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Why aren’t cancer drugs better? The targets might be wrong

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Twenty years ago, the fight against cancer seemed as if it were about to take a dramatic turn. Traditionally, cancer doctors fought the disease with crude weapons, often simply poisoning fast-growing cells whether they were cancerous or healthy. But then a team of researchers hit on a new strategy: drugs targeting proteins produced by cancer cells that seemed necessary to their survival.


Once such drug, Gleevec, worked spectacularly in patients with chronic myeloid leukemia. But the clinical trials that followed mostly have produced disappointments. According to a study published earlier this year, only three per cent of cancer drugs tested in clinical trials between 2000 and 2015 have been approved to treat patients.


A study published on Wednesday in the journal Science Translational Medicine offers one reason for the failure: Scientists are going after the wrong targets.


“I hope people will really wake up to the need to be much more rigorous,” said William Kaelin, a professor of medicine at Harvard University who was not involved in the new study.


Jason Sheltzer, a cancer biologist at Cold Spring Harbor Laboratory in New York State, and his colleagues made the discovery as they were trying to come up with a new test for breast cancer.


In certain forms of the disease, cancer cells make high levels of a protein called MELK. Extremely high levels can mean poor odds of survival for the patient.


Earlier studies had indicated that MELK was essential to the spread of the cancer; indeed, researchers were already testing a drug for breast cancer that targets the MELK protein.


Two undergraduates in Sheltzer’s lab, Ann Lin and Christopher J Giuliano, used Crispr, the revolutionary DNA-editing tool, to snip out the gene for MELK in cancer cells. The cells should have stopped growing, but to the surprise of the scientists, they did not.


“The cancer cells did not care whatsoever,” Sheltzer said.


It was odd that the cells didn’t need a supposedly essential gene. Odder still was what happened when the scientists exposed the cells to the MELK-targeting drug. It stopped the cancer cells anyway — even though they lacked the gene that the drug targeted.


Seltzer wondered if he simply had stumbled across a peculiar case. So he widened his research, running the same experiment with 10 other drugs. All were protein-targeting medications currently in clinical trials.


With each drug, the scientists got the same results. Every supposedly essential protein turned out to be expendable in the cancer cells, yet all these cells stopped growing when the scientists applied the drug.


This sort of mistake may lead to failures in clinical trials, Sheltzer said. “When you design a clinical trial, you want to pick out the patients who are most likely to respond,” he said. “That trial may fail because you’re picking the wrong people to give that drug to.”

Why aren't cancer drugs better? The targets might be wrong


The mistakes Sheltzer has uncovered may have come about because the scientists who were hunting for drug targets used unreliable tools.


“A lot of the drug targets that are in clinical trials today were discovered with the best technology from five or 10 years ago,” he said.


That technology, known as RNAi, seemed at the time like it could zero in on cancer targets with high precision. “Everyone thought finally we had the genie in the lamp,” Kaelin said.


RNAi allows scientists to craft a molecule to block cells from making a particular protein. If blocking a protein’s production stopped cancer cells from growing, scientists looked for a drug that also targeted that protein.


But some critics questioned whether RNAi was all that precise. The technique may block not just a target protein, but certain others as well. Sheltzer tested this possibility with one of the drugs in his experiment, OTS964.


The researchers gave the drug to colonies of cancer cells with the target protein removed. Most still died — but a few did not.


The researchers sequenced the DNA of the surviving cells. It turned out they all had mutations in the same gene, which encodes a protein called CDK11B.


No one had any idea that the protein was essential to the survival of the cancer cells. But Sheltzer’s experiment suggested it was: The mutant cells survived because they had an altered form of the protein, with which the drug could not interfere.


When the researchers cut out the CDK11B gene, the cancer cells died — further evidence that the protein was necessary to the cancer cell.


Traver Hart, a cancer biologist at M D Anderson Cancer Center in Houston who was not involved in the new study, said that scientists need to take another look at cancer drugs now undergoing testing.


“There clearly exists a legacy of RNAi-guided bad targets that needs to be purged from the drug development pipeline,” he said.


That doesn’t mean that targeting essential proteins is pointless. Scientists just need to make sure they’re going after the right ones.


Searching for mutations in the genes of cancer cells may be one way to avoid false positives. Instead of relying on hunches about what is a good target, cancer cells might speak for themselves.


“There is probably a whole universe of unexplored drug targets in the cancer cell,” Sheltzer said.





