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Study Provides Clues to Developing Better Treatments for Lung … – Duke University School of Medicine

By adminNovember 17, 2023Stell Cell Research

Scientists and clinicians at the Duke University School of Medicine have discovered new details about how lung tissue heals after injury caused by toxins such as air pollution or cigarette smoke.

The researchers found that a cascade of interacting steps involving two different cell types is crucial for healing. An imbalance in these steps can lead to damage that resembles emphysema or lung fibrosis, the study found.

The study, published November 2, 2023, in the journal Cell Stem Cell, paves the way for future investigations to identify possible new treatments to prevent or reverse these diseases.

"A long-standing question in the field of wound healing is how our body organs know to regrow and build the same structure after a wound," said co-senior author Purushothama Rao Tata, PhD, assistant professor of cell biology and medicine, and co-director of the Duke Regeneration Center. The study's other senior author was Aleksandra Tata, PhD, assistant research professor of cell biology.

Tata explained that lung tissue is like a big balloon draped by a structure akin to a fishnet: the extracellular matrix scaffold, which creates multiple compartments with strong, flexible walls that expand and contract as we breathe. This study focused on how the lungs rebuild this scaffold after injury.

To study this question, the scientists used a variety of methods, including single cell transcriptome analysis and other computational tools, to build "time-lapse molecular circuits" to reconstruct wound repair in mouse lungs.

"We refer to it as molecular circuits because we are not looking at one or two genes, but a collection of genes associated with a particular cell state or phenotype," Tata said. "These are like electrical circuits that all come together to switch on a light, for example. All of these genes together exert a collective function."

"Disruption of these circuits revealed key druggable molecules to target two currently incurable lung diseases emphysema and fibrosis," he said. "These diseases are like two sides of the same coin. In a lung with emphysema, we lose the walls of the scaffold. In the case of fibrosis, the wall thickness increases so they are no longer flexible."

The study revealed that after a healing "program" is activated, a cascade of events ensues, involving both epithelial cells (cells that line the lungs) and mesenchymal cells (support cells).

The researchers outlined three crucial steps or "transitional states" that happen during this process. If certain transitional states involving epithelial cells persist too long, the result is fibrosis (buildup of scar tissue). "If there is a blockade in the transition of these cell states, the result is loss of tissue that resembles emphysema," Tata said.

In a preview article highlighting the work, scientists not affiliated with the Duke study pointed out that one of the intermediate cell states identified as crucial in the healing process has previously been termed a "bad actor" in lung fibrosis research. Two drugs currently approved for fibrosis (nintedanib and pirfenodone) actually kill this cell state, Tata said. "Our study shows that treating with these drugs may actually be a bad thing," he said.

Other authors of the study are: Arvind Konkimalla, MD, PhD, currently a resident at Duke University Hospital; postdoctoral associate Satoshi Konishi, MD, PhD; laboratory research analyst Lauren Macadlo; PhD candidates Jeremy Morowitz and Zachary Farino; postdoctoral fellow Naoya Miyashita, PhD; and bioinformatician Pankaj Agarwal, all in the Duke Department of Cell Biology; Department of Pediatrics postdoctoral research associate Lea El Haddad, MD, PhD; Mai K. ElMallah, MD, associate professor of pediatrics; Christina E. Barkauskas, MD, associate professor of medicine; and Tomokazu Souma, MD, PhD, assistant professor in medicine; and Yoshihiko Kobayashi, PhD, now an assistant professor at Kyoto University in Japan.

Mutation in Brain’s Immune Cells Linked to Alzheimer’s Risk – Neuroscience News

By adminNovember 17, 2023Stell Cell Research

Summary: A genetic mutation affecting microglia, the brains immune cells, can increase the risk of Alzheimers disease up to threefold.

The mutation, known as TREM2 R47H/+, impairs microglia function and contributes to Alzheimers pathology. It causes inflammation, reduces debris clearance, impairs response to neuronal injury, and leads to excessive synapse pruning.

The study highlights the complex impact of this mutation, offering insights for potential therapeutic interventions in Alzheimers disease.

Key Facts:

Source: MIT

A rare but potent genetic mutation that alters a protein in the brains immune cells, known as microglia, can give people as much as a three-fold greater risk of developing Alzheimers disease.

A new study by researchers in The Picower Institute for Learning and Memory at MIT details how the mutation undermines microglia function, explaining how it seems to generate that higher risk.

This TREM2 R47H/+ mutation is a pretty important risk factor for Alzheimers disease, said study lead author Jay Penney, a former postdoc in the MIT lab of Picower ProfessorLi-Huei Tsai. Penney is now an incoming assistant professor at the University of Prince Edward Island.

This study adds clear evidence that microglia dysfunction contributes to Alzheimers disease risk.

In the study in the journalGLIA, Tsai and Penneys team shows that human microglia with the R47H/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimers pathology. Mutant microglia are prone to inflammation yet are worse at responding to neuron injury and less able to clear harmful debris including the Alzheimers hallmark protein amyloid beta.

When the scientists transferred TREM2 mutant human microglia into the brains of mice, the mice suffered a significant decline in the number of synapses, or connections between their neurons, which can impair the circuits that enable brain functions such as memory.

The study is not the first to ask how the TREM2 R47H/+ mutation contributes to Alzheimers, but it may advance scientists emerging understanding, Penney said. Early studies suggested that the mutation simply robbed the protein of its function, but the new evidence paints a deeper and more nuanced picture.

While the microglia do exhibit reduced debris clearance and injury response, they become overactive in other ways, such as their overzealous inflammation and synapse pruning.

There is a partial loss of function but also a gain of function for certain things, Penney said.

Misbehaving microglia

Rather than rely on mouse models of TREM2 R47H/+ mutation, Penney, Tsai and their co-authors focused their work on human microglia cell cultures. To do this they used a stem cell line derived from skin cells donated by a healthy 75-year-old woman.

In some of the stem cells they then used CRISPR gene editing to insert the R47H/+ mutation and then cultured both edited and unedited stem cells to become microglia. This strategy gave them a supply of mutated microglia and healthy microglia, to act as experimental controls, that were otherwise genetically identical.

The team then looked to see how harboring the mutation affected each cell lines expression of its genes. The scientists measured more than 1,000 differences but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses.

Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.

In further experiments with the cells, the team exposed them to three kinds of the debris microglia typically clear away in the brain: myelin, synaptic proteins and amyloid beta. The mutant microglia cleared less than the healthy ones.

Another job of microglia is to respond when cells, such as neurons, are injured. Penney and Tsais team co-cultured microglia and neurons and then zapped the neurons with a laser.

For the next 90 minutes after the injury the team tracked the movement of surrounding microglia. Compared to normal microglia, those with the mutation proved less likely to head toward the injured cell.

Finally, to test how the mutant microglia act in a living brain, the scientists transplanted mutant or healthy control microglia into mice in a memory-focused region of the brain called the hippocampus. The scientists then stained that region to highlight various proteins of interest.

Having mutant or normal human microglia didnt matter for some measures, but proteins associated with synapses were greatly reduced in mice where the mutated microglia were implanted.

