Category Archives: Cell Medicine

Kira MacDougall, MD, and Muhammad Rafay Khan Niazi, MD, spoke with CancerNetwork about their research into the significance of peripheral blood biomarkers of response to immunotherapy in nonsmall cell lung cancer published in the journal ONCOLOGY.

Kira MacDougall, MD, a first year fellow at the University of Oklahoma, and Muhammad Rafay Khan Niazi, MD, a third year resident of Internal Medicine at Staten Island University Hospital, spoke with CancerNetwork about research published in the journal ONCOLOGY titled, The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated With Pembrolizumab: A Clinical Study.

MacDougall and Niazi discuss the clinical utility of absolute lymphocyte count (ALC) and the ratio of absolute neutrophil count to ALC for predicting outcomes with pembrolizumab (Keytruda) in advanced nonsmall cell lung cancer. They also talked about future research in the space and what unanswered questions remain in this treatment setting.

Dont forget to subscribe to the Oncology Peer Review On-The-Go podcast on Apple Podcasts, Spotify, or anywhere podcasts are available.

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Oncology Peer Review On-The-Go: The Prognostic Significance of Peripheral Blood Biomarkers in Patients With Advanced NonSmall Cell Lung Cancer Treated...

image:Chromosome segregation In dividing cells. Cell cytoskeleton is depicted in red, DNA is depicted in blue and a protein that marks dividing cells is depicted in green. view more

Credit: Tom Winkler, Ben David lab.

The researchers caution: "The CRISPR genome editing method is very effective, but not always safe. Sometimes cleaved chromosomes do not recover and genomic stability is compromised which in the long run might promote cancer."

A new study from TAU identifies risks in the use of CRISPR therapeutics an innovative, Nobel-prize-winning method that involves cleaving and editing DNA, already employed for the treatment of conditions like cancer, liver and intestinal diseases, and genetic syndromes. Investigating the impact of this technology on T-cells white blood cells of the immune system, the researchers detected a loss of genetic material in a significant percentage up to 10% of the treated cells. They explain that such loss can lead to destabilization of the genome, which might cause cancer.

The study was led by Dr. Adi Barzel from the School of Neurobiology, Biochemistry and Biophysics at TAU's Wise Faculty of Life Sciences and Dotan Center for Advanced Therapies, a collaboration between the Tel Aviv Sourasky Medical Center (Ichilov) and Tel Aviv University, and by Dr. Asaf Madi and Dr. Uri Ben-David from TAU's Faculty of Medicine and Edmond J. Safra Center for Bioinformatics. The findings were published in the leading scientific journal Nature Biotechnology.

The researchers explain that CRISPR is a groundbreaking technology for editing DNA cleaving DNA sequences at certain locations in order to delete unwanted segments, or alternately repair or insert beneficial segments. Developed about a decade ago, the technology has already proved impressively effective in treating a range of diseases cancer, liver diseases, genetic syndromes, and more. The first approved clinical trial ever to use CRISPR, was conducted in 2020 at the University of Pennsylvania, when researchers applied the method to T-cells white blood cells of the immune system. Taking T-cells from a donor, they expressed an engineered receptor targeting cancer cells, while using CRISPR to destroy genes coding for the original receptor which otherwise might have caused the T-cells to attack cells in the recipient's body.

In the present study, the researchers sought to examine whether the potential benefits of CRISPR therapeutics might be offset by risks resulting from the cleavage itself, assuming that broken DNA is not always able to recover.

Dr. Ben-David and his research associate Eli Reuveni explain: "The genome in our cells often breaks due to natural causes, but usually it is able to repair itself, with no harm done. Still, sometimes a certain chromosome is unable to bounce back, and large sections, or even the entire chromosome, are lost. Such chromosomal disruptions can destabilize the genome, and we often see this in cancer cells. Thus, CRISPR therapeutics, in which DNA is cleaved intentionally as a means for treating cancer, might, in extreme scenarios, actually promote malignancies."

To examine the extent of potential damage, the researchers repeated the 2020 Pennsylvania experiment, cleaving the T-cells' genome in exactly the same locations chromosomes 2, 7, and 14 (of the human genome's 23 pairs of chromosomes). Using a state-of-the-art technology called single-cell RNA sequencing they analyzed each cell separately and measured the expression levels of each chromosome in every cell.

