Gangrene, hearing loss suggest Delta variant more severe, say doctors

Delta, the coronavirus variant that triggered India's devastating second wave of the pandemic, is definitely highly contagious, according to experts and multiple studies. Now, doctors in India draw from their experience that it is also possibly more severe than most other known variants. Blood clots and hearing impairment are just two of the many severe conditions Indian doctors have linked with the new strain.

: What is the Delta variant of COVID-19?

Delta or B.1.617.2 variant was first detected in India last year and has spread to 60 countries over the past six months. A recent study by an Indian government panel stated the variant was the "primary cause" behind India's deadly second wave and is 50% more infectious than a strain first identified in the UK. It is now sparking outbreaks in numerous other countries.

Conditions: Several patients developed blood clots, leading to gangrene

Some coronavirus patients in India developed micro thrombi - small but severe blood clots that caused the affected tissue to die and develop gangrene, said Ganesh Manudhane, a Mumbai-based cardiologist, according to Bloomberg. Manudhane treated eight such patients at the Seven Hills Hospital during the past two months, as compared to three or four cases throughout last year.

Fact: What is gangrene?

Gangrene is the death of body tissue due to a lack of blood flow or a bacterial infection. Signs and symptoms of the condition may include discoloration of the skin, swelling, and severe pain, among others. Treatments typically include surgery, antibiotics, and hyperbaric oxygen therapy.

Conditions: Hearing impairment, tonsillitis also seen in several patients

Meanwhile, some COVID-19 patients sought treatment for hearing loss, swelling around the neck, and severe tonsillitis, said Dr. Hetal Marfatia, an ENT surgeon at Mumbai's King Edward Memorial Hospital. "Every person is showing different symptoms" during the current wave, she was quoted as saying. Cases of Mucormycosis or "Black fungus" - a rare fungal infection - also reached record highs in India this year.

Vaccinations: How does it affect the course of vaccinations?

Emerging scientific evidence indicates that Delta and other variants may be able to evade antibodies generated from vaccination. Experts hence want pharmaceutical companies to tweak the formula for existing vaccines or develop new ones. "New vaccines have to prepared with new variants in mind," said Dr. Abdul Ghafur. "We can't get ahead of the virus, but at least we can keep up with it."

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Discovery about how cancer cells evade immune defences inspires new treatment approach

A recent discovery about the process of evasion by cancer cells has led researchers towards a new approach to treat the disease.

Cancer cells are known for spreading genetic chaos. As cancer cells divide, DNA segments and even whole chromosomes can be duplicated, mutated, or lost altogether. This is called chromosomal instability, and scientists at Memorial Sloan Kettering have learned that it is associated with cancer's aggressiveness.

The more unstable chromosomes are, the more likely that bits of DNA from these chromosomes will end up where they don't belong: outside of a cell's central nucleus and floating in the cytoplasm.

Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumour and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall.

"The elephant in the room is that we didn't really understand how cancer cells were able to survive and thrive in this inflammatory environment," said Samuel Bakhoum, a physician-scientist at MSK and a member of the Human Oncology and Pathogenesis Program.

According to the new study from Dr. Bakhoum's lab in the journal Cancer Discovery, the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighbouring immune cells.

The findings help to explain why some tumours do not respond to immunotherapy, and -- equally important -- suggest ways to sensitize them to immunotherapy.

Detecting Dangerous DNA

The warning system Dr. Bakhoum studies is called cGAS-STING. When DNA from a virus (or an unstable cancer chromosome) lands in a cell's cytoplasm, cGAS binds to it, forming a compound molecule called cGAMP, which serves as a warning signal. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral invader.

In addition, much of the cGAMP also travel outside the cell where it serves as a warning signal to neighbouring immune cells. It activates their STING pathway and unleashes an immune attack against the virally infected cell.

Previous work from the Bakhoum lab had shown that cGAS-STING signalling inside of cancer cells causes them to adopt features of immune cells -- in particular, the capacity to crawl and migrate -- which aids their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process.

The new research shows how the cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. A scissor-like protein shreds the signals, providing a second way the cells can thwart the threat of immune destruction.

The scissor-like protein that coats cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 chops it up and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also quells inflammation.

Through a battery of experiments conducted in mouse models of breast, lung, and colorectal cancers, Dr. Bakhoum and his colleagues showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning it on suppresses immune responses and increases metastasis; turning it off enables immune responses and reduces metastasis.

The scientists also looked at ENPP1 in samples of human cancers. ENPP1 expression correlated with both increased metastasis and resistance to immunotherapy.

