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Comment by Dr. Krishna Kumari Challa on April 16, 2023 at 1:25pm

How a virus causes chromosomal breakage, leading to cancer

The Epstein-Barr virus (EBV) is easily spread through bodily fluids, primarily saliva, such as kissing, shared drinks or using the same eating utensils. Not surprisingly then, EBV is also among the most ubiquitous of viruses: More than 90% of the world’s population has been infected, usually during childhood.

EBV causes infectious mononucleosis and similar ailments, though often there are no symptoms. Most infections are mild and pass, but the virus persists in the body, becoming latent or inactive, sometimes reactivating. Long-term latent infections are associated with several chronic inflammatory conditions and multiple cancers.

In a new paper, published April 12, 2023 in the journal Nature, researchers describe for the first time how the virus exploits genomic weaknesses to cause cancer while reducing the body’s ability to suppress it.

These findings show “how a virus can induce cleavage of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate a major tumor suppressor”.

It’s the first demonstration of how cleavage of a ‘fragile DNA’ site can be selectively induced.

Throughout every person’s genome or full set of genes are fragile sites, specific chromosomal regions more likely to produce mutations, breaks or gaps when replicating. Some are rare, some are common; all are associated with disorders and disease, sometimes heritable conditions, sometimes not, such as many cancers.

In the new study, the researchers focused on EBNA1, a viral protein that persists in cells infected with EBV. EBNA1 was previously known to bind at a specific genomic sequence in the EBV genome at the origin of replication. The researchers found that EBNA1 also binds a cluster of EBV-like sequences at a fragile site on human chromosome 11 where increasing abundance of the protein triggers chromosomal breakage.

Other prior research has shown that EBNA1 inhibits p53, a gene that plays a key role in controlling cell division and cell death. It also suppresses tumor formation when normal. Mutations of p53, on the other hand, are linked to cancer cell growth.

When the scientists examined whole-genome sequencing data for 2,439 cancers across 38 tumor types from the Pan-Cancer Analysis of Whole Genomes project, they found that cancer tumors with detectable EBV revealed higher levels of chromosome 11 abnormalities, including 100% of the head and neck cancer cases.

This discovery suggests that susceptibility to EBNA1-induced fragmentation of chromosome 11 depends on the control of EBNA1 levels produced in latent infection, as well as the genetic variability in the number of EBV-like sequences present on chromosome 11 in each individual. Going forward, this knowledge paves the way for screening risk factors for the development of EBV-associated diseases. Moreover, blocking EBNA1 from binding at this cluster of sequences on chromosome 11 can be exploited to prevent the development of EBV-associated diseases.

https://www.nature.com/articles/s41586-023-05923-x

Comment by Dr. Krishna Kumari Challa on April 16, 2023 at 1:16pm

Sex of blood donor has no effect on recipient survival, finds clinical trial

A large clinical trial of more than 8,700 patients published in the New England Journal of Medicine concluded that the sex of a donor has no effect on the survival of recipients of red blood cell transfusions.

The possible impact of the sex of a blood donor on recipient survival has been an unanswered question in transfusion medicine since 2015, when the American National Heart, Lung and Blood Institute identified it as a research priority. Some evidence suggested that sex-related differences such as hormone levels in male and female blood might affect recipient survival, but the results of observational studies have been conflicting.

"To answer this question definitively, researchers needed a large, randomized clinical trial, but those studies are incredibly expensive. By embedding this trial in real-world practice and using practical methods, they answered this question for a fraction of what a trial would normally cost.

And most importantly, the study found no statistically significant differences in overall survival between recipients of male donor blood and recipients of female donor blood.

 The effect of donor sex on recipient mortality in transfusion, New England Journal of Medicine (2023). DOI: 10.1056/NEJMoa2211523

Comment by Dr. Krishna Kumari Challa on April 15, 2023 at 9:51am

Researchers use skin-colonizing bacteria to create a topical cancer therapy in mice

While studying a type of bacteria that lives on the healthy skin of every human being, researchers  may have stumbled on a powerful new way to fight cancer.

After genetically engineering the bacteria, called Staphylococcus epidermidis, to produce a tumor antigen (a protein unique to the tumor that's capable of stimulating the immune system), they applied the live bacteria onto the fur of mice with cancer. The resulting immune response was strong enough to kill even an aggressive type of metastatic skin cancer, without causing inflammation.

Millions of bacteria, fungi and viruses live on the surface of healthy skin. These friendly colonists play a crucial role in maintaining the skin barrier and preventing infection, but there are many unknowns about how the skin microbiota interacts with the host immune system. For instance, unique among colonizing bacteria, staph epidermidis triggers the production of potent immune cells called CD8 T cells—the "killer" cells responsible for battling severe infections or cancer.

The researchers showed that by inserting a tumor antigen into staph epidermidis, they could trick the mouse's immune system into producing CD8 T cells targeting the chosen antigen. These cells traveled throughout the mice and rapidly proliferated when they encountered a matching tumor, drastically slowing tumour growth or extinguishing the tumours altogether.