In this way, a significant loss of genetic material was detected in some of the cells. For example, when Chromosome 14 had been cleaved, about 5% of the cells showed little or no expression of this chromosome. When all chromosomes were cleaved simultaneously, the damage increased, with 9%, 10%, and 3% of the cells unable to repair the break in chromosomes 14, 7, and 2 respectively. The three chromosomes did differ, however, in the extent of the damage they sustained.

Dr. Madi and his student Ella Goldschmidt explain: "Single-cell RNA sequencing and computational analyses enabled us to obtain very precise results. We found that the cause for the difference in damage was the exact place of the cleaving on each of the three chromosomes. Altogether, our findings indicate that over 9% of the T-cells genetically edited with the CRISPR technique had lost a significant amount of genetic material. Such loss can lead to destabilization of the genome, which might promote cancer."

Based on their findings, the researchers caution that extra care should be taken when using CRISPR therapeutics. They also propose alternative, less risky, methods, for specific medical procedures, and recommend further research into two kinds of potential solutions: reducing the production of damaged cells or identifying damaged cells and removing them before the material is administered to the patient.

Dr. Barzel and his PhD student Alessio Nahmad conclude: "Our intention in this study was to shed light on potential risks in the use of CRISPR therapeutics. We did this even though we are aware of the technology's substantial advantages. In fact, in other studies we have developed CRISPR-based treatments, including a promising therapy for AIDS. We have even established two companies one using CRISPR and the other deliberately avoiding this technology. In other words, we advance this highly effective technology, while at the same time cautioning against its potential dangers. This may seem like a contradiction, but as scientists we are quite proud of our approach, because we believe that this is the very essence of science: we don't 'choose sides.' We examine all aspects of an issue, both positive and negative, and look for answers."

Link to the article:

https://www.nature.com/articles/s41587-022-01377-0

Nature Biotechnology

Frequent aneuploidy in primary human T cells after CRISPRCas9 cleavage

30-Jun-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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CRISPR therapeutics can damage the genome - EurekAlert

image:Drug B binds to the surface of the cell and is transported to the Golgi apparatus. The drug contains an endoplasmic reticulum (ER)-specific sequence to further guide its transport to the ER. Transport to the ER is stopped if the drug bears N-glycosylation Y. view more

Credit: Ayano Satoh from Okayama University

Proteins usually undergo modifications during or after their synthesis in the endoplasmic reticulum (ER) and Golgi apparatus network inside eukaryotic cells. One such modification is glycosylation, whereby sugars, such as glycans, are added to newly synthesized proteins. Glycans allow proteins to fold properly, in turn making them stable and biologically active for various cell processes. However, the exact mechanism of glycosylation in the ER and Golgi are still not known. One way to study the process of glycosylation during protein synthesis is to deliver synthetic proteins to specific cell organelles and observe their subcellular dynamics. But this is often hindered by the lack of specific delivery methods to organelles like the ER and Golgi.

To this end, Dr. Ayano Satoh from Okayama University and Dr. Yuta Maki, Kazuki Kawata, Dr. Yanbo Liu, Kang-Ying Goo, Dr. Ryo Okamoto, and Prof.Dr. Yasuhiro Kajihara from Osaka University, Japan investigated the feasibility of modifying cholera toxin (CT) for targeted delivery to the ER and Golgi. CT is a protein produced by the bacterium Vibrio cholerae and is responsible for the hallmark symptoms of diarrhearepeated loose, watery stools. The toxin is made up of two subunits: CTA, which causes diarrhea, and CTB, which helps the toxin enter cells. CT enters the cell through the membrane into small cellular vehicles called endosomes that deliver it to the Golgi bodies. From there, an ER-specific amino acid sequence of CTA takes CT into the ER, where the toxin springs into action to cause diarrhea. CT is a protein that naturally gets delivered specifically to the Golgi and ER. This made it an attractive candidate for our investigation, says Dr. Satoh, explaining the reason behind selecting this protein for their study, which was first published on May 23, 2022, in Chemistry A European Journal.

The team synthesized an artificial, glycosylated form of the non-toxic CTB and tracked its intracellular journey using the HiBiT bioluminescence system engineered from the luciferase enzyme. In the system that the team used, the larger fragment of luciferase was added to particular receptors on the ER and Golgi. CTB was tagged with the smaller fragment of luciferase. The system works by emitting light when the two fragments bind to each other. Thus, the team tracked the artificial CTBs movement through the organelles in real time by checking for the emittance of light. Talking about the highlights of their study, Dr. Satoh says, We designed and chemically synthesized the glycosyl-CTB and demonstrated its trafficking into the ER and Golgi of living cells. We also established a method to quantitatively monitor the trafficking of CTB to these organelles.

