engineered to make them more sensitive to those signals.

The modified stem cells were transplanted back into mice and human tissue samples and the researchers found that they flocked to the retina cells in large numbers.

In turn, that kept the tissue of the retina alive and functioning.

The new technique is a breakthrough in stem cell research as it suggests stem cells could help to improve sight, and potentially could cure blindness in the future.

Retinal damage is currently incurable and can cause visual disabilities and blindness, especially in older people.

How can stem cells treat conditions?

Stem cells can already be used to treat a number of conditions where the bone marrow is damaged and unable to produce its own healthy blood cells.

Transplants can be used to treat people suffering from different forms of cancer, with someone elses tem cells replacing the patients blood cells that are damaged or destroyed.

Conditions that stem cell transplants can treat include leukemia and lymphoma, which are cancers affecting white blood cells, myeloma, which affects plasma cells, severe aplastic anaemia (bone marrow failure), and other blood disorders.

A stem cell transplant will usually only be carried out if other treatments have been exhausted, but it could save someones life.

How can I donate stem cells?

When its not possible to use someones own stem cells to treat their condition, they need to come from a donor.

However, to improve the chances of the transplant being successful, the donated cells need to have a very similar genetic marker to the patients.

As the number of donors has recently decreased, charities are urgently encouraging healthy people to donate stem cells.

You are able to register to be a donor on the NHS Blood and Transplant website.

The Anthony Nolan charity also takes sign ups, and is specifically looking for younger donors between age 16 and 30.

You will be asked to fill out an application form and will be sent a swab pack so you can be added to the register.

If you ever come up as a match for a patient, you will be contacted by the charity.

Even if you cant join the register, you can donate to Anthony Nolan to help to grow the stem cell register.

Read the original:
How do you donate stem cells? Donating cells can help treat cancer, blindness and other conditions - heres how - The Scotsman

Groundbreaking research in stem cells has propelled scientists understanding of neurodegenerative diseases, including Parksinsons. Could stem cell therapies one day help cure Alzheimers?

Clinical trials of stem cell therapies are now underway to repair the damaged cells of people with Parkinsons disease and age-related macular degeneration. Being Patient spoke with Jack Price, professor of developmental neurobiology at Kings College London and author of the book The Future of Brain Repair, about the potential and challenges of repairing the brain with stem cell therapy.

Being Patient: What is stem cell therapy?

Prof. Jack Price: Its the transplantation of stem cells, either directly into the brain or in a way that gives them access to the brain and influence the brain, to bring about a therapeutic effect.

Being Patient: Are there stem cells in the brain?

Prof. Jack Price: For many years, neuroscientists didnt think there were stem cells in the brain. We now know there are. We know about a population [of stem cells] thats become very important in our understanding of Alzheimers disease and in mood disorders like anxiety and depression. These are stem cells that are found in a part of the brain called the hippocampus.

But by and large, the brain doesnt have stem cells, unlike skin and other tissues in the body. The blood is the classic [example]: Theres a population of stem cells in the bone marrow that regenerates blood all the time.

Being Patient: What makes stem cells so special and why are they a focus of research?

Prof. Jack Price: The definition of stem cells is a population of cells that gives rise to other types of cells. In neural stem cells, precursor cells can make adult brain cells, nerve cells, glial cells, all the different cell types that make up the brain. If you have a disease like Alzheimers or any other neurodegenerative disease, where we know the key pathology is the loss of nerve cells, your brain doesnt normally have the ability to replace those lost brain cells. The idea was [that] if you put stem cells where the loss of brain cells has taken place, maybe those stem cells would replace the lost cells.

Being Patient: What is the potential of stem cell therapy in treating neurodegenerative diseases?

Prof. Jack Price: Theres a piece of absolutely brilliant stem cell science that was done by Shinya Yamanaka in Kyoto in 2006. He showed you could effectively take any cell through a very straightforward genetic manipulation that he discovered, [and] turn them into what we call pluripotent stem cells, which are cells that can make any cell type in the body. They also have an ability that other stem cells generally dont: They can build tissue. If you grow them in a little culture dish, they can start to make little pieces of brain called organoids or cerebroids. This was a groundbreaking technology.

In Parkinsons disease, theres enormous progress and clinical trials are underway now. We know more about the pathology of Parkinsons disease [than in Alzheimers]. The pathology of Alzheimers turns out to be quite complex, and weve had, over the years, quite a few ideas about how it worked. But [turning] those into actual therapies hasnt quite worked as we expected, and we keep having to go back and rethink whats going on in Alzheimers.

The pathology of Parkinsons disease is also difficult. Its not trivial. But at the same time, one thing is clear: a lot of the pathology is associated with the loss of a particular population of nerve cells the midbrain dopaminergic cells. We can start with these pluripotent stem cells and make them make precisely the right type of dopaminergic cell that we know is lost in Parkinsons disease.

This is built on 30 [to] 40 years of research of people trying to find exactly the right cell type to work [with] in Parkinsons disease. They had some early success and fell backwards. But this technology looks much more precise than everything anybodys ever tried before.

In age-related macular degeneration, the disease of the eye where you lose your retinal photoreceptors, there are very clever strategies now where people are using these pluripotent stem cells to make a thing called a retinal pigment epithelium. It lies behind the retina, but its what supports the photoreceptors. It turns out, thats what goes wrong in age-related macular degeneration.

