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Comment by Dr. Krishna Kumari Challa on July 5, 2024 at 7:08am

The circuit has two genes, or switches. Switch one acts like a selection gene, allowing the researchers to turn drug resistance on and off, like a light switch. With switch one turned on, the genetically modified cells become temporarily resistant to a specific drug, in this case, to a non-small lung cancer drug.

When the tumor is treated with the drug, the native drug-sensitive cancer cells are killed off, leaving behind the cells modified to resist and a small population of native cancer cells that are drug-resistant. The modified cells eventually grow and crowd out the native resistant cells, preventing them from amplifying and evolving new resistance.
The resulting tumor predominantly contains genetically modified cells. When switch one is turned off, the cells become drug-sensitive again. Switch two is the therapeutic payload. It contains a suicide gene that enables the modified cells to manufacture a diffusible toxin that's capable of killing both modified and neighboring unmodified cells.

It not only kills the engineered cells, but it also kills the surrounding cells, namely the native resistant population.
That's critical. That's the population you want to get rid of so that the tumor doesn't grow back.
The team first simulated the tumor cell populations and used mathematical models to test the concept. Next, they cloned each switch, packaging them separately into viral vectors and testing their functionality individually in human cancer cell lines. They then coupled the two switches together into a single circuit and tested it again. When the circuit proved to work in vitro, the team repeated the experiments in mice.

However, the team didn't just want to know that the circuit worked; they wanted to know it could work in every way. They stress tested the system using complex genetic libraries of resistance variants to see if the gene drive could function robustly enough to counter all the genetic ways that resistance could occur in the cancer cell populations.
And it worked: Just a handful of engineered cells can take over the cancer cell population and eradicate high levels of genetic heterogeneity. It's one of the biggest strengths of the paper, conceptually and experimentally.
The beauty is that they're able to target the cancer cells without knowing what they are, without waiting for them to grow out or resistance to develop because at that point it's too late.
The researchers are currently working on how to translate this genetic circuit so that it can be delivered safely and selectively into growing tumors and eventually metastatic disease.

 Programming tumor evolution with selection gene drives to proactively combat drug resistance, Nature Biotechnology (2024). DOI: 10.1038/s41587-024-02271-7. www.nature.com/articles/s41587-024-02271-7

Part 2

Comment by Dr. Krishna Kumari Challa on July 5, 2024 at 7:02am

Re-engineering cancerous tumors to self-destruct and kill drug-resistant cells

Treating cancer can sometimes feel like a game of Whac-A-Mole. The disease can become resistant to treatment, and clinicians never know when, where and what resistance might emerge, leaving them one step behind. But a team of researchers has found a way to reprogram disease evolution and design tumors that are easier to treat.

They created a modular genetic circuit that turns cancer cells into a "Trojan horse," causing them to self-destruct and kill nearby drug-resistant cancer cells. Tested in human cell lines and in mice as proof of concept, the circuit outsmarted a wide range of resistance.

The findings were published today, July 4, in the journal Nature Biotechnology. The researchers also filed a provisional application to patent the technology described in the paper.

Selection gene drives are a powerful new paradigm for evolution-guided anticancer therapy.The idea that we can use a tumor's inevitability of evolution against it is an excellent strategy.

Newer personalized cancer medicines often fail, not because the therapeutics aren't good, but because of cancer's inherent diversity and heterogeneity. Even if a frontline therapy is effective, resistance eventually develops and the medication stops working, allowing the cancer to return.

Clinicians then find themselves back at square one, repeating the process with a new drug until resistance emerges again. The cycle escalates with each new treatment until no further options are available.

You are dealing with an unpredictable opponent. You don't know what is going to be the best drug to treat the tumor. You're always on your back foot, unprepared.

The researchers wondered if, instead, they could get one step ahead. Could they potentially eliminate resistance mechanisms before the cancer cells have a chance to evolve and pop up unexpectedly? Could they force a specific "mole" to pop out on the board, one that they prefer and are prepared to fight?
What started as a thought experiment is proving to work. The team created a modular circuit, or dual-switch selection gene drive, to introduce into non-small lung cancer cells with an EGFR gene mutation. This mutation is a biomarker that existing drugs on the market can target.
Part1

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 11:05am

Some animals can have babies without a sexual partner

Science explains how

A boa constrictor in the U.K. gave birth to 14 babies—without a mate.

 The result of a secret rendezvous? Probably not. Females of species have the ability to reproduce asexually, without sperm from a male. The process is called parthenogenesis, from the Greek words for "virgin" and "birth."

Some plants and insects can do it, as well as some amphibians, reptiles, birds and fish. A stingray named Charlotte that was thought to have become pregnant by this method died this week at an aquarium in North Carolina, though she never delivered and it is unclear if she was ever pregnant.