The successful monitoring and delivery of the artificial CTB may pave the way for a new phase of research in understanding protein modification in compartments of living cells. The team emphasizes that their method of preparing CTB allows for developing various mutant forms of the protein as well as CTB bearing different glycans on its surface to help investigate the functions of N-glycan in cells.

Not only the study of glycans but CTB-mediated delivery can also be a promising tool for target-specific drug delivery in cells and organelles. Dr. Satoh observes, Our system for targeting specific organelles may help treat diseases caused by the absence of enzymes localized in specific organelles.

What is her vision for the future? Current drug delivery techniques are limited because they only target the cell surface. Our system may extend the limits of current technology and enable the delivery of drug wherever it is needed, says a hopeful Dr. Satoh.

We have our fingers crossed for her vision to come true and revolutionize the field of medicine!

About Okayama University, Japan

As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.

Website: https://www.okayama-u.ac.jp/index_e.html

About Professor Ayano Satoh from Okayama University, Japan

Dr. Ayano Satoh is an Associate Professor of the Graduate School of Interdisciplinary Science and Engineering in Health Systems and the Faculty of Engineering at the Okayama University, Okayama, Japan. She obtained her Bachelors and Masters degrees in Chemistry from Ochanomizu University, Tokyo, Japan. She then received her PhD at the Graduate School of Humanities and Sciences, Ochanomizu University, where she worked on affinity interactions among lipids, glycans, and proteins with Dr. Isamu Matsumoto. Before joining Okayama University, she worked with Dr. Graham Warren at Yale University, first as a Postdoctoral Researcher, and then as a Research Scientist. At Yale University, she worked on transport within the Golgi apparatus.

Chemistry - A European Journal

Experimental study

Cells

Design and Synthesis of Glycosylated Cholera Toxin B Subunit as a Tracer of Glycoprotein Trafficking in Organelles of Living Cells

23-May-2022

The authors declare no conflict of interest.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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To cell surface and beyond: Tracing subcellular glycoprotein transport using modified cholera toxin - EurekAlert

Event Date:July 27, 2022Time:11:00 am 3:00 pm ET

Advanced cell therapies continue to be a fantastic success story for both the biotech and life sciences industries, but most importantly for patients who have witnessed first-hand the lifesaving potential of these biotherapeutics. In addition, cell therapies are at the vanguard of many precision medicine initiatives, from off-the-shelf products designed to treat a broad range of patients, to personalized therapeutics that have been engineered to compliment patients genetics. Yet, with all their success comes the challenges that researchers face dailydonor access, scaling manufacturing operations, and safety, to name a few. Understanding the current cell therapy landscape and incorporating the lessons learned from previous successes and failures will allow the industry to keep pushing the limits of whats possible scientifically while helping speed up new safe, efficacious therapies to market.

ThisGENSummit has amassed an extraordinary selection of thought leaders to discuss the latest trends, newest technologies, and practical solutions to common challenges that face organizations devoting their time to cell therapy research. Our summit will kick off with an exciting keynote address fromWilliam Ho,President, CEO, and Co-Founder of IN8bio, which is focused on delivering a novel off-the-shelf cell therapy for the treatment of cancer. Together, during this half-day conference, we will discover the current state of the cell therapy space and hear about the amazing potential that many novel cell therapies have to truly impact patients lives.

Register now and reserve your spot for what is sure to be an exciting and immensely informative event!

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From Donor to Patient: Advancing the Future of Cell Therapies - Genetic Engineering & Biotechnology News

An ad hoc committee has been appointed to undertake a routine review of the Biomedical Research Imaging Center and the leadership of its Director, Weili Lin, PhD, Dixie Lee Boney Soo Distinguished Professor of Neurological Medicine. The review is a standard procedure of the University of North Carolina at Chapel Hill and will take place on September 13.

The review committee invites your participation and input:

The deadline to request time on the review committee agenda, or to share written comments, is Sept. 2, 2022.

Note that North Carolina law requires that any written materials developed or received by the committee during the review may be made available to the person reviewed upon request.

All requests from the person reviewed will be handled by the Legal Department and any identifying information will be redacted prior to release of the material.

