Once the UK left the EU, it would be free to invest in gene editing of crops and livestock to feed the world. Thats what the prime minister, Boris Johnson, told the House of Commons in 2019. And following the UKs formal departure from the EU in January 2021, the government quickly launched a public consultation on the issue.

Yet media reporting might cause plant scientists to have unpleasant flashbacks to the 1990s, when genetically modified (or GM) crops were first being commercialised in Europe. Some of the language used to report on the consultation is eerily similar: the Daily Mail asks its readers whether Frankenstein food is about to hit UK plates. Two decades ago, GM crops were also labelled Frankenfood.

Whereas GM crops typically contain the DNA of two different species, gene editing is more precise and allows scientists to tweak the DNA of a single species by itself. Today, many plant scientists see a clear difference between first-generation genetic modifications and the new plant breeding techniques of gene editing. These include tools like CRISPR, which can be used like genetic scissors to make changes to a plant that mimic natural variation.

In the US and Canada, for example, a non-browning mushroom has found a quick path to market thanks to breeders ability to knock-out the gene that controls the browning enzyme, improving shelf-life and potentially minimising food waste.

Although this was done in a laboratory, natural processes at the genetic level and in response to environmental conditions turn genes on and off in a similar fashion. These tools have health applications, too. CRISPR is being used to treat cancer and has the potential for many more medical applications.

Because gene-edited plants can be indistinguishable from their conventional cousins unlike GM crops countries around the world are grappling with how they should be regulated. In the European Union, a landmark 2018 ruling by the Court of Justice said that new gene-edited crops should be governed by existing legislation that was developed in response to first-generation GM crops and said that if you breed something that could not occur in nature, it counts as genetically-modified.

However, this does not mean as was widely reported that gene-edited crops are automatically GM crops, which by definition could not occur in nature. The EU, like the UK, is now revisiting this issue through a consultation.

As recipients of European plant science funding, we have seen that scientists and the public often talk past one another on the issue of biotechnology. Scientists, for their part, tend to view it in terms of risk (or lack thereof) and invoke humanitys long history of modifying plants for our own purposes. But we need to move beyond this framework and instead take account of the questions and concerns that the general public has about who benefits from this technology, who owns it and what impacts it will have.

First-generation genetic modification tended to focus on farm productivity. Protecting crops from pests was the top priority. Gene-edited crops could contribute to a wider variety of sustainability and health goals in future though, such as by improving nutrition or using resources more efficiently. In fact, a whole raft of technologies could be about to revolutionise the way we make food.

However, as we learned with GM crops, technologies are most effective when the wider public and key stakeholders, such as farmers, are actively included in their development.

There is greater and greater recognition among researchers and policymakers of the need to ensure that new technology meets the needs, expectations and values of the public. We have seen that the involvement of patients can make new health technologies more relevant and effective. Already, there is more talk of democratising new genomic tools like CRISPR.

So although plant scientists will hope to avoid repeating the same debates about biotechnology that they had two decades ago, there is still opportunity to gain public trust in these technologies through active and open dialogue. We must ask ourselves whether the gene editing consultation goes far enough to gain that trust, particularly for those that see this as Frankenstein-like technology.

Link:
Gene-edited crops are now a reality but will the public be on board? - The Conversation UK

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As the air continues to dry and temperatures drop, the yearly battle against dry hands and skin has officially begun. New research from Northwestern University has discovered new evidence deep within the skin about the mechanisms controlling skin renewal and repair.

Skins barrier function gives it the unique ability to fight winter woes and keep water for our bodies. The outer layer of the skin, the skin, is constantly turning over to replace damaged or dead cells, creating new cells to reinforce the barrier function and heal damage. The gene regulatory mechanisms that control epidermis turnover remain incompletely understood.

Every month were covered with a new layer of the epidermis, said Northwesterns Xiaomin Bao, who headed the study. The next question is what does that procedure involve?

The newspaper will be published on Jan. 19 in the journal Nature Communications.

GeneticjunkThe scientific community has developed a wide breadth of knowledge about proteins, the workhorses of various cellular activities. Many mysteries remain about the nature of introns, non-coding segments of DNA that make up 24% of the human genome.

Regardless of the general belief that introns are nothing butgenetic junk, they actually play critical roles in modulating RNA transcription throughout a tissues lifespan. RNA transcription is the first step of gene expression, in which the data from DNA is copied into RNA, which is then subsequently used as a template for synthesizing proteins to drive the specific function of a cell.

Based on where transcription terminates within an intron or at the conclusion of a gene an epidermal stem cell will either remain a stem cell or become a specified cell barrier function. Bao said while its well-known that transcription ends at the end of a gene, her labs research found conflicting data.

Future research could have implications for carcinoma research.

Technology critical to the discovery of the phenomenonSkin cells are gaining popularity with researchers in part because of their regenerative properties and readiness to grow in cultures. This allows researchers to apply an assortment of state-of-the-art technologies. By growing skin cells and regenerating skin tissue in a petri dish, the Bao Lab can experiment with this fast-growing tissue to determine molecular mechanisms and regulatory elements within DNA.

Technology development is an integral driver that enabled us to uncover this new phenomenon, Bao said.

The group used a novel genomic technique that maps where transcription stops. The integration of proteomic approaches identified RNA-binding proteins which read specific regulatory sequences in the introns.

The team further leveraged CRISPR technologies to delete genomic sequences in the intron, which provided direct evidence demonstrating that the crucial roles of introns in modulating gene expression.

Before this study, mechanisms between introns to govern the switch between a skin stem cell and a terminally differential state (for example, a cell that participates in forming a skin barrier), were unknown. Most studies ignored introns, despite them accounting for 10 to 20 times more sequences than the protein-coding regions (exons) in the human genome.

The study demonstrates that different genes may involve different sets of RNA-binding proteins to recognize the regulatory sequences in their introns. These RNA-binding proteins help to mature RNAdecide whether to cut transcription early or dismiss termination sites within an intron during differentiation due to changes in protein availability.

We are only starting to appreciate the roles of the intron in human health and diseases, Bao said.

Results of this study could have broader impacts because, according to Bao, the procedures regulating skin cells are almost definitely not restricted to skin cells. Future research on other systems, including other epithelial tissues, will likely uncover similar patterns.

We are extremely hopeful that what weve found is the first step to knowing what we have ignored in the past, Bao said. My students also wish to know more about the RNA binding proteins which provide specificity in governing which site to use to terminate transcription.

Source:

Originally posted here:
Research finds new proof about the systems controlling skin repair and regeneration - Microbioz India

Recommendation and review posted by Bethany Smith

While the thought of dozens of tiny needles aimed directly at our faces sounds like a scare, microneedling may be worth it for the radiant skin it delivers. As with any trending procedure, it has its pros and consheres what four top doctors want you to know before scheduling an appointment.

It Opens Up the Skin BarrierMicroneedling creates little puncture sites in the skin, which allow for deeper product penetration, says Highland Park, IL plastic surgeon Steven P. Bloch, MD, who recommends combining the treatment with TCA peels that include hydrogen peroxide, exosomesthe healing, skin-calming growth factors derived from stem cellsor vitamins to stimulate collagen and elastin production. Applying medical-grade skin-care products after the procedure offers the best results because the skin will soak everything up much more effectively.

It Stimulates Collagen ProductionAs we age, our bodies produce less collagen (starting as early as our 20s), and therefore our skin begins to lose elasticity. However, Birmingham, AL dermatologist Corey Hartman, MD explains that microneedling promotes collagen production in our skin cells, helping it look as young as possible. Microneedling, which works on all skin types, administers small injuries to kick the bodys natural healing process into gear and rejuvenate the skin, he explains. Though there are only a few procedures in cosmetic dermatology that are truly preventive, microneedling delivers on the promise to stimulate fibroblasts, which synthesize the production of collagen.

ItCanBeEffectiveforTreatingMelasmaOne of the most common concerns women walk into our office with is melasma, says Grand Rapids, MI plastic surgeon Bradley Bengtson, MD. More often than not, melasma is not optimally treated with high-heat laser devices, so microneedling is a great tool to break up the pigment. The procedure banishes dark patches by allowing brightening creams and serums with ingredients like vitamin C to penetrate deep into the epidermal and dermal layers.

ItRequiresNoSkilltoUseAny Tom, Dick, Sally or Jane can buy a microneedling machine, set up a strip-mall shop and offer it to people, says Eagan, MN dermatologist Charles E. Crutchfield III, MD, who stresses that complications can arise if you dont visit a board-certified doctor for the treatment. Instead, he recommends an ablative laser, which also boosts collagen and tightens the skin with much more sophistication.

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4 Doctors Reveal the Pros and Cons to Microneedling Treatments - NewBeauty Magazine

Recommendation and review posted by Bethany Smith

Body Shop stans, assemble! We have collated the best the brand has to offer to optimise your bathroom cabinet.

But before you start shopping, here are a few did you knows. This cruelty-free, British brand was the first international cosmetics brand to prohibit the use of ingredients tested on animals and one of the first to promote Fair Trade with third world countries. Earning its place as a household name over the past four decades plus a cult following, thanks to a diverse range of over 900 products, suitable for different skin tones and types and half of which are vegan.

For some insight, this Brighton-born beauty story dates back to 1976. It was founded by the iconic entrepreneur and human rights activist Dame Anita Roddick, pioneer to ethical consumerism, who wanted to create a high quality, revolutionary skincare range that would be a positive force in the beauty landscape. What differentiated Roddicks vision to other beauty giants was her desire to create the perfect harmony between quality, accessibility, environmental consciousness (starting out with refillable containers etc) and profit. That passion filtered through to employees - and the brand's ideology hasnt much changed along the years.

Helping disadvantaged communities is a brand priority and they have been sourcing their Community Fair Trade (CFT) shea butter from Tungteiya Womens Association in Northern Ghana since 1994. Where 640 women from 11 villages, handcraft shea butter using an 18-stage process of traditional techniques, successfully creating generational opportunities passed from mother to daughter. Their CFT handcrafted paper and gift packaging is also sustainably sourced from Kathmandu, Nepal.

A B Corp certified brand is amongst the 3,000 businesses worldwide to have the highest social and environmental standards for people and the planet. One focus is on using plant-based and recycled plastic (rather than oil-based plastics) and creating initiatives to aid consumers around the world to reuse, repurpose and recycle. In 2019, we reintroduced our pioneering refill scheme, a recycling programme and removed 21 tonnes of plastic from our gifts. says says Linda Campbell, Managing Director for the UK.

The ideals of The Body Shops founder had a direct impact on the direction of the brand. They havent shied away from supporting feminist movements, constantly raising the bar on ethical consciousness and fighting to empower girls and women across all demographics. The Body Shop have spent the last few years initiating and aligning with campaigns, most recently the Covid-19 response derived #IsolatedNotAlone campaign. With the objective of raising awareness on domestic abuse and providing potentially life-saving resources for survivors and bystanders at increased risk during lockdown measures." says Campbell.

If all this doesnt make you feel more passionate about the brand, we dont know what will. And that's before we even get the quality products at consumer friendly prices. But dont let the Body Shop name fool you though, as not only extensive bath and body sup, but skincare, haircare and vegan makeup.

If youre a lover of newness, you might want to investigate the latest drop, which includes Hemp Dry Body Oil, 14, and the Drops of Youth Bouncy Jelly Mist, 16. A gel-to-mist formula protect the skin from indoor and outdoor pollution as well as the effects of blue light from all the Zooming.

But the beauty giant is just as loved for its cult products, from the nourishing glow masks to their world famous body butters (which sell at a rate of one every three seconds). If you want to know what the hype is really about, here is a selection of the 10 bestselling products and why they deserve a spot in your bathroom cabinet.

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Here's Why The Body Shop Is A Cult Brand to Know Plus The Best-Sellers To Buy - GLAMOUR UK

Recommendation and review posted by Bethany Smith

Led by genetic counselor Jennifer Roggenbuck, MS, LGC, a one-year grant awarded by the ALS Association is funding Ohio States formal development of national clinical guidelines for ALS genetic testing that will be used by healthcare centers nationwide. We have cared for thousands of patients since opening our ALS/MND Clinic in the mid-1990s and have extensive experience with genetic testing, says Roggenbuck. We believe its extremely important to establish national testing standards, to ensure that all persons with ALS can benefit from genetic advances, and to fuel further research.

Genetic testing and counseling directly benefits our patients, explains clinic director Stephen J. Kolb, MD, PhD. Genetic characterization of our patients also opens the door to research opportunities. In addition to formal genetic counseling, our clinic has an ALS Clinical Research Coordinator who meets with every patient to explain our basic science and clinical trial opportunities and answer any related questions. Our patient partnerships are a key factor in the size and scope of our research program. Because Ohio State is now among the largest ALS research sites in the country, were regularly asked to participate in or lead high profile National Institutes of Health (NIH) and foundation studies.

A major focus of our program is to connect the individuals that we serve in clinic to the critical research efforts that are happening in laboratories here at Ohio State as well as those throughout the world. One example of this is the development of individualized models of disease, says Dr. Kolb. We and our collaborators are able to biopsy a persons skin cells and turn them into a type of stem cell that allow us to reproduce each patients exact ALS condition in the laboratory. We can then study the models to look for causes and develop therapies on a case-by-case basis.

The ALS/MND Multidisciplinary Clinic and Research Program is part of Ohio States Neurological Institute, with one of the largest neuromuscular centers in the country, so there is an established team of multidisciplinary experts to help each patient, even those with unusual or difficult symptoms. The ALS/MND program is led by Kolb, a physician-scientist, and in addition to the full-time research coordinator, he is joined by a clinical neurologist, genetic counselor, clinical nurse practitioner, social worker and nutritionist, as well as physical, occupational, respiratory and speech therapists. The Ohio State Department of Neurology is a member of NeuroNEXT: Network for Excellence in Neuroscience Clinical Trials and a contributing member to the Northeast ALS Consortium (NEALS).

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Ohio State establishing national standards for ALS genetic testing, research and patient care | Ohio State Medical Center - Wexner Medical Center -...

Recommendation and review posted by Bethany Smith

Global Plant Stem Cell Market 2020 by Company, Regions, Type and Application, Forecast to 2026

Plant stem cells are undifferentiated cells within the meristems of plants.Plantstem cellsserve as the origin of plant vitality as they maintain themselves and provide a steady supply ofprecursor cellsto form various tissues and organs in plants. Plant stem cells are characterized by two distinctive properties namely its ability to create differentiated celltypes and to self-renew such that the number of stem cells remain stable. The plant stem cell market focuses on this ability of plant cells and thus, processed extracts from the buds, roots and shoots are in high demand and are widely used for topical uses.

This report is an essential reference for those who look for detailed information on the Global Plant Stem Cell Market. The report covers data on global markets including historical and future trends for supply, market size, prices, trading, competition and value chain as well as Global major vendor information. In addition to the data part, the report also provides an overview of Plant Stem Cell market, including classification, application, manufacturing technology, industry chain analysis and the latest market dynamics.

Global Plant Stem Cell Market Research Reports provides information regarding market trends, competitive landscape, market analysis, cost structure, capacity, revenue, gross profit, business distribution and forecast 2024.

Plant Stem Cell Market was valued at xx million US$ in 2020 and will reach xx million US$ by the end of 2025, growing at a CAGR of xx% during 2020-2025.

The Global Plant Stem Cell market is highly competitive and consists of a number of major manufacturers like Oriflame Holding AG, MyChelle Dermaceuticals, LLC, Natura Therapeutics Inc, Aidan Products LLC, Mibelle Biochemistry, Phyto Science SDN BHD, and Renature Skin Care Inc.

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Scope of the Report:

The segmentation has been done on the basis of types, applications, technology, and users. Each segment has been further explained with the help of Table of Content, Tables and Figures. This breakdown of the market gives the readers an objective view of the global Plant Stem Cell market, which is essential to make sound investments. Both these assess the path the market is likely to take by factoring in strengths, weaknesses, opportunities, and threats.

This report also includes the overall and comprehensive study of the Plant Stem Cell market with all its aspects influencing the growth of the market. This report is an exhaustive quantitative analysis of the Plant Stem Cell industry and provides data for making strategies to increase the market growth and effectiveness.

The Global Plant Stem Cell market 2019 research provides a basic overview of the industry including definitions, classifications, applications and industry chain structure. The Global Plant Stem Cell market analysis is provided for the international markets including development trends, competitive landscape analysis, and key regions development status.

Development policies and plans are discussed as well as manufacturing processes and cost structures are also analyzed. This report also states import/export consumption, supply and demand Figures, cost, price, revenue and gross margins.

In addition to this, regional analysis is conducted to identify the leading region and calculate its share in the global Plant Stem Cell market. Various factors positively impacting the growth of the Plant Stem Cell market in the leading region are also discussed in the report. The global Plant Stem Cell market is also segmented on the basis of types, end users, geography and other segments.

On the basis of geography, the market is segmented into North America, Europe, Asia Pacific, Latin America, and the Middle East and Africa.

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The major factors defined in this report are:

The study objectives of this report are:

To study and analyze the global Plant Stem Cell consumption (value & volume) by key regions/countries, product type and application, history data from 2014 to 2018, and forecast to 2024.

To understand the structure of Plant Stem Cell market by identifying its various subsegments.

Focuses on the key global Plant Stem Cell manufacturers, to define, describe and analyze the sales volume, value, market share, market competition landscape, SWOT analysis and development plans in next few years.

To analyze the Plant Stem Cell with respect to individual growth trends, future prospects, and their contribution to the total market.

To share detailed information about the key factors influencing the growth of the market (growth potential, opportunities, drivers, industry-specific challenges and risks).

To project the consumption of Plant Stem Cell submarkets, with respect to key regions (along with their respective key countries).

To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the market.

To strategically profile the key players and comprehensively analyze their growth strategies.

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Table of Content:

Chapter One: Industry Overview of Plant Stem Cell

Chapter Two: Manufacturing Cost Structure Analysis

Chapter Three: Development and Manufacturing Plants Analysis of Plant Stem Cell

Chapter Four: Key Figures of Major Manufacturers

Chapter Five: Plant Stem Cell Regional Market Analysis

Chapter Six: Plant Stem Cell Segment Market Analysis (by Type)

Chapter Seven: Plant Stem Cell Segment Market Analysis (by Application)

Chapter Eight: Plant Stem Cell Major Manufacturers Analysis

Chapter Nine: Development Trend of Analysis of Plant Stem Cell Market

Chapter Ten: Marketing Channel

Chapter Eleven: Conclusion

Continued here:
Plant Stem Cell Market- Growth Opportunities by Manufacturers, Regions, Type and Application; Trends Forecast to 2026 | Coherent Market Insights - The...

Recommendation and review posted by Bethany Smith

Regenerative Medicine Market Major Players:

Players active in the global regenerative medicine market include Osiris Therapeutics, Cook Biotech, Organogenesis, Baxter International, Inc., Stryker and RTI surgical, LifeSciences, CryoLife, Advanced Cell Technology, Sanofi, BioMimetic Therapeutics, Medtronic, StemCellsInc, and LifeCell Kinetic Concepts, among others.

ALSO READ :https://sapanas.tumblr.com/post/631130245458739200/regenerative-medicine-market-competitive-analysis

Regenerative Medicine Market Outlook

Global regenerative medicine market is growing continually, witnessing a massive uptake. Market growth primarily attributes to the increasing advancement in healthcare technology and the growing prevalence of chronic diseases. Besides, improvements in the field of regenerative medicine and stem cell technology drive the growth of the market excellently.

Moreover, the rising uptake of therapeutics such as stem cell biology, cellular therapy, tissue engineering in applications, including cord blood, oncology, urology, orthopedics, neurology, dermatology, and others accelerate the market growth. According to Market Research Future (MRFR), the global regenerative medicine market is poised to grow at 25.4% CAGR throughout the forecast period (2016 2022).

ALSO READ :https://yarabook.com/read-blog/138540

Additionally, the rising uptake of stem cell & tissue engineering processes in the treatment of health issues ranging from orthopedics, musculoskeletal & spine, dental, and skin/integumentary to cancer, neurology, and cardiology substantiate the market growth. Furthermore, the increasing rate of road accidents, injuries, and trauma cases drive the market exponentially, driving the demand for transplants & surgical reconstruction procedures.

