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

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.

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

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

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).

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

Highly Cited Researchers 2023 – EurekAlert

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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Highly Cited Researchers 2023 - EurekAlert

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

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

Kyverna Therapeutics Announces Publication in The Lancet … – PR Newswire

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

Sylvester Cancer Support Services Grow – InventUM – University of Miami

By: Alan Gomez | November 14, 2023 | 6 min. read| Share

Sylvester Comprehensive Cancer Center department features seven new specialists and incorporates a range of integrative oncology services and therapies to assist patients and caregivers.

Maria Rueda-Lara, M.D., is used to educating patients.

As the medical director of psycho-oncology for Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, her goal is to help patients suffering from the physical and emotional toll of cancer. However, she often must overcome hesitance from patients who are unfamiliar with mental health therapy or view it as a sign of weakness.

It is challenging, she said. When we meet a patient, we do a lot of psychoeducation.

After years of educating patients, Sylvesters Cancer Support Services Department includes 38 specialists who help survivors and their caregivers get through a cancer diagnosis and treatment. As each therapist explains to their patients, complementary services are backed by a large and growing body of scientific research.

Sylvesters second annual Cancer Survivorship Symposium incorporated a daylong patient/caregiver conference focused acutely on current research and finding solutions for the challenges many patients face.

Dr. Rueda-Lara knows the impact her work provides firsthand. She is the co-author of a paper published in the International Review of Psychiatry nine years ago that showed how psychiatric and psychological interventions can help hematopoietic stem cell transplant patients who suffer from high levels of depression, post-traumatic stress disorder and other neurocognitive deficits, which can result in shorter survival rates.

In the years since, Dr. Rueda-Lara and other researchers have produced a steady stream of research that echoes those results across all types of cancer patients.

Everything we do is based on science, Dr. Rueda-Lara said.

The success explains why the Cancer Support Services Department continues to expand, adding seven new specialists this year. The department has licensed specialists offering acupuncture, art therapy, exercise physiology, massage therapy, music therapy, spiritual care and yoga. A separate team provides wigs and head coverings. The department also features 26 social workers, patient navigators and clinic assistants who help patients juggle medical appointments, travel and lodging arrangements, finances and therapy sessions.

I know that I work with a team, which was a huge draw that attracted me to this department, said Zili Huma Khan, a psychotherapist who joined the Sylvester team in 2020. We talk about how the patients are doing, who has been attending treatment regularly, how we can best serve each patient. I never feel like Im alone.

When patients are first referred to Lindsey Weaver, a board-certified art therapist, some of them dismiss the idea because they think its arts and crafts or theyre scared of having their art judged. But Weaver assures them these preconceptions are wrong.

Weaver said patients can reveal so much about their inner selves through their art. For instance, she often asks them to draw a volcano. The drawing is then used as a tool for insight and communication, and can reveal certain emotions. If the volcano is spewing out lava, it could suggest a release of emotions. No lava may indicate suppressed emotions.

Weavers art exercises can also be used as treatment. She often encourages patients to use certain materials depending on how theyre feeling. With a patient who is feeling powerless, Weaver often suggests they use pens over watercolors because watercolors are more difficult to control.

With this population, theyre not given many choices. A lot of people are making choices for them, Weaver said. This allows them to feel a little bit in control.

Research demonstrates the benefits of art therapy for cancer patients. Weaver points to a study published in the Journal of Pain and Symptom Management that found cancer patients who participated in a one-hour art therapy session each week experienced significant reductions in eight of nine symptoms on the Edmonton Symptom Assessment Scale. A separate study published in BMC Cancer found that patients who underwent art therapy realized immediate reductions in pain, emotional distress, depression and anxiety.

Claudia Marin points to 3,000 years of proof as evidence that acupuncture works.

The senior acupuncturist at Sylvester said there are two ways to explain acupunctures effectiveness. The Eastern understanding, which originated in China, says the body is lined with pathways carrying a flow of energy known as chi. When that energy is disrupted or destroyed, disease follows. Inserting needles into those pathways helps restore the natural flow.

The Western understanding is that needles tap into the bodys nervous system, improving blood flow and releasing endorphins and serotonin to help manage chronic pain.

The proof that acupuncture works, Marin said, is so overwhelming the World Health Organization has published guidelines since 1999. But Marin uses another barometer. Her schedule is booked solid through January 2024.