Some wasps, crustaceans and lizards reproduce only through parthenogenesis. But in other species it's rare and usually only observed in captivity. Scientists have a good idea how it happens, though they aren't clear why it happens.

A female's egg fuses with another cell, often a cell leftover from a process that allows the female to create the egg. That cell, known as a polar body, gives the egg the genetic information it would normally get from sperm. The cell starts dividing and that leads to the creation of an embryo.

The snake, a 6-foot, 13-year-old Brazilian Rainbow Boa named Ronaldo, gave birth last week after having no contact with any other snakes for at least nine years, according to the City of Portsmouth College, which kept the snake.

AP

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 10:17am

Human crying stresses out dogs more than pigs

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 9:51am

PI3K gamma promotes the movement of myeloid cells into cancerous tissues, as found in the team's work with cancer twelve years ago. In the current work, they show that PI3K gamma also helps move myeloid cells into tissues infected with SARS-CoV-2.

That led them to reason that a cancer drug that inhibits PI3K gamma, called eganelisib, might be effective in suppressing inflammation in COVID-19 by suppressing PI3K gamma's ability to move myeloid cells into infected tissue.

Using a combination of bulk RNA sequencing and bioinformatics, the scientists analyzed tissues from humans and mice to see how SARS-CoV-2 changed the cellular and molecular makeup of infected tissues. They then treated the tissue with eganelisib to see if suppressing PI3K gamma made a difference.
The researchers sequenced COVID-19 patient lung tissue and showed that when patients have COVID-19, a lot of their lung cells are killed and there's a huge increase in myeloid cells. They also found the same thing in infected mice.

When they treated with the drug, they showed that eganelisib prevents entry of myeloid cells into tissue so they can't do all that damage. Further studies will determine if it can actually reverse damage. The team also had the same results in mice infected with MRSA.

Ryan Shepard et al, PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adi6887. www.science.org/doi/10.1126/scitranslmed.adi6887

Part 2

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 9:49am

Fighting COVID-19 with a cancer drug: A new approach to preventing irreversible organ damage in infectious diseases

Twelve years ago, cancer researchers identified a molecule that helps cancer cells survive by shuttling damaging inflammatory cells into tumor tissue. In new research, they show that the same molecule does the same thing in lung tissue infected with COVID-19—and that the molecule can be suppressed with a repurposed cancer drug.

The work, published in Science Translational Medicine, represents a new approach to preventing irreversible organ damage in infectious diseases like COVID-19 and methicillin-resistant Staphylococcus aureus (MRSA).

The two key players in this scenario are inflammatory cells called myeloid cells, and an enzyme called PI3K gamma (phosphatidylinositol 3,4,5-kinase gamma). Myeloid cells belong to our innate immune system—the immunity we're born with before we're exposed to pathogens in the environment—and work very quickly to kill deadly agents like SARS-CoV-2, the virus that causes COVID-19.

This work shows that drugs that can prevent the recruitment of damaging myeloid cells into tissues that are infected with severe agents like COVID-19 or MRSA have a significant benefit in preserving tissue function if given early enough in an infection.

Most other COVID-19 drugs target the virus, either preventing infection in the first place or preventing the virus from making more of itself after infection. The current approach targets the host, keeping the immune system from overreacting or fibers building up in the lungs.

Myeloid cells protect us, but they can also do a lot of damage. 

If you have a little infection, myeloid cells come in, kill bacteria, release alerts that recruit even more potent killer immune cells, and produce substances that can heal the damage. But if you get an infection that's too strong, you get overproduction of these alert signals, and the substances they release to kill these infective agents can also kill yourself. That's what happens in COVID-19.

Part 1

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 9:41am

Scientists discover PVP-037, a potent vaccine adjuvant

Many vaccines are only partially effective, have waning efficacy, or do not work well in the very young or the very old. For several years researchers have tried improving vaccines by adding compounds known as adjuvants to boost vaccine recipients' immune responses.

Now they've identified a new and promising adjuvant of their own, dubbed PVP-037. The finding is published in Science Advances.

In principle, this compound can be added to any vaccine to enhance its action.

 Adjuvants are like rocket fuel for the immune system. PVP-037 is one of the most active adjuvants scientists 've discovered, and they think it induces a greater, more durable, and broader immune response to vaccines.

The researchers began by screening more than 200,000 small molecules from a Harvard Medical School library in human immune cells—specifically, in primary peripheral blood mononuclear cells, obtained from donors and cultured in their own plasma using a method developed within the Precision Vaccines Program. This yielded about 25 confirmed hits, with PVP-037 being the most active.