On the other hand, factors such as the lack of awareness, skilled professionals, and stringent regulatory policies are projected to act as significant impeders for market growth. Nevertheless, funding support for the development of regenerative medicines would support the growth of the market throughout the predicted period. Also, widening application areas of regenerative medicines in the field of stem cell reconstructive and skin grafting would increase the market growth.

Global Regenerative Medicine Market Segments

The analysis is segmented into four dynamics;

By Material: Synthetic Materials, Genetically Engineered Materials, Pharmaceuticals, and others.

By Therapy: Stem Cell Biology, Cellular Therapy, Tissue Engineering, and others.

By Application: Cord Blood, Oncology, Urology, Orthopedics, Neurology, Dermatology, and others.

ALSO READ :http://www.marketwatch.com/press-release/fram-market-2021-industrytrends-opportunities-market-volume-competitive-landscape-possible-challenges-and-forecast-to-2025-2021-01-06

By Regions: Americas, Europe, Asia Pacific, Middle East & Africa, and Rest-of-the-World.

Regenerative Medicine Market Regional Analysis

North America is projected to continue dominating the globalregenerative medicine marketthroughout the forecast period. In 2015, North America accounted for more than 44% of the overall market share. This huge market growth attributes to the presence of a large number of major players and pharma & biotechnology companies. Moreover, huge investments made by public & private organizations drive the regenerative medicine industry in the region.

Besides, the rising prevalence of chronic diseases and orthopedic issues and increasing clinical trials to evaluate the therapeutic potential of products foster regional market growth. Also, the well-spread awareness towards the therapeutic potency of regenerative medicines impacts the market growth positively. The North American regenerative medicine market is expected to grow at a robust CAGR of 22.3% over the review period.

Europe stands second in the global regenerative medicine market. Factors such as the increasing per capita healthcare expenses and penetration of healthcare sectors in the region boost the market growth. Additionally, the rising government support and R&D funding in the life science developments substantiate the regional market growth. Markets in the UK, Germany, and France, contribute to the regional market majorly. The European regenerative medicine market is estimated to grow at 22.5% CAGR during the assessment period.

ALSO READ :http://www.marketwatch.com/press-release/m2m-communication-market-demand-to-rise-amid-industrial-automation-industry-analysis-with-business-trends-covid19-outbreak-competitor-strategyforecast-to-2023-2021-01-05

The Asia Pacific regenerative medicine market has emerged as a rapidly growing market. Factors such as the large advances in biotechnology and increasing government support for R&D are fostering the growth of the regional market. Regenerative medicine markets in highly populated countries such as China, India, and Japan support the regional market growth excellently, heading with huge technological advances. The APAC Regenerative Medicine market is predicted to demonstrate huge growth potential.

Global Regenerative Medicine Market Competitive Analysis

The well-established regenerative medicine market appears to be highly competitive with the presence of several notable players. To gain a larger competitive advantage, market players incorporate strategic initiatives such as mergers & acquisitions, expansions, and product/technology launch. Also, they make substantial investments to drive R&D to develop their capabilities and to expand their global footprints. Simultaneously, R&D funding programs initiated by the governments to enhance regenerative medicine capabilities are offering high growth potential. This is further going to attract several new entrants to the market and intensify the market competition further.

Regenerative Medicine Industry/Innovations/Related News:

March 15, 2020 - Research team at the University of Sheffield published their study on stem cell mutations that could improve regenerative medicine in the magazine Stem Cell Reports. Their study gives new insights into the cause of mutations in pluripotent stem cells and potential ways of stopping these mutations from occurring. It also suggests ways to reduce the likelihood of variations occurring in these cells when cultured. There is considerable interest in using Pluripotent stem cells to produce cells that can replace diseased or damaged tissues in applications referred to as regenerative medicine.

ALSO READ :http://www.marketwatch.com/press-release/waste-to-energy-market-share-size-key-players-regional-study-and-forecast-2024-2020-12-30

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Women with attention-deficit/hyperactivity disorder (ADHD) may be more vulnerable to hormone-related mood disorders such as premenstrual dysphoric disorder (PMDD), postpartum depression (PPD), and climacteric mood symptoms during their lifespan, researchers found in a study that was recently published in the Journal of Psychiatric Research.

The study included 209 adult female patients with ADHD (mean age of 34.5 years, standard deviation (SD) of 11.5 years) who were in care in April and May 2016 at the PsyQ outpatient clinic for Adult ADHD in The Hague, the Netherlands.

Of the participants, 174 were of reproductive age, 35 were peri-or-postmenopausal and 70 had irregular menstrual cycles. Of the 85 participants who had at least 1 biological child, 53 (62.4%) reported having complications antepartum, peripartum and/or postpartum after their first childbirth.

The researchers assessed the patients using the Diagnostic Interview for ADHD in adults 2.0 based on DSM-IV criteria, the Neuropsychiatric Interview Plus (the M.I.N.I. Plus), the Edinburgh Postnatal Depression Scale (EPDS), the Greene Climacteric Scale (GCS) and the Munich Chronotype Questionnaire (MCTQ).

More women with ADHD and PMDD used contraceptives (50.6%) than those who did not have PMDD (68.1%, 2 (1) = 5.82; P =.016, odds ratio (OR) = 2.09). PMDD symptoms were associated with the use of antidepressants (t = 1.991, P =.048), contraceptives (t = 2.515, P =.013), complications during pregnancy (F = 5.385, P =.008) and a mood disorder in remission (t = 2.500, P =.013). Adjusting for covariates and correcting for age and education level, use of contraceptives was associated with lower PMDD symptoms, and using antidepressants was associated with higher PMDD symptoms.

The prevalence of PPD indications (49 of the 85 who had at least 1 biological child) after the first childbirth was higher among the women included in the study than groups included in 2 systemic reviews: 19.6% among low-to middle-income countries and 14.5% in high-income countries. PMDD symptoms were significantly higher in the PPD-group compared to the no-PPD-group, with a medium effect size, (M = 7.38, SD = 3.28 vs. M = 5.53, SD = 4.07; t (81) = 2.30, P =.024, d = 0.50). The PPD-group used significantly more antidepressants (49% of the patients) than the no-PPD-group (25%, 2 = 6.330; P =.010).

The researchers found significant differences on GCS subscores for depression between the 11 women with PMDD and the 14 without PMDD (F (1) = 5.105, P =.030) and sexual dysfunction (F (1) = 5.191, P =.029) as well as a significant correlation between more PMDD symptoms and higher total GCS (r = 0.511, n = 38, P =.001) and the subscores psychosocial (r = 0.441, n = 38, P =.006), anxiety (r = 0.381, n = 38, P =.020), depression (r = 0.0418, n = 38, P =.010) and somatic (r = 0.425, n = 38, P =.009) complaints. The PPD group (n = 18) showed significantly higher GCS scores (vs. no PPD, n = 8) on the total score (F = 7.18 (1), P =.013), the subscores psychosocial (F = 6.01 (1), P =.021), anxiety (F = 5.84 (1), P =.023), depression (F = 4.51 (1), P =.043), vasomotor (F = 7.03 (1), P =.013) and sexual dysfunction (F = 4.56 (1), P =.043).

Limitations of the study include possible recall bias and the inability to find significant association between a broad spectrum of psychiatric disorders and PMDD.

Reference

Dorani F, Bijlenga D, Beekman ATF, van Someren EJW, Kooij JJS. Prevalence of hormone-related mood disorder symptoms in women with ADHD. J Psychiatr Res. Published online December 3, 2020. doi:10.1016/j.jpsychires.2020.12.005

Link:
Women With ADHD May Have More Severe Symptoms of Premenstrual Dysphoric Disorder, Postpartum Depression, and Menopause - Psychiatry Advisor

Recommendation and review posted by Bethany Smith

Lets face it, guys: getting old isnt easy. Whether youre just entering your 40s or youre in the middle of your retirement years, you know that your body doesnt look or function the same way it did 5, 10, 20, or even 30 years ago. However, the first step toward slowing the aging process is knowing what signs to look out for. Once you know what age looks like, you can start implementing methods to combat physical signs of aging at their source. So, lets take a closer look at the four signs of aging in men that you should be aware of!

Erectile dysfunction is one of the most common medical issues in men aged 40 or over. While some men feel uncomfortable talking about this problem, theres no shame in it. It is extremely common and is in no way a reflection of your masculinity. As men age, their blood vessels shrink, their hearts weaken, and their circulation slows. As a result, it can become harder to get and maintain an erection. While there are plenty of short-term fixes available on the market, you can also try out GAINSWave therapy through the ThriveMD clinic. In fact, GAINSWave therapy is one of the best ways to improve your sex life for the long-term!

The jury is still out on whether or not the dad bod is a good look for men, but either way, its a common sign that youre getting older. Testosterone is the hormone in your body that is responsible for building muscle mass. As you age, your levels of testosterone begin to taper off and eventually decline. This leads to decreased muscle production throughout the body, including the abdomen. When your abs become weaker, a belly will form. However, regular exercise and even hormone therapy can easily reverse or prevent this issue.

Unfortunately, theres only so much you can do about your genetics. Some men begin balding in their 20s, while others keep a full head of hair well into their 80s, 90s, and beyond! It all depends on your genetics. However, the vast majority of men will start to experience some degree of hair loss when they reach 40. As you age, your hairline will likely continue to recede. However, there are plenty of products that can slow or even reverse this process. If you dont mind taking the artificial route, hair plugs are a great way to cover up bald patches as well.

Though age spots can occur in both men and women, they are a little more common in men. These spots often appear as dark brown or tan spots on the skin. Age spots can appear just about anywhere, though they are most common on the hands, arms, face, neck, and back. Sometimes known as liver spots, age spots are often the result of excessive sun exposure over a long period of time. Thus, you can reduce the risk of getting age spots by limiting your sun exposure and wearing protection against the sun (like sunscreen).

Photo: Shutterstock

Link:
4 Signs of Aging In Men That You Should Be Aware Of - The Good Men Project

Recommendation and review posted by Bethany Smith

DEAR MAYO CLINIC: My mom was diagnosed with breast cancer. During her care, she was found to have a BRCA2 mutation. Her doctor suggested that my brothers and I get tested for this mutation, too. I am a 26-year-old woman, and I am not sure what this means for me and my risk of cancer.

ANSWER: Having a loved one with a breast cancer diagnosis can be scary. It also can become confusing when you start to hear about genetic mutations. The good news is that the information can help guide your family regarding screening and future cancer risk.

BRCA2 is a genetic abnormality that can be passed down from a parent to children. It is autosomal dominant, which means there is a 50% chance that each of your moms biological children could have the mutation. Being positive for the mutation would mean that you or your brothers may be at increased risk of developing certain cancers, compared to the general population.

In addition to breast cancer, these cancers are also known to be associated with BRCA2: ovarian cancer, melanoma, prostate cancer and pancreatic cancer.

To understand your risk, you would want to meet with a genetic counselor who can help you understand the implications of undergoing genetic testing and whether this is something you want to do. Typically, genetic testing is performed using a blood or saliva sample. The counselor would review the results with you and, if you are positive, recommend next steps to learn more about personalized screening and specific risk reduction options.

Generally speaking, it is recommended that women who have a BRCA2 mutation begin monthly breast self-examinations, beginning at 18. Clinical breast examinations are recommended every six months, beginning at 25, or before if there is an earlier breast cancer in the family. Annual breast MRIs should begin at 25. Tomosynthesis mammograms are recommended annually, beginning at 30. They are usually alternated with breast MRIs every six months. Based on risk and family history, some woman may choose to undergo a preventive mastectomy to remove their breast tissue and hopefully decrease their risk of developing breast cancer.

There is no screening test for ovarian cancer. However, women can have transvaginal ultrasounds and a blood test called CA 125 every six to 12 months, beginning at ages 30-35, while their ovaries are still in place.

If desired, women can undergo surgery to remove their ovaries and fallopian tubes once they are done having children. Ideally, this would occur between the ages of 40-45. As this surgery results in women going through menopause, some women may be started on hormone therapy until ages 50-51 to alleviate menopausal symptoms and offset some long-term risks associated with early menopause.

Research has shown that many ovarian cancers begin in the fallopian tubes. With this knowledge, women have recently been having surgery to remove their fallopian tubes and delay surgery to remove their ovaries for a few years though the recommended age for a woman to have her ovaries removed is still 40-45 in a BRCA2 mutation carrier. The benefit of removing just the fallopian tubes is that this allows women to preserve their natural hormonal function longer. The safety of this strategy is being studied, and this type of surgery is being performed as part of clinical trials.

Women who undergo surgery to remove their ovaries before menopause have a 50% reduction in their risk of developing breast cancer. In addition to surgeries, there are medications that can be given to help decrease the risk of developing breast and ovarian cancers. Selective Estrogen Receptor Modulators (SERMS) and Aromatase Inhibitors (AIs) are types of medications that can reduce the risk of developing breast cancer. Oral contraceptives can decrease the risk of developing ovarian cancer by 50%.

Since the BRCA2 mutation can be passed down to offspring, understanding your status and that of a future partner is important, as there is a genetic condition called Fanconi anemia that can occur if both the male and female partners have a BRCA2 mutation.

Thus, for men and women who test positive for BRCA2 and have not yet had biological children, it may be worthwhile to meet with a specialist in reproductive endocrinology and infertility to discuss options.

There are no standard screening guidelines for pancreatic cancer or melanoma. Based on your situation, a consultation with a pancreatic specialist may be worthwhile to discuss whether to pursue MRI or endoscopic ultrasound. Likewise, a referral to a dermatologist can be made to initiate skin cancer screenings.

Understandably, you may be nervous about your risk for cancer, given your mothers diagnosis. However, you are young, and you should not feel rushed to make any decisions regarding genetic testing. If you choose to undergo testing and are found to have a BRCA2 mutation, your health care providers will give you the information that you need so that you can begin to think about what makes sense for your life and your priorities.

Casey Swanson, physician assistant, Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota

As an Amazon Associate I earn from qualifying purchases.

Originally posted here:
Genetic abnormalities and cancer risk | Mind and Body | nny360.com - NNY360

Recommendation and review posted by Bethany Smith

Transcranial magnetic stimulation (TMS) is a type of brain stimulation therapy.

Its a noninvasive treatment that uses electromagnetic pulses to stimulate nerve cells, which may improve symptoms of neurological or mental health disorders.

TMS is mainly used to treat depression. Its had success helping people who dont respond to antidepressant medication and psychotherapy. In fact, in 2008 the Food and Drug Administration (FDA) approved TMS for this purpose.

Theres also some evidence that TMS may help other disorders, like anxiety and Parkinsons disease.

Since TMS uses repetitive electrical impulses, its sometimes called repetitive transcranial magnetic stimulation (rTMS). The terms are often used interchangeably.

If youre curious about the benefits and side effects of TMS, read on.

The therapy is done by a TMS technician or TMS physician. Its an outpatient procedure, so it may be done in a medical clinic. If its done in a hospital, you wont need to stay overnight.

Before the procedure, youll need to remove items that are sensitive to magnets, like jewelry.

Heres what you can expect during TMS:

Youll need to repeat the procedure 5 days a week, for about 4 to 6 weeks. The exact length of your treatment depends on your response and specific condition.

There are many possible benefits of TMS therapy. Researchers are still studying the procedure, but it may help the following conditions:

TMS is primarily used to treat major depressive disorder (MDD), sometimes simply called depression.

Its generally recommended for those who havent found relief from medication and psychotherapy. This is called treatment-resistant depression. Approximately 30 percent of people with depression dont respond to these treatments.

According to 2015 research, depression is linked to reduced activity in the prefrontal cortex. This part of the brain is involved with depression symptoms, like low energy levels and appetite changes.

TMS may help by stimulating nerve cells and increasing activity in this area.

TMS may improve symptoms of obsessive-compulsive disorder (OCD).

The FDA approved TMS for OCD in 2018. As with depression, TMS is recommended if a person with OCD hasnt responded to medication and psychotherapy.

According to one study, people with OCD often have increased activity between the prefrontal cortex and striatum. This hyperconnectivity is associated with severe OCD symptoms.

TMS can be used to inhibit the activity in this part of the brain, thus reducing OCD symptoms.

As TMS treats psychological disorders like depression and OCD, it may also ease anxiety. Thats because these conditions often cause anxiety symptoms.

TMS could also be beneficial for generalized anxiety disorder (GAD).

In anxiety, theres often increased nerve cell activity in the prefrontal cortex. TMS may reduce the activity in this region, according to a 2019 study.

According to a 2019 review, TMS showed effectiveness for post-traumatic stress disorder (PTSD). As mentioned, TMS can target the prefrontal cortex, which regulates how you process fear and worry.

A 2018 trial found that TMS alongside cognitive processing therapy was effective for PTSD. The therapeutic effect of this combination lasted for 6 months.

Theres some evidence that TMS may help stroke rehabilitation.

A stroke happens when blood flow to the brain is blocked or reduced, causing brain cells to die. This can result in long-term loss of muscle movement.

According to research, using TMS after a stroke could promote motor recovery. The idea is that the magnetic impulses can alter the activity of the motor cortex, the part of the brain that controls voluntary movement.

A 2017 article also shares that TMS may improve dysphagia, or difficulty swallowing, by stimulating the motor cortex. They add that dysphagia affects 50 percent of people who have experienced a stroke.

Schizophrenia is a chronic, and often severe, psychiatric disorder.

A main symptom of the condition is auditory hallucinations, which affect 75 percent of people with schizophrenia.

According to a 2019 review, targeting the temporoparietal cortex could be beneficial for auditory hallucinations. This part of the brain, which is involved in language, is typically overactive in schizophrenia.

Parkinsons disease is a neurological disorder. It causes motor dysfunction, including tremors, balance issues, and freezing of gait. Freezing of gait occurs when you feel frozen and cant move while walking.

A 2020 study found that TMS may improve freezing of gait. According to the researchers, TMS normalized the connections between parts of the brain involved in gait freezing.

TMS might have benefits for Alzheimers disease, a form of dementia. This disorder causes progressive memory loss and cognitive decline.

According to newer research, its thought that TMS could help Alzheimers disease by altering the neural connections involved in memory and learning. However, more research is necessary to understand how TMS can manage Alzheimers disease.

TMS could potentially improve chronic pain conditions, such as fibromyalgia. A 2017 analysis shares that it may help by stimulating the motor cortex and controlling neurotransmitters involved in pain.

Its worth noting that depression and chronic pain often occur together. Depression can worsen chronic pain, so TMS may help by treating depression symptoms.

Nicotine releases dopamine, also called the happy hormone. It sends signals to the reward system of your brain, including the prefrontal cortex, resulting in nicotine cravings and addiction.

According to a 2013 study, TMS could help reduce nicotine cravings by targeting the prefrontal cortex.

The researchers think that TMS promotes the release of dopamine, which reduces the need for nicotine.

Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the nervous system. It commonly causes spasticity, or muscle tightness that makes it difficult to move.

In a 2019 study, researchers used TMS on the motor cortex of people with MS. The treatment, combined with physical therapy, was found to decrease spasticity.

To date, TMS therapy has mostly been studied as a treatment for depression.

The success rate of TMS for depression is promising. Response rates for depression are between 30 and 64 percent.

More research is needed to understand the success rate for other medical conditions.

If you have depression, a doctor will likely recommend antidepressants and psychotherapy before TMS.

However, you may be a good candidate for TMS if you:

If youre young, TMS might be an ideal choice. Thats because younger people are more prone to developing adverse side effects from antidepressants.

TMS is considered safe, but its not for everyone.

You should avoid this treatment if you have metal in your head, such as:

The magnetic fields in TMS can make these implants heat up or move, which can cause serious injuries.

Its OK to get the treatment if you have braces or dental fillings.

You may also need to avoid TMS if you:

TMS side effects are uncommon. If complications do occur, they may include:

Symptoms like headaches and lightheadedness usually go away after several treatments.