© 2019 The New York Times


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Health

Has the time come to quit vaping forever?

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Allegations of illegal marketing tactics. More than 500 cases of severe lung illness in 38 states. Eight deaths. A proposed federal ban of most flavoured e-cigarettes, and new efforts in many states to counter an epidemic of youth vaping.


There’s been an avalanche of vaping news this month, which leaves many users facing a crucial question: Is it time to quit? Here’s a look at the issues.


First, how big is vaping?


E-cigarettes swept onto the market about a decade ago. They’re now a $2.6 billion industry in the United States, and roughly 20,000 vape and smoke shops have sprung up across the country in the past few years. There is also a thriving black market for vape pods. A survey last year found that 10.8 million American adults used e-cigarettes — and that more than half were also smoking cigarettes.


E-cigarettes have become especially popular among teenagers. Preliminary results from an annual survey sponsored by the National Institute on Drug Abuse and released on Wednesday found that one in four 12th graders said they had vaped in the previous month, a sharp rise from the previous year.


Young people are especially susceptible to nicotine addiction and may be more likely to take up regular cigarettes once they are hooked.


Is vaping safer than smoking?


There was an idea for a while that e-cigarettes, because they don’t generate smoke and tar, were safer than smoking cigarettes, or at least that they could help a smoker shift to a less dangerous alternative. But the mysterious spate of illnesses thrust concerns about vaping’s health effects into the spotlight. Many of the people who got sick were vaping THC, and the authorities are investigating what else black-market pods contain.


Albert Rizzo, chief medical officer for the American Lung Association, noted that the organisation’s opposition to vaping predated the outbreak.


He disputed the perception that e-cigarettes are a safer alternative, and pointed to the lack of information about what chemicals they contain and the paucity of research about the effects of vaping.


“To say that something is safer than a product like cigarettes that kills seven million people in the world each year because of tobacco-related disease, and half a million people in this country, is not saying a lot,” Rizzo said.


“We have no evidence of whether it’s safe at all. There’s just no scientific basis for that.”


A new generation of young people addicted


The rise of vaping comes after at least two decades of great success in decreasing smoking rates across the country, and has health experts concerned that those gains could be reversed.


Most e-cigarettes contain nicotine, which is highly addictive and especially harmful to young people, whose brains are still developing. (The human brain is still developing until you turn 25 or so.) Nicotine can harm the parts of the brain that handle memory, attention and learning.


It’s also illegal for minors to vape. (A growing number of states have even raised the vaping age to 21.) And using e-cigarettes may make teenagers more likely to smoke real cigarettes in the future. Rizzo noted that the vast majority of current smokers became addicted before they were 18.


Some people may not realise how much nicotine they’re ingesting as they puff away. A typical pod made by Juul can contain as much nicotine as a pack of cigarettes and is designed to last for about 200 puffs.


“We have a new generation of young people in high school and middle school that are now nicotine addicted,” Rizzo said. “We don’t know what the dangers of e-cigarettes are.”


What about THC?


While many people use e-cigarettes to inhale nicotine, some use it for THC, the high-inducing chemical found in marijuana. A large portion of the recent cases of lung illness were in patients who vaped THC.


The Food and Drug Administration said that a significant subset of samples of vaping fluid used by sick patients also contained a compound called vitamin E acetate, which has been a subject of further investigation. The FDA has warned people to avoid vaping THC.


A minority of the people who got sick said they had used e-cigarettes containing only nicotine — but there were also concerns that some young people were not being entirely forthcoming about their vaping habits.


Public health officials are warning people against vaping


Public health officials at the Centers for Disease Control and Prevention have recommended that people refrain from vaping as the agency investigates the illnesses. They stressed that young people, pregnant women and nonsmokers should never vape. They also cautioned people who do use e-cigarettes to monitor themselves for symptoms of lung illness, like coughing and chest pain.


An editorial in The New England Journal of Medicine this month stated bluntly that doctors should discourage people from vaping and reiterated that e-cigarettes should never be used by nonsmokers.


The acting commissioner of the FDA, Ned Sharpless, has said that the issue of tobacco control in the e-cigarette era keeps him up at night. The agency got authority over what it calls “electronic nicotine delivery systems” only in 2016, and is now working on new research and regulations.


In a statement, Sharpless noted the inherent paradox of e-cigarettes: While they were pitched as a way to get smokers to stop lighting up, they hooked a new generation that may end up smoking traditional cigarettes to get that fix.