Members of the Review Committee

Henrik Dohlman, PhD Review Committee Chair, Distinguished Professor, Pharmacology

Jan Busby-Whitehead, MD Distinguished Professor,Geriatric Medicine

Leon Coleman, MD,PhD Assistant Professor, Pharmacology

Felicia Williams, MD,FACS Associate Professor, Surgery, Burn Center

Mark Shen, PhD Assistant Professor, Psychiatry, Carolina Institute for Developmental Disabilities

Benjamin Philpot, PhD Distinguished Professor, Cell Biology and Physiology

Dirk Dittmer, PhD-Professor, Microbiology and Immunology

Joyce Besheer, PhD Professor, Psychiatry, Bowles Center for Alcohol Studies

Morika Williams, DVM, PhD, DACLAM Assistant Professor, Pathology and Lab Medicine

Aysenil Belger, PhDProfessor, Psychiatry

Original post:
Five-Year Review of Biomedical Research Imaging Center, Center Director | Newsroom - UNC Health and UNC School of Medicine

Patients with high-grade ovarian cancer and uterine serous cancer (USC) often respond well to surgery and chemotherapy. At first.

But these can be highly aggressive tumors that often spread into the space within the abdomen known as the peritoneal cavity. According to a recent study, one rare but aggressive type of uterine cancer is propelling an increase in deaths from the disease in the United States, particularly among Black women.

Moreover, resistance to chemotherapy often develops, and the disease recurs. This results in ovarian cancer causing more deaths than any other cancer of the female reproductive system.

For one possible treatment, clinical trials demonstrated the effectiveness of injecting a drug known as epothilone B (EB) into the abdominal cavity, targeting tumor cells that have grown resistant to standard chemotherapy medications. However, the drugs high toxicity when delivered this way causes severe side effects, preventing further use.

Now, thanks in part to research begun more than a decade ago with funding from Womens Health Research at Yale, our colleagues are closing in on a way to deploy effective cancer-fighting medication safely with the help of ultra-tiny non-toxic biodegradable objects known as nanoparticles. Developed by Dr. W. Mark Saltzman, the Goizueta Foundation Professor of Biomedical and Chemical Engineering, these nanoparticles have organic chemicals on their surface that allow them to stick to cells in the abdominal cavity so they are not cleared from the area before they can do their job.

With bioadhesive nanoparticles, we can safely entrap a drug and deliver it so it slowly releases in a high concentration, directly to our target, over a long time, Saltzman said. By localizing the delivery of the drug, we are decreasing toxicity and increasing effectiveness.

With data funded through WHRYs grant, Drs. Saltzman and Alessandro Santin, professor of obstetrics, gynecology, and reproductive sciences, secured funding from the National Institutes of Health to demonstrate the safety and efficacy of this technique in a model system, publishing their results in 2016.

Saltzman then partnered with Dr. Michael Girardi, Evans Professor of Dermatology, to develop a non-surgical treatment for skin cancer using injections of nanoparticles carrying a chemotherapy agent. In a paper published last year, they demonstrated the capacity for this method to bind to the tumors and kill a significant number of cancer cells. In addition, the treatment involves triggering an immune response to rid the body of cancer cell waste and respond against any remaining cancer cells.

Drs. Saltzman and Girardi founded a company called Stradefy Biosciences, which has licensed patents to this technology from Yale, while continuing to develop these techniques for clinical use.Dr. Nita Ahuja, William H. Carmalt Professor of Surgery and chair of surgery, serves as an advisor for abdominal cancer applications.

We are thrilled that the work we sponsored many years ago continues to produce such varied applications for serious health concerns, said WHRY Director Carolyn M. Mazure, PhD. This is the model for how investing in Yales most innovative and collaborative individuals can produce steady progress that will improve and even save lives.

Dr. Saltzman also used a WHRY grant to create a vaginal ring that provides contraception while protecting against sexually transmitted infections. Yale has filed a patent application on this unique ring design, and Saltzman continues to seek funding to further develop the product and possibly adapt it to treat endometriosis.

The type of funding WHRY provides is critical for the innovation-based work I do, Saltzman said. I could say, We are going to make these particles with this unique property. But to get substantial buy-in from a company or the NIH, you need to have the data to demonstrate that this works. Early funding, particularly for collaborative projects with unproven technologies, is critical.