Theres also the risk of seizures, but this side effect is rare. Theres a 0.1 percent risk of developing seizures during a course of TMS therapy.

One course of TMS can cost between $6,000 to $12,000 out of pocket.

Your health insurance provider might offer coverage, but this depends on your medical history. You may be required to try at least four antidepressants before receiving TMS coverage.

Alternatively, they might provide coverage if you experience negative reactions when using antidepressants.

If antidepressants and psychotherapy dont work for you, Medicare will cover TMS therapy.

Since youre expected to get treatment 5 days a week for multiple weeks, you may have to miss a few hours of work each day. This depends on your schedule, the location of the clinic, and the time of your appointments.

One session can take anywhere from 30 to 60 minutes, so you may be able to do the treatment before or after work.

TMS targets the activity of nerve cells in your brain, which may alleviate depression symptoms. It could also have benefit for disorders like OCD, anxiety, and PTSD as well.

The procedure may even improve motor dysfunction, making it potentially helpful for Parkinsons disease, multiple sclerosis, or stroke rehabilitation.

If youre interested in TMS, talk with a doctor. You may be a good candidate if youre young, have a low risk of seizures, and havent felt relief from antidepressants.

Link:
TMS Therapy: What It Treats, Benefits, Side Effects, and Costs - Healthline

Recommendation and review posted by Bethany Smith

breathe ilo, OCON Healthcare and Eli are three femtech startups innovating in the fertility and ... [+] contraception space

Its not a secret that finally, after years of being overlooked, womens health is having its moment. According to Frost & Sullivans report, the femtech (female technology) market revenue is expected to reach $1.1 billion by 2024, growing at a compound annual growth rate (CAGR) of 12.9%. The report states that, through solutions targeting early diagnosis and leveraging connected healthcare services, these technologies can reduce healthcare costs, decreasing the overall cost burden of a country while elevating healthcare standards and quality of life for women. But it took a long time for female healthcare to be where it is today.

Ever since the FDA (The United States Food and Drug Administration) in 1977 issued a guideline banning most women of childbearing potential from participating in clinical research studies (since certain drugs at that time were causing serious birth defects), women werent included (at least not enough) in medical research. In 1985, new guidelines were issued to encourage more inclusion of women in studies. However, even that wasnt enough to close the gender gap in medical research - analyses found that women were still seriously underrepresented in important studies on common diseases such as heart disease. Finally, in 1993, the FDA issued a new guideline which was followed by Congress writing the NIH inclusion policy into Federal law through a section in the NIH Revitalization Act of 1993 titled Women and Minorities as Subjects in Clinical Research.

Fast forward to today, womens health as a category has gone beyond just healthcare, is hugely impacted by the use of technology, and is all but a niche - it affects more than just females - fertility, for example, is not just a womens issue, despite the misconception that (in)fertility is still a largely female problem (40-50% of all fertility problems are due to the male factor).

The femtech industry has generated just over $376 million in venture capital across 57 deals in 2020 and some of the largest exits in recent years include femtech companies - Progynys $130 million IPO in 2019 and Bayers acquisition of KaNDy Therapeutics in 2020 for $425 million. $688.8 million has been invested in digital health companies targeting fertility and pregnancy/motherhood through H1 2020, which represents 65% of all femtech funding. The potential of it is massive - female health is not just female health, it affects men, children, and whole families as women are primary caregivers more often than not. Female health is a public health issue and should be treated as a priority.

Below are three startups leading the way in innovation in this space, proving that no area within the femtech space is saturated with innovative companies and that there is still so much growth potential in this market.

Breathe ilo is the worlds first fertility tracker that uses breath analysis to identify a womans ovulation pattern and fertile window in a way that is easy and comfortable. Its technology is based on measuring the PCO2 parameter, which means the partial pressure within the carbon dioxide. Simply said, the device measures a decrease in womens breath before ovulation. What most women dont know (I certainly didnt!) is that they have a type of hyperventilation 4-5 days prior to ovulation. Through consistent daily use, the breath analysis tracker enables women to understand their body and cycle phases better. Additionally, the breathe ilo app, which is compatible with iOS and Android, features a calendar that displays a clear overview of fertile days and a cycle diary to learn more about individual cycle patterns and also enables users to document further cycle symptoms like breast tenderness, PMS, cervical mucus, or headaches to help prepare women for their next cycle.

breathe ilo is the worlds first fertility tracker that uses breath analysis to identify a womans ... [+] ovulation pattern and fertile window

The technology behind our device means women no longer need to track their cycles by urinating on a stick or by measuring their temperature early in the morning. All they need to do is simply breathe into the device which will display the result in just 60 seconds on the mobile phone, with no consumables or maintenance needed. Another positive thing is that you can use it at any time of the day, which makes it accessible for every woman, even those who have no daily routine, Lisa Krapinger, CMO of Vienna-based Carbomed Medical Solutions, the company behind breathe ilo, shares with me in an interview.

The idea for this type of product came from Prof. Dr. Ludwig Wildt from the University Clinic Innsbruck, who dedicated decades of research on the relationship between the female cycle and CO2. Something that started as a side project for the breathe ilo co-founder and CEO Bastian Rther. Investing in combined hardware and software products needs brave investors. First of all, the funds needed until profitability are usually higher than in pure software products. Furthermore, the skill set of the organization needs to be much broader and the organization will be much more complex because of managing all the supply-chain complexity. Our latest round was a Pre-Series A round of $3.6 million, led by the AWS Grnderfonds, one of the largest Austrian Venture Capitalists, with the participation of our existing shareholders, he shares with me.

We want to continuously improve breathe ilo and make it truly accessible to every woman. Unfortunately, there are a variety of different diseases such as PCOS, which havent been well researched. Therefore, we are trying to research different areas to try and have a holistic view of women's health. We really want to help all women to fulfill their desire to have children, even if there are physical impairments. However, this requires very expensive, time-consuming studies. Furthermore, in the future, we would also like to provide breathe ilo for natural contraception and further breath analysis applications. We have achieved to make breath analysis tremendously affordable and can really see a mass market for it, so I think we are on a good track to revolutionize cycle tracking, concludes Krapinger.

Among the 1.9 billion women of reproductive age (15-49 years) living in the world in 2019, 1.1 billion have a need for family planning, that is, they are either current users of contraceptives - 842 million use modern methods of contraception. Approximately 160 million women (17%) use IUDs (intrauterine devices) globally - varying in market share between countries, IUDs are the most widely used long-term, reversible contraceptive method in the world. Yet there has been no OCON Healthcare innovation in the IUD space since the 1990s with current devices using a deficient delivery platform invented in 1970.

OCON Healthcare, an Israel-based company is here to change that. Its first product is the IUB Ballerine - the first and only 3D intrauterine device shaped for women's anatomy and is a long term, reversible, hormone-free contraceptive method replacing the 2D traditional T-shaped IUDs. But contraception is not the only reason for OCONs innovation in this space. On top of the IUB Ballerine, any drug or substance that can be introduced into the uterus can be potentially put on the flexible, smart memory shape IUB (Intra Uterine Ball) frame to be non-invasively delivered to the uterus and treat various medical conditions, replacing invasive procedures.

OCON's IUB Ballerine is the first and only 3D intrauterine device shaped for women's anatomy and ... [+] is a long term, reversible, hormone-free contraceptive method replacing the 2D traditional T-shaped IUDs

Abnormal Uterine Bleeding (AUB) affects up to 25% of women globally with a $1B annual addressable market, more than 70% of women develop uterine fibroids by the age of 50, which is 9 million women in the U.S. alone, and hormone replacement therapy, of which the market size was valued at $21.8 billion in 2019, are all areas we are looking into and in which we are developing innovative solutions to cater to women who need them, Keren Leshem, CEO of OCON Healthcare, shares with me.

Leshem joined the company in September 2019, and very quickly put the company on the trajectory of growth. The company now has 100,000-plus women who had the IUB Ballerine inserted by their doctor and this innovative contraceptive is currently sold in 30 markets in Europe, Middle East, Africa, and Latin America. Its a company led by women for women, as Leshem says, with 85% of its team being women now, including their newly appointed Chairwoman, California based life science VC leader Dr. Anula Jayasuriya.

In 2020 OCON raised a total of $4.5 million in funding from both internal and external investors as well as non-dilutive government funding for their R&D projects. To date, the company has raised almost $20 million and our investors include Pontifax VC, Docor VC, Rhia Ventures, Merchavia Investments, and other angel groups. This year, for the first time in my life, Ive witnessed the fundraising process being done completely online. It's weird to have such a connection and find amazing support when we haven't met personally with the teams in the U.S. that placed their confidence and money on us, adds Leshem. The company is now actively raising a Series B round to bring their innovative platform to the USA, so investors, what are you waiting for?

Eli is a Canada-based startup developing a hormone tracking product designed to be used at home. From the users perspective, there are three simple steps. You take a saliva sample with the cartridge, you insert it in the small portable device that captures your daily hormone fluctuations, and shortly after, the app provides powerful information tailored to you. This information includes your hormonal profile and precise fertile days. With this data, customers can achieve different goals, including avoiding pregnancy naturally or conceiving a baby. The product will initially be available only for people trying to conceive, while Elis team complete the clinical and regulatory work for the contraception use-case.

Fertility is a booming market, with 1 in 7 couples who experience infertility. This number is still growing because we are waiting longer than any generation ever to have children, and fertility declines with age, but the effects of age are much greater in women compared to men. In their 30s, women are about half as fertile as they are in their early 20s, and womans chance of conception declines significantly after age 35. Male fertility also declines with age, but more gradually.

So what makes Elis product so unique? We first asked ourselves what the ideal solution would look like and asked the same question to hundreds of women and dozens of physicians. It was clear that we had to make no compromise on ensuring its effective and delightful to use, in addition to being hormone-free and non-invasive. That process led us to build technology from the ground up because no existing product met all of those criteria. The technology's ability to measure multiple hormones (instead of proxy variables like temperature or cervical fluid) and to have saliva as an input (instead of urine or blood) is some of the elements that make our product unique. Because we built the technology by keeping contraception in mind, it was critical for the product to be reliable and simple to integrate into a routine that you keep for a long time. Measuring hormones can give the effect we were looking for, and using saliva is the foundation for delivering the best long-term experience, explains Marina Pavlovic Rivas, co-founder, and CEO of Eli.

Eli is developing a hormone tracking product designed to be used at home using woman's saliva

But its not only about fertility, for that matter. After using hormonal contraception for years, many women just want to stop at some point, not for the sake of getting pregnant, but because of many other reasons. Although hormonal contraception is one of the most significant advances of the last century for women and all of society, up to 51% of women using hormonal birth control report unwanted side effects. The problem is that when you want to avoid hormones and invasive devices, youre left with very few effective options. That means you either continue to use a method you no longer want to use or opt for a less effective option, and both cases should be unacceptable. Women's contraceptive needs have evolved, but innovations to meet those needs haven't followed. On top of that, hormones are at the root of so many transitions and conditions women experience, and yet they are still a black box for most of us, Rivas adds.

Since the company's creation a little over a year ago, Eli has raised over $2 million. This includes a $1.5 million seed round that the company closed in December 2020. Vectr Ventures and 2048 Ventures co-led the round with the participation of Real Ventures, Techstars, Panache Ventures, Ramen Ventures, MEDTEQ+, and serial entrepreneur Steven Arless, who also joined the board. Before this round, Eli received around $700,000 in external funding. Most of it came from equity-free sources, such as government programs rewarding companies developing breakthrough technologies. It also includes an initial investment startup received in fall 2019 a few weeks after starting the company from Techstars and Real Ventures, via Techstars Montral AI. Both investors subsequently invested in Eli's seed round.

No one could have predicted the challenges of raising during a pandemic. We were aware that some stats were not favorable even before that new context. Only 90 Latina founders have ever raised $1-plus million, and less than 3% of all VC funded companies have a woman CEO. However, it turns out that the pandemic reduced VC funding for female founders even more. With a 48% drop in funding to female founders from Q2 to Q3 2020, it hit its lowest since 2017. We were operating for a few months only when the global health crisis hit. It certainly added a layer of complexity at first. As a deep tech company with a hardware portion, we couldn't become entirely remote because we still needed to work with specialized equipment and controlled testing environments in the lab. We now have been running for longer under the global pandemic than in the pre-COVID era. It turns out that the current context holds several opportunities that accelerated our operations and amplified the need for our product, concludes Pavlovic Rivas.

Read the rest here:
These 3 Women Are Shaping The Future Of Womens Health By Bringing Next Generation Of FemTech Products To The Market - Forbes

Recommendation and review posted by Bethany Smith

Indiana State Sen. J.D. Ford introduced Senate bill 32 last week calling for a ban on the use of conversion therapy for minors. Ford is recognized as Indianas first openly gay state legislator and spoke of the bill as a lifesaving issue. However, the bill will most likely face stiff opposition from the Republican supermajority in the Statehouse.

Conversion therapy is used as an umbrella term to describe practices that involve an attempt to change a persons sexual orientation or gender identity through psychological, spiritual or physical intervention. A therapist can recommend an unsubstantiated medication plan consisting of antipsychotics or hormone injections as a psychological treatment.

[Related: OPINION: Indianas first openly gay senator is right. A vote for Mike Pence is one for homophobia.]

Conversion therapy perpetuates harmful stereotypes by suggesting people can be cured of their deviance. The vile practice treats homosexuality and gender identity as an illness and invalidates any reality other than one consisting purely of heterosexuality and cisnormativity.

Religious leaders might insist homosexuality is a sin, therefore repentance is the answer. Health professionals may perform aversive treatments in the form of electroconvulsive therapy to punish an individual for indulging in thoughts which deviate from the arbitrarily defined sexual norm.

An estimated 700,000 LGBTQ adults in the United States have experienced some form of conversion therapy, and half of which received it while they were adolescents.

Conversion therapy is torture.

Nevertheless, it remains legal in a majority of states, including Indiana.

Indiana lawmakers proposed a ban on conversion therapy in 2019 but it never appeared before the entire chamber for a vote. The measure quickly died in committee.

Although Indianas reconsideration of a conversion therapy ban is a step towards progress, the bill is unlikely to pass. Republicans hold a nearly identical supermajority in the Indiana General Assembly as they did two years ago when similar legislation failed.

If the ban passes, however, legislators should acknowledge the long-term implications of conversion therapy and provide LGBTQ communities with further resources and support.

The American Psychological Association and the World Psychiatric Association are just a few of the many health organizations that denounce the use of conversion therapy and reject its asserted scientific premise.

[Related: IU students conduct LGBTQIA+ health care needs survey to establish free student-run clinic]

The trauma that forced conversion creates for young people in particular is alarming, and the inequality it legitimizes is damaging to the LGBTQ community.

Upwards of 77% of former conversion therapy participants report signifcant long-term psychological distress, according to the American Medical Association. LGBTQ youth who experience extreme rejection from their caregivers are eight times more likely to report a suicide attempt and six times more likely to report chronic depression, according to GLAAD. Furthermore, almost one in five transgender people claim they have been denied healthcare because of their gender identity.

Forced sexual orientation transformation efforts make LGBTQ youth indefinitely reliant on a medical system which is unequipped and unwilling to serve them.

This nation has invested more effort into forcing LGBTQ individuals to conform than acknowledging their humanity. We are now left with a system ill-equipped to provide equal access and service to all communities. The legislation currently moving through the Indiana General Assembly is the bare minimum.

Katelyn Balakir (she/her) is studying Policy Analysis and World Political Systems. She is a member of Indiana Model United Nations.

Excerpt from:
OPINION: Indiana might finally ban conversion therapy. That's too little, too late. - Indiana Daily Student

Recommendation and review posted by Bethany Smith

Is there a link between hypothyroidism and infertility? 5 lifestyle changes to manage thyroid disorders  |  Photo Credit: iStock Images

New Delhi: Hypothyroidism, or underactive thyroid, can make you feel unpleasant and affect many different systems in your body. In fact, a Harvard Medical School study reported that having even a slightly underactive thyroid may interfere with a womans ability to get pregnant. For women, treating this condition is a crucial part of any effort to improve fertility. Butlifestyle measures can help improve thyroid function and ease the symptoms of hypothyroidism.

Hypothyroidism is a medical condition in which your thyroid gland doesnt produce enough of certain crucial hormones. It occurs when the thyroid hormone regulations and production is disturbed and can lead to a wide range of issues like fatigue, low energy, weight gain, and constipation accompanied by infertility symptoms such as menstrual irregularity, difficulty in ovulation, and difficulty in conception.

The thyroid is a small butterfly-shaped gland in front of the neck which helps to regulate our hormones. The pituitary gland in the brain produces a hormone called thyroid-stimulating hormone which helps produce other two hormones known as triiodothyronine (T3) and thyroxine (T4) from the thyroid gland. These hormones aid in the normal functioning of the body.

Experts and medical doctors have known for some time that low levels of thyroid hormone can interfere with the release of an egg from the ovary (ovulation), which impairs fertility. Moreover, some of the underlying causes of hypothyroidism -such as certain autoimmune or pituitary disorders - may impair fertility, as per Mayo Clinic.

Even men suffer from hypothyroidism. In men, hypothyroidism can reduce the sperm volume and motility of sperm leading to decreased fertility. Ideally, anyone with a sedentary lifestyle and weight gain issues need to get their thyroid levels checked to rule out hypothyroidism, said Dr Richa Jagtap, clinical director & consultant - reproductive medicine, Nova IVF Fertility.

Hypothyroidism is commonly found alongside polycystic ovary syndrome (PCOS). There is a 2-4 per cent prevalence of hypothyroidism in women of the reproductive age group (20-40 years). Around 20-30 per cent of women with infertility may have hypothyroidism, added Dr Jagtap.

How to identify a thyroid problem

Once your doctor diagnoses the clinical symptoms, he or she will ask you to do a blood test called TSH or thyroid-stimulating hormone test and T3, T4 levels. Normal TSH levels fall between 0.5 to 4.5.

For a woman trying to conceive, even a mild increase in TSH should be appropriately corrected. This ideally needs to be corrected so that the TSH levels fall around the range of 2.5. These levels are safer for a woman to conceive because then her hormones will be in appropriate range while she is trying to get pregnant. The good news is that appropriate medication will help the thyroid hormones to get back to normal, added the doctor.

Usually, when one starts medication, it will take around 3 weeks for thyroid levels to start correcting. It also depends on how much the initial thyroid level was. For instance, if the TSH level is high then it will take a longer time to get back to the normal range. If it is borderline high then it wont take much time for the levels to get back to the recommended range. Lifestyle changes that can help manage thyroid disorders include:

Medication and lifestyle changes will help patients get back on track.If you are pregnant and have hypothyroidism, you mustget appropriate treatment. Also, you should not discontinue the medication without informing your doctor.

Disclaimer: Tips and suggestions mentioned in the article are for general information purposes only and should not be construed as professional medical advice. Always consult your doctor or a professional healthcare provider if you have any specific questions about any medical matter.

Read this article:
Is there a link between hypothyroidism and infertility? 5 lifestyle changes to manage thyroid disorders - Times Now

Recommendation and review posted by Bethany Smith

As a country, Japan is known for being at the forefront of technological advances, especially robotic tech. Japan has acted as the global leader in the revolution in robotics over the last several decades.

Bryan Brochu of rocketspace.com correctly notes that the island nation drives the advancement of artificial intelligence, machine learning, and machine vision technologies which are essential to powering the new age of innovation in robotic hardware.

Thus, it is no wonder that the newest and most innovative massage chair, the JPMedics Kawa Massage Chair, comes from the Japanese stable of innovative massage chair technology.

TheKawa Massage Chairincludes features such as:

At this juncture, it is reasonable to ask the question, why massage? Why is massage so important that massage chairs are designed to give expertly choreographed human-like massages?

The straightforward answer to this question is that massage is integral to maintaining human mental health and well-being, especially during the seemingly never-ending COVID-19 pandemic.