We notice a change in mood. It takes the edge off the pain. Theyre sleeping better, she said.

Khan sees a similar pattern play out with her patients. She specializes in dialectical behavior therapy (DBT), which arms patients with tools and skills they can use on their own to better manage their emotions, reduce their stress, and learn to accept their situation by being more mindful and present in each moment.

Its a survival guide to managing life, said Khan, because it empowers patients to tackle mental health obstacles without becoming overly dependent on a therapist.

Studies have long shown that DBT helps people who are contemplating suicide. In recent years, the practice has been extended to cancer survivors, with encouraging results.Sylvester recently opened the Fields Galley Cancer Survivorship Emotional Wellness Clinic for people in people in remission, who sometimes experience more cancer-related mental health issues than they did while in active treatment.

Khan said the studies that demonstrate the positive affect of support services are seen every day by caregivers.

A patient may enter our services feeling distressed about their particular situation but leaves much more emotionally anchored and regulated, she said.

Tags: Cancer Support Services, cancer survivorship, Dr. Maria Rueda-Lara, Sylvester Comprehensive Cancer Center

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Sylvester Cancer Support Services Grow - InventUM - University of Miami

Meet the Providers Aiming to Make Fertility Care More Accessible – Rewire News Group

Jessicas second-trimester abortion was the day of the 2016 presidential election. Earlier that year, she was diagnosed with polycystic ovary syndrome, which was causing her body not to ovulate. Jessicas doctor referred her to a nearby fertility practice in Connecticut, which thankfully took her insurance. After a battery of tests, the medical team triggered her ovulation, then sent her home to try and conceive. Two weeks later, Jessica was pregnant.

Well, that was easy, Jessica thought, and she continued to go to her fertility appointments until she graduated from the practice at about ten weeks pregnant. Then her obstetrician referred her to a maternal-fetal medicine doctor for her 13-week scan and bloodwork. When those tests showed concerning markers for trisomy 21, or Down syndrome, Jessica went back for more testing: a self-read DNA test, which again pointed to trisomy 21, and finally an amniocentesis and another ultrasound. She remembers being at about 15 weeks by the time all the tests were done.

Her doctors counseled her on the wide spectrum of possible prognoses for a fetus with Down syndrome. Then, they told her the abortion ban in Connecticut started at 24 weeks, so she had some time to decide whether she wanted to continue the pregnancy or terminate it.

After the counseling, Jessica and her husband drove home. They pulled the car into the garage, which is when she remembers looking at her husband and saying, I think we have to let him go. The next day she called to schedule an abortion.

Im not saying it was an easy decision, but it was a quick decision, she told me.

Because of the stigma surrounding abortion for Down syndrome across the political spectrum, Jessica wanted me to know that there were other abnormalities with the pregnancy: The fetus had multiple organ and growth problems that are common comorbidities of Down syndrome. One fact that stuck out to Jessica from her counseling was that many fetuses with Down syndrome never make it to term (roughly 25 percent of Down pregnancies spontaneously abort). The thought of waiting to miscarry horrified her.

The procedure was scheduled for November 6 and 7, at Jessicas hospital with her own care team, where it would be covered fully by her insurance, just as her fertility care had been.

I went to the polls, I voted for Hillary, and I went to get seaweed put in my cervix, she said about laminaria used for dilation. Then the next day I woke up, I saw the news [about Trump] and went, Well, I cannot deal with this today.

Then she went to the hospital to finish the two-day abortion procedure.

I always talk about how it was the worst day of my life, she said. But everyone was very compassionate. Everything was arranged for me.

Even so, while her physical recovery was smooth, mentally she was a mess, and is still dealing with grief and trauma seven years later.

Fertility care and abortion care are intimately linked. While abortion care is more stigmatized, marginalized, and criminalized than fertility care, both are difficult to access and impacted by systemic racism and classism. Fertility care, like abortion care, is rarely covered by insurance: the most common barrier to fertility care reported by participants in a 2021 study was insurance coverage. A standard in vitro fertilization (IVF) cycle can cost anywhere between $10,000 and $25,000, which is often paid out of pocket. Genetic testing adds thousands more dollars.

Black and Latinx women, regardless of income, are less likely to access fertility care and, when they do, less likely to have a successful treatment cycle than the rest of the population. Meanwhile, half of abortion seekers live below the federal poverty line and abortion patients are disproportionately Black and Latinx. The central tenet of reproductive justiceto be free to parent, or not, in a time and manner of your choosingis stymied whether you are starting a pregnancy or ending one.