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Using Particles That Are Smaller Than the Head of a Pin to Treat Cancer - Yale School of Medicine

DUBLIN--(BUSINESS WIRE)--The "Stem Cell Assays Market by Type (Viability, Proliferation, Differentiation, Apoptosis), Cell Type (Mesenchymal, iPSCs, HSCs, hESCs), Product & Service (Instrument), Application (Regenerative Medicine, Clinical Research), End User - Global Forecast to 2027" report has been added to ResearchAndMarkets.com's offering.

The stem cell assay market is projected to reach USD 4.5 Billion by 2027 from USD 1.9 Billion in 2022, at a CAGR of 17.7% during the forecast period.

The growth of the market is projected to be driven by collaborations and agreements among market players for stem cell assay products & services, the launch of new stem cell analysis systems such as flow cytometers, and increase in R&D expenditure by biopharmaceutical and biotechnology companies.

The viability/cytotoxicity assays accounted for the largest share of the type segment in the stem cell assays market in 2021

Cell viability assays help to determine the number of live and dead cells in a culture medium. The viability/cytotoxicity assays include various types such as tetrazolium reduction assays, resazurin cell viability assays, calcein-AM cell viability assays, and other viability/cytotoxicity assays. The cell viability/cytotoxicity market is likely to be driven by rising R&D spending on stem cell research, an increase in demand for stem cell assays in drug discovery, and development of new stem cell therapies..

The adult stem cells segment accounted for the largest share of the cell type segment in the stem cell assays market in 2021.

Adult stem cells account for the largest share of the stem cell assay market. The adult stem cells include mesenchymal stem cells, induced pluripotent stem cells, hematopoietic stem cells, umbilical cord stem cells, and neural stem cells. The growth of the adult stems cells segment is driven by the increasing usage of adult stem cells in regenerative medicine and the development of advanced therapies.

Asia Pacific: The fastest-growing region in the stem cell assays market

The Asia Pacific is estimated to be the fastest-growing segment of the market, owing to the rising prevalence of cancer & other diseases, increasing R&D spending on biopharmaceutical projects, and focus on developing stem cell-based therapies. In this region, China and Japan are the largest markets.

Key Topics Covered:

1 Introduction

2 Research Methodology

3 Executive Summary

4 Premium Insights

4.1 Stem Cell Assays Market Overview

4.2 North America: Stem Cell Assays Market, by Product & Service and Country (2021)

4.3 Stem Cell Assays Market Share, by Type, 2022 Vs. 2027

4.4 Stem Cell Assays Market Share, by Application, 2021

4.5 Stem Cell Assays Market: Geographic Growth Opportunities

5 Market Overview

5.1 Introduction

5.2 Market Dynamics

5.2.1 Drivers

5.2.1.1 Increasing Awareness About Therapeutic Potency of Stem Cells

5.2.1.2 Increasing Funding for Stem Cell Research

5.2.1.3 Rising Demand for Cell-Based Assays in Drug Discovery

5.2.1.4 Collaborations and Agreements Among Market Players for Stem Cell Assay Products & Services

5.2.1.5 Rising Incidence of Cancer

5.2.2 Restraints

5.2.2.1 Issues in Embryonic Stem Cell Research

5.2.2.2 High Cost of Stem Cell Analysis Instruments

5.2.3 Opportunities

5.2.3.1 Emerging Economies

5.2.3.2 Government Initiatives to Boost Stem Cell Research

5.2.4 Challenges

5.2.4.1 Lack of Infrastructure for Stem Cell Research in Emerging Economies

5.2.4.2 Dearth of Trained and Skilled Professionals

5.3 Ranges/Scenarios

5.4 Impact of COVID-19 on Stem Cell Assays Market

5.5 Trends/Disruptions Impacting Customers' Business

5.6 Pricing Analysis

5.6.1 Average Selling Prices of Products Offered by Key Players

5.6.2 Average Selling Price Trend

5.7 Technology Analysis

6 Stem Cell Assays Market, by Type

6.1 Introduction

6.2 Viability/Cytotoxicity Assays

6.3 Isolation & Purification Assays

6.4 Cell Identification Assays

6.5 Proliferation Assays

6.6 Differentiation Assays

6.7 Function Assays

6.8 Apoptosis Assays

7 Stem Cell Assays Market, by Cell Type

7.1 Introduction

7.2 Adult Stem Cells

7.3 Human Embryonic Stem Cells

8 Stem Cell Assays Market, by Product & Service

8.1 Introduction

8.2 Instruments

8.3 Kits

8.4 Services

9 Stem Cell Assays Market, by Application

9.1 Introduction

9.2 Regenerative Medicine & Therapy Development

9.3 Drug Discovery & Development

9.4 Clinical Research

10 Stem Cell Assays Market, by End-User

11 Stem Cell Assays Market, by Region

12 Competitive Landscape

13 Company Profiles

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/hvgp4o

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Stem Cell Assays Market Report 2022-2027: Increasing Awareness About Therapeutic Potency of Stem Cells Driving Growth - ResearchAndMarkets.com -...