By combining evidence from the gene expression measurements and the evidence from microglia function experiments, the researchers were able to formulate new ideas about what drives at least some of the microglial misbehavior. For instance, Penney and Tsais team noticed a decline in the expression of a purinergic receptor protein involving sensing neuronal injury perhaps explaining why mutant microglia struggled with that task.

They also noted that mice with the mutation overexpressed complement proteins used to tag synapses for removal. That might explain why mutant microglia were overzealous about clearing away synapses in the mice, Penney said, though increased inflammation might also cause that by harming neurons overall.

As the molecular mechanisms underlying microglial dysfunction become clearer, Penney said, drug developers will gain critical insights into ways to target the higher disease risk associated with the TREM2 R47H/+ mutation.

Our findings highlight multiple effects of the TREM2 R47H/+ mutation likely to underlie its association with Alzheimers disease risk and suggest new nodes that could be exploited for therapeutic intervention, the authors conclude.

In addition to Penney and Tsai, the papers other authors are William Ralvenius, Anjanet Loon, Oyku Cerit, Vishnu Dileep, Blerta Milo, Ping-Chieh Pao, and Hannah Woolf.

Funding: The Robert A. and Renee Belfer Family Foundation, The Cure Alzheimers Fund, the National Institutes of Health, The JPB Foundation, The Picower Institute for Learning and Memory and the Human Frontier Science Program provided funding for the study.

Author: David Orenstein Source: MIT Contact: David Orenstein MIT Image: The image is credited to Neuroscience News

Original Research: Open access. iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss by Jay Penney et al. Glia

Abstract

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimers disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution.

We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature.

TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuronmicroglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia.

Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism.

These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

Link:
Mutation in Brain's Immune Cells Linked to Alzheimer's Risk - Neuroscience News

The largest biotech city in Europe will soon be built, with an … – BioPharma Dive

By adminNovember 17, 2023Stell Cell Research

VILNIUS, Lithuania

The largest biotech city in Europe will soon be built, with an investment amounting to 7 billion euros

Northway Group is embarking on a project to establish Europes largest biotechnology hub, BIO CITY, in Vilnius, the capital of Lithuania. It includes 6 large biotechnological complexes 4 state-of-the-art GMP manufacturing plants and 2 advanced scientific research centres that will be built in an area equivalent to 10 football fields.The total investment for this biotech campus is projected to reach approximately 7 billion euros over the next decade.

A science-based economy, supported by bright minds and intelligent entrepreneurs, is the foundation for Lithuanias long-term economic prosperity. In the past, our growth was constrained by a lack of fossil resources, but today, we are boldly moving forward, relying on modern technologies. The new biotechnology hub embodies the direction of Lithuanias innovative economy. It also promises new inventions that will enable people with serious illnesses to become full members of society, thereby reducing exclusion, says the President of the Republic of Lithuania, Gitanas Nausda.

Prof. Vladas Algirdas Bumelis, founder and CEO of Northway Biotech and Celltechna, key components of the Northway Group, highlighted Lithuanias strong global standing in biotechnology. The aim of the BIO CITY project is to further solidify this position with four advanced biomanufacturing facilities and two innovative research centres, significantly boosting Lithuania's prominence in the international biotech sphere.

The Speaker of the Seimas, parliament of Lithuania, states that the new biotech city being developed in Vilnius will strengthen the competitiveness of our country. Lithuanian life sciences industry has ambitions and potential to become a global leader in this field: a leader who will significantly contribute to the development of scientific research for the well-being of man, nature and planet, and will facilitate new opportunities to deal with global health, sustainable development and other challenges, says Viktorija milyt-Nielsen.

Vision of BIO CITY: A European Biotechnology Leader

We envision BIO CITY as a frontrunner in the European biotechnology, by uniquely integrating various biotech segments into a single, synergistic ecosystem. This multifunctional complex will catalyse interdisciplinary collaborations, the quick realisation of ideas and technological advancements. Our unique model, which brings together diverse biotechnology fields in one location, is set to revolutionise the European biotech landscape, said Prof. V. A. Bumelis.

Gene Therapy Centre will Open in 2024

The first facility to open its doors in the biotech hub BIO CITY will be the Gene Therapy Centre, which is currently under construction and is being built by Northway Groups subsidiary, Celltechna. This centre, the first and so far the only one of its kind in the Baltic States, will bolster Lithuania's role in gene therapy, addressing the needs of the 280 million individuals worldwide who are affected by genetic diseases.

Our state-of-the-art facility will be instrumental in both research and production, offering new treatments for previously incurable diseases. This will not only augment our CDMO (Contract Development and Manufacturing Organisation) capabilities, but also position us for global competition and collaborations, added Prof. V. A. Bumelis.

The Gene Therapy Centre, which is expected to become operational in the second quarter of 2024, will specialise in gene therapy research and GMP manufacturing. Representing an investment of 50 million euros, the facility will span 8,000 square metres and is anticipated to create over 100 high-value jobs. The centre will work in synergy with Northway Biotech. Established in 2004, Northway Biotech is a leading provider of CDMO services in the field of biologics, with a focus on the development and manufacturing of recombinant proteins and antibodies.

A Comprehensive Lithuanian Biotech Hub

By 2030, BIO CITY will see the inauguration of five additional complexes, including centres for R&D and Virology, Life Sciences Industry Smart Services, Stem Cell Research and 3D Bioprinting, as well as two large-scale production centres for mammalian and microbial products. The entire BIO CITY complex will span an area equivalent to 10 football fields, with the total investment expected to reach around 7 billion euros over the next decade.

We will not only focus on contract development and manufacturing services, but will also invest significantly in the operation of scientific research centres. Scientific activity enhances a countrys competitiveness and generates value in various forms, beyond just the economic aspect. Modern biotechnologies, such as gene editing and cell therapies, are advancing rapidly. Lithuania can pride itself on having some of the most talented scientists and robust expertise in these areas. The development of the biotech campus in Vilnius means we are poised to foster new partnerships with innovative startups, research institutions and pharmaceutical companies on a global scale. We are actively seeking partnerships and offer a warm invitation to investors who are enthusiastic about joining this exciting venture, said Prof. V. A. Bumelis.

Upon its completion, BIO CITY is expected to offer employment to approximately 2,100 highly skilled professionals, including scientists, biotechnologists, and medical engineers.

Lithuania is Among the Leaders in the Global Biotechnology Market

The global biotechnology market, currently valued at over 1,130 billion euros, is anticipated to grow to be worth more than 2,775 billion euros by 2030. Lithuania holds a strong position in this market, ranking among the Top 35 innovative countries in the biotechnology field, according to Scientific American Worldview.

Every year, Lithuania is mentioned in the field of Life Sciences more often, and the ambitious BIO CITY project will contribute to our leadership. Our vision is coming to life we are talking about world-class Life Sciences infrastructure and a competitive sector capable of building innovative products. In 2022, companies in the sector posted combined revenues of 1.5 billion euros, while exporting their goods to more than 100 countries. Overall, Life Sciences is a leading sector in Lithuania, when it comes to creating and implementing innovative solutions, states Aurin Armonait, the Minister of the Economy and Innovation.