If a person can access fertility care at all, however, they are by definition accessing a kind of early pregnancy care the rest of the population is often denied. Traditional prenatal practices typically wont see patients until eight to 12 weeks of pregnancy. Yet the most common complication of pregnancyearly pregnancy losshappens in that two- to three-month window. Fertility clinics follow patients from conception to that point, then hand them off to an obstetrician, just like Jessicas doctor did.

Dr. Cori Schreiber founded the Pregnancy Early Access Center (PEACE) at the University of Pennsylvania in part to give pregnant people in those first eight to 12 weeks a place to receive care besides the emergency room.

The counseling and technical skills for managing unintended pregnancy and abortion are very similar to whats required for patients who may be concerned about miscarriage or have an early pregnancy loss diagnosis, she said. PEACE fills that gap in early pregnancy care, while also providing abortion care to 24 weeks of pregnancy.

Schreiber said miscarriage is rarely a true emergency in the United States, but the fact that early pregnancy loss is not a life-threatening emergency does not mean patients do not deserve timely care.

While emotionally devastating, Jessicas ease in accessing both fertility and abortion care was shockingly unusual. Dr. Sheila Ramgopal, CEO and medical director of Allegheny Reproductive Health Center in Pittsburgh, wants to change that.

Ramgopals clinic is majority queer people of color led and staffed, and Ramgopal said they are proud to reflect the people they serve. Still, they feel frustrated at the ever-more defensive stance of abortion care after the Supreme Court overturned Roe v. Wade in June 2022.

I think whats so hard is that this could all fucking be different, Ramgopal said. I feel like the movement is always in a defensive position. So, how do we actually become proactive and actually create ways that we can do the work more effectively?

For Ramgopal, part of the answer was to offer fertility care as part of their clinics services. Since 2017, the Allegheny center has offered basic fertility care within their scope of practice: intrauterine and intracervical insemination, basic fertility testing, and ovulation induction. But in 2020, Ramgopal met Traci Keen, the CEO of Mate Fertility, and started discussing how to make IVF a reality at Allegheny. Mate focuses on offering lower-cost fertility care in geographically underserved areas of the country. They also explicitly welcome LGBTQ+ clients, which not all fertility practices do.

Ramgopal thought the match was solid. Allegheny would own the practice and perform the procedures, while Mate would handle hiring and provide access to specialists, training, and quality control services. In exchange, Ramgopal would pay Mate a portion of the proceeds from fertility care on a monthly basis. Ramgopal also plans to partner with Posterity Health to provide additional services for male fertility, an underserved area in fertility care.

Mate Fertility is a young company that has closed multiple successful rounds of venture capital funding. The company has partnered with a clinic in Oklahoma City and two clinics in California, one in San Luis Obispo and one in Fresno. Pittsburgh, where Ramgopals clinic is located, would continue Mates interest in what Keen describes as underserved secondary and tertiary markets for fertility care.

Keen said her company wants to lower the barriers to fertility care for all people. To that end, Mate has been working on partnering with abortion clinics in states that ban abortion, to repurpose their spaces for fertility care. When asked if Mate had any concerns about providing fertility services in states with staggering maternal mortality rates and no access to abortion, Keen said, I think Id be remiss if I didnt say that its concerning just as a human being when youre in the business of getting people pregnant. Mate, however, has no formal plans to help clients access abortion services in the event they need this health care in a state that bans abortion.

We havent encountered any patients who are paying to get pregnant and then wanting to get an abortion, Keen said.

Ramgopal is putting about three-quarters of the clinics savings into opening a full services fertility clinic. They anticipate roughly $2.2 million total, of which about $1.8 million is just for the buildout of the new facility. But finding a new physical space has proven most challenging.

Im trying to find places to lease where they actually are comfortable with leasing to an abortion facility, Ramgopal said. As of late September, they still had not secured a location. When asked if the clinic had a GoFundMe for the new space, Ramgopal directed me to Western Pennsylvania Fund for Choice.

Keen expressed a general lack of concern with the anti-abortion movement insofar as it might impact fertility care.

Its hard to argue pro-life and then not support IVF, Keen said. Yet Risa Cromer, author of Conceiving Christian America: Embryo Adoption and Reproductive Politics, disagrees.