A common plant from west Africa works as a treatment for sickle cell disease, new research has found.

Scientists at Aberystwyth University isolated a chemical in the Alchornea cordifolia plant, also known as the Christmas Bush, which could help relieve the symptoms of the life-threatening and painful disease suffered by 15,000 people in the UK.

In sufferers of sickle cell anaemia, red blood cells change from their usual soft disc shape to a curved "sickle" shape and also become sticky and hard, which means they don't move properly around the body.

Blood is blocked from flowing, particularly to joints, the chest and abdomen, leading to severe pain, swelling of hands and feet, delayed growth and problems with eyesight, among other symptoms. It can lead to stillbirth and is also fatal in some cases.

A genetic disease, it is more common among people of African, Mediterranean and Middle Eastern descent, with over 20m people around the world affected.

In Nigeria around 150,000 children are born with sickle cell anaemia each year. Half of them are likely to die before their 10th birthday.

Juice from the plant, which grows widely across the tropical regions of Africa, has been used in a "blood tonic" as a traditional remedy for generations, but it has never been scientifically proven to work until now.

Dr Olayemi Adeniyi, a researcher at the university who suffers from the condition herself, interviewed traditional healers from south western Nigeria, who said the plant had been used for years as a treatment.

Leaves are crushed manually or blended, and can also be brewed into a tea.

Dr Adeniyi said the research had shown that quercitrin, the active ingredient in the plant, could both prevent and reverse the "sickling" caused by the disease.

She said: "Until now there has been no scientific proof of the plants effectiveness.

The research is particularly important because so many people affected by sickle cell disease live below the poverty line and have no access to medicine. The plant grows in bushes and is relatively easy to grow on fertile land - all you need are seeds.

Its crucial that people in the countries affected, Africa in particular, hear that this plants benefits have now been scientifically proven. Our findings show that this is a treatment that has firm scientific foundations, not just psychological ones.

Existing treatments are expensive, and some involve blood transfusions. It can only be cured with a stem cell or bone marrow transplant, but this is rarely done because of the risks involved.

The finding "could inform efforts directed to the development of an anti-sickling drug", the paper concluded.

The study formed part of an Aberystwyth University project looking at the scientific effectiveness of traditional and herbal remedies, which has also focused on developing new antibiotics to counter the growing problem of antimicrobial resistance.

Professor Luis Mur, who led the research, said: "We're running out of drug leads. There is a recognition, especially with diseases, that they are evolving, and they're evolving through misuse of antimicrobials for example, and so we need to look at new sources.

"So let's go back to where traditional practices have actually given a hint that this particular plant or fungus has some efficacy."

The results were published in the Journal of Clinical Medicine.

See the article here:
Sickle cell disease could be treated with common plant, study finds - The Telegraph

From left, Vincent Cryns, Mo Chen and Richard A. Anderson. Photo by Tianmu Wen

Two of the most common genetic changes that cause cells to become cancerous, which were previously thought to be separate and regulated by different cellular signals, are working in concert, according to new research from the University of WisconsinMadison.

To date, researchers have focused on finding drugs that block one or the other to treat cancer. Understanding their cooperative effects may lead to more effective treatments.

Cells muster a protein, called p53, which acts inside the cell nucleus to respond to stress, but mutations of the gene that produces p53 are the most frequent genetic abnormalities in cancer. Mutations activating a cellular pathway called PI3K/Akt, located on the surface of cells, are also often implicated in runaway cell growth in cancer.

Outlined in green, this nucleus of a cancerous cell contains DNA in blue and red blobs marking the cells p53 protein binding with parts of the Akt cellular signaling pathway, a partnership that will prevent the cancerous cell from dying as it should and instead prolong its life and lead it to divide into more cancer cells. Image by Mo Chen

Cellular signaling pathways allow cells to accomplish important communications tasks that maintain healthy cell functions. The process is a bit like sending mail, which requires a specific series of steps and appropriate stamps and marks on the envelope to deliver a letter to the correct address.