Over 80 life science companies operate in Lithuania, contributing about 2.5% to the countrys GDP. The Northway group, a key player in Lithuanias biotech sector, manages seven companies: five in Lithuania and one each in the UK and the US, with the US entity being recognised as the largest biotech investor from the Baltic region in recent years. Employing more than 200 specialists, these companies provide services to a diverse array of international biopharmaceutical firms, ranging from small to large enterprises, predominantly operating in both Europe and the US.

BIO CITY Contacts:

Vladas Algirdas Bumelis

CEO and Chairman of the Board

[emailprotected]

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The largest biotech city in Europe will soon be built, with an ... - BioPharma Dive

The Song of the Cell: An exploration of medicine and the new human – Reformed Journal

By adminNovember 17, 2023Stell Cell Research

The Song of the Cell: An exploration of medicine and the new human

Siddhartha Mukherjee

Published by Scribner in 2022

496pp / $$17.89 / 978-1982117351

Ive spent more than thirty years studying cells of various types. First cells like those that make up human bodies (and their misbehaving counterpartscancer cells) and now bacterial cells. Its not at all difficult for me to tap my inner Miss Frizzle, hop on the Magic School Bus, and take a ride to the inside a cell. Its easy for me to picture ribosomes translating mRNA in the cytosol above my head, imagine importins carrying proteins through nuclear pores, and signal transduction cascades activating one protein after another like dominos falling. While I am familiar with the vivid molecular details, I know that visualizing those molecular details, much less cells, is not easy for most non-scientists. I believe that in spite of this, many people carry some curiosity about how cells work. Perhaps this curiosity arises when they encounter a disease or diagnosis, when something goes wrong with their bodies, or simply when they ponder the wonders of the natural world. At least I hope this is true. If you are someone who wonders about cells but thinks it would take too much time and effort to learn about them, The Song of the Cell: An Exploration of Medicine and the New Human is a book for you.

The author, Siddhartha Mukherjee, is an Associate Professor of Medicine in the Division of Hematology and Oncology at Columbia University where he is an oncologist and researcher, specializing in the physiology of cancer cells, stem cells in bone, and immunological therapy for cancers of the blood, such as leukemia and lymphoma. He is a prolific author with scientific publications in Nature and The New England Journal of Medicine, as well as the author of this and three other books for lay audiences. Mukherjees first book, The Emperor of All Maladies: A Biography of Cancer, won the Pulitzer Prize in 2011. His second book, The Gene: An Intimate History, was a New York Times bestseller. Mukherjees success as a popular nonfiction writer is not surprising. He has an uncanny ability to make complicated scientific processes accessible without sacrificing beauty, complexity, or accuracy. He is a master storyteller, especially gifted at using metaphors to help non-scientists picture and understand the inner workings of cells and other complicated biological processes.

What made this book especially compelling for me (and for my Cell Biology students, to whom I assigned the book last semester) was how Mukherjee was able to weave together basic cell biology with touching stories of patients who were dealing with cellular diseases as well as how our current understanding of how cells work was being used and applied to treat his patientssometimes with seemingly miraculous outcomes and sometimes with heartbreaking disappointment. He explores cancer, infertility, heart disease, bacterial and viral infections, autoimmune disease, depression, and organ/tissue transplantation in this nearly 400-page book. Despite its length, it reads quicklyperhaps because Mukherjee carefully intersperses history and complex science with personal stories of researchers, patients, and his own research.

In Emperor of All Maladies and The Gene, I found Mukherjees presentation of the science a bit too linear, giving the impression that one discovery led neatly to the next and then the next. As a scientist who spent ten years studying cancer cell biology and genetics, I know too well that the path to understanding how cells, cancer cells in particular, is laden with failures, misinterpretations, and mistakes. We zig-zag toward understanding much more than we take a straight path to it. In this book, Mukherjee makes more room for the missteps, arguments, and biases that shape scientific advances as much as the successes and collaborations, presenting what seemed to me a truer picture of how science actually works.

I didnt need much encouragement to read this book but why should a non-scientist pick it up? think this book helps a non-scientist to better appreciate the crooked path science takes toward understanding whatever it is they are studying. Readers will come away with a better understanding of how cells work and why sometimes the cells in our bodies fail. A deeper understanding of cells generates better questions when faced with health issues, greater appreciation of the available treatments and those who work to develop those treatments. Most importantly, I think readers will come away with a new level of awe at the wonder of Gods good creation and a deeper reason to worship the author of these wonder-filled, smallest units of life we call cells.

Sara Sybesma Tolsma, PhD is Professor of Biology at Northwestern College, Orange City, IA. She is currently working to discover novel bacteriophages (viruses that infect bacteria) and characterize their genomes.

Link:
The Song of the Cell: An exploration of medicine and the new human - Reformed Journal

Ethics education among obstetrics and gynecologists in Saudi … – BMC Medical Education

By adminNovember 17, 2023Stell Cell Research

Descriptions of the characteristics of the respondents

A total of 391 out of 1,000 OB/GYN practitioners responded to the survey questions by email; therefore, the response rate was 39.1%. Participants responded from all provinces of Saudi Arabia. Female respondents totaled 257 (66.4%), which was almost double the rate of male respondents. The married respondents totaled 291 (75.6%), whereas 94 (24.4%) were unmarried.

The study included participants of all ages, with approximate percentages of the participants between 30 and 50years is more than 60%.

Saudi physicians accounted for 213 (55.9%) participants and 371 (94.8%) Muslims. Approximately 247(63.1%) of the respondents were working in a tertiary government teaching hospital, whereas government non-teaching and private hospitals accounted for 107 (27%) of the participants.

Fifty-five percent of the participants were OB/GYN Board certified under different types of boards. Most of the physicians were certified by the Saudi Arabian board (18.2%), followed by the Arab board and Egyptian board (10.5%) and (6.9%) respectively; however, physicians holding Western certificates from Canada, England, US, or Indian boards were minimal in numbers.

The participants had equal percentages in relation to their tier position. The consultants and registrars in the sample numbers were 119 (30.4%) and 126 (32.23%), respectively; the remaining were residents.

Around 192 (49%) physicians had more than 10years of experience in the field of OB/GYN. Currently, 61 (15.6%) of the practitioners face 110 ethical issues monthly in their practice, while the majority 309 (79.03%) face less than one issue per month (Table 1).

Approximately 85 (21.7%) of the participants received mixed ethics education (formal ethics education and informal bioethics education), whereas 74 (18.9%) received only formal ethics education and 85 (21.7%) received only informal ethics education. In addition, 78 (19.95%) did not have any type of bioethics education.

Approximately 75% of the respondents received different types of formal and informal bioethics education. Of the respondents, 25% had no bioethics education; 137(35%) of physicians received a formal education during medical school; however, only 46 (11.8%) throughout residency programs. Self-learning was the method used for informal bioethics education in 124 (31.7%) cohorts (see Table 2 & Fig.1).

Modes of formal and informal bioethics education

No differences relatedto genderor the type of ethics education received in medical school during residency programs, postgraduate programs, conferences, courses and workshops and daily practice were detected. However, male respondents, more so than female respondents, agreed to have received ethics education in sub-specialty programs. The same finding was true regarding self-learning and online training.

