Tag: 3/10/23

Categories : Cancer UrogenitalTags :

New Treatment Combination could Prevent Cystectomy in Invasive Bladder Cancer

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Photo by cottonbro studio

Mount Sinai investigators have developed a new approach for treating invasive bladder cancer without the need for surgical removal of the bladder, they report in their study published in Nature Medicine. At present, cystectomy (removal of the bladder) is currently a standard approach when cancer has invaded the muscle layer of the bladder.

In a phase 2 clinical trial that was the first of its kind, doctors found that some patients could be treated with a combination of chemotherapy and immunotherapy without the need to remove their bladder. Radical cystectomy can be curative in muscle-invasive bladder cancer, but the procedure is a life-changing operation due to the need for urinary diversion and is associated with a 90 day mortality risk of up to 6–8%.

“Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint,” said Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, a part of the Tisch Cancer Center at Mount Sinai. “If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer.”

The 76 patients received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Approximately 43% (33 patients) achieved a complete response (no detectable cancer) when treated with this combination of chemotherapy and immunotherapy. Patients with a clinical complete response were offered the opportunity to proceed with additional immunotherapy, without surgical removal of the bladder. Among patients opting to proceed without surgical removal of the bladder, about 70% had no evidence of recurrent cancer after two years.

The most common adverse events were fatigue, anaemia, neutropenia and nausea. Somatic alterations in pre-specified genes or increased tumour mutational burden did not improve the positive predictive value of complete response.

Based on the results of this trial, two follow-up studies were launched to build on this approach; one is ongoing, and another will open in the next six months.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Categories : GeneticsTags :

A Gene for ‘Explosive’ Cell Death Drives Runaway Inflammation

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Australian researchers at Walter and Eliza Hall Institute have found that a genetic change that increases the risk of inflammation, through necroptosis, a process described as ‘explosive’ cell death, is carried by up to 3% of the global population.

The study, which is published in Nature Communications, may explain why some people have an increased chance of developing conditions like inflammatory bowel disease or suffer more severe reactions to infections with bacteria like Salmonella.

Immune power of ‘explosive’ cell death

Programmed cell death is a normal part of the body’s immune system and maintenance, removing unwanted, damaged or dangerous cells, and preventing the spread of viruses, bacteria, and even cancer.

First author WEHI’s Dr Sarah Garnish is first author on the paper and said that while there are various types of cell death, necroptosis is distinguished by its ferocity – the cells essentially explode, which sounds an alarm for other cells in the body to respond.

“This is a good thing in the case of a viral infection, where necroptosis not only kills the infected cells but instructs the immune system to respond, clean things up, and start a more specific, long lived immune response,” Dr Garnish said.

“But when necroptosis is uncontrolled or excessive, the inflammatory response can actually trigger disease.”

Genetic brakes

The gatekeeper of necroptosis is the gene MLKL. When the body needs to trigger a cell death response with plenty of firepower, the cellular brakes that normally keep MLKL in-check are released. However, some of us make a form of MLKL with flimsy brakes.

Dr Garnish and her co-authors have been able to quantify this at a population level for the first time.

“For most of us, MLKL will stop when the body tells it to stop, but 2-3% of people have a form of MLKL that is less responsive to stop signals,” Dr Garnish said.

“While 2-3% doesn’t seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of this gene variant.”

Project leader Dr Joanne Hildebrand said the research proposes that a common genetic change like this can combine with a person’s lifestyle, infection history and broader genetic makeup to increase the risk of inflammatory diseases and severe reactions to infections.

This is known as polygenic risk, the combined influence of multiple genes on developing a certain trait or condition.

“Taking Type 2 diabetes as an example, it’s rare that just one gene change determines whether someone will develop the condition,” Dr Hildebrand said.

“Instead many different genes play a role, as do environmental factors, like diet and smoking.”

Dr Hildebrand said it’s not as simple as directly connecting this difference in the MLKL gene with the chance of someone developing a specific condition.

“We haven’t tagged this MLKL gene variant to any one particular disease yet, but we see real potential for it to combine with other gene variants, and other environmental cues, to influence the intensity of our inflammatory response.”

Towards personalised medicine

Our understanding of MLKL has come a long way since it surfaced by chance in a WEHI lab more than 20 years ago. Today’s research opens the door for future tests and screening to determine disease risks.

Genome sequencing is becoming cheaper and more readily accessible. As more genomic data becomes available to researchers, it increases the likelihood that they can link common genetic variants, like the one described for MLKL, with disease.

In the future researchers hope to pinpoint the genetic changes that might mean someone is more likely to have a severe case of COVID-19, or less likely to bounce back after chemotherapy.

“Every piece of information like this helps us make personalised medicine more of a reality,” said Dr Garnish.

The WEHI team is also investigating whether uncontrolled necroptosis could be beneficial in some circumstances. For example, could people with the MLKL gene variant have a stronger cellular defensive response to certain viruses?

“Gene changes like this don’t usually accumulate in the population over time unless there is a reason for it – they generally get passed on because they do something good,” said Dr Garnish.

“We’re looking at the downsides of having this gene change, but we’re looking for the upsides as well.”

Source: Walter and Eliza Hall Institute

Categories : DermatologyTags :

The Untapped Potential of Phages for the Treatment of Atopic Dermatitis

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Credit: CC0

Researchers in Austria have discovered a new approach to treating atopic dermatitis: bacteriophages, which colonise the skin as viral components of the microbiome and can drive the development of innovative atopic dermatitis therapies. The research results were recently published in the scientific journal Science Advances.