Empowering Immunotherapy

From a treatment perspective, perhaps the most notable finding of the study is that flipping the ENPP1 switch off could increase the sensitivity of several different cancer types to immunotherapy drugs called checkpoint inhibitors. The researchers showed that this approach was effective in mouse models of cancer.

Several companies -- including one that Dr. Bakhoum and colleagues founded -- are now developing drugs to inhibit ENPP1 on cancer cells.

Dr. Bakhoum says it's fortunate that ENPP1 is located on the surface of cancer cells since this makes it an easier target for drugs designed to block it.

It's also relatively specific. Since most other tissues in a healthy individual are not inflamed, drugs targeting ENPP1 primarily affect cancer.

Finally, targeting ENPP1 undercuts cancer in two separate ways: "You're simultaneously increasing cGAMP levels outside the cancer cells, which activates STING in neighbouring immune cells, while you're also preventing the production of the immune-suppressive adenosine. So, you're hitting two birds with one stone," Dr. Bakhoum explains.

The pace of the research has been incredibly fast, he says. "One of the things I would be really proud of is if this research ends up helping patients soon, given that we only just started this work in 2018."

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Cancer Cells Can Go Into Bear-Like Hibernation to Evade Chemotherapy

Cancer cells are able to hibernate like "bears in winter" when a threat like chemotherapy treatment attacks them, according to new research – apparently adopting the tactic used by some animals (though long since lost in humans) to survive through periods when resources are scarce.

Knowing exactly how cancers evade and stand up to drug treatments is an important part of working towards defeating them for good, which is why understanding this hibernation behaviour could play a crucial role in future research. Cancers can often return after staying dormant or apparently disappearing for several years following treatment.

Preclinical research on human colorectal cancer cells revealed that they were able to slow down into a low-maintenance, "drug-tolerant persister" (DTP) state, which would help explain some failures in therapy and tumour relapses.

"The tumour is acting like a whole organism, able to go into a slow-dividing state, conserving energy to help it survive," says a researcher, from the Princess Margaret Cancer Centre in Canada.

"There are examples of animals entering into a reversible and slow-dividing state to withstand harsh environments. It appears that cancer cells have craftily co-opted this same state for their survival benefit."

Collecting human colorectal cancer cells in a petri dish and exposing the cells to chemotherapy, the researchers observed the colorectal cancer cells go into the same hibernation state, in a coordinated way, when chemotherapy drugs were present. The cells stopped expanding, which means they required very little in the way of nutrients to carry on living.

These observations also "fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs", which suggests these survival strategies could be seen in all cancer cells.

Researchers also used xenografts of colorectal cancer cells on different sets of mice. Once the mice developed tumours of certain sizes, researchers treated the mice with standard chemotherapy regimens. Scientists observed negligible tumour growth in mice receiving treatments during an eight-week period. When treatment stopped, tumour growth began again.

Cancer cells taken from the tumours following a regrowth period were then grafted into different mice and treated again. The regrown cells remained sensitive to treatments, and their growth stopped and started in the same fashion, findings consistent with cancer cells entering a DTP state.

This DTP state closely resembles a hibernation-like state called embryonic dispause that mice embryos fall back on as a sort of emergency survival mode. Embryonic diapause enables many animals, including mice, to effectively put embryonic development on pause until environmental conditions are more favourable.

Here, cancer cells have been found doing a similar trick. Another link between the DTP state and embryonic diapause is their reliance on a biological mechanism called autophagy, in which cells essentially eat themselves to find the sustenance they need. Autophagy happens naturally in the body as a way of clearing out waste, but in this case cancers are using it to stay alive.

"We never actually knew that cancer cells were like hibernating bears,"  says an oncologist, from the Princess Margaret Cancer Centre. "This study also tells us how to target these sleeping bears so they don't hibernate and wake up to come back later, unexpectedly."

"I think this will turn out to be an important cause of drug resistance, and will explain something we did not have a good understanding of previously."

By targeting and inhibiting the autophagy process, the researchers were able to break the hibernation (or DTP) state and kill the cancer cells off for good with chemotherapy. This could be one approach for tackling cancer tumours that are resistant to conventional treatments in the future.

Scientists already know about several other ways that cancers can hide away in the body, so this new study adds to a growing collection of evidence about how to take on the cancer cells that are most resistant to current drugs and approaches.

"This gives us a unique therapeutic opportunity," says the researcher. "We need to target cancer cells while they are in this slow-cycling, vulnerable state before they acquire the genetic mutations that drive drug-resistance.

"It is a new way to think about resistance to chemotherapy and how to overcome it."

The research has been published in Cell. 

 

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