PVP-037 belongs to a family of molecules called imidazopyrimidines, which the study found to be active immunomodulators. PVP-037 and its analogs target the innate immune system, stimulating the pattern-recognition receptors TLR7 and TLR8 on antigen-presenting cells such as monocytes and dendritic cells.

An optimized version of PVP-037 demonstrated broad innate immune activation in the donor immune cells, inducing NF-κB and production of TNF and other cytokines, signaling molecules that rally a wider immune response. Notably, PVP-037 did not provoke such a response in cultured cell lines. In live mice, it enhanced antibody responses against influenza and SARS-CoV-2 vaccine proteins.

In addition to inducing robust immune activity, the compound is stable, easy to work with, and lends itself to chemical optimization for medical use. It can be formulated in most standardly-used drug delivery systems, such as oil-in-water emulsions.

 Dheeraj Soni et al, From Hit to Vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation, Science Advances (2024). DOI: 10.1126/sciadv.adg3747. www.science.org/doi/10.1126/sciadv.adg3747

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 9:27am

While some factors that favor scratching—such as the cat's personality or the presence of children—cannot be changed, others can, the researchers said. Placing scratch posts in areas the cat frequently passes or near to their preferred resting spot, or the use of pheromones, for example, can lessen cats' scratching on furniture.

Providing safe hiding places, elevated observation spots, and ample play opportunities can also help alleviate stress and engage the cat in more constructive activities.

The key is to establish multiple short play sessions that mimic successful hunting scenarios. These play sessions are more likely to sustain cats' interest and reduce stress, which ultimately can reduce excessive scratching on furniture. They can also foster the bond between cats and their caretakers, the researchers say.

Understanding the underlying emotional motivations of scratching behavior, such as frustration, which seem to be linked to personality traits and environmental factors, allows caregivers to address these issues directly.

Evaluating Undesired Scratching in Domestic Cats: A Multifactorial Approach to Understand Risk Factors, Frontiers in Veterinary Science (2024). DOI: 10.3389/fvets.2024.1403068

Part 2

Comment by Dr. Krishna Kumari Challa on July 4, 2024 at 9:25am

Strategies that could stop cats from scratching your furniture, according to science

Many cat owners are familiar with torn cushions, carpets, and couches. The feline instinct to scratch is innate, but is often perceived as a behavioral problem by cat owners, and sometimes leads to interventions that are not cat-friendly.

Now, an international team of researchers has investigated which factors influence undesired scratching behavior in domestic cats. The team has published its findings in Frontiers in Veterinary Science.

Scientists found that  certain factors—such as the presence of children at home, personality traits of cats, and their activity levels—significantly impact the extent of scratching behaviour.

The researchers' results showed that there are several factors that influence cats' scratching behaviour. They saw a clear link between certain environmental and behavioural factors and increased scratching behaviour in cats.

Specifically, the presence of children in the home as well as high levels of play and nocturnal activity significantly contribute to increased scratching. Cats described as aggressive or disruptive also exhibited higher levels of scratching.

Stress, the researchers said, was found to be a leading reason for unwanted scratching. For example, the presence of children, particularly while they are small, might amplify stress and be one of several causes that can make felines stress-scratch. The link between increased scratching and children in the home, however, is not fully understood and further study is needed. Another factor that could also be connected to stress is playfulness. When cats play for a long time, their stress levels can rise because of the uninterrupted stimulation.

Part 1

Comment by Dr. Krishna Kumari Challa on July 3, 2024 at 1:11pm

In the past, some other observational studies have also linked artificial light at night to insulin resistance, but these experiments did not measure indoor, artificial light sources nearly as closely or for as long.

Emerging evidence in animals and humans suggests exposure to artificial light can disrupt circadian rhythms, leading to reduced glucose tolerance, altered insulin secretion, and weight gain – all of which are tied to an increased risk of metabolic disorders like type 2 diabetes.

One major limitation of the study is that researchers were not able to take into account meal times, which can have an impact on both circadian rhythms and glucose tolerance. Furthermore, some socioeconomic factors, like a person's housing situation, were accounted for at a regional, not an individual level, and only older adults were considered.

There's also the fact that individual bodies respond very differently to light, with some studies suggesting the intensity of light needed to suppress the production of melatonin, which helps regulate our circadian rhythm, can range from 6 to 350 lux.
Nevertheless, previous experiments suggest that when melatonin is disrupted and the circadian rhythm is thrown out of whack, it can lead to the pancreas secreting less insulin. This could be a contributing factor to the development of diabetes.

Far more rigorous studies are needed before scientists can truly understand how light at night impacts the circadian rhythm and what that may do, in turn, to the health of the body's metabolism.

Some studies suggest that even a weekend of camping without artificial light can help reset a person's circadian rhythm. Perhaps that's just what the doctor should order.

https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(24)00110-8/fulltext

Part 2

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