Im not interested in fanning the flames of fear at all, Cromer, who has written for Rewire News Group, said. But there has been clear critique of IVF from the anti-abortion movement since before Roe. Since IVF became non-experimental in 1978, there has been anti-abortion pushback against it. However, Cromer noted that IVF never became a strategic site of anti-abortion political advocacy in the United States.

Cromer also said President Ronald Regans neoliberal administration aligned with reticence from Democrats to regulate fertility services, lest such regulations impact abortion care. Fertility care became deregulated.

Eventually it became politically untouchable, Cromer said. It would remain that way until the advent of human embryonic stem cell research, when the anti-abortion movement put pressure on President George W. Bush to regulate this new field of science.

This looks like it has nothing to do with abortion, Cromer said. But it really does.

While Cromer noted that IVF is not a current target, the internal logics of the anti-abortion movement remain hostile to IVF and fertility care more generally, particularly when it becomes accessible to non-cishet, affluent, nuclear family structures: the precise people Mate and Ramgopal are trying to help.

When Jessica originally contacted me, she wanted to put her last name on the record. But as we spoke, the stigma of an abortion after undergoing fertility treatment, particularly an abortion for Down syndrome, even and especially among her progressive colleagues, worried her.

Ive been told what I did was eugenics, she said.

Cromer tied Jessicas discomfort to the overarching appropriation of disability rights rhetoric by the anti-abortion movement.

There is a deep history of conservative movements appropriating progressive rhetoric to use it for their own political gains, Cromer said.

She highlighted Dagmar Herzogs book Unlearning Eugenics, which shows how the modern anti-abortion movement came to embrace a pro-disability logic in Germany, specifically around Down syndrome. Though with different historical antecedents, disability rights and reproductive rights have also intentionally been made to compete in U.S. politics.

At the end of the day, Jessica neither wanted to opt into parenting a child with complex medical needs, nor undergo the remainder of what was now a high-risk pregnancy.

I still feel funny saying this, Jessica said. But we [pregnant people] matter too.

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Meet the Providers Aiming to Make Fertility Care More Accessible - Rewire News Group

Brother-in-law of surf industry fixture who died on medical retreat … – BeachGrit

Ire in the autumn air.

It is October in America, that time of year when Laird Superfood Pumpkin Spice fills the air and baseball the soul. Yes, while the World Surf League may claim to be the nations pastime, baseball has long occupied that slot. The season, which kicks off in spring, consists of 162 games winding through the dog days of summer and culminating in autumn.

The Fall Classic.

Now, in times past, the top three teams from each of the three division, both National and American Leagues, punched their playoff ticket to the playoffs alongside the National and American League team with the best record that didnt win its division as wildcards.

The Major League Baseball powers that be, though, wanted to add some spice and expanded the wildcard portion, allowing a few more teams a shot at the Big Dance. These teams play a three game series, then the winner plays the team with the best record in its league.

This tinkering has been compared to the World Surf Leagues decision to implement Finals Day wherein the top five surfers, male and female, head to Lower Trestles to compete in a winner-take-all showdown.

While the intention was to increase excitement in both baseball and surfing, the results have also benefited upstarts that just so happened to get hot.

Take Stephanie Gilmores worst-to-first 2022 performance in which Carissa Moore, the champion all year, was unseated.

Or, over on the baseball side, the Arizona Diamondbacks sweeping the Los Angeles Dodgers even though the Dodgers were ahead of the D-Backs by sixteen games at season end.

Last year, the Dodgers were undone by the San Diego Padres in similar fashion, leaving Dodger fans furious and wanting the playoff format changed back to the way it was.

Furious.

Message boards and op-eds are filled with salty messages from Dodgers, and Braves, fans decrying the Carissa Moore-ing of teams that proved their worth all season only to get Lower Trestled.

Surf fans not named Richard Toledo nodding quietly.

Will the grousing lead to changes?

Do you have thoughts on the matter or a horse in the race?

The Texas Rangers take on the Houston Astros tonight for the American League pennant.

All action, no lulls.