The Mayo Clinic reports that a sixty-minute massage lowers the stress hormone cortisol by 30% after one session. Additionally, a study titled Effectiveness of Therapeutic Massage for Generalized Anxiety Disorder: A Randomized Controlled Trial, reported that participants who underwent regular massage therapy for twelve weeks showed a 50% reduction in anxiety symptoms. And the 50% reduction in anxiety remained constant for over twenty-six weeks, even though the massage therapy had ended.

Lets take an in-depth look at some of the JPMedics Kawa features as a way to describe its health benefits to reduce stress and anxiety.

1. 3D humanistic massage mechanism

The 3D robotic engine moves along an extended L-track that reaches from the neck to the glutes. The 3D rollers move left, right, up, down, in, and out, mimicking the action of human hands, working deep into the shoulders and back, penetrating the shoulder and back muscles. The robotic engine plus the 3D rollers provides the most human-like massage found on any massage chair.

Lastly, a deep massage is designed to work out muscle knots, relax the muscles, and improve the blood flow to the areas massaged, helping the body relax and reduce stress and anxiety levels.

2. Air cell technology to position the body for an improved massage

The JPMedics Kawa massage chair uses air cell technology inside the chair to position the body for a more accurate and improved massage experience.

What is air cell technology?

In summary, air cell technology replaces the traditional foam inside the massage chairs back and seat with millions of individually constructed air pockets. These air pockets release air when weight bears down on them, acting as shock absorbers. And because these air pockets are separately built, they help spread the body weight evenly across the chair, resulting in increased blood circulation, the faster recovery of tired and tense muscles, and greater oxygen intake. When combined with a relaxing massage, this technology helps lower stress and anxiety levels, especially after a day plagued by low-grade anxiety and panic.

3. Foot rollers expertly massage the feet

The foot rollers supply a combination of pressure point massage and compression massage. Compression massage is when pressure is applied to the muscle or underneath of the foot in this instance. This pressure is held and released, facilitating relaxation and activation of the parasympathetic nervous system.

Juxtapositionally, pressure point massage is where direct pressure is applied to specific points on the foot, relieving muscle tension, and providing pain relief. Pressure point massage in the feet is also known as Reflexology, where pressure is applied to specific reflex points on the foot, triggering relaxation and healing of the corresponding organs and areas of the body.

In summary, the combination of Reflexology and compression massage on the feet relax the foot muscles and assists with stress and anxiety relief for the whole body.

Final Thoughts

There is no doubt that the information presented above shows that the JPMedics Kawa massage chair is a valuable purchase.

The Modern Back is the leading brick-n-click retailer in the United States, with the best and latest massage chairs are on offer both online and at The Modern Back's showrooms in Boynton Beach and Sarasota, Florida.

The company's virtual and land-based showrooms have the largest selection of massage chairs available for sale, including many different brands and models ofmassage chairsto suit every budget. Lastly, should clients require sales assistance, The Modern Back's friendly, knowledgeable staff are always on hand to answer questions and assist with their massage chair purchase.

Google Map Link: https://g.page/the-modern-back-boynton-beach?gm

Media ContactCompany Name: The Modern Back - Boynton BeachContact Person: Jessica HopeEmail: Send EmailPhone: 800-416-4304Address:1054 Gateway Blvd STE 108 City: Boynton BeachState: FL 33426Country: United StatesWebsite: https://themodernback.com

Original post:
JPMedics Kawa: The Newest Japanese Massage Chair and Its Health Benefits to Reduce Anxiety and Stress - Press Release - Digital Journal

Recommendation and review posted by Bethany Smith

Can you see this? Do you have to focus to read this text on your screen? Do you feel your eyesight is still strong or have your eyes deteriorated recently as well?

With the lockdown, homeschooling, and working from home, we are all staring at screens, tablets, and mobile phones even more than we already did before the COVID-19 pandemic. Most people spend endless amounts of time at home now and rarely go outside. But that means our eyes are constantly focused on objects in close range inside, and we're lacking the benefits of looking into the distance.

A lack of exercise is particularly noticeable in children including exercise for their eyes. Recent studies from the Netherlands and China show that as a result of COVID-19 restrictions, myopia has increased dramatically, especially in children. The phenomenon has been called "quarantine myopia".

Data from more than 120,000 Chinese school children showed that kids between the ages of six and eight were up to three times more likely to have myopia in 2020 than children of their age in previous years. In this age group, visual acuity shifted by a substantial 0.3 diopters towards myopia.

This drastic deterioration of eyesight in young children is particularly frightening because being nearsighted (not being able to see objects that are farther away) isdetermined at an early age. Once someone is nearsighted, they stay that way. In most cases, nearsightedness begins in primary school and it increases as children grow up. The earlier it starts, the more severe it becomes. The grown eye does not shrink again.

If the eyeball grows too much between the ages of six and 10, it means the child has a harder time seeing objects farther in the distance. Severe nearsightedness also increases the risk of retinal detachment, cataracts due to high pressure inside the eye, or even blindness later in life.

Focusing on objects in close range for too long can harm your eyesight

According to the Brien Holden Vision Institute, by the middle of the century around five billion people, or roughly half of the world's population, will be nearsighted. Especially in industrialized countries, the number of nearsighted people has risen rapidly in recent decades.

There is even a direct correlation between increased educational opportunities and poorer vision the higher the level of education, the higher the risk of myopia.

"The increase is mainly due to very early and intensive use of PCs, smartphones and tablets, combined with increasingly shorter amounts of time spent outdoors during the day," said Nicole Eter, Director of the Department of Ophthalmology at the University of Mnster.

Asian countries have above-average rates of nearsighted children and adolescents. For example, after World War II, about 20-30% of 20-year-olds in Hong Kong, Taiwan and South Korea were nearsighted; today the figure is more than 80%. In China, four out of five young people are now nearsighted. In other Asian countries, the rate is as high as 95%. In Europe too, about half of young adults are nearsighted.

Close to 85% of Chinese university students are nearsighted, raising the prospect of a significant swath of the country's population suffering loss of sight or blindness in old age

The risk of myopia can be reduced by not staring too long at an object in close range, regardless of whether it is a smartphone or an exciting book. The important factor is distance. The observer needs to look up regularly so that the gaze can wander into the distance.

The risk of myopia is reduced primarily by longer amounts of time spent outdoors, because daylight inhibits further growth of the eyeball. In enclosed rooms, the light intensity averages 300 to 500 lux (a measure of light levels), whereas on a bright summer day it can be around 100,000 lux outside. Studies from Scandinavia also show that myopia increases in the darker seasons, while it stagnates during brighter times of the year.

The blue light of smartphones robs us of sleep because it inhibits the release of the hormone melatonin.

Excessive use of electronic media does not justlead to more nearsightedness. It can also irritate, tire and dry out children's eyes. Constantly looking at screens also affects spatial awareness. Blurred vision or squinting can result from too much time spent on devices.

In addition, smartphone use in the evening may lead to sleep disorders.

"The high blue light content of the screens inhibits the release of the hormone melatonin, which makes you sleepy," explained Eter.

Although many devices now have a night mode that reduces the blue light, we should stop looking at them around two hours before bedtime.

Parents should limit their children's use of digital media, especially for the youngest age groups.

Parents should limit their children's screen time to help protect their eyesight

"From an ophthalmological point of view, PCs, smartphones and tablets are completely unsuitable for children up to the age of three," said Bettina Wabbels from the Bonn University Eye Clinic. The eye expert recommends daily use of no more than thirty minutes for four- to six-year-olds.

"At primary school age, media time of a maximum of one hour per day would be acceptable from an ophthalmological point of view, and up to two hours per day from the age of about ten," explained Wabbels.

However, her advice doesn't just apply to children and adolescents. Adults' eyes also need a break. So look up from the screen more often, let your eyes wander and spend more time outdoors.

Link:
COVID-19 and eyesight: Myopia on the rise during lockdown - DW (English)

Recommendation and review posted by Bethany Smith

A new womens health charity created by a Shelly Beach family is helping a whole generation of women find understanding, confidence and comfort as they undergo the change before the change.

The Debbie Gaunt Foundation was launched to build awareness about perimenopause, an often-challenging life event that can have devastating impacts on a womans physical and mental health.

The transitional period before a womans final menstrual period (menopause), perimenopause most commonly occurs in women in their mid-40s and signifies the ovaries winding down.

Lasting anywhere between one to ten years, women going through perimenopause often experience the same or even more intense symptoms of menopause.

Irregular periods, hot flushes and exhaustion are as common among perimenopausal women as they are during menopause, as are mood swings, anxiety and depression.

But unlike menopause, perimenopausal women often manage their condition independently and in private.

Medical research into health problems and complications linked to perimenopause is also surprisingly scant, something Foundation Founder, Craig Gaunt, became painfully aware of after losing his wife Debbie to suicide in 2019.

A wife, mother, friend and colleague, Debbie became severely mentally unwell shortly before her death, an episode that has since been partially attributed to the hormonal effects of perimenopause.

Vowing to honour Debbies memory to help other women and their families experiencing perimenopause, through the Debbie Gaunt Foundation, the Gaunt family now works tirelessly to raise awareness and understanding of perimenopause as well as funds for Australian led studies and projects that explore the mental health impacts of the condition.

Improving general awareness of perimenopause is also high atop the Foundations to do list.

Debbies perimenopause was very retrospective for my family.

We had never even heard of it before and sadly thats the case for most people, even women, so they just suffer throughout it all.

Thats why we made a promise to do something about it, Craig said.

The Foundations first major project has been to fund the development of a womens midlife mental health module for doctors to be delivered by Melbournes Monash Alfred Research Centre, the only specialised clinic in the country dedicated to helping women experiencing perimenopause.

The module will address perimenopausal depression, menopause and hormone replacement therapy, complex trauma disorder in perimenopause and family violence.

So far, the Foundation has donated $20,000 for the project and has committed to raising an additional $24,500 for it throughout 2021.

According to Craig, the Foundations long term goal is to help fund the opening of more specialist clinics like Monash Alfred around the country, including one here on the Coast.

Dilon Luke

Original post:
Debbie Gaunt Foundation putting perimenopause in the spotlight - Central Coast Community News

Recommendation and review posted by Bethany Smith

The medical group has locations throughout the Greater Los Angeles area and beyond.

LOS ANGELES (PRWEB) January 20, 2021

A December 18 article on 9Honey reports on a 27-year-old woman in New Zealand who was able to shed an astonishing 176 pounds after undergoing weight loss surgery. The patient, Claire Burt, said she battled eating disorders, depression, and isolation as a result of her excessive weight but was unable to slim down despite frequent dieting and medication. The article reports that Ms. Burt was finally able to receive gastric sleeve surgery in April when 80% of her stomach was removed. Ms. Burt stated that since the surgery, she hasnt faced any obsessive thoughts over food, and her mental state has significantly improved. Health and beauty medical center Beverly Hills Physicians says that losing weight and successfully keeping it off long term can be difficult to achieve naturally, and getting medical assistance for a healthier and better quality of life simply makes sense.

Beverly Hills Physicians says that, while most people have less weight to lose, what Ms. Burt experienced while attempting to lose weight on her own is exactly what many severely obese individuals face. The clinic says that, while it is possible for some people to lose weight naturally on their own, keeping the weight off is nearly always unsustainable because the body fights what it perceives as the threat of starvation. Beverly Hills Physicians says that, because the body becomes accustomed to receiving a certain number of calories every day, it sends hunger signals to the brain in an attempt to encourage the individual to eat more when that intake is significantly reduced.

The health and beauty medical group says that this is why medical intervention is often necessary to lose and maintain a healthy weight for those fighting obesity. By removing a portion of the stomach in such procedures as sleeve gastrectomy, the hormone center responsible for sending the hunger pangs is often minimized. In addition, Beverly Hills Physicians says that, with a drastically smaller stomach, patients are only able to eat smaller portions comfortably, further helping individuals maintain weight loss.

The bariatric center adds that when patients can lose a significant amount of weight, they are not only reducing the likelihood of developing health issues such as diabetes or cardiovascular disease, but they are also improving their overall quality of life. Mobility, energy levels, and more can all be subtle benefits of losing significant amounts of weight.

Readers interested in learning more about weight loss surgery or any other of Beverly Hills Physicians offerings can call 1-800-788-1416 or visit the health groups website at https://www.beverlyhillsphysicians.com/.

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Weight Loss Surgery Advantages Emphasized in New Zealand Woman's 175 Pound Weight Reduction, says Beverly Hills Physicians - PR Web

Recommendation and review posted by Bethany Smith

The Telegraph

Schools could open before Easter, Gavin Williamson has suggested, saying he will give a two-week warning to headteachers. The Education Secretary said he "would certainly hope" that children would be back in the classroom by early April, adding that he wants this to happen at the "earliest possible opportunity". It is the first time Mr Williamson has hinted at a possible timeline for the reopening of schools, and comes after Dr Jenny Harries, the deputy chief medical officer, suggested schools in some parts of the country will reopen sooner than those in others. Primary and secondary schools were ordered to close at the start of the month to all but the children of key workers and the most vulnerable youngsters. Announcing the latest national lockdown on January 4, Boris Johnson said schools would need to remain shut until the February half-term at the earliest. On Thursday, Mr Williamson said a key factor in determining when schools could reopen would be whether pressures on the NHS had eased sufficiently. He told BBC Radio 4's Today programme that headteachers will be given "absolutely proper notice" about when they need to prepare to reopen, adding that a "clear two-week notice period" will be factored in so schools have time to prepare for pupils' return. "Schools were the last to close, schools will be the first to open," the Education Secretary said. "I want to see that as soon as the scientific and health advice is there to open at the earliest possible stage, and I would certainly hope that that would be before Easter. "Any decision to reopen schools to all children as all decisions in terms of schools will be based on the best health advice and the best scientific advice."

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One Killed as Motorcyclists Ride in Wrong Direction on San Francisco's Bay Bridge - Yahoo News UK

Recommendation and review posted by Bethany Smith

DILLON Dylan Pope concurs that 2020 was, by and large, not a great year. But he still found a way to make the most of it.

"It was a pretty tough year but having this to look forward to and reflect on has been something pretty big for me," he said.

Pope, a Montana Western defensive back, made the decision to donate bone marrow in December.

"I was nervous, but I was excited to help somebody," Pope said.

At the encouragement of his sister, Mariah, Pope registered with a non-profit called Be The Match in March, shortly after coronavirus knocked the world off kilter.

According to the organization's website, only one out of every 430 registered members will actually go on to donate bone marrow. Pope's sister has been registered for years without a match.

So, Pope was understandably taken aback when, after a little more than three months, he received a call telling him that he had been deemed a suitable donor for an anonymous recipient to receive his blood stem cells, which are derived from bone marrow.

"At first I thought it was fake," Pope said. "I didn't think there was any way it was going to happen after just three months."

With a donation date set in December -- because of confidentiality policies, Pope can't disclose what state or hospital the procedure took place at -- the next months were what one would expect: a lot of paperwork and a lot of blood tests.

The week before the donation, he began receiving daily injections to increase his stem cell count. He then made the trip with his younger brother, Brayton.

The process took eight hours and required only local anesthesia. A needle in his right arm drew blood, ran it through a machine that extracted stem cells and then a needle in his left arm injected blood back into his body.

"It's really not nearly as scary when you get there as you think it's going to be," Pope said.

It'll be a year before Pope learns the identity of who received his bone marrow. He's certain it'll be a moving, powerful experience.

"I bet it'll be pretty emotional thing for both of us, because it was pretty cool to be able to help them," Pope said.

Ryan Nourse, Montana Western's head football coach, said he wasn't surprised by Pope's willingness to donate bone marrow and said he and the program supported him the entire way.

"I think that's a really brave thing, courageous thing for Dylan to go do," Nourse said. "I think that selflessness will shine through to the other guys knowing that maybe I could help somebody in a similar position someday."

More here:
'I was excited to help somebody': Montana Western's Dylan Pope reflects on donating bone marrow - MontanaSports

Recommendation and review posted by Bethany Smith

Mesoblast, MESO, is an Australian based biopharmaceutical company that has been a market favorite, even though the companys ups and downs have confused many investors.

The MESO share price has been inconsistent lately. This has prompted many investors to ask why. Analyzed carefully, MESO has done better than many stem cell businesses. Most stem cell businesses fail to ever make a profit and fail to even get a product to market. This can cause long-term problems with the stock price of any company.

ByMichael A. Mannen, MS

Mesoblast as a company is committed to offering groundbreaking cellular therapies for the treatment of many severe diseases using Mesenchymal Stem Cells. They are dedicated to cellular medicines and leveraging their stem cell technology. There are not many successful companies in this niche.

Adult stem cells are undifferentiated cells that divide and rebuild the damaged tissue. Mesenchymal Stem Cells are a type of adult stem cells generated from some of the adult tissues present in the body.

Stem cells have been found by scientists to have two properties: self-renewal and the potential to divide into specialized cell types. Multi-potent, mesenchymal stem cells are found to be present in many adult tissues. The bone marrow is considered by many scientists to be the most usable reservoir of adult human stem cells.

For several disorders, such as heart failure, the capacity to rebuild tissue may be groundbreaking for treatment. And this has been the inspiration for many companies exploring stem cell therapies.

However, what differentiates Mesoblast from other stem cell companies is its approach to treating inflammatory diseases. Their products have the potential to make breakthroughs a reality for many diseases.

The company has developed and manufactured its own patented mesenchymal lineage cells to be used for a range of ailments. These have a potential for the regeneration of tissues. These cells, however, secrete a number of biomolecules which can help the body heal more than just tissue damage. They may be important to supporting immune responses needed for recovery in many diseases.

Possible rejection of the patients immune system is the biggest problem with the use of stem cell therapies in heart diseases and other diseases. This can worsen many illnesses.

MESO does appear committed to the quality of its product. For MESO it is a question of the effectiveness and safety of their products. Its a long and winding road to provide adequate scientific proof when presenting breakthrough treatments to regulators. Many less reputable organizations have touted stem cells without doing the necessary scientific investigation or seeking the necessary regulatory approval. Mesoblast is trying to do things the right way. Committing to doing science the right way leads to a lot of inevitable ups and downs. This raises financial speculation and can lead to wild fluctuations in the stock price of any company.

A further significant advantage of some of Mesoblasts products is that they apparently can be administered to patients without needing donor matching. This increases their viability. Moreover, it allows for a wide spectrum of patients to be treated from their products. This gives them an advantage in comparison with other firms and should potentially allow them to increasingly gain a larger market share.

Of great interest to investors include the many clinical trial phase 3 products that Mesoblast has in its pipeline. These include MPC-06-ID, Remestemcel-L, and REVASCOR.

Remestemcel-L is a Mesoblast therapy that may theoretically have properties to help with the treatment of ventilator-dependent patients with COVID-19 patients. However, a clinical trial reported some concerns with the therapy meeting its primary endpoint. And it sent the stock down in December 2020. Obviously, there is a large demand for the treatment of complications linked to Covid-19, so this bad news disappointed investors.

However, another therapy has shown promise in the DREAM-HF Phase 3 for patients with chronic heart failure. Although the Revasacor did not stop heart failure, it did seem to deliver dramatic reductions in heart attacks and other negative cardiovascular events that plague heart failure patients.

Heart failure is a pathology that involves ones heart having trouble pumping. The condition impacts millions of people worldwide. In order to feed and maintain it working, the heart muscle depends on a continuous supply of oxygen rich blood. Having stem cell therapies is highly desirable to treat cardiovascular diseases. Hopefully, many Cardiovascular disorders can be treated with stem cell therapies in the future.

Other conditions such as hypertension and Coronary artery disease can help lead to heart failure. According to the Mayo Clinic, heart failure can cause significant health complications and lead to Liver and Kidney damage in patients.

Some scientists believe that Mesenchymal Stem Cells when used to treat cardiovascular diseases can preserve the myocardium by reducing the intensity of inflammation and supporting angiogenesis. Angiogenesis is a mechanism used by the body to create new blood vessels. Their low immunogenicity once more makes them a perfect treatment. This helps ensure that the immune system of the patient does not produce a negative response to the therapy. This theoretically can give stem cell therapies an advantage over some protein-based treatments that are easily recognized by the patients immune system.