Regarding marital statusand type of ethics education, no significant differences during residency programs, sub-specialty programs, in conferences, online training, in courses and workshops were found. Single respondents agreed to receive an ethics education in medical school compared to married people. Married respondents received a greater degree of informal bioethics education through daily practice and self-learning, while others received it through self-learning. There exists a significant difference between marital status and medical school (P=0.00), postgraduate programs (P=0.009), daily practice (P=0.007) and self-learning (P=0.002).

Regarding age,no significant differences were found in ethics education,except in medical schools. Respondents under 30yearsof age showed higher results (57.9%), followed by people between 3039years old (37.1%) and people aged between 4049years (28.8%). Participants>50years of age received minimum ethics education at medical school (19.4%).

No significant statistical differences regarding nationality and the type of ethics education were found except in medical schools, whereSaudi Arabian physicians (41.3%) had a significant statistical difference (P=0.007) compared to non-Saudi Arabians (28%). However, in postgraduate programs, there was a significant statistical difference (P=0.002) between non-Saudi Arabians (11.9%) and Saudi Arabians (3.8%).

There was no significant statistical difference inrelation to positionor the type of ethics education, except that residents showed the highest agreement in relation to education in medical school (P=0.00), followed by registrar/specialists and then consultants. The statement is correct regarding ethics education during sub-specialty programs (P=0.00) too.

No significant statistical difference was found between thetype of board certificateandbioethics education, except for online training (P=0.029) and daily practice (P=0.01). The participants that received Westernsub-specialist certificateshad the highest agreement to learning from daily practice, while Saudi Arabian physicians had the least (Table 1).

Significant statistical difference was found in relation tothe current workplaceand bioethics education during residency programs (P=0.015), during sub-specialty programs (P=0.04), in postgraduate programs (P=0.025) and Online learning (P=0.004). Online learning had a higher percentage of physicians who worked in private hospitals.

There was no significant statistical difference in relationto experienceand the type of ethics education, except for education in medical schools (P=0.00) and during sub-specialty programs (P=0.005). Physicians having experience of<5years showed the highest positive agreement followed by participants of 510years, and then>10years. A high percentage of less experienced physicians had bioethics education in medical college, while those with more than 10years' experience were found to have a significant statistical difference from those who had bioethics education through subspecialty training.

There was a significant statistical difference between the number of ethical challenges per month and bioethics education in medical school (P=0.007), in courses and workshops (P=0.009) and daily practice (P=0.00). Most of the respondents with ethics education from medical school and in courses and workshops had faced more than 10 challenges per month (47.60% and 28.60% respectively), whereas respondents with ethics education from daily practice had a maximum of 110 challenges per month (39%) (Table 1).

There was no significant statistical difference in relationto sub-specialtyand the type of ethics education except for the general OB/GYN, which showed the least agreement compared to other types of subspecialties. The same finding is true regarding online training too.

No significant statistical difference was observed between the type of ethics education and ethical principles. Irrespective of the mode of ethics education, most of the respondents had a positive attitude towards various ethical principles. The highest positive attitude was towards respecting privacy of people and respecting confidentiality. Solidarity And Cooperation had the least positive attitude across all modes of ethics education (see Table 3).

The attitude of the OB/GYNs towards various ethical challenges in their daily practice were investigated. No statistical significance was observed between various forms of formal ethics education and ethical challenges, except there exists a significant statistical difference between post-graduate program and termination of pregnancy for non-medical (P=0.05) and between residency program and contraception issues (P=0.021). The respondents with postgraduate ethics education had a high positive response (agreed and strongly agreed, 31%) to the ethical challenge "Termination of pregnancy for a non-medical reason," and the respondents without residency program ethics education had a high positive response (agreed and strongly agreed, 46%) to the ethical challenge "contraception issues."

Pertaining to the informal mode of ethics education, significant statistical difference was observed between courses and workshops and paternity issues (P=0.006); female consent (P=0.004); breach of confidentiality (P=0.007). There also exists a significant difference between breach of confidentiality and conference and workshop (P=0.007) and daily practice (P=0.023). The respondents without courses and workshop mode of ethics education had agreed to the ethical challenges of paternity issues (33.92%), female consent (58%), and breach of confidentiality (33.6%). The respondents who did not have ethics education through conference (33%) and daily practice (33.8%) also agreed to the ethical challenge breach of confidentiality (Table 4).

Personalized care makes all the difference for senior patient – City of Hope

By adminNovember 17, 2023Stem Cell Clinic

Ive been very active all my life. I love playing tennis and walking, says Susan Reid, 72, who lives in Santa Barbara, California, with her husband Gary. We live right by the ocean where there are birds, waves crashing, turtles. Thats my place of letting go.

A dramatic shift in her health a decade ago has meant Reid has had quite a bit to let go of. But assessment guidelines specifically for older adults developed by a national team of experts, including City of Hope physicians, helped her get through it all, ensuring the best outcome while managing side effects.

It all started back in 2013. Reid was riding a new bike when the chain hit her leg. Her wound would not stop bleeding, so she went to urgent care. My doctor told me I may have polycythemia vera, she recalled.

Polycythemia vera (PV) is a rare blood cancer in which the bone marrow manufactures too many red blood cells. These excess cells make the blood too thick, slowing its flow, which may cause serious problems like blood clots. Still, it didnt connect that this was cancer, she said.

Reid sought a second opinion at City of Hope with specialist David Snyder, M.D. He agreed with the first physician. That was really hard, she said.

Reid started treatment with an oral medication to keep the PV under control. For the next several years, it remained stable. But in February 2022, she started experiencing fatigue and pain. Id be out walking every day, and it got harder and harder.

She returned to City of Hope, where she met Andrew Artz, M.D., M.S. Artz specializes in blood cancers in older adults.

A bone marrow biopsy showed that Reids PV had evolved into a rare cancer called myelofibrosis, which disrupts red blood cell production and causes bone marrow scarring. Symptoms include fatigue, itching and bone pain.

As bone marrow damage increases, blood counts fall, said Artz, professor in the Division of Leukemia in the Department of Hematology & Hematopoietic Cell Transplantation, director of the Aging and Blood Cancers Clinic and deputy director of outcomes in the Center for Cancer and Aging. The goal is to prevent it from progressing to acute leukemia. Once it goes there, options are limited.

Experts recommended a stem cell transplant. City of Hope has the largest transplant programs in the country, with nearly 19,000 stem cell and bone marrow transplant procedures performed to date. In Reids case, the slower pace of her disease allowed time to prepare. Artz began screening for stem cell donors.

He also brought in two colleagues: William Dale, M.D., Ph.D., the George Tsai Family Chair in Geriatric Oncology in the Department of Supportive Care Medicine, and Jeanine Moreno, M.S., APRN, AGNP-C, geriatric nurse practitioner. Both work in City of Hopes Center for Cancer and Aging, where Dale is the director.

To improve outcomes and quality of life for older adults, Dale had helped develop the first-ever American Society of Clinical Oncology geriatric oncology guidelines in 2018. The guidelines recommend thorough assessment of physical and emotional health history before deciding on treatment.