Even when melanoma had metastasized to the lungs, treatment with the bacteria drastically shrank the size of tumors or eliminated them, significantly improving survival times for the mice. 

When the researchers combined the new treatment with a second type of immunotherapy designed to bolster T cell activity, called "checkpoint blockade," the benefit was even more pronounced: 15 out of 16 established tumors disappeared. When the mice were re-injected with more cancer cells 30 days later, tumors still didn't grow.

"This appears to be evidence of a memory immune response, similar to what happens after a vaccine."

The researchers now think that the host organism produces these T cells to essentially vaccinate itself against the colonists, protecting against inevitable cuts and scrapes that could allow bacteria to breach the skin barrier.

In these experiments, they have basically tricked the host into thinking that the tumour is bacterially infected and then the host is going after that tumour aggressively.

The researchers have discovered that the host is vaccinating itself, day in and day out, against organisms that live at barrier surfaces. If they can direct even a bit of this immune attention toward specific cancers—or potentially infectious diseases—they will have a very effective, low-cost therapy that can simply be applied to the skin.

Will this therapy work in human beings? This has to be tested now.

 Y. Erin Chen et al, Engineered skin bacteria induce antitumor T cell responses against melanoma, Science (2023). DOI: 10.1126/science.abp9563

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 1:28pm

Bladder ‘Memory’ Influences Urinary Tract Infection Recurrence in Mice

Urinary tract infections leave permanent epigenetic marks in the mouse bladder epithelium, reprogramming its response to subsequent infections, a study finds.

One of the main challenges for treating urinary tract infections is their high recurrence, especially in women. The underlying mechanisms of this high recurrence rate are not well understood, but having suffered from a previous UTI is a significant risk factor. A study in mice published April 10 in Nature Microbiology proposes that this may be partially explained because an initial urinary infection with Escherichia coli—the culprit of most UTI cases—modifies the host’s epithelial epigenome in such a way that it alters the morphology of the bladder in the long term, influencing the response to future infections by the same bacteria.

When people think about how our body fights pathogens, they focus on the immune system. However, this work shows “clear evidence that changes that occur to epithelial cells . . . have long-term consequences for how we react to infections". 

Some of the researchers behind the new study had already reported in 2016 that mice infected with an initial E. coli UTI resulted in either spontaneous resolution or a chronic cystitis, respectively reducing or increasing susceptibility to future infections. The researchers found then that, in each scenario, the E. coli UTI had differentially modified the bladder epithelium in terms of architecture, morphology, and molecular signatures. 

Translating these findings to humans—for instance, to treat recurrent UTIs—is still a distant goal, all sources agree. A lot of other technologies would need to be in place and we need a “better understanding of how you can manipulate the epigenome in a very directed way” in order to develop such therapies.

https://www.nature.com/articles/s41564-023-01346-6

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:36pm

A more than 10% decrease in waist circumference was associated with a 2.14-fold higher risk of all-cause mortality for men and a 34% higher risk of all-cause mortality for women.

There was no significant association between weight gain and increases in waist circumference and all-cause mortality.

The researchers state it is likely that weight loss is an early indicator of the presence of various life-shortening diseases. While weight loss may precede a cancer diagnosis, the study revealed that weight loss also precedes increased mortality from all causes, including deaths from cardiovascular disease, trauma, dementia, Parkinson's disease, and other less common causes.

The weight loss was primarily associated with reduced appetite, leading to reduced food intake. The paper describes appetite as a complex process governed by both the central nervous system and various circulating hormones, any of which might be disrupted ahead of more pronounced disease presentation.

The researchers conclude that physicians and their patients should be aware of the significant association between mortality and elder weight loss.

 Sultana Monira Hussain et al, Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults, JAMA Network Open (2023). DOI: 10.1001/jamanetworkopen.2023.7482

Part 2

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Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:35pm

Significant association found between all-cause mortality and weight loss in the elderly

An international team of researchers  has examined the associations of changes in body weight and waist circumference with all-cause and cause-specific mortality. In the paper, "Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults," published in JAMA Network Open, the team highlights the startling connection between weight loss and increased risk of death.

The researchers used data from a past study looking at aspirin use in 16,703 Australian participants aged 70 and above. They focused on weight recordings, waist circumference measurements and mortality information over time. The cohort consisted of 7,510 men and 9,193 women. All the individuals were without evident cardiovascular disease, dementia, physical disability, or life-limiting chronic illnesses.

Both body weight and waist circumference changes were categorized as change within 5% (stable), decrease by 5% to 10%, decrease by more than 10%, increase by 5% to 10%, and increase by more than 10%.

Using men with stable weight as a control, men with a 5% to 10% weight loss had a 33% higher risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 289% higher risk.

Compared to women with stable weight, women with a 5% to 10% weight loss had a 26% higher risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 114% higher risk.

Part 1

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:29pm

It appears that there is something about movement that keeps Hsp47 at an appropriate level. It could be that the mechanical forces involved in moving around actually have an impact on gene expression, dramatically increasing the amount of Hsp47 that circulates in the blood.
Now we know that Hsp47 is so important, we can begin to look for new or existing medicines that might be able to inhibit the function of this protein in blood clotting and protect mobile people who are prone to clots.