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Brother-in-law of surf industry fixture who died on medical retreat ... - BeachGrit

Faeth Therapeutics Announces National Academy of Medicine … – BioSpace

AUSTIN, Texas--(BUSINESS WIRE)-- Faeth Therapeutics, a leader in metabolic oncology research and treatment innovation, proudly announces the induction of its co-founder, Dr. Siddhartha Mukherjee, Assistant Professor at Columbia, Pulitzer Prize Winner, and one of Time 100's Most Influential People, into the esteemed National Academy of Medicine (NAM).

Dr. Mukherjee was honored for contributing important research in the immunotherapy of myeloid malignancies, such as Acute Myeloid Leukemia, for establishing international centers for immunotherapy for childhood cancers, and for the discovery of tissue-resident stem cells. His book, The Emperor of All Maladies, won the Pulitzer Prize and was nominated by Time as among the centurys 100 most influential books, introducing millions to modern cancer research. This recognition accentuates the collective dedication and caliber of Faeth's team and the company's commitment to advancing the realm of cancer care.

With Dr. Mukherjee's recent induction into the National Academy of Medicine, he joins fellow Faeth co-founders who have previously received this honor from the National Academy of Science: Karen Vousden, PhD, Chief Scientist of CRUK, Group Leader at the Crick Institute, and Director at Bristol Myers Squibb; Lew Cantley, PhD, Professor of Cell Biology at the Dana Farber Cancer Institute at Harvard University; Greg Hannon, PhD, Director of CRUK Cambridge Institute; and Scott Lowe, PhD, Chair of Cancer Biology & Genetics at Memorial Sloan Kettering, underlining the depth of Faeth Therapeutics' commitment to scientific excellence and innovation.

"Dr. Mukherjee's induction into the National Academy of Medicine reaffirms Faeth Therapeutics' dedication to unparalleled scientific rigor and innovation. We are immensely proud to have such an impressive team of co-founders driving our mission to redefine and elevate standards in oncology care," said Anand Parikh, J.D., Chief Executive Officer of Faeth Therapeutics.

Mukherjee is one of 100 new members announced by the academy. In the National Academy of Medicine, members are elected by their colleagues as a testament to their exceptional accomplishments. Being inducted into the academy represents one of the most prestigious accolades within the realm of medicine.

About Faeth Therapeutics

Faeth Therapeutics is a clinical-stage biotechnology company focused on bringing breakthrough research in metabolic oncology into the clinic. The company leverages its machine-learning platform to identify therapeutic programs that combine traditional therapeutics and a dietary metabolic regimen to enhance outcomes, with the goal of transforming the treatment landscape. Lead asset, FTH-001, combines serabelisib and an insulin-suppressing regimen to slow tumor growth via PI3K pathway inhibition. Faeths scientific founders include industry leaders Drs. Lew Cantley, Sid Mukherjee, Karen Vousden. For additional information, visit http://www.faeththerapeutics.com.

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Faeth Therapeutics Announces National Academy of Medicine ... - BioSpace

Regulation of dermal fibroblasts by human neutrophil peptides … – Nature.com

Materials

The following reagents were used in this study: HNP1, HNP2 and HNP3 (Peptide Institute, Inc., Japan); TGF- (BioLegend Inc., CA, USA); Dulbeccos Modified Eagles Medium (Cytiva, Marlborough, MA, USA); Fetal Bovine Serum (Gibco, Grand Island, NY); ProLong Gold Antifade Mountant with DAPI (Invitrogen, CA, USA); LDH-Cytotoxicity Colorimetric Assay Kit II (BioVision Inc., CA, USA); RNeasy Mini Kit (QIAGEN Inc., Hilden, Germany); iScript Reverse Transcription Supermix, SsoAdvanced Universal Probes Supermix (Bio-Rad Inc., CA, USA); Pierce BCA Protein Assay Kit (Thermo Fisher Scientific Inc., NY, USA); 1X Protease/Phosphatase Inhibitor Cocktail, Rabbit anti-COL1A1 antibody, Mouse anti-Ki-67 antibody, Rabbit anti--actin antibody, Mouse anti-rabbit IgG antibody (HRP conjugate), Anti-rabbit IgG Alexa Fluor 555, Anti-mouse IgG Alexa Fluor 488 (Cell Signaling Technology Inc., MA, USA); Amersham ECL Western Blotting Detection Kit (GE Healthcare Life Sciences Inc., MA, USA); Alliance Q9 chemiluminescence imaging system (Uvitec Inc., UK); Tissue-Tek O.C.T. Compound (Sakura, Alphenaan den Rijn, Netherlands).