Dale is lead author on the updated 2023 guidelines, published in the Journal of Clinical Oncology in July. These latest guidelines were based on two large, randomized trials published in The Lancet and JAMA Oncology, Dale said. The trials evaluated the use of a comprehensive questionnaire called a validated geriatric assessment (GA).

The trials showed that using the GA with assessment-based management led to better outcomes: less toxicity, fewer medicines and better quality of life, Dale said. That led ASCO to say it was time for an update. The evidence is so strong now.

The assessments are conducted through City of Hope's three OASIS (Older Adults Specialized Interdisciplinary Services) clinics at the main campus in Duarte. The OASIS program was created to offer custom care for older adults so that they and their loved ones are supported, can make informed choices and get the care that they want based on what is most important to them.

Until recently, Dale continued, no one would do stem cell transplants for patients older than 70. Andy [Artz] and I said it should really be about your fitness and ability to go through it based on individual assessment.

Dale and Moreno used the GA to help Reid prepare for her transplant.

The transplant would involve a four-week hospital stay. Reid's nutritional needs were assessed. Exercise training was another strategy put in place. These are things you can do in the hospital, like the stationary bike and walking. Its important to build leg strength to be able to get up out of bed, Artz said.

Reid had had a fall in the past, so they strategized mobility management.

The team also looked at her social support system. If social support vanishes, its very stressful for the family. We plan for a backup caregiver, said Artz.

They also worked on emotional health, because transplants can trigger mood issues. I had a month of psychological preparation, Reid said. They helped my mind get into a quiet place. That was important. There were breathing exercises, and they would take my blood pressure after I practiced. It usually went down 10 points.

Reid felt the benefits. I went into this with absolutely no anxiety, and that is the truth.

Before her transplant could occur, Reid had to undergo chemotherapy to destroy her cancerous bone marrow. Dales team used the GA to calculate her chemotherapy toxicity risk, which guided Artz in determining the optimal dose for Reid.

Susan received an intermediate dose of chemo that a lot of centers understandably dont give people 70 and older, because its very difficult, Artz said. And frankly, it was difficult for her.

Reid experienced nausea, diarrhea and loss of balance. But Artz and his team anticipated and managed her side effects.

In February 2023, one day after Valentines Day, it was time for the stem cell transplant. The City of Hope team had prepared in other ways, too.

They had party hats and a cake, Reid laughed.

The nurse was giving me the stem cells through an IV line, she recalled. You see this life going into your body. The cells looked like little hearts going in. I was ready.

Three days later, she was in pain. Artz prescribed medication to manage neuropathy. Moreno adjusted Reids anxiety and sleep medications. Together, the strategies reduced pain, dizziness and her risk of falling.

Occupational therapists helped Reid with fatigue and mobility. Were big fans of assistive devices to get you back on your feet safely, Artz said. He prescribed a walker. Reid was initially hesitant to use it, but that changed. The walker is my best friend now, she said. I have stability!

Six months out from her stem cell transplant, Reid reflected at home. Pretransplant, her pain level had been 8 or 9 out of 10. Now, it was in the 3 to 4 range, although some days are harder than others.

Our goal is to cure myelofibrosis, Artz said. The fibrosis takes time to resolve. We perform a test that distinguishes donor cells from patient cells. The fewer of the patients cells we detect, the less likely residual myelofibrosis exists.

Reid mused about the donor cells. The stem cell donor was a 21-year-old female. So, Im waiting to be 20 years younger, she joked. So far, the cells like me very much.

Shes still a bit wobbly, she said, and uses the walker regularly. Meanwhile, Artz monitors her medications to prevent graft-versus-host disease and infection, which are very gradually reduced after transplant.

My outlook has definitely changed, Reid said. I always thought I was so appreciative, but this is way different. Some people dont make it to 72. I feel so fortunate because Im here, and Im doing really well. And it brings joy because these little stem cells are working in my bone marrow to make me better, day by day.

The Department of Supportive Care Medicine at City of Hope was the first in the United States to fully integrate across supportive care specialties and into the patients clinical care and is one of the largest programs of its kind today. The program provides cancer patients with comprehensive physical, psychological, social and practical support services, including care navigation; survivorship programs; specialists in cancer and aging; child life specialists; psychological and spiritual counseling; pain management; integrative medicine, such as yoga, massage and meditation; and more all with a focus on maximizing patient and family strengths, quality of life and the ability to best engage in their treatment journey and be-yond. Thanks to a gift from The Sheri and Les Biller Family Foundation, City of Hope is working to expand this offering across its cancer care system and to advocate for establishing supportive care as a standard best practice for cancer care in the United States.

Main image: An illustration of myelofibrosis.

Validation of the transplant conditioning intensity (TCI) index for … – Nature.com

By adminNovember 17, 2023Stem Cell Clinic

Characteristics of the validation cohort

The validation cohort comprised 4060 adult patients with AML who were transplanted in first complete remission in the most recent period (median year 2019, range 20182021). In contrast to the discovery cohort which included patients between 45 and 65 years of age (median 55.6 years), patients in this validation dataset were one decade older (median 63.4 years, range 5575). In total, 48 different conditioning regimens were used (Supplementary Table2). Baseline characteristics are shown by TCI group in Table1. In this validation cohort, 1934 (48%) and 1948 (48%) patients were assigned to the low, and intermediate TCI group, respectively, while a high TCI was less prevalent (n=178, 4% of patients). As expected, there was an inverse relationship between age and TCI, with a median age of 65 years (interquartile range [IQR], 61.368.4), 62 years (IQR, 58.865.9) and 59 years (IQR, 56.863.3) for the low, intermediate, and high TCI groups, respectively (p<0.0001). About 1833% of patients among TCI groups had a low (80%) Karnofsky Performance Score (KPS) and/or high (3) HCT-CI, with patients in the low TCI category more likely to have a lower KPS80% and a higher HCT-CI3 (p<0.0001). Except for the more frequent use of matched sibling donors in the high TCI cohort (p<0.0001), other characteristics were distributed equally between the 3 TCI groups. The most often used immunosuppressive drug combination for graft versus host disease (GvHD) prophylaxis was cyclosporine/mycophenolate mofetil (34.8%, 31.3% and 31.6%) or cyclosporine/methotrexate (34.9%, 32.5% and 39%), whereas post-transplant cyclophosphamide (PTCY) was used in 8.8%, 11.3% and 13.9% of TCI low, intermediate, and high groups, respectively (Table1). The median follow-up of survivors was 22.3 months (IQR, 20.823.2). The outcomes for the entire population were as follows: cumulative incidence of d100 NRM was 6.2% (95% CI 5.57), of d180 NRM was 10.2% (95% CI 9.311.2), of 2-year NRM was 19.2% (95% CI 17.820.5), of REL was 25.7% (95% CI 24.227.3), of acute graft-versus-host disease (GVHD) grades II-IV was 22.1% (95% CI 20.823.4), of acute GVHD grades was III-IV 7.6% (95% CI 6.88.5), of chronic GVHD was 31.7% (95% CI 30.133.4) and of extensive chronic GVHD was 14.2% (95% CI 1315.5). The estimate of LFS and OS at 2 years was 55.1% (95% CI 53.356.9) and 62.2% (95% CI 60.463.9), respectively. Graft failure was low and did not differ between TCI groups (p=0.34), results not shown. Causes of death are given in Supplementary Table3 with original disease the main cause in each TCI category.