Until now, the importance of bacteriophages in the human body has been known primarily from analyses of the intestine. In the search for innovative therapeutic measures for atopic dermatitis (AD), the MedUni Vienna research team led by Wolfgang Weninger, Head of the Department of Dermatology, has now investigated the interaction of phages and bacteria in the skin for the first time. After all, it has long been known that the progression of AD is accompanied by massive changes in the skin microbiome. The microbiome is the sum of all microorganisms on the skin and has been primarily investigated for its bacterial constituents. It has been unknown whether viruses also contribute to the nature of the bacterial microbiome in healthy and diseased skin. Phages are viruses of different types and functions whose sole aim is to infect bacteria, thereby either destroying them – or stimulating them to multiply.

New phages identified

“In our study, we discovered previously unknown phages in the microbiome of the skin samples of AD patients, which help certain bacteria to grow faster in different ways,” note first authors Karin Pfisterer and Matthias Wielscher from the Department of Dermatology at MedUni Vienna. The resulting shift in the balance between phages and bacteria was not detected in the comparative samples from healthy individuals and may be one explanation for the overpopulation of the skin microbiome with bacteria called Staphylococcus aureus found in AD. These findings contribute significantly to a better understanding of the skin bioflora in AD patients and pave the way for the development of new targeted therapeutic interventions: By identifying and culturing phages specialised for Staphylococcus aureus, a promising new option is available.

Specialists for targeted therapy

Bacteriophages are found not only in the body, but in every habitat populated by bacteria. There are a staggering 1031 different phage species. One of their characteristics is that they prove to be extremely specific when it comes to choosing their target of infection: most phages specialise in a particular genus, and in many cases in only a single species of bacteria. While that makes it a challenge for scientists to identify the type of phage needed for a particular purpose, it also enables them to use them in a targeted manner. Bacterial viruses do not make any difference between antibiotic-resistant and other bacteria, thus they are being researched as possible weapon in the fight against multi-resistant pathogens. Further studies are now planned to confirm phage therapy for topical use in atopic dermatitis.

Source: Medical University of Vienna

Categories : Gender Medical Research & TechnologyTags :

A New Model of the Liver Will Help Improve Drug Safety for Women

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Improved modelling of male and female livers can help lead to safer drugs

Photo by Danilo Alvesd on Unsplash

Researchers report in PLOS Computational Biology that they developed a powerful new tool to understand how medications affect men and women differently, and that will help lead to safer, more effective drugs in the future.

Women are known to suffer a disproportionate number of liver problems from medications but also usually underrepresented in drug testing. To address this, University of Virginia scientists have developed sophisticated computer simulations of male and female livers and used them to reveal sex-specific differences in how the tissues are affected by drugs.

The new model has already provided unprecedented insights into the biological processes that take place in the liver, the organ responsible for detoxifying the body, in both men and women. But the model also represents a powerful new tool for drug development, helping ensure that new medications will not cause harmful side effects.

“There are incredibly complex networks of genes and proteins that control how cells respond to drugs,” said UVA researcher Jason Papin, PhD, one of the model’s creators. “We knew that a computer model would be required to try to answer these important clinical questions, and we’re hopeful these models will continue to provide insights that can improve healthcare.”

Harmful side effects

Papin, of UVA’s Department of Biomedical Engineering, developed the model in collaboration with Connor Moore, a PhD student, and Christopher Holstege, MD, a UVA emergency medicine physician and director of UVA Health’s Blue Ridge Poison Center. “It is exceedingly important that both men and women receive the appropriate dose of recommended medications,” Holstege noted. “Drug therapy is complex and toxicity can occur with subtle changes in dose for specific individuals.”

Before developing their model, the researchers first looked at the federal Food and Drug Administration’s Adverse Event Reporting System to evaluate the frequency of reported liver problems in men and women. The scientists found that women consistently reported liver-related adverse events more often than did men.

The researchers then sought to explain why this might be the case. To do that, they developed computer models of the male and female livers that integrated vast amounts of data on gene activity and metabolic processes within cells. These cutting-edge liver simulations provided important insights into how drugs (xenobiotics) affect the tissue differently in men and women and allowed the researchers to understand why.

They found that xenobiotic metabolism was more active in untreated males, while pentose and glucoronate interconversions were female-biased, suggesting a difference in pretreatment gene expression, which may result in different initial responses of phase I and phase II metabolism to hepatotoxic drugs. They also observed sex-bias in bile acid biosynthesis, which in combination with xenobiotic metabolism, this result may suggest differences in bacterial deconjugation driven by sex differences in the gut microbiome. Differences were also found in several essential metabolic pathways, such as glycolysis/gluconeogenesis, nucleotide metabolism, and lipid metabolism with supporting evidence in human or rat hepatocytes.

“We were surprised how many differences we found, especially in very diverse biochemical pathways,” said Moore, a biomedical engineering student in Papin’s lab. “We hope our results emphasise how important it is for future scientists to consider how both men and women are affected by their research.”

The work has already identified a key series of cellular processes that explain sex differences in liver damage, and the scientists are calling for more investigation of it to better understand “hepatotoxicity” — liver toxicity. Ultimately, they hope their model will prove widely useful in developing safer drugs.

“We’re hopeful these approaches will be help address many other questions where men and women have differences in drug responses or disease processes,” Papin said. “Our ability to build predictive computer models of complex systems in biology, like those in this study, is truly opening all kinds of new avenues for tackling some of the most challenging biomedical problems.”

Source: University of Virginia Health System