This product could be a major development for Mesoblast moving forward, although further analysis and testing is still needed.

Stem cell therapies are not without experimental and medical challenges. For example, there are concerns with the ability of stem cell migration to tissues that require regeneration. There may also be cases whereby stem cells are divided into unintended cells. There may also be difficulties with the manufacturing and culturing of stem cells. Identification of Mesenchymal stem cells in cell populations can be problematic. From a scientific point of view, bone marrow derived Mesenchymal Stem Cells are known to be the best source for obtaining these cells in the human body.

Mesoblast has a wide range of advanced research programs related to different stem cell therapies. MPC-06-ID could potentially be a viable therapy for treating chronic low back pain attributable to degenerative disc disease.

These are products that consumers should be thrilled about.

The company has solid financials for a stem cell company and has a lot of cash on hand. The stock had a market cap of over 2 billion on 9/30/2020 and a 52-week high of 21.28. Lately the news surrounding the companys clinical trials has been a potpourri of both good and bad, so the share price has settled at around $9. It has a float of 93.7 million shares.

Mesoblast is a really exciting healthcare business. The business has made a commitment for the future. And it should be a stock that investors continue to follow.

Follow this link:
Mesoblast Limited: Is Stemcell Therapy Ready For Prime Time? - Sick Economics

Recommendation and review posted by Bethany Smith

Introduction

Chronic myeloid leukemia (CML) is a hematological malignancy that develops when the 9;22 translocation in a single hematopoietic stem cell (HSC) results in the expression of BCR-ABL1 tyrosine kinase fusion protein. If left untreated, CML progresses over approximately 5 years, from relatively benign chronic phase to accelerated phase, and then to fatal blast crisis. The introduction of tyrosine kinase inhibitors (TKIs) specifically targeting the BCR-ABL1 fusion protein was a breakthrough in the management of CML, leading to a significant reduction in mortality and improved 5-year survival rates. However, despite the high annual acquisition costs of all the TKIs; first-, second-, and-third line TKIs1 induce only transient responses in the 10% to 15% of CML patients diagnosed in advanced phase, suboptimal responses in approximately 30% of CML patients during chronic phase (CP) cases that experience disease progression each year during, and only 1020% chance of successful treatment discontinuation due to disease persistence.2 Among the causes of disease persistence, studies have shown that CML leukemia stem cells (LSC) play a major role in inducing therapeutic resistance and disease progression because they are able to self-renew.3,4 These LSC a rare subset of immature cells residing in the bone marrow niche are protected from the action of TKI5 because these cells are normally quiescent and the TKIs are designed to target malignant blast cells that proliferate. That is why current strategies are not able to effectively eliminate the LSC or the disease.3 In CML, LSC are primitive cells expressing CD34+ CD38- with the 9;22 translocations, or the Philadelphia chromosome (Ph).6 However, these markers cannot distinguish the cancer hematopoietic cells from normal ones. Additionally, the BCR-ABL fusion gene encodes for an intracellular tyrosine kinase protein rather than a surface protein, calling for the need to identify unique surface biomarkers for efficient targeting of this cell population with subsequent eradication of the root of the disease.

In 2010, a single biomarker, Interleukin 1 receptor accessory protein (IL1RAP), was found to be up-regulated on the cell surface of BCR-ABL+ LSC. They were able to distinguish Ph+ from Ph- LSCs using IL1RAP.7 A polyclonal anti-human IL1RAP was generated that not only targeted the LSC population but also killed normal peripheral blood mononuclear cells, indicating that this marker was not specific to the LSC.7 Another characteristic cell surface marker has been investigated; ThomsenFriedenreich antigen (TF, or CD176) a tumor-associated carbohydrate epitope. The CD176 antigen was found to be expressed on the surface of various cancer-initiating cells, such as breast carcinomas,8 colorectal carcinomas,9 several leukemias,10 and other types of cancer, but was absent from almost all normal adult cell types.11 CD176 was also found to be expressed on the surface of CD34+ hematopoietic stem cells of the K562 erythroblastic leukemia cell line; a cell line derived from a CML patient. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a suitable target for cancer biotherapy8 with the development of an anti-CD176 antibody that induced apoptosis of leukemic cells.12

Using monoclonal antibodies (mAb) as a tool for cancer therapy still has its limitations. Patients who receive mAb therapy may develop drug resistance or fail to respond to treatment owing to the multiple signaling pathways involved in the pathogenesis of cancer and other diseases.13 Targeting more than one molecule has proven to circumvent the regulation of parallel pathways and avoid resistance to the treatment.14 Bi-specific antibodies (Bis-Ab) are antibodies that can recognize two different epitopes. They can redirect specific immune cells to the tumor cells to enhance tumor eradication, enable the simultaneous blocking of two different targets that have common signaling pathways, or interact with two different cell-surface antigens instead of one with subsequent boosting of the binding specificity.13 Thus, the identification of two surface markers specific to the cancer stem cells would be useful in characterizing and targeting CML stem cells, without affecting other blood cells.

In this study, we evaluated co-expression of IL1RAP, linked to BCR-ABL+ expression, and the CD176 antigen, carried on the hematopoietic stem cell marker CD34 molecule, in CML patients. We identified PBMCs co-expressing CD34, IL1RAP, and CD176 antigens using flow cytometry, a finding that allowed for subsequent separation and targeting of such cells from normal HSCs. A bi-specific antibody (TF/RAP), was generated in order to target the IL1RAP+ and CD176+ cell population among PBMCs in patients with CML. We used a flow-cytometry assay as a cell-based assay to measure the antibody binding capability of the TF/RAP Bis-Ab to the cell surface antigens. Our TF/RAP Bis-Ab, increased targeting of the IL1RAP+ and CD176+ cell population among CML PBMCs but not corresponding normal cells, using complement-dependent cytotoxicity assay (CDC). This novel TF/RAP Bis-Ab may provide a novel strategy for the eradication of CML stem cells.

Deidentified samples of peripheral blood from healthy volunteers were obtained from Gulf Coast Regional Blood Bank (Houston, TX, USA) after signing informed consent and used as reference samples. Deidentified samples of peripheral blood mononuclear cells (PBMCs) from consented patients with CML were obtained from Oncology Research Gundersen BioBank (https://www.gundersenhealth.org/research/biobank/, La Crosse, WI, USA). While the samples were de-identified, necessary CML patient characteristics were collected (Table 1). The collection and dissemination protocols for the samples are approved by The Gundersen Human Subjects Committee/Institutional Review Board (IRB) and are in full compliance with National Cancer Institute Best Practices for Biospecimen Resources. Because the de-identified samples were received through Biobanks and not through direct intervention/interaction with a research subject, the Tulane University Human Research Protection Office was notified and this study was classified by the IRB as exempt as the study did not meet the definition of human subjects research according to US Federal policy (HHS regulations, 45 CFR part 46, subpart A, also known as the Common Rule). The study was conducted in accordance with the Declaration of Helsinki.

Table 1 CML Patients Characteristics

HEK 293FT cell line (Invitrogen # R70007) was cultured in DMEM (Life Technologies, Carlsbad, CA, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 U/mL penicillin, 100 g/mL streptomycin sulfate, and 4.0 mM L-glutamine (Gibco BRL products, Gaithersburg, MD), at 37C in a humidified 5% CO2 incubator. The KG1 cell line (ATCC #CCL-246) and transduced derivative cells were cultured in Iscoves Modified Dulbeccos Medium (Life technologies) supplemented with 20% FBS at 37C in a humidified 5% CO2 incubator. K562 cell line (ATCC# CCL-243) was maintained in RPMI-1640 (Life technologies) supplemented with 10% FBS, 100 U/mL penicillin, 100 g/mL streptomycin sulfate at 37C in a humidified 5% CO2 incubator.

The IL1RAP cDNA was PCR amplified from an expression plasmid containing Human IL-1RAcP/IL-1R3 Gene ORF cDNA (Sino biological Inc., HG10121-CM) using Clone Amp HiFi PCR Premix (Takara Bio USA, Inc.), and primers that included either a BamHI or an XhoI site (F-IL1RAP: acgggatccccaccaagcttggtaccatgac; R-IL1RAP: acgctcgagttatacatttttcaaagatg). The PCR fragment was gel extracted as above, sub-cloned into BamHI and XhoI sites in the pHRST-MPSV vector according to standard protocols and confirmed by restriction mapping and sequencing.

Transient production of lentiviral particles in adherent HEK293T was modified from previously described.15 Briefly, HEK293T cells were seeded in a T-75 flask, where we used 4.0 g of envelope plasmid pMPSV-VSV-G, 10.0 g packaging plasmid psPAX2, and 26 g transfer plasmid that has the gene of interest. In our case, the transfer plasmid is either the antibody plasmid or the control. The plasmids were mixed into 500 L 0.25 M CaCl2 (Sigma Aldrich, St. Louis, MO) and incubated at room temperature for 5 minutes, and then mixed with 500 L 2xHBS and briefly vortexed. The mixed transfection cocktail was then incubated for 3 minutes at room temperature, and added into the medium of the cells, and mixed gently to make an even distribution. After 16 hours of incubation, the medium was replaced with fresh medium and collected every 24 hours for 3 days. The conditioned medium that contained the vector virus was then pelleted for 10 minutes at 1500 g and passed through a 0.45-m filter to remove the cell debris, and then frozen at 80C for long-term storage, or used for the transduction of target cells.

Lentiviral transduction was done as previously described.1618 In brief, lentiviral supernatant was added to KG1 cells cultured in complete IMEM. After overnight incubation, the lentiviral vector was removed, and fresh media was added. After 48 hours, IL1RAP expression was demonstrated by flow cytometry using anti-Human IL-1 RAcP/IL-1 R3 PE-conjugated antibody (#FAB676P, R&D Systems, Minneapolis, MN).

The CH and CL constant domains in the pLM219 plasmids were amplified with 0.5 nM overlapping mutant primers (Table S1), Deep Vent Polymerase (New England Biolabs), and reaction buffer for forty cycles at 94C for 10 seconds, 60C for 45 seconds, and 72C for 2 minutes. Initial fragments were purified, combined, and used to amplify the entire heavy or light domains (Table S2). The mutated fragments were then gel purified and sub-cloned into their corresponding vectors using restriction enzymes according to standard protocols (Table S2). Sequences were then verified by restriction digestion and sequencing.

For antibody sequences towards CD176 (TF) and IL1RAP, the VH and VL domains from two clones with the most conserved amino acid sequences (TF Clone 1 and Clone 2 called TF1 and TF2 for CD176; Clone 4B6 and Clone 4G9 called RAPa and RAPb for IL1RAP, respectively) were chosen from published sequences.20,21 IL1RAP antibody was designed to target the extracellular membrane anchor-proximal region that comprises an amino acid primary sequence VPAPRYTVELAC within 10 to 15 amino acids of amino acid 361 of human ILR1AP (Gene bank accession Q9NPH3) while the TF antibody was designed to target the same Gal(13)GalNAc disaccharide epitope20 as the Bis-Ab. Variable domains (VD) were codon-optimized and synthesized (Gene Art, Invitrogen) to be compatible with 15 base pairs of homologous sequences on both the 3 and 5 ends of pLM2 recipient plasmid flanking the EcoRI restriction enzyme site.

The pLM2 expression vector was digested with EcoRI to generate a double-stranded break. An In-Fusion HD cloning kit (Clontech, Inc) was used to clone the VD regions of the antibodies between the leader and constant regions of the pLM2 vectors. The correct clones were identified by PCR and restriction mapping and then verified by sequencing.

Adherent HEK cells were transfected as above. A total of 14 g high-quality plasmid-DNA, 10% GFP plasmid for assessment of transfection efficiency, while the rest was heavy and light chain plasmid DNA combined at a ratio of 1:1. Six to 8 hours later, cells were gently washed once with PBS and fresh growth medium added. Sixteen hours post-transfection, the medium was replaced with DMEM supplemented with 5% FCS and incubated at 5% CO2 for 24 hours prior to the initial collection of antibody supernatant. A second collection was made after a further 24 hours.

Flow antibodies used were as follows: anti-TF/CD176 mAb mouse IgM (Glycotope, Berlin, Germany) targeting Gal1-3GalNAc epitope; FITC-conjugated anti-mouse IgM secondary antibody (-chain specific, #F9259; Sigma); PE-conjugated mouse anti-human IL-1 RAcP/IL-1 R3 monoclonal IgG1 antibody, epitope Ser21-Glu359 (#FAB676P, R&D Systems); APC-conjugated mouse anti-human CD34 monoclonal IgG1 antibody (#QBEnd10, FAB7227A-025, R&D Systems); APC-conjugated mouse antihuman IgG monoclonal antibody (Clone G18-145, mouse IgG1 , #550,931, BD Pharmingen).

LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (#L34957, Invitrogen); Vibrio Cholera Neuraminidase (VCN; Sigma Aldrich Inc), an enzyme used to expose the CD176 on the surface of expressing cells. Flow cytometric analyses were performed in a BD LSR Fortessa (BD Biosciences, USA) and flow cytometric cell sorting was done in a FACSAriaII (P0010) cell sorter (BD Biosciences, USA). The amount of bi-specific antibody bound to the receptors was calculated from the frequency of total IgG bound receptors.

Sorted cells were received in RPMI media and then fixed using the standard 3:1 methanol: acetic acid fixative. Standard procedures were used for FISH hybridization and washing.22 The BCR/ABL1 Plus translocation, dual fusion probe set (Cytocell Inc., Tarrytown, NY) was used. Slides were analyzed using Leica Biosystems Cyto Vision. FISH nomenclature was described according to the ISCN 2016.23

CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- cells were sorted from PBMC samples derived from patients with CML. Cells (1 x 103) were plated in Metho Cult Express (#04437, Stem Cell Technologies, Vancouver, Canada) semi-solid media containing recombinant human IL-3, IL-6, G-CSF, GM-CSF, SCF, TPO and cultured for 2 weeks in a humidified atmosphere at 37C with 5% CO2. Fourteen days after plating, the number of colonies was counted by microscopy.24,25

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% v/v) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

The capacity to induce CDC was assessed essentially as has been described.2628 Briefly, target cells (1105 cells) were pre-incubated at 37C for 60 min with diluted antibodies. Human serum from human male AB (Sigma Aldrich) (20% (v/v)) was added to the cells as a source of complement and incubated at 37C for an additional 45 min. Cells were then put on ice and viability was determined by staining with LIVE/DEAD staining and detected using a FORTESSA flow cytometer (BD Biosciences). CDC activity was expressed as a percentage of lyses as determined from the increase in the percentage of cells stained positive with the LIVE/DEAD marker compared to the control samples. Cycloviolacin O2 (CyO2, 0.05nM), a pore-forming peptide, was used as a positive control because it kills cells with the similar mechanisms as CDC by causing pores in the cell membrane.

We measured the production of the Bis-Ab by ELISA. Plates were initially coated with goat anti-Human IgG heavy chain antibody (Axell) and blocked with PBS containing 0.5% Tween 20 (Fisher), 10% FBS (FetalPlex Animal Serum Complex, GeminiBio, Cat#100-602), 4% whey protein (BiPRO, AGROPUR). Undiluted or diluted supernatant was added, including the standard curve samples (human IgG MAb 1.7B, kindly provided by Dr. James Robinson), and negative blocking buffer. After incubating at 37C for 60 min, the plates were washed. Then, goat anti-Human lambda antibody conjugated to HRP (Southern Biotech, Cat# 207005) was added at 1:300 in blocking buffer for 60 min and washed five times. A mixture of 0.1M Na Acetate (pH 6), peroxide, and TMB substrate were added. The reaction was terminated by adding 1M phosphoric acid, and the absorbance of each well was measured at 450 nm using a Synergy H1 microplate reader (BioTek).

For each experiment, more than three independent replicates were conducted, and the results were expressed as average standard deviation. Comparison of multiple groups was conducted using ANOVA-based Test and p< 0.05 (*) represented significances with statistical meaning. Calculation of the Kd was done using the equation % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody and Kd is the equilibrium dissociation constant.

In order to analyze the co-expression of CD176 and IL1RAP antigens on CD34+ cells, peripheral blood mononuclear cells from a normal volunteer (NPBMCs), patients with CML, and K562 cells were isolated and stained with anti-CD34, anti-CD176, and anti-IL1RAP monoclonal antibodies and analyzed by flow cytometry (Figure 1A). It has been previously established that these markers were not expressed on normal PBMCs nor on stem cells7,10 CD34+ cell expression ranged from an average 938% in CML samples versus 83.7% in K562 cells (Figure 1A, upper panel). Within the CD34+ cell population, CD176 and IL1RAP antigens were variably expressed in CML samples, ranging from 1.35% in CML-4 to over 50% in CML-1 (Figure 1A, lower panel), while CD176+ IL1RAP+ was detected in 78% of CD34 cells in K562 cells. Surprisingly, surface co-expression of CD176 and IL1RAP was not only detectable on CD34+ cells in patients with BCR-ABL positive CML but was also demonstrable in cells from a treated patient who was BCR-ABL negative (CML-2) (Figure 1B). In Figure 1C, CD34+ cells revealed higher frequency of CD176+ IL1RAP+ in CML group compared to control sample (17.5% versus 3.4%, p<0.001).

Figure 1 CD176 and IL1RAP antigens are co-expressed on CD34+ Leukemia stem cells. Peripheral blood mononuclear cells from patients with CML and healthy volunteers were isolated and stained for flow-cytometry analysis. (A) FACS Dot Blot showing expression of CD34 (top row) and co-expression of CD176 and IL1RAP antigens on the CD34+ cells (bottom row) in PBMCs from patients with CML compared to NPBMCs. (B) Bar graphs showing the BCR-ABL status relative to the percentage of IL1RAP and CD176 co-expression in the CD34+ subsets from patients with CML as compared to the normal control and the positive control (K562 cells). The BCR-ABL status is indicated below the sample. The error bars represent the variation in two independent experiments. (C) Average percentage of CD34+ and CD34+ CD176+ IL1RAP+ subsets in normal versus CML patients respectively. (D) Bar graphs showing the average count of colony-forming units (CFU) per 1000 CD34+CD176+IL1RAP- cells (open bar) or CD34+CD176+IL1RAP+ cells (solid bar) obtained from CML-2 and CML-4 samples. **p< 0.01, n.s represents that there is no significant difference between groups.

In order to analyze the progenitor activity of the various subpopulations, CML-2 and CML-4 were flow-sorted for CD34+CD176+IL1RAP+ and CD34+CD176+IL1RAP- then plated in media t support hematopoietic colony formation. The number of colonies, or colony-forming units (CFU), in CD34+CD176+IL1RAP+ pool represented 6% of the sorted cells with a significant difference between both populations, p<0.01 (Figure 1D and Figure S1).

To facilitate correct interaction of the VH and VL domains, site-directed mutagenesis was used to generate knob-in-hole mutations in the heavy and light chains of the constant domains (Figure 2A) via polymerase chain reaction overlap extension (Figures S2 and 3). Two PCR reactions were performed to generate two amplicons with the specific mutations included in the overlapping primers. The two fragments were then combined in a subsequent fusion reaction, in which the overlapping ends anneal, allowing the 3 overlap of each strand to serve as a primer for the 3 extension of the complementary strand. The resulting fusion product served as a template for amplification of the entire constant domain. In order to circumvent the light chain mismatching, an Orthogonal Fab interface was generated. In one Fab, complementary mutation was introduced and verified at the heavy chain constant domain (CH1_H172A_ F174G) and at the light chain constant domain (CL_L135Y_S176W), respectively (Figures S46). For the heavy chain heterodimerization, we used the Knob-in-Hole strategy, where we inserted the CH3 mutations (S354C and T366W) into different heavy chains (Figures S7 and 8). The VH and VL sequences were synthesized and cloned into the new pLM2-CH and -CL plasmids (Figure 2A) where CD176 was represented by TF1 (VH1 and VL1) and TF2 (VH2 and VL2) while IL1RAP was represented by Clone 4B6 (VHa and VLa) and Clone 4G9 (VHb and VLb). Then, we generated the four different bi-specific antibody mixtures (TF1RAPa, TF1RAPb, TF2RAPa, and TF2RAPb) to evaluate the most effective Bis-Ab (Figure 2B). The bispecific antibody was quantified by ELISA at 283 ng/mL. Since ELISA used the human IgG heavy chain antibody as the primary antibody and a goat anti-human lambda antibody conjugated to HRP as the secondary antibody, these data also confirm the correct association of the heavy and light chains and ensure that monomers are excluded.