The New York Times


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Superfoods for a thriving heart

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Heart ailments are the leading cause of mortality around the world. Moderating your salt intake is, perhaps, the most important thing one can do to protect the heart. Researchers have also found certain foods that can contribute in keeping the heart healthy. Here’s a list of the most commonly available ones.


Berries: Blueberries and strawberries contain anthocyanins, which can help reduce a person’s blood pressure.


Bananas: Bananas contain plenty of potassium, a mineral that plays a vital role in managing hypertension. Other potassium rich foods include avocado, cantaloupe and honeydew melon, halibut, mushrooms, sweet potatoes, tomatoes, tuna and beans.


Beets: Researchers suggest that high levels of inorganic nitrate in beets can help reduce blood pressure.


Dark chocolate: About 30 grams of chocolate that contains a minimum of 70 per cent cocoa can be had every day.


Kiwi: A daily serving of kiwi can reduce blood pressure in people with mildly elevated levels, according to results of one study. Kiwi are also rich in vitamin C, which may significantly improve blood pressure readings in people who consumed around 500 mg of the vitamin every day for about eight weeks.


Watermelon: The fruit contains an amino acid called citrulline, which can help manage high blood pressure.


Oats: They contain a type of fiber called beta-glucan, which can reduce blood cholesterol levels. Beta-glucan also lowers blood pressure according to some research.


Leafy green vegetables: They are rich in nitrates, which help manage blood pressure. Some research papers suggest that eating 1-2 servings of nitrate-rich vegetables every day can reduce hypertension for up to 24 hours.


Garlic: Eating garlic can increase a person’s nitric oxide levels. Garlic is a natural antibiotic and anti-fungal food. Its main active ingredient, allicin, is often responsible for associated health benefits.


Fermented foods: They are rich in probiotics — beneficial bacteria that play an important role in maintaining gut health.


Lentils: They are an excellent source of vegetarian protein and fiber.


Pomegranate: Drinking a cup of pomegranate juice daily for 28 days can lower high blood pressure.


Cinnamon: An analysis has showed that cinnamon decreased short-term systolic blood pressure by 5.39 mm Hg & diastolic blood pressure by 2.6mm Hg.


Mushroom: It’s consumption is associated with less plaque formation in the brain.


Fatty Fish: Like Salmon, Trout and sardines are rich source of Omega 3 fatty acids.


Green Tea: it is loaded with antioxidants that can prevent cell death and ageing by targeting free radicals.


Chia Seeds: It’s a plant alternate to fatty fish and has highest amount of Omega 3 fatty acids that reduce triglycerides, It’s also rich in Magnesium, calcium, Fiber, which are beneficial for the heart.


Avocados: Another superfood to lower bad cholesterol.


Walnuts and Almonds: Great source of fiber and micronutrients.


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India’s healthcare system might struggle to keep pace by 2030, says report

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Indian healthcare system will “struggle to keep pace” in 2030 when 140 million Indian households are expected to enter the middle-class, said a report by Bain & Company report on Tuesday.


The healthcare industry will face challenges due to a rapid increase in patient volume accompanied by pricing and margin pressures, said the India Life Sciences Report 2019, which was conducted among 325 doctors.



The report, done in collaboration with Confederation of Indian Industry (CII), said the demand from “developed rural” areas along with the increase in middle-class households will drive about two-times hike in healthcare consumption. PM Narendra Modi’s flagship scheme Ayushman Bharat, which was launched in September 2018 to provide 500,000 poor people annual health cover of Rs 500,000, is also likely to increase healthcare demand.


It said doctors will find it difficult to keep pace with disease and treatment protocol due to lack of high-quality care. Most doctors said the situation will be adverse as greater proportion of patients have chronic diseases compared with five years ago.


The use of disease management tools could result in $8.5 billion in additional drug sales by 2024, the report said, showcasing the unique opportunity that the boom in digital health presents for the life sciences industry.


Doctors are looking for multiple types of support to manage this complexity—with 85 per cent of then upgrading their own clinical skills.


According to the report, complex generics and biosimilars will be the key growth drivers, a shift away from the dominating commoditised generics. Generics prices have already seen 4 to 6 per cent deflation since 2017 and a growing buyer consolidation will continue to put further pressure on prices and margins.


While Ayushman Bharat has the potential to drive dramatic healthcare access, efforts must be made to have a quality lens on it as well, the report said, adding the industry must work with the government to deliver comprehensive and high-quality care through co-development of protocols and standard treatment.


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