The risk of NRM in the validation group followed the same pattern as in the discovery cohort, with a monotonic increase in NRM rate from lower to higher TCI (Fig.1). In the unadjusted comparison, the TCI provided a highly significant risk stratification for d100, d180 and 2-year NRM, with the cumulative incidences being 4.5% (95% CI, 3.75.5), 8.2% (95% CI, 79.6) and 16.5% (95% CI, 14.718.5) in the low TCI group, rising to 7.3% (95% CI, 6.28.5), 11.6% (95% CI, 10.113.1) and 21.4% (95% CI, 19.423.5) in the intermediate TCI group, and further increasing to 12.4% (95% CI, 8.117.8), 17% (95% CI, 11.823.1) and 23.5% (95% CI, 17.230.5) in the high TCI group, respectively (p<0.0001 for all comparisons) (Table2). In a multivariable model including baseline characteristics known to impact NRM such as age, KPS, and HCT-CI score (complete case analysis n=3791), TCI group assignment was found to be strongly and independently associated with NRM (Table3). Relative to the low TCI group, the HRs for d100, d180 and 2-year NRM in the intermediate TCI group were 1.95 (95% CI 1.422.69, p<0.0001), 1.62 (95% CI 1.262.08, p<0.0001) and 1.44 (95% CI 1.201.74, p<0.0001), and in the high TCI group were 4.00 (95% CI 2.27.28, p<0.0001), 2.86 (95% CI 1.764.64, p<0.0001) and 1.87 (95% CI 1.252.80, p=0.003), respectively. In a pairwise comparison between high and intermediate TCI groups, high TCI was associated with an increased risk for early NRM (d100 NRM: HR 2.05; 95% CI 1.173.57, p=0.012; 180 NRM: HR 1.76; 95% CI 1.122.78, p=0.015) but not for 2-year NRM (p=0.19). Besides TCI category, other independent prognostic factors for NRM were incremental age, HCT-CI score 3, KPS score 80%, unrelated donor (early NRM) and a female to male transplantation (2-year NRM) (Table3).

Non-relapse mortality (NRM) for entire validation cohort stratified by Transplant Conditioning Intensity (TCI) category (low, intermediate, high).

In univariate analysis, the REL rate was significantly higher in the low TCI group (29.7%, 95% CI 27.432.1) when compared to the intermediate (21.9%, 95% CI 19.824.0) and the high (25%, 95% CI 17.932.6) TCI group (p<0.0001) (Fig.2). By using the multivariable complete case analysis previously mentioned, TCI group was found to be an independent predictor for REL (Table3). When compared with the low TCI group, the REL risk was significantly decreased in the intermediate TCI group (HR 0.66; 95% CI 0.570.78, p<0.0001), however, we observed only a non-significant reduced REL risk trend in the recipients receiving high TCI regimens (HR 0.79; 95% CI 0.551.13, p=0.20). REL was significantly influenced by adverse cytogenetics and the use of a bone marrow graft (Table3). There were no significant associations between TCI group and LFS or OS (data not shown), except a borderline better OS for high versus low TCI (HR 1.35; 95% CI 1.011.81, p=0.043).

Relapse (REL) for entire validation cohort stratified by Transplant Conditioning Intensity (TCI) category (low, intermediate, high).

Highly Cited Researchers 2023 – EurekAlert

By adminNovember 17, 2023Stem Cell Clinic

image:

Highly Cited: Dominic Grn, Christoph Wanner, Rainer Hedrich, Jos Pedro Friedmann Angeli. and Hermann Einsele.

Credit: Latest Thinking / Tristan Vostry UKW Uni Wrzburg Andreas Heddergott / TU Mnchen Benedikt Knttel

Once again professors of Julius-Maximilians-Universitt Wrzburg (JMU) in Bavaria, Germany, are on the list of Highly Cited Researchers: Botanist Rainer Hedrich, medical scientists Hermann Einsele and Christoph Wanner, cell researcher Jos Pedro Friedmann Angeli, and system biologist Dominic Grn.

The current Highly Cited List was established by Clarivate Analytics, a company specialising in citation data, and published on November 15th, 2023. The analysis is based on the Web of Science database. For their 2023 assessment, the analysts looked at the time between 2012 and 2022.

Highly cited papers rank in the top one percent of most-cited publications in their field in the year of publication. Only such scholars who have co-authored particularly multiple highly cited papers may join the ranks of "Highly Cited Researchers" comprising 7,125 scientists from 67 countries in 2023.

JMU President Congratulates

JMU President Paul Pauli congratulates the researchers: "The fact that Wrzburg scientists are repeatedly among the Highly Cited Researchers is impressive proof of the international visibility of our university. Congratulations to the honourees!"

LINK: HCR 2023

Prof. Dr. Hermann Einsele

The head of the Chair of Internal Medicine II and director of the Medical Clinic and Polyclinic II is an expert in stem cell transplantation against blood cancer and multiple myeloma and infectious diseases in immune-compromised patients. Immunotherapeutic studies for many tumour diseases are underway under his direction. Einsele has developed a cancer therapy with specifically modified immune cells and used it clinically for the first time in Europe. He has received the 2003 van Bekkum Award of the European Society for Cell and Stem Cell Therapy, 2012 Nobel Lecture Stem Cell Biology/Transplantation, Nobel Forum Karolinska Institute Sweden. In 2014 he was accepted as a member of the Academy of Sciences and Literature Mainz. In 2022, he was the first European to receive the prestigious Erasmus Hematology Award for special achievements in cancer immunotherapy as well as the Bavarian Constitutional Order and in 2023 the highest prize of the German Society for Transfusion Medicine and Immunohematology (DGTI), the Emil-von-Behring Lecture. He is co-spokesperson of the Collaborative Research Centres 124, 221, and 338 and spokesperson of the National Centre for Tumour Diseases WERA with headquarters in Wrzburg.

Prof. Dr. Jos Pedro Friedmann Angeli

The Professor for Translational Cell Biology at the Rudolf Virchow Center for Integrative and Translational Bioimaging at the University of Wuerzburg is a pioneer in the field of ferroptosis, a recently described cell death modality involved in an evergrowing list of (patho)physiological processes. Work in his group aims to understand and exploit specific metabolic pathways that regulate ferroptosis sensitivity. Their long-term goal is to exploit this knowledge to selectively target these key survival pathways in cancer entities inherently sensitive to ferroptosis, including B-cell malignancies, melanomas and neuroblastomas.

Prof. Dr. Dominic Grn

The head of the JMU Chair for Computational Biology of Spatial Biomedical Systems and director at the Institute of Systems Immunology investigates processes of cell differentiation in bone marrow and liver tissue using high-resolution methods. His research group has developed numerous bioinformatics algorithms to decipher data obtained with single-cell RNA sequencing. Using these methods, the physicist was able to create the first cell type atlas of the human liver and contribute to a better understanding of tissue architecture and cell differentiation in the liver. His work was awarded the GlaxoSmithKline Prize for Basic Medical Research in 2020. His research on the tissue architecture of the bone marrow has been funded by a two-million-euro ERC Consolidator Grant from the European Research Council since 2019.