Manuela Thienel et al, Immobility-associated thromboprotection is conserved across mammalian species from bear to human, Science (2023). DOI: 10.1126/science.abo5044. www.science.org/doi/10.1126/science.abo5044

part 2

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:27pm

Preventing dangerous blood clots

Hibernating bears, paralyzed humans, and pigs kept in small enclosures all avoid dangerous blood clots, despite being immobile for extremely long periods. Recent research shows that reduction of a key protein prevents the formation of blood clots in all three mammal species when they are still for days, weeks, months, or even years at a time. The study is published recently (April 13, 2023), in Science.

If you've ever taken a long haul flight, you might have taken advice to prevent a dangerous blood clot—deep vein thrombosis—from forming in one or both of your legs, while you sit still for multiple hours. Perhaps you set a reminder to get up and walk around, and you wore compression socks to keep the blood from pooling in your legs.

Most people won't experience a clot if they take care on a flight, but there is a serious risk for some people who are pre-disposed to blood clots due to genetic factors.

The discovery that a protein known as Hsp47 is dramatically reduced—by 55 times—when someone is immobilized for a much longer period than a flight, could lead to new medicines to help those who have inherited blood clotting disorders that put them at risk for pulmonary embolism, heart attack, and stroke.

It seems counterintuitive that people who have severe paralysis don't appear to be at higher risk of blood clots. This tells us that something interesting is happening. And it turns out that reducing levels of Hsp47 plays a key role in preventing clots, not just in humans, but in other mammals, including bears and pigs.

"When we see something like this in multiple species, that reinforces its importance. Having Hsp47 must have been an evolutionary advantage."

Hsp47 is released by platelets—the sticky blood cells that trigger blood clotting. Usually clotting is an important response to an injury, to prevent blood loss, and Hsp47 is one of the necessary ingredients to enable platelets to do their job. Examining the role of Hsp47 in clotting function the team found that when released into the blood of bears, mice and humans that it promoted conditions that may give rise to deep vein thrombosis.

Part 1

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:00pm

The team's experiments yielded interesting results, identifying a new neuronal and molecular mechanism through which the brain re-gains consciousness after general anesthesia. They also showed that the ventral posteromedial nucleus (VPN), part of the thalamus, is a key brain region associated with re-emergence of consciousness.

Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4. Phosphorylation of KCC2 at Thr1007 promotes interaction between KCC2 and Fbxl4. KCC2 downregulation leads to γ-aminobutyric acid type A receptor-mediated disinhibition, enabling accelerated recovery of VPM neuron excitability and emergence of consciousness from anesthetic inhibition. This pathway to recovery is an active process and occurs independent of anesthetic choice.

Overall, the recent work by this team of researchers shows that the degradation of KCC2 transporter neurons located in the VPM, through the means of ubiquitin, a compound in living cells that contributes to the degradation of superfluous or faulty proteins in the brain, is a key step in the mice's emergence of consciousness after general anesthesia. This key finding could potentially inform the development of strategies to wake patients who are in a  vegetative state or minimally conscious state, which is a long-standing medical challenge.

Jiang-Jian Hu et al, Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus, Nature Neuroscience (2023). DOI: 10.1038/s41593-023-01290-y

Part 2

Comment by Dr. Krishna Kumari Challa on April 14, 2023 at 12:00pm

Study unveils neural processes underpinning the re-emergence of consciousness after anesthesia

Before undergoing surgeries and other invasive medical procedures, patients typically undergo anesthesia. Anesthesia consists in giving patients a class of drugs (i.e., anesthetics) that cause them to lose feeling in specific areas of the body (i.e., local anesthesia) or fully lose awareness during a procedure (i.e., general anesthesia). These anesthetics can be administered to patients via injection, inhalation, skin-numbing lotions, and other means.

In the past, doctors and medical researchers viewed general anesthesia as a passive process that could not be influenced or interrupted once anesthetic drugs were administered. More recently, however, studies showed that it is in fact an active brain process that can be experimentally controlled and acted on. A research team  recently carried out a study investigating the processes underpinning brain states while under general anesthesia and those associated with the subsequent re-emergence of awareness. Their findings, published in Nature Neuroscience, highlight possible strategies that could help anesthesiologists to extend and deepen or shorten periods of anesthesia.

In the experiments with mice , when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K⁺/Cl⁻ cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness.

To examine the neural processes linked to the re-emergence of consciousness after anesthesia, the researchers carried out a series of experiments on adult mice. They gave the mice one of three different anesthetic drugs (i.e., ketamine, propofol and pentobarbital) and then looked at the molecular mechanisms that emerged while they were re-gaining awareness.

To assess the mice's levels of consciousness they measured the so-called loss of righting reflex (LORR), a point in which animals no longer act on their instinct to avoid laying with their stomach facing up. In addition, they observed the animals' behavioral responses to external stimuli.

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