Figure 2 The bi-specific antibody arms. (A) Schematic diagram of the bi-specific antibody showing the mutant arms and the antigen-binding domains. Thomsen-Freidenrich or CD176 domains (TF); IL1RAP domains (RAP); variable domain-heavy chain (VH); variable domain-light chain (VL); L135Y and S176W mutations (Y-W) in constant domain-light chain; H172A and F174G mutations in CH1 domain (A-G); S354C (C) or T366W (W) mutations in CH3. (B) Antibody mixtures generated by transient transfection of HEK 293T cells. TF1 and TF2 was paired with RAPa and RAPb to generate four Bis-Ab mixtures. The bispecific antibody concentration was 283 ng/mL as measured with ELISA. The correct association of the human IgG heavy chain and the lambda light chain was confirm and monomers were excluded by using anti-IgG primary antibodies and anti-light chain secondary antibodies.

KG1 cell line is an acute myeloid leukemia cell line that is known to be a positive control for CD176. For optimizing the staining protocol of CD176, KG1 cells were pre-treated with VCN to expose CD176 antigens for better staining (Figure S9). In order to test the binding capability and functional potential of our bi-specific antibody, we generated a dual-positive cell line for expressing both IL1RAP and CD176 through lentiviral transduction (Figure S10A and B). IL1RAP expression was increased by 1.5 folds in KG1/RAP cells as verified by flow cytometry (Figure S10C and D).

CD176 antigen is a glycosylated antigen; a protein antigen bound to GAL-NAC moiety which makes the antigen displayed on the cell surface yet not easy to isolate.21 For this reason, a flow-cytometry assay was used to evaluate both the binding capability and toxicity of our Bis-Ab using the gating strategy in Figure S11. KG1 and KG1/RAP cell lines were treated with the various Bis-Ab mixtures. Binding percentage was calculated from the percentage of IgG positive cells, where the secondary IgG antibody is bound to the primary Bis-Ab. The TF1RAPa Bis-Ab showed the highest binding in KG1/RAP cells (Figure 3A) as compared to other mixtures (p<0.001). In contrast, the TF1RAPb antibody revealed slightly reduced binding in KG1/RAP cells. On treating KG1/RAP cells with increasing amounts of TF1RAPa, more binding to the dual-positive KG1/RAP cells was observed (Figure 3B). To demonstrate the specificity of the Bis-Ab, we measured the competition with the CD176 and the IL1RAP monoclonal antibodies. Increasing concentrations of the Bis-Ab specifically inhibited the binding of both the IL1RAP and CD176 mAbs (Figure S12). Then, our KG1/RAP cells were treated with the Bis-Ab TF1RAPa and complement prior to staining with the LIVE/DEAD Fixable Aqua Dead Cell Stain Kit, in order to evaluate whether CDC could be achieved using IL1RAP and CD176 as targets. Flow cytometric analysis revealed a significant increase in dead cells in the Bis-Ab treated CD176/IL1RAP dual-positive KG1/RAP population as antibody binding also increased (Figure 3C), p<0.001.

Figure 3 Validation of TF-RAP Bi-specific antibody in KG1 cell line and CML samples. (A) MFI for binding of different Bis-Ab mixtures in KG1/RAP (p <0.001). (B) Binding (%) of the Bis-Ab in KG1/RAP cell lines. (C) Shows live/dead (LD) staining (%) in KG1/RAP cell lines after treatment with the Bis-Ab and complement. (D) MFI for binding of different Bis-Ab mixtures p <0.001 in CML cells. (E) Binding of the Bis-Ab (%) in PBMCs from patients with CML. The binding affinity (Kd) of our bispecific antibody was 21ng/mL, calculated using the % RO = [Ab]/([Ab]+Kd) 100%, where RO is the receptor occupancy, Ab is the concentration of antibody, and Kd is the equilibrium dissociation constant. This Bis-Ab platform used in this study had the correct molecular weight (95 KDa) and assembled properly (93%) as revealed by SDS-PAGE analysis.38 (F) Live/dead (L/D) staining (%) from patients with CML after treatment with the Bis-Ab and complement. The red square were L/D positive cells treated with CyO2; the percent of L/D staining in normal PBMCs is shown in blue. Each point represents the mean increase in L/D staining SEM with three to four replicates. Data from normal samples were low for all doses (data not shown).

Binding of TF1RAPa, TF2RAPa, and TF2RAPb was also tested in PBMCs from patients with CML. Again, TF1RAPa showed the highest binding relative to other mixtures (p<0.001) (Figure 3D) and with increasing doses (Figure 3E). Based on the CML binding curve, the binding affinity (Kd) of our bispecific antibody was 21 ng/mL. Other therapeutic antibodies, such as ofatumumab directed against CD20, have shown significant CDC against peripheral blood cells obtained from CML patients in chronic phases26 and B cells in CLL,29 respectively. Thus, the TF1RAPa cocktail was used to generate the doseresponse curve and to evaluate whether CDC could be achieved using both IL1RAP and CD176 as targets. The ability of the TF1RAPa cocktail was compared to human anti-IL1RAP and anti-CD176 monoclonal antibodies to induce cell death in PBMCs from patients with CML. PBMCs from CML1-4 were tested in CDC assays in parallel to cells from healthy control samples. In CML cells, the binding of TF1RAPa mediated CDC at higher levels than in normal peripheral blood mononuclear control cells, correlating with the expression level of IL1RAP and CD176, particularly at lower antibody concentrations (Figure 3F). More strikingly, among peripheral blood cells, TF1RAPa did not induce CDC of normal cells, whereas a clear dose-dependent CDC effect was observed in CML cells (Figure S13A and B). To address the selectivity of IL1RAP/CD176-targeting antibodies, we also validated the bispecific antibody cytotoxicity on the various subpopulations in peripheral blood. The dual-positive CD176+IL1RAP+ cell populations showed the highest CDC activity as compared to CD176+IL1RAP-, CD176-IL1RAP+, and CD176-IL1RAP- populations (Figure 4 and S13CF, S14).

Figure 4 Dose-response curve of TF1RAPa Bis-Ab on CDC in CML samples. A dose-response curve showing the selective killing potential of CD176+IL1RAP+ subpopulation by the TF1RAPa Bis-Ab as compared to other subpopulations in PBMCs from patients with CML. Each point represents the mean SEM of the four samples.

Targeting molecules involved in multiple pathways is proving to be one of the most reliable strategies for eradicating cancer stem cells. In this report, we present a novel bi-specific antibody, TF/RAP, capable of targeting ThomsenFriedenreich (TF, CD176) and IL1RAP antigens on CD34+ HSCs in CML and on cell lines. TF is a glycoprotein that has many domains and motifs (eg, LGALS3, Gal(1,3)GalNAc, LGalS3BP), many related to signaling pathways. It is a known marker for ongoing tumorigenesis and metastasis, as it is expressed on various cancer-initiating cells.8 Interestingly, CD34 and LGALS3 were found to be co-expressed in myeloid cells.30,31 LGALS3 and ABL1 are involved in regulating RUNX1 and the transcription of genes involved in differentiation of hematopoietic stem cells,32 especially myeloid cells33 (Figure S15) IL1RAP, on the other hand, is a member of the Toll-like receptor superfamily and is a well-known co-receptor of IL1R1.34 IL1RAP plays a role in mediating the effect of the pro-inflammatory cytokine IL-1 and is also involved in activating T cells and mast cells after mediating the signal of IL-1 cytokine.35 It has previously been characterized as a tightly related marker for BCR-ABL positive cells.7 Together, both TF and IL1RAP were related to apoptotic pathways; IL1RAP up-regulation was associated with decreased apoptosis in AML,36 and anti-CD176 antibody induced apoptosis of CD176-positive leukemic cells through multiple pathways.12 Although we did not find a direct link between IL1RAP, CD176 and leukemogenesis, previous studies have shown that each of them is separately expressed on CD34+ cells in leukemia cell lines8,10,12 and patients with CML7

Therefore, we conducted this pilot study, in order to assess the co-expression of IL1RAP and ThomsenFriedenreich (CD176) antigens on CD34+ HSCs in peripheral blood of patients with CML, using FACS gene expression analyses. Flow-drop FISH and CFU assays were used for the separation of CD34+CD176 BCR-ABL+ and BCR-ABL CML stem cells, based on IL1RAP expression.7 CFU numbers were significantly lower in CD34+CD176+IL1RAP- cells than in CD34+CD176+IL1RAP+ cells, obtained from CML-2 and CML-4 samples (Figure 1D), particularly CML-2 sample which was obtained from a patient in remission (BCR-ABL-). We found that the frequency of clonogenic hematopoietic progenitor cells was increased in the CD34+ CD176+IL1RAP+ cells in these samples. Testing the stem-cell characteristics of these two cell populations in immune-deficient mice would have been advantageous. Yet, the low numbers of sorted CML cells acquired from the CD34+CD176+ IL1RAP and IL1RAP+ cell subpopulations, alongwith the general low engrafting efficiency of chronic phase CML cells in these mice7 prevented us from successfully performing such experiments. Importantly, as IL1RAP expression was correlated with changes from chronic phase (CP) into accelerated phase (AP) and blast phase (BP)37, we also found that the level of IL1RAP/CD176 co-expressionwas increased, in our patient samples, as the disease progressed, independent of the treatment status(Table S3).

To target both TF and IL1RAP simultaneously, we developed a Bis-Ab specific for both antigens. Because antibodies are normally heterodimers of two heavy and two light chains, we modified the constant domains in the Bis-Ab to maximize the correct interactions of the four immunoglobulin chains within single cells. Here, we used the orthogonal Fab design; CH1_H172A_F174G and CL_L135Y_S176W38 to facilitate selective assembly of the Fab arms for correct dimerization of the antigen-binding domains.39 Therefore, we mutated CH1 and CL binding sites to restrict the assembly of the Fab with the correct VD pairs. The RAP VDs were cloned with the wild type Fab; and the TF VD was linked to the mutant orthogonal Fab design. Published data have shown that the component proteins of this Bis-Ab platform proper assembly were detected at 93% and the complex had a molecular weight of 95 KDa, as revealed by SDS-PAGE analysis.38 Additionally, the CH3 for each Fab was mutated with previously described knob-into-hole mutations40,41 to facilitate hetero-dimerization between the TF and the RAP heavy chains. In our study, we used ELISA to demonstrate that both the VD and Fc were properly paired. Here, because the primary antibody was anti-human VL and the secondary antibody was anti-human IgG, quantifying the Bis-Ab also demonstrated the VD-Fc interactions.

To efficiently validate the specific binding of our Bis-Ab, we generated a dual-positive cell line; KG1/RAP. KG1 cell line expresses CD176+, but IL1RAP is low or absent. Therefore, we induced IL1RAP expression in KG1 cells by lentiviral mediated-gene transfer, as previously usedin both immune42 and leukemic cells.43 In the competitive binding assay, increasing concentrations of the Bis-Ab blocked the binding of CD176 and IL1-RAP monoclonal antibodies to the KG1/RAP and KG1 parental cells, demonstrating the specific binding of the Bis-Ab. The level of CD176 expression in KG1 cell line was detected before and after VCN treatment. Increased staining of the KG1/RAP cells compared to the parental KG1 cells indicated that expression of the IL1RAP facilitates the interaction of the Bis-Ab with the target cell. This increased binding of the Bis-Ab to the KG1/RAP cells also increased their susceptibility to complement-dependent cytotoxicity (CDC). We also observed increased binding and increased CDC in the CD176+ IL1RAP+ population of the peripheralblood from patients with CML. As a pilot study and given that on average, 50% of the cells within the CD34+ subpopulation in the patients tested were dual positive for CD176 and IL1RAP antigens, in addition to the almost undetectable CDC in CD34+ cells in normal controls, our data strongly support the idea that the bi-specific antibody (TF/RAP) indeed induces CDC preferentially in CD176+ IL1RAP+ CML CD34+ cells. In generating a bi-specific antibody that targets CD176 and IL1RAP, we are unique in providing proof of concept that CML CD34+CD176+ IL1RAP+ cells can be targeted while preserving corresponding normal cells. The potential to target multiple antigens is supported by studies that demonstrated increased or synergistic CDC activity by non-cross blocking CD20 antibody combinations.44

Therapeutic antibodies are commonly administered intravenously, yet selectivity and specificity are a major concern for reduced toxicity. CD176/IL1RAP co-expression was not present in monocytes unlike the reported weak but present IL1RAP expression in monocytes.7 Both antigens were low or absent in most types of normal bone-marrow progenitor and mature cell types, suggesting that CD176/IL1RAP dual targeting antibodies are expected to show low toxicity on normal hematopoietic cells. Being strongly expressed on the surface of cancer cells and virtually absent from normal tissues, CD176 was evaluated as a potential target for cancer biotherapy with the development of anti-CD176 antibody that induced apoptosis of leukemic cells.8 Added to this, antibodies against IL1RAP were found to be capable of blocking IL-1 signaling as well as inhibiting tumor cells' growth in AML,34 CML,7 breast cancer,45 prostate cancer, breast cancer, lung cancer, colorectal cancer, melanomas, bladder cancer, brain/CNS cancer, cervical cancer, esophageal cancer, gastric cancer, head/neck cancer, kidney cancer, liver cancer, lymphomas, ovarian cancer, pancreatic cancer, and sarcomas46 especially in cancer stem cells, or (CSCs) and progenitor cells, which are responsible, directly or indirectly, for the development of a solid tumor.47 Thus, it may be thatour Bis-Ab will not only eradicate the CD176+IL1RAP+ drug-resistantCML stem cells but also may have universal therapeutic potential for preventing relapses in both solid and hematological cancers.Given that the mode of action in CDC is having the antibody direct the complement pathway to target cell killing, we suggest that this therapeutic strategy would be independent of known mechanisms of TKI resistance in CML. Thus, the concept of complement-mediated killing of IL1RAP/CD176 expressing cells may also have the potential to eradicate such cells in patients, either alone or in combination with current regimens, in order to increase their therapeutic effectiveness. And finally, expanded studies need to be performed in order to confirm the co-expression of both markers, especially in resistant and relapsed cancer patients as well as in patient-derived xenografts (PDX).

The experimental research was mostly supported by a fellowship to REE from the Egyptian Ministry of Higher Education, Cultural, and Missions Section (JS 3577). The lentiviral vectorHRST-cmvGFPand the packaging plasmids were akind gift from Richard C.Mulligan in the Harvard Gene Therapy Institute. The human IgG heavy and light chain constant genes were provided by JE Robinson (Tulane University). C Wu and SEB were supported by AI110158 and/or OD01104-51; EUA and SEB were supported by the Applied Stem Cell Laboratory.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. All authors have given approval of the final version of the article; and have agreed to be accountable for all aspects of the work.

The abstract of this paper was presented at the AACR annual Meeting 2019; March 29 April3, 2019; Atlanta, GA, as a poster presentation with interim findings. The posters abstract was published in Poster Abstracts in the AACR meeting proceedings and as a supplement in the AACR Cancer Research Journal [https://cancerres.aacrjournals.org/content/79/13_Supplement/1222A].

Raghda Eldesouki reports grants from Egyptian Ministry of Higher Education. Stephen EBraun reports grants from Egyptian Ministry of Education, Alliance for Cardiovascular Research, NIAID OD01104, and Braun/McGroarty Charitable Fund, during the conduct of the study. In addition, Dr Raghda Eldesouki, Dr Stephen Braun, Dr Fouad Badr and Dr Eman Abdel-Moemen Mohammedhave apatent, PCT/EG2019/000014, pending. The authors report no other conflicts of interest in this work.

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19. Robinson JE, Hastie KM, Cross RW, et al. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat Commun. 2016;7:11544. doi:10.1038/ncomms11544

20. Goltez S, Karasten U Cancer stem cell markers and uses thereof. WIPO, WO2011089004A1 2011 Jul 28.

21. Jiang Y, Tso J, Karsunky H. Antibodies that bind membrane-bound IL1rap. European patent EP2935334A1. 2015 Oct 28.

22. Keaglen MB, Gersen SL. Basic cytogenetics laboratory procedures. In: Gersen SL, Keagle MB, editors. The Principles of Clinical Cytogenetics. NewYork, NY: Springer NewYork; 2013:5365.

23. International Standing Committee on Human Cytogenetic Nomenclature. ISCN2016: An International System for Human Cytogenetic Nomenclature. Karger Medical and Scientific Publishers; 2016.

24. Broxmeyer HE, Etienne-Julan M, Gotoh A, et al. Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function. Stem Cells Dev. 2013;22(6):9981006. doi:10.1089/scd.2012.0478

25. Balduini A, Broxmeyer HE, Braun SE, Cornetta K, Lyman S. Comparative effects of retroviral mediated gene transfer into primary human stromal cells of flt3ligand, interleukin 3 and gmcsf on production of cord blood progenitor cells in longterm culture. Stem Cells. 1998;16:3749. doi:10.1002/stem.5530160807

26. Tatake RJ, Maniar HS, Chiplunkar SV, et al. Antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity on leukemic cells mediated by anti K562 monoclonal antibodies. J Clin Lab Immunol. 1990;31(2):8791.

27. Lindorfer MA, Beum PV, Taylor RP. CD20 mAb-mediated complement dependent cytotoxicity of tumor cells is enhanced by blocking the action of factor I. Antibodies. 2013;2:598616. doi:10.3390/antib2040598

28. Gerlach SL, Chander PK, Roy U, et al. The membrane-active phytopeptide. Cycloviolacin O2 simultaneously targets HIV1-infected cells and infectious viral particles to potentiate the efficacy of antiretroviral drugs. Medicines (Basel). 2019;6(1):E33. doi:10.3390/medicines6010033

29. Zen CS, Secreto CR, LaPlant BR, et al. Direct and complement dependent cytotoxicity in CLL cells from patients with high-risk early-intermediate stage chronic lymphocytic leukemia (CLL) treated with alemtuzumab and rituximab. Leuk Res. 2008;32(12):18491856. doi:10.1016/j.leukres.2008.05.014

30. Marer N. Galectin3 expression in differentiating human myeloid cells. Cell Biol Int. 2000;24:245251. doi:10.1006/cbir.1999.0501

31. Labbaye C, Testa U. The emerging role of MIR-146A in the control of hematopoiesis, immune function and cancer. J Hematol Oncol. 2012;5:13. doi:10.1186/1756-8722-5-13

32. Huang H, Woo AJ, Waldon Z, et al. A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev. 2012;26(14):15871601. doi:10.1101/gad.192054.112

33. Zhang HY, Jin L, Stilling GA, et al. RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors. Endocrine. 2009;35(1):101111. doi:10.1007/s12020-008-9129-z

34. gerstam H, Karlsson C, Hansen N, et al. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2015;112(34):1078610791.

35. McEntee CP, Finlay CM, Lavelle EC. Divergent roles for the IL-1 family in gastrointestinal homeostasis and inflammation. Front Immunol. 2019;10:1266.

36. Barreyro L, Will B, Bartholdy B, et al. Over expression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood. 2012;120(6):12901298. doi:10.1182/blood-2012-01-404699

37. Zhao K, Yin LL, Zhao DM, et al. IL1RAP as a surface marker for leukemia stem cells is related to a clinical phase of chronic myeloid leukemia patients. Int J Clin Exp Med. 2014;7(12):47874798.