A team led by UWMadison cancer researchers Richard A. Anderson and Vincent Cryns has discovered a direct link between the p53 and PI3K/Akt pathways. The findings, published today in the journal Nature Cell Biology, identified links in the pathways that make promising targets for new cancer treatments.

We have known for some time that lipid messenger molecules that activate the PI3K/Akt pathway found in membranes are also present in the nucleus of cells, says Anderson, a professor at the UW School of Medicine and Public Health. But what they were doing in the nucleus separate from membranes was a mystery.

Mo Chen, an associate scientist and first author of the new study, used chemotherapy drugs to stress cancer cells and damage their DNA as they were replicating, or creating new copies of themselves (which cancer cells do often). She discovered that proteins called enzymes that are part of the PI3K/Akt pathway bind to the mutated p53 protein in the nucleus of the cell and attach lipid messengers to p53, showing the two are directly linked.

Instead of entering apoptosis the proactive process of cell suicide which removes damaged cells the cancer cells repaired their chemotherapy-damaged DNA and went on growing and dividing, promoting cancer growth.

These results also have critical implications for cancer treatment,

Vincent Cryns

Our finding that the PI3K/Akt pathway is anchored on p53 in the nucleus was entirely unexpected, says Cryns, a physician-scientist and professor at UW School of Medicine and Public Health.

The PI3K/Akt pathway was thought to be confined to membranes.

These results also have critical implications for cancer treatment, Cryns says. Current treatments that target PI3K may not work because they operate on a different enzyme than the one in the pathway the research team discovered.

The enzyme in the new pathway is called IPMK and rendering it inactive keeps p53 proteins from binding with and activating the Akt pathway, like correcting the address on an envelope so it doesnt go to the wrong place. This prevents the pathway from benefitting cancer cells, making IPMK a promising new drug target.

The researchers, whose work is supported by the National Institutes of Health, the Department of Defense and the Breast Cancer Research Foundation, have also identified another enzyme, called PIPKIa, that is a key regulator of both p53 and Akt activation in the cell nucleus.

The team had previously shown that PIPKIa stabilizes the p53 protein, allowing it to be active. When PIPKIa was turned off, p53 levels inside the cell fell sharply. In the new study, the team showed that blocking PIPKIa by genetic approaches or a drug triggered cancer cell death by preventing p53 from activating Akt in the cell nucleus.

What this means is that drug inhibitors of PIPKIa will reduce mutant p53 levels and block Akt activation in the nucleus, potentially a very powerful one-two punch against cancer cells, Cryns says. Their team is actively searching for better PIPKIa drug inhibitors that could be used to treat cancers with p53 mutations or abnormally active PI3K/Akt pathway.

In addition to searching for drugs to block the newly discovered cancer pathway, the scientists are investigating whether other proteins in the cell nucleus are targets of the PI3K/Akt pathway.

We know other nuclear proteins are modified by lipid messengers like p53, but we have no idea how broad the landscape is, Anderson says.

However, the evidence suggests that this could be a feature shared among many kinds of cancers, a mechanism we are calling a third messenger pathway, he adds.

This research was supported in part by grants from the National Institutes of Health (R35GM114386), the Department of Defense (W81XWH-17-1-0258, W81XWH-17-1-0259, W81XWH-21-1-0129) and the Breast Cancer Research Foundation.

Continue reading here:
Unexpected link between most common cancer drivers may yield more effective drugs - University of Wisconsin-Madison

With no current treatments for hepatitis A, UNC School of Medicine scientists led by Stanley M. Lemon, MD, discovered how a protein and enzymes interact to allow hepatitis A virus to replicate, and they used a known drug to stop viral replication in an animal model.

CHAPEL HILL, NC The viral replication cycle is crucial for a virus to spread inside the body and cause disease. Focusing on that cycle in the hepatitis A virus (HAV), UNC School of Medicine scientists discovered that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases. They also found that the oral compound RG7834 stopped replication at a key step, making it impossible for the virus to infect liver cells.

These findings, published in the Proceedings of the National Academy of Sciences, are the first to demonstrate an effective drug treatment against HAV in an animal model of the disease.

Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts viral replication and reverses liver inflammation in a mouse model of hepatitis A, providing proof-of-principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreak settings, said senior author Stanley M. Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, and member of the UNC Institute for Global Health and Infectious Diseases.