Neonatal foreskin tissues were obtained by surgical circumcision of healthy male neonates at the Pediatric Surgery clinic, King Chulalongkorn Memorial Hospital with parental informed consent and assent forms. Ethical approval for this study was granted by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB 120/63). We confirm that all methods and experiments were performed in accordance with relevant guidelines and regulations. Dermal fibroblasts were isolated as described previously17 and cultured in medium containing DMEM supplemented with 10% FBS and gentamicin (1mL/L). The cells were incubated in a 5% CO2 incubator at 37C, and the cells derived from the 2nd to 5th passage were used in experiments.

Dermal fibroblasts (5103 and 1104 cells/well) in 100 L of DMEM with 10% FBS were seeded into 96-well clear round bottom, ultra-low attachment plates. The medium was replaced with fresh medium every 3days18. Spheroids were imaged at days 3, 5 and 7 and diameters were measured by ImageJ.

Cell proliferation was analyzed by methylene blue staining. Dermal fibroblasts were seeded into a 96-well plate (3103 cells/well) with 1% FBS DMEM overnight. HNP1-3 (0.62510M) were added into the wells, and the cells were incubated for 24h. The supernatant was collected, and the cells were fixed with 20% (v/v) formaldehyde for 48h and stained with methylene blue for 30min. The cells were washed and eluted with 100 L of ice-cold HCl (0.1M) in absolute ethanol solution (1:1 ratio). The absorbance was measured at 650nm using microplate reader. Cytotoxicity was analyzed using LDH-Cytotoxicity Colorimetric Assay Kit II. Collected supernatants (2.5 L) were mixed with 25 L of LDH reaction mix for 30min. Stop solution (2.5 L) was added and the absorbance was measured at 450nm using microplate reader. Spheroids derived from dermal fibroblasts (5103 cells/well) were treated with HNP1-3 at 10M for 4days. All experiments were performed in triplicates.

Dermal fibroblasts were seeded into a 6-well plate (2.5105 cells/well) in DMEM containing 1% FBS overnight. The cells were treated with HNPs (2.5, 5 and 10M) for 24h. Total RNA was extracted and converted to cDNA with the following conditions: 25C for 5min, 46C for 20min and 95C for 1min. COL1A1 and Ki-67 gene expressions were determined by real-time PCR. ABL gene expression was used as internal control. Primers and probes are listed in Supplementary Table S1 online. Real-time PCR was performed for 40 cycles with the following program: 95C for 2min, 95C for 5s and 60C for 30s.

Dermal fibroblasts were seeded into a 6-well plate (2.5105 cells/well) in 1% FBS in DMEM overnight. HNPs (2.5, 5 and 10M) were added into the wells and the cells were incubated for 48h. Cells were lysed by 1X RIPA Lysis Buffer containing 1X Protease/Phosphatase Inhibitor Cocktail. Total protein concentration was measured by Pierce BCA Protein Assay Kit. Protein lysates (10g) were mixed with 2X SDS dye and heated at 100C for 5min. Proteins were loaded in 7.5% SDS-PAGE and gel electrophoresis was performed at 100V for 1.5h. Proteins were transferred to PVDF membrane with electrophoresis at 15V for 50min. Blotting membranes were blocked with 1X PBS with 0.1% Tween-20 (PBST) containing 5% skimmed milk, followed by incubation with primary antibodies; COL1A1 (1:2000) and -actin (1:4000), overnight at 4C. The membranes were washed with PBST, and mouse anti-rabbit IgG (HRP conjugate) secondary antibody (1:4000) was added. The membranes were incubated for 1h with shaking before washing. The membranes were soaked in chemiluminescent substrate (Amersham ECL Western Blotting Detection Kit) and chemiluminescence signals were directly scanned with Alliance Q9 chemiluminescence imaging system. The band intensity was quantified by densitometry using ImageJ.

Dermal fibroblasts were seeded into a Lab-Tek II Chamber Slide System (1.5104 cells/well) in 1% FBS in DMEM overnight. HNPs (2.5, 5 and 10M) were added into the cells and incubated for 24h. The cells were washed with PBS and fixed with 4% paraformaldehyde for 10min. The cells were treated with 0.2% Triton-100 in PBS for 2min and blocked with 1% BSA in PBS for 30min. Primary antibody: Ki-67 (1:1000), diluted in 1% BSA in PBS was added and the cells were incubated at 4C overnight. After washing, secondary antibody: anti-mouse IgG Alexa Fluor 488 (1:2000), diluted in 1% BSA in PBS was added and the cells were incubated for 1h. After washing, the sections were mounted and proteins were observed.