Prof. Dr. Rainer Hedrich

The head of the Chair of Botany I Molecular Plant Physiology and Biophysics is considered one of the fathers of researching electric signal transmission in plants. He has been included in the list of Highly Cited Researchers continuously since 2003 two decades of outstanding research at the university. He was the first researcher worldwide to determine the functioning of plant ion channels in the laboratory of Nobel Laureate Erwin Neher. Hedrich studies carnivorous plants within the scope of the "Carnivorom" project funded by an ERC Grant of the European Research Council. Among other things, he discovered that the Venus flytrap counts the number of times it is touched by its prey and only allows the trap to shut and digest after a sufficient number of stimuli. To find out how the plant counts, the German Research Foundation is funding Hedrich with the renowned Koselleck Research Award. In recent years, he has used light-activated ion channels to expose experimental plants to different numbers of external calcium-electric stimuli in order to elucidate the mechanism of plant counting.

Prof. Dr. Christoph Wanner

The former Head of Nephrology at the Medical Clinic and Polyclinic I of Wrzburg University Hospital is an expert in kidney disease in diabetes mellitus and cardiovascular disease in dialysis patients and after kidney transplants. Through worldwide clinical studies, he was able to show for the first time that a drug that is effective in the kidney can significantly delay the progression of kidney disease in diabetics up to renal replacement therapy. His work also focuses on the diagnosis, prognosis, and treatment of lipid metabolism disorders in kidney patients. He was awarded the Franz Volhard Medal in 2018. He has been a senior professor at JMU since the beginning of 2023.

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Kyverna Therapeutics Announces Publication in The Lancet … – PR Newswire

By adminNovember 17, 2023Stem Cell Clinic

No adverse events related to CAR T-cell therapy 60 days post-infusion in patient suffering from severe, treatment-refractory, generalized myasthenia gravis

KYV-101 is a fully human CD19 CAR T-cell therapy designed for use in patients with B cell-driven autoimmune diseases

In addition to the use of KYV-101 in investigator-initiated trials and named patient activities, open-label Phase 1and Phase 1/2 clinical trials for KYV-101 are actively recruiting patients with autoimmune disease at multiple sites in the US and Germany

EMERYVILLE, Calif., Nov. 15, 2023 /PRNewswire/ -- Kyverna Therapeutics, Inc. (Kyverna), a patient-centered clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases, today announced the publication inThe Lancet Neurologyof a Letter to the Editor by a group of German investigators describing the first case of treatment using KYV-101 in a 33 year-old patient with severe, treatment-refractory, anti-acetylcholine receptor auto-antibody positive, generalized myasthenia gravis (MG), who was treated on a named patient basis outside of a clinical trial setting.

Within the 2-month post-treatment follow-up period, the patient was not observed to experience any adverse events related to chimeric antigen receptor (CAR) T-cell therapy, such as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). In this period, the patient experienced improved muscle strength and reduced fatigue, along with elimination of B cells and a 70% reduction in pathogenic anti-acetylcholine receptor autoantibodies.

"We believe this case report provides compelling evidence for the potential of anti-CD19 CAR T-cell-mediated deep B cell depletion in inducing remission and improving symptoms in severe, treatment-refractory MG," said Aiden Haghikia, M.D., Director, Department of Neurology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany, and lead author of the Letter.

KYV-101 is an autologous, fully human CD19 CAR T-cell product candidate for use in B cell-driven autoimmune diseases such as MG.

"We are extremely happy with the outcome so far, which suggests that a different CAR T-cell approach targeting CD19 with a stably expressed CAR, delivered following a conventional lymphodepleting regimen, has the potential to be safe and effective in severe and refractory MG," said Dimitrios Mougiakakos, M.D., Director, Clinic of Hematology, Oncology, and Stem Cell Transplantation, Otto-von-Guericke University, Magdeburg, Germany, and senior author of the Letter.

"This groundbreaking case report rewards and reinforces our commitment to provide potentially paradigm-shifting therapeutic options to patients suffering from autoimmune diseases," said Peter Maag, Ph.D., chief executive officer of Kyverna. "We want to commend patients and their medical care teams that are helping advance the field of treatment options for B cell-driven autoimmune diseases."

CAR T-cell therapy involves modifying a patient's T cells to recognize and remove B cells in the patient's body. Kyverna's CD19 CAR T-cell therapy, KYV-101, specifically targets CD19, a protein expressed on the surface of B cells, which is involved in various types of autoimmune diseases. Kyverna plans to continue to explore additional indications for KYV-101 and develop a robust pipeline of promising product candidate immunotherapies aimed at addressing unmet medical needs in autoimmune diseases.

About Myasthenia Gravis (MG) Myasthenia gravis is an autoimmune disorder associated with muscle weakness in tissues throughout the body, potentially manifesting in partial paralysis of eye movements, problems in chewing and swallowing, respiratory problems, speech difficulties and weakness in skeletal muscles. MG patients develop antibodies that lead to an immunological attack on critical signaling proteins at the junction between nerve and muscle cells, thereby inhibiting the ability of nerves to communicate properly with muscles. The symptoms of the disease can be transient and in the early stages of the disease can remit spontaneously. However, as the disease progresses, symptom-free periods become less frequent and disease exacerbations can last for months. Disease symptoms reach their maximum levels within two to three years in approximately 80% of patients. Up to 20% of MG patients experience respiratory crisis at least once in their lives.

About KYV-101KYV-101 is an autologous, fully human CD19 CAR T-cell product candidate for use in B cell-driven autoimmune diseases. The CAR in KYV-101 was designed by the National Institutes of Health (NIH) to improve tolerability and tested ina 20-patient Phase 1 trial in oncology. Results were published by the NIH in Nature Medicine1.

Kyverna iscurrently conducting two trials of KYV-101 in patients with lupus nephritis, an autoimmune disease in whichmore than half of patients do not achieve a complete response to current therapies and are at risk of developing kidney failure. Additional clinical trials of KYV-101 in systemic sclerosis, myasthenia gravis, and multiple sclerosis are in preparation. We believe that the differentiated properties of KYV-101 are critical for the potential success of CAR T cells as autoimmune disease therapies.

About Kyverna Therapeutics Kyverna is a patient-centered, clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases. As our lead product candidate, KYV-101 is advancing through clinical development across two broad areas of autoimmune disease: rheumatology and neurology, including two ongoing multi-center, open-label Phase 1 and Phase 1/2 trials of KYV-101 in the United States and Germany for patients with lupus nephritis. Kyverna's pipeline includes next-generation chimeric antigen receptor (CAR) T-cell therapies in both autologous and allogeneic formats with properties intended to be well suited for use in B cell-driven autoimmune diseases. By advancing more than one mechanism for taming autoimmunity, Kyverna is positioned to act on its mission of transforming how autoimmune diseases are treated. For more information, please visithttps://kyvernatx.com.

Kyverna Media Contact:Katie Dodge +1 (978) 360-3151 [emailprotected]

1. Brudno et al., Nature Medicine 2020; 26:270-280.

Note: Letters published in the Correspondence section represent the views of the authors and not necessarily the views of The Lancet journals. Letters to the Editor are not normally externally peer reviewed.