Lemon, who in the 1970s and 80s was part of a Walter Reed Army Medical Center research team that developed the first inactivated HAV vaccine administered to humans, said research on HAV tapered off after the vaccine became widely available in the mid-1990s. Cases plummeted in the 2000s as vaccination rates skyrocketed. Researchers turned their attention to hepatitis B and C viruses, both of which are very different from HAV and cause chronic disease. Its like comparing apples to turnips, Lemon said. The only similarity is that they all cause inflammation of the liver. HAV is not even part of the same virus family as hepatitis B and C viruses.

Hepatitis A outbreaks have been on the rise since 2016, even though the HAV vaccine is very effective. Not everyone gets vaccinated, Lemon pointed out, and HAV can exist for long periods of time in the environment such as on our hands and in food and water resulting in more than 44,000 cases, 27,000 hospitalizations and 400 deaths in the United States since 2016, according to the CDC.

Several outbreaks have occurred over the past several years, including in San Diego in 2017 driven largely by homelessness and illicit drug use, causing severe illness in about 600 people and killing 20. In 2022, there was a small outbreak linked to organic strawberries in multiple states, leading to about a dozen hospitalizations. Another outbreak in 2019 was linked to fresh blackberries. Globally, tens of millions of HAV infections occur each year. Symptoms include fever, abdominal pain, jaundice, nausea, and loss of appetite and sense of taste. Once sick, there is no treatment.

In 2013, Lemon and colleagues discovered that the hepatitis A virus changes dramatically inside the human liver. The virus hijacks bits of cell membrane as it leaves liver cells, cloaking itself from antibodies that would have otherwise quarantined the virus before it spread widely through the blood stream. This work was published in Nature and provided insight into how much researchers had yet to learn about this virus that was discovered 50 years ago and has likely caused disease dating back to ancient times.

A few years ago, researchers found that hepatitis B virus required TENT4A/B for its replication. Meanwhile, Lemons lab led experiments to search for human proteins that HAV needs in order to replicate, and they found ZCCHC14 a particular protein that interacts with zinc and binds to RNA.

This was the tipping point for this current study, Lemon said. We found ZCCHC14 binds very specifically to a certain part of HAVs RNA, the molecule that contains the viruss genetic information. And as a result of that binding, the virus is able to recruit TENT4 from the human cell.

In normal human biology, TENT4 is part of an RNA-modification process during cell growth. Essentially, HAV hijacks TENT4 and uses it to replicate its own genome.

This work suggested that stopping TENT4 recruitment could stop viral replication and limit disease. Lemons lab then tested the compound RG7834, which had previously been shown to actively block Hepatitis B virus by targeting TENT4. In the PNAS paper, the researchers detailed the precise effects of oral RG7834 on HAV in liver and feces and how the viruss ability to cause liver injury is dramatically diminished in mice that had been genetically modified to develop HAV infection and disease. The research suggests the compound was safe at the dose used in this research and the acute timeframe of the study.

This compound is a long way from human use, Lemon said, But it points the path to an effective way to treat a disease for which we have no treatment at all.

The pharmaceutical company Hoffmann-La Roche developed RG7834 for use against chronic hepatitis B infections and tested it in humans in a phase 1 trial, but animal studies suggested it may be too toxic for use over long periods of time.

The treatment for Hepatitis A would be short term, Lemon said, and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.

This research was a collaboration between the Lemon lab and the lab of Jason Whitmire, professor of genetics at the UNC School of Medicine. Lemon and Whitmire are members of the UNC Lineberger Comprehensive Cancer Center.

First authors of the PNAS paper are You Li and Ichiro Misumi. Other authors, all at UNC, are Tomoyuki Shiota, Lu Sun, Erik Lenarcic, Hyejeong Kim, Takayoshi Shirasaki, Adriana Hertel-Wulff, Taylor Tibbs, Joseph Mitchell, Kevin McKnight, Craig Cameron, Nathaniel Moorman, David McGivern, John Cullen, Jason K. Whitmire, and Stanley M. Lemon.

This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R01-AI131685), (R01-AI103083), (R01-AI150095), (R21-AI163606), (R01-AI143894), (R01-AI138337). The UNC Pathology Services Core and UNC High-Throughput Sequencing Facility were supported in part by a National Cancer Institute Center Core Support Grant (P30CA016086) to the UNC Lineberger Comprehensive Cancer Center.

Media contact: Mark Derewicz, 919-923-0959

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