Spheroids derived from dermal fibroblasts (5103 cells/well) were treated with HNPs (10M) for 4days. The spheroids were collected and covered with Tissue-Tek O.C.T. Compound. Frozen spheroids were cryosectioned into 8m thick layers onto glass slides. The sections were washed with PBS, fixed with 4% paraformaldehyde for 10min and treated with 0.2% Triton-100 in PBS for 2min. The sections were blocked with 5% BSA in PBS for 1h and incubated with primary antibody: COL1A1 (1:400), diluted in 1% BSA in PBS at 4C overnight. After washing, the sections were incubated with secondary antibody: anti-rabbit IgG Alexa Fluor 555 (1:1000), diluted in 1% BSA in PBS for 1h. After washing, the sections were mounted and proteins were observed.

The statistical analyses were determined by paired t-test using GraphPad Prism 9.0.0 (GraphPad Software, Boston, MA, USA). A simple linear regression analyses was performed using STATA version 15.1 (StataCorp, College Station, TX USA). The regression coefficients, 95% confidence intervals (CI), and p-value were demonstrated. The results were expressed as the meanstandard deviation (SD) and differences with a p-value<0.05 were considered statistically significant.

Dermal fibroblasts were seeded into a 6-well plate (2.5105 cells/well) in DMEM containing 1% FBS overnight. The cells were treated with HNP1 (10M) for 24h. Total RNA was extracted and the quality of extracted RNA (RNA Integrity Number6.5) was evaluated using an Agilent 2100 Bioanalyzer. The RNA-seq experiment was conducted by Vishuo Biomedical, Thailand. Purified poly-A mRNA was fragmented, and pair-end RNA sequencing was performed on the Illumina HiSeq platform. The Gene Expression Omnibus (GEO) of raw reads in FASTQ files was GEO ID: GSE230670.

Quality of raw reads in FASTQ files was inspected with the FASTQC program (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). The Trim Galore program (http://www.bioinformatics.babraham.ac.uk/projects/trim_galore/) was used to cut adaptors and sequence reads with a Phred score lower than 30. To estimate abundance of transcript, cleaned raw reads were analyzed with Salmon v1.9.019 by 2 steps; (1) indexing and (2) quantification. First, Salmon with default setting was used to build an index on human reference transcriptome (GRCh38) downloaded from Human Genome Resource at NCBI (downloaded; July 2022) (https://www.ncbi.nlm.nih.gov/projects/genome/guide/human/). Next, Salmon was used for quantification by mapping paired-end reads to the indexed reference sequence in mapping-based mode. Transcript abundances in estimated read counts were imported to R with tximeta v1.12.420 and aggregated to gene-level expression with gene model annotation (GRCh38) for further analysis. Principal component analysis (PCA) was performed on the pre-processed gene expression data, which were first log-transformed and normalized with respect to library sizes by the rlog function in DESeq221 package and standardized so that the expression level of each gene has a zero mean and a unit variance, to visualize the clustering structure of replicates. PCA plots were drawn in R using the ggplot2 package.

Differential gene expression was tested between HNP1 and control groups with DESeq2 v1.34.021 package. Gene expression was normalized with the median of ratios method from DESeq2. Since samples were derived from different donors, statistical design for DESeq2 was accounted for donor factor when fitted generalize linear model to data. Multiple hypothesis testing correction was performed using Benjamini-Hochberg's procedure. Differentially expressed genes (DEGs) were defined as genes with false discovery rates (FDR)<0.01. Boxplots were drawn in R using ggplot2.

Function of genes was analyzed with gene set enrichment analysis (GSEA) from WebGestalt (http://www.webgestalt.org/)22. The values of log fold changes were used to rank genes for the functional enrichment analysis using Gene Set Enrichment Analysis (GSEA) method. KEGG pathway and Gene Ontology databases (biological process, molecular function and cellular component) were used. Multiple hypothesis testing correction was performed using Benjamini-Hochbergs procedure with the FDR cutoff of 0.05 for enriched functions.

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Regulation of dermal fibroblasts by human neutrophil peptides ... - Nature.com