38. Lewis SM, Wu X, Pustilnik A, et al. Generation of bi-specific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol. 2014;32:191198. doi:10.1038/nbt.2797

39. Spidel JL, Vaessen B, Chan YY, Grasso LJ, Kline B. Rapid high-throughput cloning and stable expression of antibodies in HEK293 cells. J Immunol Methods. 2016;439:5058. doi:10.1016/j.jim.2016.09.007

40. Ridgway JB, Presta LG, Carter P. Knobs-into-holes engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617621. doi:10.1093/protein/9.7.617

41. Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol. 1997;270:2635. doi:10.1006/jmbi.1997.1116

42. Pan H, Mostoslavsky G, Eruslanov E, Kotton DN, Kramnik I. Dual-promoter lentiviral system allows inducible expression of noxious proteins in macrophages. J Immunol Methods. 2007;329(12):3144. doi:10.1016/j.jim.2007.09.009

43. Biagi E, Bambacioni F, Gaipa G, et al. Efficient lentiviral transduction of primary human acute myelogenous and lymphoblastic leukemia cells. Haematologica. 2001;86(1):1316.

44. Melis JP, Strumane K, Ruuls SR, Beurskens FJ, Schuurman J, Parren PW. Complement in therapy and disease: regulating the complement system with antibody-based therapeutics. Mol Immunol. 2015;67:117130. doi:10.1016/j.molimm.2015.01.028

45. Liberg D, nnervik P, Riva M, Larsson L, Forsberg G, Wachenfeldt K. Antibody Blockade of IL1RAP Signaling Reduces Metastasis in a Breast Cancer Model. Annual Meeting of the American Association for Cancer: McCormick Place North/South Chicago, Illinois, USA; 2018.

46. Fioretos T, Jaras M Method of treatment of a solid tumor with interleukin-1 accessory protein antibody. United States patent US 9403906B2. 2016 Aug 02.

47. Fioretos T, Jaras M. Anti - IL1rap antibodies and their use for treating human. European patent EP2665749A1. 2013 Nov 27.

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[Full text] Identification and Targeting of ThomsenFriedenreich and IL1RAP | OTT - Dove Medical Press

Recommendation and review posted by Bethany Smith

NEW YORK, Jan. 20, 2021 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, announced today the peer-reviewed publication of a preclinical study in the journal Stem Cell and Research Therapy. The study, entitled "MSC-NTF (NurOwn) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model," evaluated the use of NurOwn (MSC-NTF cell) derived exosomes in a mouse model of acute respiratory distress syndrome (ARDS).

ARDS is a type of respiratory failure that is frequently associated with COVID-19 and mediated by dysregulated cytokine production. While there are currently no effective therapies to prevent or reverse ARDS, mesenchymal stem cell (MSC)-derived exosomes have been suggested as a potential novel treatment option due to their ability to penetrate deep into tissues and efficiently deliver immunomodulatory molecules.

Results from the recently published study showed that intratracheal administration of NurOwn derived exosomes led to a statistically significant reduction in lung disease severity score (p < 0.05; based on criteria set forth by the American Thoracic Society Documents: Matute-Bello et al., Am J Respir Cell Mol Biol 44;725-738, 2011) and improvements in several additional clinically relevant lipopolysaccharide (LPS)-induced ARDS markers such as lung function, fibrin presence, neutrophil accumulation, cytokine expression, and blood oxygenation levels. Notably, these improvements were significantly superior to those observed following administration of nave MSC-derived exosomes.

"These exciting preclinical data suggest that NurOwn derived exosomes have the potential to treat COVID-19-induced ARDS or other severe respiratory complications, and that they are more effective than exosomes isolated from nave MSCs at combatting the various symptoms of the syndrome," said Dr. Revital Aricha, Vice President of Research & Development at BrainStorm. "This publication in a highly regarded journal provides important validation for the scientific advances and significance of BrainStorm's preclinical research programs, including on our exosome-based technology platform."

Chaim Lebovits, Brainstorm's Chief Executive Officer added, "While our primary focus is on advancing NurOwn towards regulatory approval in ALS, we continue to evaluate the potential of our exosome-based platform to address unmet medical needs. The publication of these proof-of-concept data highlights this potential, and we are now actively assessing next steps to determine how to best generate value. We are also actively discussing with possible partners several development opportunities for the exosome technology."

About NurOwn

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm is in active discussions with the FDA to identify regulatory pathways that may support NurOwn's approval in ALS. BrainStorm is also conducting an FDA-approved phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed dosing inDecember 2020, and topline results are expected by the end of the first quarter 2021.

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

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Investor Relations:Corey Davis, Ph.D.LifeSci Advisors, LLCPhone: +1-646-465-1138[emailprotected]

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BrainStorm Announces the Publication of Preclinical Data Highlighting the Potential of a NurOwn Derived Exosome-Based Treatment for COVID-19 ARDS -...

Recommendation and review posted by Bethany Smith

Introduction

Bone remodelling is a tightly coupled lifelong process, whereby old bone is removed by osteoclasts (bone resorption) and new bone is formed by osteoblasts (bone formation).1,2 Osteocytes, which act as mechanosensors/endocrine cells, and bone lining cells3 are also involved in bone remodelling.4 Myriad pathophysiological factors affecting bone remodelling have been observed in skeletal diseases such as osteoporosis, arthritis and periodontal disease.5 Oxidative stress is one of the pathophysiological factors affecting bone remodelling. Oxidative stress stimulates osteoclast differentiation, thereby enhancing bone resorption.6,7 Reactive oxygen species (ROS) stimulate the apoptosis of osteoblasts and osteocytes, thus affecting bone formation. ROS also activate mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases (ERK1/2), c-Jun-N terminal kinase (JNK) and p38, and enhance osteoclastogenesis and bone resorption.811 These phenomena skew the bone remodelling process in favour of bone loss.

Antioxidants are compounds which reduce free radicals and oxidative stress.12 Antioxidants have been reported to promote differentiation of osteoblasts, bone formation and survival of osteocytes, as well as suppressing osteoclast differentiation and activity.8,1315 Some studies associate the age-related reduction in circulating antioxidants to osteoporosis in rats and women.1618 A decline in antioxidant levels has been reported to promote bone loss by triggering the tumour necrosis factor-alpha (TNF)-dependent signalling pathway,6 while administration of antioxidants, such as vitamin C, E, N-acetylcysteine and lipoic acid, have been reported to exert favourable effects in animal models of osteoporosis1921 and individuals with osteoporosis.2225

Caffeic acid (CA) is a metabolite of hydroxycinnamate and phenylpropanoid commonly synthesized by all plant species. It is a polyphenol present in many food sources like coffee, tea, wine, blueberries, apples, cider, honey and propolis.26 CA and its major derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) are reported to possess potential antibacterial, antidiabetic, antioxidant, anti-inflammatory, antineoplastic and cardioprotective activities (reviewed in2729). As a potent antioxidant, CA has been demonstrated to decrease lipoperoxyl radicals (ROO) by donating a hydrogen atom to its corresponding hydroperoxide, which terminates the lipid peroxidation chain reaction. It also inhibits human low-density lipoprotein (LDL) oxidation induced by cupric ions.30 Furthermore, it interacts with other compounds, such as -tocopherol, chlorogenic and caftaric acids, to exert more potent antioxidant activity in a variety of different systems.3133 Therefore, the antioxidant activities of CA might protect against the negative effects of oxidative stress on bone cells and the skeletal system. This systematic review aims to summarise the effects of CA and its derivatives on bone cells and bone in literature.

A systematic literature search was conducted from July until November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases to identify studies on the effects of caffeic acid on bone and bone cells including osteoblasts, osteoclasts and osteocytes. The search string used was (1) caffeic acid AND (2) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes).

Studies with the following characteristics were included: (1) original research article with the primary objective of determining the effects of caffeic acid on bone and bone cells; (2) studies using cellular or animal models, or humans; (3) studies administering caffeic acid as a single compound but not in a mixture or food. Articles were excluded if they (1) do not contain original data; (2) use food rich in caffeic acid or mixtures containing caffeic acid. The bibliography of relevant review articles was traced for potential articles missed during database search. The search results were organised using EndNoteTM software (Clarivate Analytics, Philadelphia, USA). Duplicates were identified using EndNoteTM and confirmed by manual checking.

Two authors (S.O.E. and K.L.P.) searched the same databases using the search string mentioned and screened the search results. All the articles that did not match the selection criteria were excluded. Next, the articles which used caffeic acid in treating models other than bone-related diseases were removed. Finally, articles which used caffeic acid in combination with other compounds were also excluded. Any disagreement on the inclusion or exclusion of articles was resolved through discussion among the two authors. The corresponding author (K.Y.C.) had the final decision on articles included if a consensus could not be reached between authors responsible for screening. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklist.34 Steps in the selection process, from identification, screening, eligibility to the inclusion of articles, are shown in Figure 1.

Figure 1 Flowchart of the article selection process.

From the literature search, 381 articles were identified, of which 87 were obtained from PubMed, 182 were from Scopus, 3 from Cochrane Library and 109 from Web of Science. A total of 155 duplicate articles were identified and removed. Of the 226 articles screened, 202 articles were excluded based on the selection criteria, whereby 51 articles did not contain primary data (3 book chapters, 2 commentary and 46 review articles), 147 articles and 2 conference abstracts presented topics irrelevant to the current review, a conference abstract had been published as a full-length research article and another conference abstract did not contain sufficient experiment details (Supplementary Material). Finally, 24 articles fulfilling all criteria mentioned were included in the review.

The included studies were published between 2006 and 2020. Seven studies were in vitro experiments using mouse bone marrow macrophages (BMMs), RAW264.7, RAW D and MG63 osteoblast cell lines3541 while 19 studies were in vivo studies using Sprague Dawley/Sprague Dawley albino rats, Wistar/Wistar albino rats, Balb/c mice, lipopolysaccharide (LPS)-resistant C3H/HEJ mice, C57BL/6J mice and ICR mice.35,38,4258 No human studies on this topic were reported.

Six in vitro studies focused on the effects of CA on osteoclast differentiation from haematopoietic cells using macrophage colony-stimulating factor (M-CSF), receptor activator of NF-B (RANK) ligand (RANKL) or TNF-,3539,41 while one in vitro study focused on the effect of CA on osteoblasts using MG63 osteoblast cell line.40 Four in vitro studies used CA doses between 0.15 M.35,37,38,40 Ang et al.36 used doses between 00.3 M and Sandra et al.41 and Sandra and Ketherin39 used a dose of 10 g/mL (55.5 M). The treatment period was 57 days for the differentiation of osteoclasts.

For animal studies, Duan et al.,55 Zawawi et al.,58 William et al.,51 Wu et al.,38 Zych et al.49 and Folwarczna et al.48,52 used CA or its derivatives at doses between 0.550 mg/kg via oral or intraperitoneal (i.p.) administration. Ucan et al.,57 Erdem et al.,53 Cicek et al.,54 Yigit et al.,45 Yildiz et al.50 and Tolba et al.56 used doses between 1020 mol/kg/day (2.845.69 mg/kg/day) via i.p. administration. Kizilda et al.4244 and Kazanciolu et al.46,47 used the dose of 10 mmol/kg/day (2.843 g/kg/day) for an i.p. administration, Kazanciolu et al.47 employed 50100 mmol/kg/day (14.2228.43 g/kg/day) for a localised administration, while Ha et al.35 used a collagen sponge soaked with CAPE with the final dose of 250 g/mouse. For oral administration, first-pass effect might affect the enteric absorption of CA or its derivatives.59 For i.p. administration, the injection is commonly performed at the lower left or right quadrant of the abdomen. The peritoneum can absorb the compounds fast and reach systemic circulation with greater bioavailability with fewer handling errors.60

The bone-related disease models used included ovariectomy (OVX)- or glucocorticoids (dexamethasone)-induced osteoporosis, polyethylene particle-induced bone defect and osteolysis, electromagnetic force (EMF)-stimulated bone loss, osteotomy- or anti-collagen antibody-induced arthritis (CAIA) and rapid maxillary expansion (RME) and LPS-induced periodontitis. The endpoints studied included bone microstructure, histomorphometry, bone remodelling and oxidative status. The effects of CA and its derivatives on bone remodelling have been summarized in Table 1.

Melguizo-Rodrguez et al. reported that 24-hour CA (1 M) incubation increased the number of MG63 osteoblast cells compared with control.40 Gene expression studies revealed that CA increased the expression of osteoblast-related genes such as bone morphogenetic protein-2 and -7 (BMP-2 and BMP-7), transforming growth factor-beta 1 (TGF-1), transforming growth factor-beta receptor 1, 2 and 3 (TGF-R1, TGF-R2 and TGF-R3) and osteoblastogenesis genes including Runt-related transcription (RUNX-2), alkaline phosphatase (ALP), collagen type 1 (COL-I), osterix (OSX) and osteocalcin (OSC).40 Additionally, pretreatment of CA (10 g/mL or 55.5 M) on RAW D cells for 2 h also significantly inhibited the RANKL and TNF-induced osteoclastogenesis with the suppression of p38 MAPK phosphorylation and tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells (OCLs) formation.39 Similarly, pretreatment of CA (0.1, 1 and 10 g/mL or 0.555, 5.55 and 55.5 M) on RAW D cells and BMMs for 3 days significantly inhibited the RANKL and TNF-induced osteoclastogenesis and NF-B activity in RAW-D cells and RANKL, TNF and M-CSF-induced osteoclastogenesis in BMMs.41

On the other hand, CAPE treatment (00.3 M; 57 days) suppressed the formation of TRAP-positive OCLs on RANKL-treated RAW264.7 cells and BMMs.36 Apoptosis occurred in CAPE-treated RAW264.7 cells with the disruption of the microtubule network in OCLs.36 Similarly, Kwon et al. reported that CAPE treatment (0.15 M) for 5 days suppressed OCLs formation from RANKL-stimulated RAW264.7 cells.37 Another study by Ha et al. treating M-CSF and RANKL-stimulated BMMs with CAPE (05 M for 57 days) also showed decreased OCLs formation in a concentration-dependent manner.35 The amount of TRAP-positive OCLs was decreased upon 0.1 and 0.5 M CAPE treatment by 30% and 95% respectively.35 No OCL formation was observed upon 1 M CAPE treatment.35 The anti-osteoclastogenic activities of CAPE are mainly contributed by its anti-inflammatory and antioxidant properties. Mechanistically, CAPE reduces superoxide anion generation by downregulating the nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1) expression through the interruption of nuclear factor-kappa B (NF-B) and c-Jun N-terminal kinase (JNK) signalling pathways.37 CAPE suppresses RANKL-mediated activation of the NF-B pathway by downregulating NF-B p65 subunit expression and its nuclear translocation,37 suppressing nuclear factor of activated T cells (NFAT) activities36 and degradation of NF-B inhibitor (IB),36,37 as well as inducing the degradation of IB kinase (IKK).37 CAPE also suppresses the expression and activation of JNK and its downstream transcription factors, such as c-Fos and c-Jun, which subsequently interrupt the protein activator-1 (AP-1) complex formation.37 Additionally, CAPE suppressed RANKL-induced activation of the Nox1 by inhibiting the Nox p47PHOX subunit translocation to the cell membrane and downregulation of Ras-related C3 botulinum toxin substrate 1 (Rac1) expression.37

On the other hand, Wu et al. reported that CADPE (0.15 M for 7 days) also concentration-dependently reduced OCL formation in the M-CSF and RANKL-stimulated BMMs and RAW264.7 cells.38 Mechanistic and characterisation examination revealed that CADPE suppressed RANKL-induced tumour necrosis factor receptor-associated factor 6 (TRAF6) activation and protein kinase B (PKB or also known as Akt) and activation of major MAPKs including ERK, JNK and p38.38 Subsequently, CADPE suppressed downstream expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), nuclear translocation of c-Fos protein and expression of osteoclastic markers, such as TRAP and cathepsin K, possibly through the non-receptor tyrosine kinase c-Src signalling.38 Interestingly, CADPE did not significantly affect the NF-kB signalling pathway and M-CSF-induced proliferation and differentiation of BMMs.

Supplementation of CA in animal models of bone loss yielded heterogeneous findings.48,49,52 This observation might be attributable to oral administration. Folwarczna et al. reported that CA (5 and 50 mg/kg, by stomach tube for 4 weeks) improved the bone mechanical properties by increasing the width of the trabecular metaphysis of the femur and decreasing the transverse growth in endosteal of the femur in OVX rats.48 Folwarczna et al. then demonstrated that CA (10 mg/kg/day; oral administration for 4 weeks) could reduce the width of tibial periosteal and endosteal osteoid compared with untreated OVX rats.52 However, CA did not promote or reduce the resorption of compact bone in the tibia of OVX-induced osteoporotic rats as evidenced by negligible changes of bone mass, bone mineral mass, bone mass/body mass ratio and bone mineral mass/body mass ratio.52 On the other hand, Zych et al. reported that CA at a similar dose (10 mg/kg/day; by stomach tube for 4 weeks) worsened the bone mechanical properties of healthy female Wistar Cmd:(WI)WU rats by decreasing the load of fracture at the femoral neck, decreasing the width of periosteal osteoid in the tibia and decreasing the width of the epiphysis and metaphysis trabecular in the femur compared with the negative control group.49

CAPE is the most extensively studied caffeic acid derivative in animal studies. The beneficial effects on new bone formation and healing upon systemic administration of CAPE had been reported.46,47,53,57 Erdem et al. reported that a low dose of CAPE (10 mol/kg; i.p. injection for 22 days) increased new bone formation and bone strength by increasing maximum torsional fracture momentum and degree of rigidity compared with negative control in rats that underwent unilateral femoral lengthening (osteotomy).53 Similarly, a 30-day i.p. injection of CAPE (10 mol/kg/day) also increased bone healing level in Sprague Dawley rats with cranial critical size bone defect.57 A higher dose of CAPE (10 mmol/kg/day, i.p. for 20 days) also further promoted the RME procedure-induced new bone formation in midpalatal suture of male Sprague Dawley rats.47 Similarly, a longer treatment period of CAPE (10 mmol/kg/day; i.p. injection for 28 days) also significantly promoted bone healing by increasing the total new bone areas in surgical-induced calvarial defects of male Wistar rats compared with the negative control.46 However, localised administration of CAPE (28 days) on surgical-induced calvarial defects by pre-mixing 50 and 100 mmol/kg CAPE solutions with gelatin sponges did not significantly improve the new bone formation.46

Localised and systemic administration of CAPE was reported to be beneficial in reducing osteolysis and bone loss.35,4245,50,5456,58 Ha et al. reported that collagen sponge implant impregnated with 250 g CAPE and RANKL could reduce osteoclastogenesis with significantly lesser TRAP-stained area in mouse calvariae compared with implants with RANKL only.35 Subcutaneous injection of CAPE (1 mg/kg/day for 10 days) reduced the polyethylene particle-induced calvarial osteolysis, surface bone resorption and TRAP-positive cells formation with an increase of bone volume (BV) on LPS-resistant C3H/HEJ female mice.58 However, no significant changes were observed in carboxy-terminal cross-linked type 1 collagen (CTX-1) and osteoclast-associated receptor levels among untreated and CAPE-treated rats with calvarial osteolysis.58

Similarly, Duan et al. reported that lower dose and frequency of CAPE injection (0.5 mg/kg twice a week; i.p. injection for 4 weeks) also increased the BV and trabecular number (Tb.N) due to the decrease of bone osteoclast formation (evidenced by decreased osteoclast number/bone perimeter) in OVX mice.55 Tolba et al. also reported that i.p. injection of CAPE (10 and 20 mol/kg) for 3 weeks increased femur weight and length in rats with dexamethasone-induced bone loss.56 The preservation of skeletal health in their study was associated with an improved antioxidant defence, such as higher levels of glutathione (GSH) and superoxide dismutase (SOD), and the reduction of malondialdehyde (MDA, lipid peroxidation product).56 This event led to an increase of osteoblastogenesis indicated by upregulation of RUNX-2 and ALP (osteoblast marker) levels56 On the other hand, decreased RANKL/osteoprotegerin (OPG) ratio was observed with CAPE treatment, indicating the suppression of osteoclastogenesis, which was further confirmed by lower acid phosphatase level and TRAP activity.56 In another study by Yildiz et al., CAPE (10 mol/kg/day; i.p. injection for 22 days) also increased the spine and femur BMD in rats with EMF-induced bone loss.50 Similarly, Cicek et al. reported a longer treatment of CAPE (10 mol/kg/day; i.p. injection for 28 days) also significantly improved the mechanical strength of cortical bone by increasing the breaking force, bending strength and total fracture energy in rats with EMF-induced bone loss compared with negative control.54