SOURCE Kyverna Therapeutics

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Kyverna Therapeutics Announces Publication in The Lancet ... - PR Newswire

A new wave of treatment for Alzheimer’s disease – MIT News

By adminNovember 17, 2023Stem Cell Clinic

Alzheimer's disease, the appalling and baffling degenerative brain illness that plagues many elderly people, may be caused by several distinct mechanisms driven by various genetic and lifestyle factors, says Li-Huei Tsai, Picower Professor of Neuroscience at MIT. To fully understand such conditions, she says, we must study the aging brain as a system rather than focusing on one or two types of ailing cells.

Neurodegenerative conditions take years to develop, partly because the brain is a highly plastic organ with many ways to adapt. If there's one thing wrong, usually our nerve cells can figure out a way to continue to maintain the function of the brain, Tsai says. By the time someone shows any symptoms, the brain has already run out of any compensatory mechanism to mask the disruption. As you can imagine, this is a very systemic problem, with many things going wrong.

Her work has led to a surprising approach to treat Alzheimer's, by increasing the strength of a certain frequency of our brainwaves. This noninvasive method has done well in early clinical trials carried out both by MIT and a startup firm co-founded by Tsai.

Director of The Picower Institute for Learning and Memory, Tsai also spearheads the miBrain project to create integrated multicellular models of the human brain, with all the major types of brain cells within a network of blood vessels. The miBrain models seek to offer more realistic representations of brain tissue that will allow improved testing of drug candidates and eventually support treatments that are personalized to each patient, identified in miBrains built from their own cells. (Patients can donate skin cells that can be re-engineered to become brain cells.) Tsai is welcoming potential commercial partners to join this ambitious effort.

Catching the gamma wave

The brain bundles together nerve cells, supporting cells such as astrocytes and microglia, and blood vessels. In Alzheimer's disease, all of these cells are disrupted, Tsai says. So how do you simultaneously take care of all these different systems and different cells? Her lab has long explored stimulation methods that can engage multiple regions and cell types across the brain.

Decades ago, researchers discovered that light presented at certain frequencies in mammals can elicit nerve cells in the brain to follow along in synch, creating or strengthening brainwaves.

Tsai and MIT neuroscientist Christopher Moore examined this phenomenon in mice with a cutting-edge lab technology called optogenetics (which was originally co-developed by MIT researchers Ed Boyden and Feng Zhang when they were at Stanford University). The collaborators successfully used optogenetics to increase the power of gamma waves in rodent brains.

Tsai's former graduate student Hunter Iaccarino followed up to see if boosting gamma waves could produce meaningful effects in mice models of Alzheimer's disease. Working with Boyden and MIT Professor Emery Brown, Iaccarino discovered that enhancing 40-cycle-per-second gamma waves via flickering light stimulation could significantly reduce levels of the amyloid protein that is a lead indicator of Alzheimer's. The partners published these striking results in the journal Nature in 2016.

We subsequently identified that using gamma sound stimulation also can engage nerve cells in the brain and force them to fire at the gamma frequency, Tsai says.

The waves generated a surprising range of beneficial effects in animal models. Experiments also showed that the effect reaches key parts of the brain, such as the prefrontal cortex, where we do planning and reasoning, and the hippocampus, where we make memories.

Today, we go cell type by cell type, system by system, to comb through all of the possible mechanisms for this effect, she says. If we know how it works, people will be more willing to really embrace it.

Promise in the clinic

Early clinical trials of gamma-wave treatments have shown dramatic results.

In 2016, Tsai and Boyden were scientific co-founders of Cognito Therapeutics, a startup that has raised $93 million to commercialize gamma-wave technology. In July 2023, Cognito reported positive preliminary results for a phase 2 trial of its proprietary goggle-like device among early-stage Alzheimer's patients. Participants displayed decreased loss of brain volume and a significant slowing in functional and cognitive decline. Cognito is going forward with a phase 3 study designed to enroll 500 patients.

At MIT, Tsai and her collaborators also conducted a small-scale clinical trial on early-stage Alzheimer's subjects. Rather than giving the participants goggles, the researchers installed an LED light panel and stereo in their homes. We reduced brain volume loss and increased connectivity, Tsai says. This study was shut down by the pandemic, but she and her collaborators are now resuming clinical tests.

Despite employing very different devices, the Cognito and MIT trials produced similar benefits. Gamma-wave devices should be far more accessible, and safer, than the drugs available to date, Tsai suggests. Unlike the Alzheimer's drugs recently approved by the Food and Drug Administration (FDA), the therapy doesn't require highly expensive infusions or pose the risks of brain swelling and bleeding.

Modeling your whole brain with miBrain

The gamma-wave research is one thread among many in Tsai's lab aimed at understanding the entire aging brain, with its genetic complexities, and to use that understanding to personalize treatments for neurodegenerative illnesses.

You can think of Alzheimers disease as like breast cancer: Depending on what genes are disrupted, people will get different therapies, Tsai says. I think this is probably true for other degenerative diseases, like Parkinson's.

Her team plans to take a huge step up in modeling human brain structures with the miBrain platform, basically multicellular brain chips built with stem cell technology. (Scientists can take human skin cells and induce them to become pluripotent stem cells, which means they can be reprogrammed to become various brain and blood vessel cells. Those cells can then be cultured together to form a complex approximation of brain tissue.)

This miBrain system contains all the different cell types that normally you'll see in the brain, says Tsai. This is essential, because the cells in the brain don't exist in isolation. They're all together and they communicate with each other through secreted factors or cell-to-cell contact, and that's a very important part of how they maintain health and functionality.

The integrated miBrain system will empower both basic research and drug screening. For example, the blood-brain barrier prevents many molecules from entering the brain. she says. We can use this in-vitro-assembled blood-brain barrier to test whether a chemical targeting a brain disease can even get into the brain.

She points out that the FDA recently decided that it would not always require animal testing data before approving drug candidates for trial. This regulatory move should accelerate the use of in-vitro models such as the miBrain for drug testing.

Over time, Tsai hopes the miBrain will evolve into a translational platform to deliver precision medicine, enabling individualized treatments for brain illnesses. We can reprogram your skin cells into stem cells, and then we can make a miBrain out of your cells, she says. If you have Parkinson's disease, we can test certain therapeutic agents and see how your miBrain responds, and then further optimize how to treat you.

She and her MIT collaborators are now launching a miBrain center, aimed to boost both basic and translational medical research.

Scaling up this center, however, will be no easy task. The biggest challenge is manpower, because producing all the cell types and then assembling them into a miBrain is extremely labor-intensive, she says. It would be very helpful if we can team up with a company and develop this together.

MIT offers tremendous opportunities for such collaborations. I think MIT is in the best position to lead brain disease research, because we have people who are leaders in their disciplines here, doing not just brain research but engineering and artificial intelligence, Tsai remarks. We really hope that we can gather people together scientists, engineers, policymakers and economists to figure this out. This is the future of brain research; we need people using very different approaches to work together.

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A new wave of treatment for Alzheimer's disease - MIT News