Being Patient: Are there any stem cell therapy approved to treat brain disorders?

Prof. Jack Price: There are no licensed stem cell therapy for any brain disorders anywhere in the world for the simple reason [that] nobody has shown one works. There are a lot of stem cell clinics in the U.S. and somewhat fewer elsewhere who are offering cell therapies that are untested. Theyll put stem cells into you for any disorder youve got. Those cell therapies do not work.

A lot of genuine companies are trying to get these cell therapies to work in clinical trials and falling flat on their face quite often, despite their best efforts. 90% of clinical trials fail, and thats clinical trials of conventional drugs by drug companies that know what theyre doing.

What do you suppose is the chance with a stem cell therapy [that] we dont really understand how it works, [that] we dont quite know how to manufacture it properly, [and that] we dont quite know what cells we really want, of working? The chance is almost zero.

The interview has been edited for length and clarity.

Contact Nicholas Chan at nicholas@beingpatient.com

View original post here:
Repairing the Brain With Stem Cells? A Conversation With Prof. Jack Price - Being Patient

An effective new treatment to restore vision is on the horizon that works by injecting genetically modified stem cells into the eye to mend the damaged retina.

Researchers found that the cells of damaged retinas send out a rescue signal to attract the stem cells that repair eye damage.

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They identified two of these cell signals known as Ccr5 and Cxcr6 and then genetically engineered the stem cells to make them more sensitive to those signals.

When these modified stem cells were transplanted back into mice and human tissue samples in the lab they flocked to the retina cells in much greater numbers, keeping the tissue of the damaged retina alive and functioning.

The technique holds promise for improving sight in people with poor vision and potentially even to cure blindness altogether but the researchers cautioned that any such development was some years away and required much bigger studies to confirm their findings.

One of the main hurdles in using stem cells to treat damaged eyesight is low cell migration and integration in the retina, says Pia Cosma, at the Centre for Genomic Regulation in Barcelona.

After the cells are transplanted they need to reach the retina and integrate through its layers. Here we have found a way to enhance this process using stem cells commonly found in the bone marrow, but in principle can be used with any transplanted cells, Dr Cosma said.

There is still considerable work to be done, but our findings could make stem cell transplants a feasible and realistic option for treating visual impairment and restoring eyesight, she said.

Retinal damage, which is currently incurable, inevitably leads to visual disabilities and in most cases blindness. With a growing and ageing population, the number of people affected by retinal damage is estimated to increase dramatically over the next few decades.

Stem cell therapies have been touted as one way of treating degenerative retinal conditions. Stem cells can be transplanted into the eye, releasing therapeutic molecules with neuroprotective and anti-inflammatory properties that promote the survival, proliferation and self-repair of retinal cells. The stem cells can also generate new retinal cells, replacing lost or damaged ones.

The researchers used mesenchymal stem cells, which are found in bone marrow and can differentiate into lots of types of cells, including retinal cells that respond to light.

Mesenchymal stem cells can also be easily grown outside an organism, providing abundant starting material for transplantation compared to other cell sources such as hematopoietic stem cells.

The study is published in the journal Molecular Therapy.

Excerpt from:
Treatment to restore vision by injecting stem cells into the eye could help people with damaged eyesight - iNews

This article was originally published here

J Pharmacol Exp Ther. 2020 Nov 30:JPET-AR-2020-000277. doi: 10.1124/jpet.120.000277. Online ahead of print.

ABSTRACT

ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator that exhibits selectivity for S1P receptors 1 and 5. Treatment with ONO-4641 leads to a reduction in magnetic resonance imaging disease measures in patients with relapsing-remitting multiple sclerosis. The objective of this study was to explore the potential impact of ONO-4641 treatment based on its immunomodulatory effects. Severe aplastic anemia is a bone marrow (BM) failure disease, typically caused by aberrant immune destruction of blood progenitors. Although the T helper type-1-mediated pathology is well described for aplastic anemia, the molecular mechanisms driving disease progression remain undefined. We evaluated the efficacy of ONO-4641 in a mouse model of aplastic anemia. ONO-4641 reduced the severity of BM failure in a dose-dependent manner, resulting in higher blood and BM cell counts. By evaluating the mode of action, we found that ONO-4641 inhibited the infiltration of donor-derived T lymphocytes to the BM. ONO-4641 also induced the accumulation of hematopoietic stem cells in the BM of mice. These observations indicate, for the first time, that S1P receptor modulators demonstrate efficacy in the mouse model of aplastic anemia and suggest that treatment with ONO-4641 might delay the progression of aplastic anemia. Significance Statement ONO-4641 is a second-generation sphingosine 1-phosphate (S1P) receptor modulator selective for S1P receptors 1 and 5. In this study, we demonstrated that ONO-4641 regulates the trafficking of T lymphocytes along with hematopoietic stem and progenitor cells leading to alleviation of pancytopenia and destruction of bone marrow in a bone marrow failure-induced mouse model mimicking human aplastic anemia.

PMID:33257316 | DOI:10.1124/jpet.120.000277

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Sphingosine 1-phosphate Receptor Modulator ONO-4641 Regulates Trafficking of T Lymphocytes and Hematopoietic Stem Cells and Alleviates Immune-Mediated...