Additionally, a study by Wu et al. treated mice with an OVX-induced bone loss with a moderately high dose of CADPE (10 mg/kg; i.p. injection) every 2 days for 3 months.38 Results showed that CADPE could increase the BV fraction (BV/TV) and Tb.N, as well as decreased trabecular spacing (Tb.Sp) compared with the negative control.38 The improvement in the bone structure was contributed by reduced osteoclast number and eroded surface on the bone.38 Assessment of bone remodelling markers also revealed that serum TRAP5b and CTX-1 levels were reduced in CADPE-treated group compared with the negative control.38

On the other hand, CAPE was effective in reducing periodontitis-related bone loss and osteolysis.4245 CAPE (10 mol/kg/day, i.p. for 14 days) significantly reduced the subgingival ligature placement-induced periodontitis-mediated articular bone loss, histopathological features and severity of periodontal inflammation with lesser polymorphonuclear cells (PMNLs) infiltration in the junctional epithelium and connective tissues among Wistar albino rats.45 CAPE also suppressed the periodontitis-upregulated interleukin (IL)-1, IL-6, IL-10, TNF, MDA levels and the percentage of gingival apoptosis with the parallel restoration of periodontitis-downregulated GSH and glutathione peroxidase (GPx).45 Administration of high-dose CAPE (10 mmol/kg/day; i.p. for 15 days) in streptozotocin (STZ)-induced diabetic male Sprague Dawley rats reduced RANKL-positive osteoclast number, IL-1 levels, oxidative stress index (OSI), alveolar bone loss and histological analysis score in LPS-induced periodontitis. The treated rats also suffered lesser inflammatory reactions, ulcers and hyperemia.42 Similar changes of osteoclast number, IL-1 and OSI were observed in male Sprague Dawley rats with chronic stress and LPS-induced periodontitis treated with CAPE (10 mmol/kg/day, i.p. for 14 days).44 In addition, CAPE also increased the mesial and distal periodontal bone supports (MPBS and DPBS) in these rats.44 The effects of CAPE were sustained with a longer treatment period of CAPE (10 mmol/kg/day, i.p. for 28 days) on male Sprague Dawley rats with LPS-induced periodontitis.43

In contrast to the above findings, Williams et al. reported that subcutaneous injection of CAPE (1 mg/kg; at day 3, 7 and 10) did not reduce paw inflammation or bone loss in CAIA mice.51 Cartilage and bone degradation, as well as TRAP-positive cells on the bone surface and soft tissues, were still apparent in the supplemented CAIA group compared with the normal control.51

This systematic review found that although CA and its derivatives is a potential anti-osteoporosis agent by suppressing the formation of osteoclasts and their bone resorption activity, it worsened bone mechanical properties in some cases. The anti-osteoclastogenesis action of CA and its derivatives was mediated by the antioxidant activities, which blocked RANKL-induced TRAF6/Akt and MAPK signalling, as well as M-CSF/c-Src signalling. In animals, CA and its derivatives (mainly CAPE) prevented bone resorption in rodent calvariae when implanted in situ, facilitated the healing of bone defects, preserved bone structure and improved mechanical strength in osteoporosis models induced by OVX, dexamethasone, osteotomy, LPS-mediated periodontitis and EMF. However, CA did not alter bone resorption in OVX-induced osteoporotic rats and worsened the mechanical properties in normal rats. Additionally, CAPE did not suppress bone loss in rats with CAIA-induced bone loss.

Osteoblasts are bone-forming cells derived from bone marrow mesenchymal stem cells and are responsible for the synthesis, secretion and mineralisation of bone matrix.61 The expression of osteoblast markers was increased following CA or CAPE supplementation, an indication that CA and CAPE stimulated osteoblast proliferation, differentiation and maturation.40,56 Osteoblasts and osteocytes regulate the formation of osteoclasts through RANKL/OPG axis. Osteoblasts and osteocytes synthesise RANKL, which binds to RANK to activate the canonical pathway for osteoclastogenesis. They also secrete OPG, which is a decoy receptor for RANKL to suppress osteoclastogenesis. The production of RANKL is stimulated under conditions such as oestrogen deficiency62 and oxidative stress.63 Osteoclastogenesis can also be stimulated via a non-canonical pathway, for instance, through the binding of TNF with TNF receptor I or II.64 Glucocorticoids are potential modulators of RANKL/OPG axis, whereby dexamethasone is shown to downregulate OPG levels in osteoblasts.65 Tolba et al. showed that the RANKL/OPG level reduced in rats induced with dexamethasone with CAPE treatment.56 Other cellular studies showed that CA and its derivatives suppressed RANKL- and TNF-induced formation of OCLs from haematopoietic cells,3539 indicating that CA and its derivatives suppressed both canonical and non-canonical osteoclastogenesis.

The complex formed by the binding of RANKL to RANK causes the recruitment of the adaptor molecules tumour necrosis factor receptor-associated factors (TRAFs), including TRAF6.66 This event leads to the activation of several downstream signalling pathways, including c-Src/Akt/phosphatidylinositol 3-kinase and MAPKs (ERK/p38/JNK). CADPE was shown to suppress RANKL-induced activation of TRAF6 activation and the subsequent signalling pathways in multiple osteoclast progenitors, such as BMMs,38 RAW264.738 and RAW D cells.39 Sandra and Ketherin suggested that the downregulation of p38 is the key step of CA-mediated osteoclastogenesis.39 Upon activation, p38 initiates osteoclastogenesis by inducing NF-B and NFATc1 expression.67,68 Inhibition of p38 MAPK reduces RANKL (canonical) and TNF-induced (non-canonical) osteoclast formation.69

The NF-B pathway is another signalling pathway downstream of TRAFs critical for osteoclast differentiation and bone reabsorption activity. Upon activation, IKK (consisting of IKK, IKK and IKK) phosphorylates and degrades IB, which enables translocation of NF-B p65/p50 heterodimers into the nucleus to allow transcription of osteoclast-related genes.70 Kwon et al. demonstrated that the anti-osteoclastogenesis effects of CAPE were mediated via the degradation of total IKK, thereby preventing the phosphorylation and degradation of IB and subsequently suppresses the nuclear translation of p65.37 On the other hand, Wu et al. reported that CADPE did not affect phosphorylation or degradation of IB, as well as nuclear translocation, and DNA-binding activity of p65.38 This observation suggests that compared with CAPE, CADPE does not influence the NF-B signalling pathway.

ROS are one of the important secondary signals in the early stages of osteoclast differentiation.71,72 These ROS are mainly produced as superoxide anions by Nox1.73 Blocking of Nox1 ameliorates ROS production and the downstream MAPKs (JNK, p38 and ERK) and NF-B activation74 and subsequently suppresses the osteoclast formation.71 The reduction of Nox 1 and Rac1 expression by CAPE is accompanied by RANKL-downstream signalling, denoting that anti-osteoclastogenesis effects of CAPE are dependent on suppression of Nox1-mediated superoxide anion production. Besides, dexamethasone has been reported to increase the expression of oxidative stress-related genes in human osteoblasts.75 Tolba et al. showed that CAPE increased GSH and SOD but reduced MDA in the bone of the rats exposed to dexamethasone, indicating an improvement of redox status in the skeletal environment.56 Additionally, CAPE also reduced the OSI and bone loss with an improvement of bone support in rats with LPS-induced periodontitis.

NFATc1 is the master regulator of osteoclast-related gene expression, and it is activated by c-Fos and NF-B.76 Ha et al. observed that CAPE inhibited the recruitment of NF-B to NFATc1 promoter, and the combined effect of NF-B inhibition on c-Fos and NFATc1 may have caused CAPE to suppress osteoclastogenesis effectively.35 Holland et al. demonstrated a new fluorinated derivative of CAPE possesses potent anti-osteoclastogenic properties on RAW 264.7 cells by downregulating NFATc1 via suppression of c-Fos and NF-B signalling pathways.77 Besides, this new fluorinated CAPE also exhibits improved stability with a 2-fold higher potency than CAPE.77 On the other hand, although CADPE did not alter NF-B signalling, it still could suppress NFATc1 and other osteoclast-related markers, indicating other mechanisms of suppression could be involved, for instance, c-Src and MAPKs signalling pathways.38

Matrix metalloproteinases (MMPs), including gelatinases (MMP-2 and MMP-9) are examples of zinc-dependent extracellular matrix-degrading enzymes, which actively participate in bone resorption.78 MMPs are expressed as inactive proenzymes or zymogens that can be activated by several mediators including AP-1, NF-B, TNF and TGF.78 Currently, there is no study conducted to investigate the inhibitory effects of CA and CAPE on osteoclastic MMPs activity and its subsequent linkage in bone resorption; interestingly, CA and CAPE were reported to inhibit MMP-9 activity in human hepatocellular carcinoma HEP3B cells.79,80 This observation renders an interesting research gap in osteoclastic MMP inhibition upon CA and its derivatives treatment.

Suppression of osteoclastogenesis by CA or its derivatives have significant therapeutic potential against bone disorders induced by excessive bone resorption. Bone loss after osteotomy is a rapid process that affects both fractured and unfractured bone and may be incompletely reversible.81 CAPE was reported to improve bone formation and mechanical strength of bone in osteotomy.53 Exposure to EMF radiation caused by high-voltage transmission lines and transformers could affect bone health through decreased BMD, serum calcium and ALP level leading to the increase of bone resorption.82 CAPE increased the spine and femur BMD levels50 and increased mechanical strength of bones54 in rats exposed to EMF radiation. Total hip arthroplasty without cement often caused osteolysis induced by polyethylene particles.83 CAPE was shown by Zawawi et al. to prevent calvarial bone resorption in a murine polyethylene particle-induced osteolysis model.58 Therefore, biomaterials impregnated with CA or its derivatives could be adopted to prevent osteolysis in the arthroplasty procedure. CA has been incorporated in chitosan/(3-chloropropyl) trimethoxysilane scaffold for hard-tissue engineering applications and this adopted material exhibits antibacterial and anticancer effects.84 Ucan et al. observed that CAPE increased cranial bone healing in rats with critical size bone defect, suggesting that it could be administered systematically or locally to treat bone fracture/defect healing.57

Similarly, CAPE also effectively reduced the articular bone loss, inflammatory cytokines production and oxidative stress in rats with LPS-mediated periodontitis. Additionally, Wu et al.38 and Duan et al.55 demonstrated that CADPE prevented the ovariectomy-induced bone loss by suppressing osteoclast activity in a mouse model, while Folwarczna et al. showed increased width of trabecular metaphysis in the femur of OVX rats.48 Similarly, Tolba et al. showed improved bone formation and skeletal health in rats with dexamethasone-induced bone loss upon receiving CAPE.56 Additionally, CA and its derivatives may be involved in oestrogen production and signalling. Zych et al. reported that an oral administration of CA (10 mg/kg/day for 4 weeks) significantly restored the serum oestradiol levels in OVX rats.85 Interestingly, CA at 10 and 100 M did not cause any alteration in calcium content in the femoral-diaphyseal and metaphyseal ex vivo culture, suggesting its bone-protecting effect may not involve calcium metabolism and regulation.86 Additionally, CAPE was reported as a selective human oestrogen receptor agonist with the EC50 value of 3.72 M in oestrogen-responsive element transcription.87 A recent in silico study by Zhao et al. suggested potential osteoimmunological effects of CAPE, which may explain its biological activities on both immune and skeletal systems.88 However, the findings from this modelling study requires further validation through in vitro and in vivo models. As oestrogen deficiency due to menopause and glucocorticoids present the most significant cause of primary and secondary osteoporosis globally, CA and its derivatives have the potential to be used as an adjuvant therapy to existing osteoporosis management strategies. The mechanisms of action of CA and its derivatives in osteoclastogenesis have been summarized in Figure 2.

Figure 2 Mechanism of action of caffeic acid and its derivatives.

Abbreviations: , decrease or downregulate; ?, unknown mechanism; Akt, protein kinase B; AP-1, activator protein 1; CA, caffeic acid; CADPE; caffeic acid 3,4-dihydroxy-phenethyl ester; CAPE, caffeic acid phenethyl ester; c-Src, cellular sarcoma tyrosine kinase; ERK1/2, extracellular signal-regulated kinases 1/2; GM-CSF, granulocyte-macrophage colony-stimulating factor; Grb2, growth factor receptor-bound protein 2; IFN-, interferon-gamma; IL, interleukin; IL1R, interleukin-1 receptor; IB, NF-B inhibitor protein; IKK, IB kinase; LPS, lipopolysaccharide; M-CSF, macrophage colony-stimulating factor; M-CSF-R, M-CSF receptor; MAPKs, mitogen-activated protein kinases; NFAT, nuclear factor of activated T cells; NF-B, nuclear factor kappa B; NIK, MAPK kinase kinase 14; Nox1, nicotinamide adenine dinucleotide phosphate oxidase 1; OPG, osteoprotegerin; PI3k, phosphoinositide 3-kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; ROS, reactive oxygen species; TAK, MAPK kinase kinase 7; TLR4, Toll-like receptor 4; TNF, tumour necrosis factor-alpha; TNFR1/2, TNF receptor 1/2; TRAF2, tumour necrosis factor receptor-associated factor 2; TRAF6; tumour necrosis factor receptor-associated factor 6.

Regardless of the positive effects of CA on bone status, some studies have reported negative effects associated with supplementation of CA and its derivatives. CA supplementation did not affect the bone resorption52 and reduced transverse growth of endosteal in femur48 of rats with OVX-induced osteoporosis. In normal rats, CA supplementation even negatively affected their bone mechanical properties.49 Moreover, CAPE supplementation has been reported to stimulate the synthesis of PGE2,89 which mediates osteoclastogenesis through RANKL stimulation and activation of the NF-B pathway.90 This event will eventually increase TRAP-positive OCLs. Similarly, Williams et al. showed that CAPE did not suppress osteoclastogenesis in rats with CAIA.51

In term of safety, the International Agency for Cancer Research classifies CA as Class 2B (possibly carcinogenic to humans),91 and it was reported to induce renal tubular cell hyperplasia, forestomach hyperplasia, renal cell adenoma and forestomach cancer in rodents.9294 CA has been reported to be non-mutagenic and non-clastogenic.91 Therefore, its carcinogenicity may involve epigenetic modification. Human toxicity and carcinogenicity of CA and its derivatives remain unknown. CA also showed anti-implantation activity in pregnant mice at a median effective dose of 4.26 mg/kg/day.95 Similarly, 5 mg/kg/day and 150 mg/kg of CA in mice demonstrated anti-implantation activity in early pregnancy.96 On the other hand, 0.15 mg/kg/day, 5 mg/kg/day and 150 mg/kg/day of CA for 21 days in mice showed no maternal toxicity, foetal teratogenesis or post-natal effects on pup development and mortality.96 The same experiment stated that the no-observed-adverse-effect level of CA for pregnant female mice was 0.15 mg/kg/day.96 Therefore, high-dose CA should be cautioned in humans, especially pregnant women.

Several common limitations can be identified from the studies reviewed. Most studies did not adopt a positive control to compare against the anti-osteoclastogenesis or anti-osteoporosis effect of CA. Therefore, the therapeutic effects of CA and currently available anti-resorptive therapy cannot be compared. Although osteoblastogenesis and bone formation are also important in bone remodelling, evidence of CA on these processes is limited in the literature. The actions of CA in humans cannot be confirmed due to the lack of human clinical trials. These aspects can be improved in future studies.

The current review also has several limitations. We only considered articles indexed by PubMed, Scopus, Cochrane Library and Web of Science; therefore, non-indexed articles could be overlooked. We only selected articles studying CA or its derivatives as a single compound to understand its mechanism of action properly without other interference, but not a mixture of compounds or natural products rich in CA. CA are present in foods, and interaction with other compounds in the food matrix might alter its absorption, bioavailability and action on the target tissue. Moreover, the heterogeneous findings of CA in bone loss reduction upon oral administration further emphasise these possibilities.

The current preclinical evidence agrees that CA and its derivatives exert promising skeletal protective effects by inhibiting osteoclastogenesis and bone resorption, but literature on bone formation is limited. Notwithstanding that, the skeletal effects of CA and its derivatives in models of normal bone health should be investigated because the limited studies available show undesirable effects. Human clinical trials to validate the skeletal effects of CA are lacking. Therefore, a well-planned clinical trial should be conducted to confirm the potential of CA as an antiresorptive agent. This information is critical for CA and its derivatives to be incorporated as part of the strategies to prevent bone loss.

The researchers are funded by Universiti Kebangsaan Malaysia through Research University Grant (GUP-2020-021). S.O.E. and K.L.P. are post-doctoral researchers funded by Universiti Kebangsaan Malaysia through FPR-1 and RGA-1 grants.

The authors report no conflicts of interest in this work.

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October 30th brought a second challenge to Vinton-Shellsburg Kindergarten teacher, Carly Meyer. After battling her first round of leukemia, she suffered another relapse with a second diagnosis of leukemia.

"I thought I was done with these updates... but should have known 2020 wasnt done messing stuff up yet!" Carly shared. "For those of you who don't know, I was diagnosed with Acute Myeloid Leukemia in August 2019 and completed chemo treatments in December 2019, but unfortunately my lab results on October 30, showed some "blasts", which are the cancerous cells in my blood." She explained back in November that her lab results also showed that my WBC's the infection fighting cells, were very low.

At the beginning of November, she had another bone marrow biopsy which Wes, her husband believes is her 6th. She was then admitted to the University of Iowa Hospital for a month long stay.

Carly finished up her 5 days of chemotherapy on November 11th with only a couple of side effects (fatigue and loss of appetite) which are a couple of the more common side effects with chemotherapy treatments. Unfortunately, she suffered from dehydration as well and this caused her to pass out a couple of times, and one of the falls caused her to hit her head. This of course triggered a trip for a CT Scan just to make sure she was alright, fortunately, she didn't have any side effects from the fall.

"It is fairly common for leukemia patients to spike fevers and to get random bugs because we are neutropenic and our body cant fight off simple things they normally would," Carly explained. She did come down with an infection during this time but it was able to be pinpointed and treated right away. On Thanksgiving, she was able to return home 10 days earlier from her hospital stay than had been anticipated,

Her journey continues to beat cancer with a trip back to the hospital at the end of December, to begin preparation for her bone marrow transplant. "My hero of a brother started getting shots December 30 to prep and will be donating his Stem Cells on Monday, January 4th." Carly explained how the process works. Her brother Kyle was hooked up to a machine she said it is similar to donating blood/plasma and that the procedure lasts for about 5 hours. Fortunately, her brother Kyle was a 100% perfect match to be her donor.

The stem cells were then put into her IV Powerline over about 30 minutes while they closely monitored Carly for any side effects. "Then its just a waiting game after that," she said.

After the transplant, Carly's immune system was down to zero. Unfortunately, it is common for SCT patients to spike fevers and even get an infection after transplant.

New Year, New Me has never rang more true than this year Carly said.

She is hoping to be home at the end of the week. She said that this last stay has been "extremely exhausting mentally and physically." Developing mucositis, extreme sores and pain in her mouth, it has made it very hard to eat or drink anything. Mucositis is very common after receiving the strong chemo that she received just before her bone marrow transplant. She is slowly recovering from this.

She said that she is excited to be coming home with her husband and fur-baby Maverick if all goes well, by the end of the week.

"I am so lucky to have an amazing support system (especially my husband) to get me through this tough time," she said.

Please keep the couple in your prayers as Carly continues to heal.

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Cancer requires more tutoring, with Meyer continuing to Teaching Cancer a lesson - News - vintontoday.com

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