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Gene editing can help treat congenital disease before birth Updated Oct 09, 2018 | 20:02 IST | IANSPrenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. Representational image Photo Credit: ThinkstockRepresentational Image New York: In a first, a team of scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory mice, offering the potential to treat human congenital diseases before birth. The study led by research from Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania used both CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools and reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1). Advertising Advertising HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders. "Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy, " said William H. Peranteau, a paediatric and foetal surgeon at CHOP. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants, " he added. In the study, published in the journal Nature Medicine, the team used BE3, joined it with a modified CRISPR-associated protein 9. After birth, the mice carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites. In the subgroup of the mice bio-engineered to model HT1, BE3 improved liver function and preserved survival. However, "a significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach", said Peranteau. He added: "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."
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Harvard medical school Post stroke: Addressing thinking and memory problems A stroke can disrupt your ability to think clearly and can cause problems with your memory, attention, and organizational abilities. Both speech and occupational therapists work with people to improve these areas and to develop strategies to compensate for problems — for example, using cue cards and detailed lists or simplifying daily routines. Coping with spatial neglect. One fairly common effect of stroke is called "neglect." This is a lack of awareness of one side of the body and the space around that side of the body. The left side is more commonly affected than the right. If you have neglect, you may bump into things on your left without noticing them, shave or apply makeup only on the right side of your face, or eat food on only the right side of your plate. Skin Care and Repair Protect your brain: That’s the strategy that Harvard doctors recommend in this report on preventing and treating stroke. Whether you’ve already had a mini-stroke or a major stroke, or have been warned that your high blood pressure might cause a future stroke, Stroke: Diagnosing, treating, and recovering from a "brain attack" provides help and advice. If you have this problem, occupational and speech therapists will cue you to look frequently toward your neglected side and then teach you to cue yourself. One example: A red line down the left margin of the page you are reading may help remind you to look all the way to the marker so you see all the words on that line. A variety of software programs and games can also help train people to pay attention to the things on the neglected side. Caregivers and family members can help by setting important objects (food, writing implements) on the person's neglected side to train him or her to focus more on that side. Prism glasses — which are shaped in a way that changes the focus point of your eyes — can be helpful to shift your view more toward the neglected side. To learn more about strokes and how they can affect you, read Stroke: Diagnosing, treating, and recovering from a "brain attack", a Special Health Report from Harvard Medical School.
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When it comes to protein, how much is too much? Published: May, 2018 You've probably heard the claims by now: Here's a diet that's delicious, easy to stick with, and guaranteed to help you lose weight effortlessly. Or, perhaps it's supposed to build muscle, protect your joints or prevent Alzheimer's. Whatever the diet and whatever the claim, there's a good chance that it is, indeed, too good to be true. In recent years, high protein diets are among the most popular, whether the protein is consumed as a supplement (protein shakes for body builders!) or simply a larger than usual portion of a balanced diet (such as The Zone, Atkins or Paleo Diets). Perhaps you're curious about one of these diets or have already tried them – did you ever wonder whether too much protein might be a problem? How much protein do you need? Protein is essential for life – it's a building block of every human cell and is involved in the vital biochemical functions of the human body. It's particularly important in growth, development, and tissue repair. Protein is one of the three major "macronutrients" (along with carbohydrates and fat). So, consuming enough protein is required to stave off malnutrition; it may also be important to preserve muscle mass and strength as we age. And, in recent years, some have advocated a higher protein diet to rev up metabolism to make it easier to lose excess weight, though success in this regard is highly variable. The ideal amount of protein you should consume each day is a bit uncertain. Commonly quoted recommendations are 56 grams/day for men, 46 grams/day for women. You could get 46 grams/day of protein in 1 serving of low-fat greek yogurt, a 4 oz. serving of lean chicken breast and a bowl of cereal with skim milk. A weight-based recommended daily allowance (RDA) of 0.8 grams per kilogram of body weight. For a 140 pound person, that comes to 51 grams of protein each day. (You can convert your body weight from pounds to kilograms by dividing by 2.2; so, 140 pounds is 64 kg; multiplying this by 0.8 equals 51). Active people – especially those who are trying to build muscle mass - may need more. Based on percent of calories – for an active adult, about 10% of calories should come from protein To pay more attention to the type of protein in your diet rather than the amount; for example, moderating consumption of red meat and increasing healthier protein sources, such as salmon, yogurt or beans. But, some experts suggest that these recommendations are all wrong and that we should be consuming more protein, up to twice the standard recommendations. Still others claim that the average American diet already contains too much protein. (Read more about the thinking of experts on this subject in this summary of two "Protein Summits" in 2007 and 2013 organized "to discuss the role of protein in human health and to explore the misperception that Americans overconsume protein." Note, these meetings were sponsored in part by animal-based food industry groups.) Can too much protein be harmful? The short answer is yes. As with most things in life, there can be too much of a good thing and if you eat too much protein, there may be a price to pay. Among the conditions linked to high protein diets are: High cholesterol and a higher risk of cardiovascular disease Increased cancer risk Kidney disease and kidney stones Weight gain (yes, this seems odd for a proposed weight loss strategy) Constipation or diarrhea However, keep in mind these are only associations – that is, some studies have noted these conditions among people on high protein diets; but that doesn't mean the protein actually caused the condition. Also, some of these are not necessarily due to the protein itself but rather due to how the protein is consumed or what the protein replaces – for example, a high protein diet that contains lots of red meat and high fat dairy products might lead to higher cholesterol, and a higher risk of heart disease and colon cancer while another high protein diet rich in plant-based proteins may not carry similar risks. And one study found weight gain was more likely when protein replaced carbohydrates in the diet but not when it replaced fat. So, when it comes to protein, how much is too much? It's hard to provide a specific answer since so much is still uncertain and the experts themselves don't agree. However, for the average person (who is not an elite athlete or heavily involved in body building) it's probably best to avoid more than 2 gm/kg; that would be about 125 grams/day for a 140 pound person. New information could change our thinking about the maximum safe amount, but until we know more about the safety, risks and benefits of high protein diets, this seems like a reasonable recommendation. What's a protein lover to do? If you want to maintain a high protein diet, the details matter: Find out from your doctor if you have any health conditions (such as kidney disease) that might make such a diet risky Get your protein from healthy sources such as low-fat dairy products, fish, nuts and beans, lean chicken and turkey; avoid proteins sources that contain highly process carbohydrates and saturated fat Spread your protein consumption across all of your meals throughout the day Choose a well-balanced diet that includes lots of vegetables, fruits, and fiber; the Mediterranean diet or the DASH diet are good starting points.
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GEN News HighlightsMore » May 10, 2018 Cancer Drug Resistance Predicted by CRISPR Screens Source: Cambridge University Scientists at the Institute of Cancer Research (ICR) in the U.K. have harnessed CRISPR-Cas9 genome-editing technology to uncover why some tumors are resistant to poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib and talazoparib. The studies, headed by Chris Lord, Ph.D., professor of Cancer Genomics at ICR, found that mutations in the PARP1 gene prevent the enzyme from being trapped by the drugs when it binds to DNA, resulting in resistance to PARPi therapy in vitro and animal models in vivo, as well as in an ovarian cancer patient who had developed resistance to olaparib. The researchers hope that their results will help clinicians select the most appropriate treatments and drug regimens for patients with breast and ovarian cancer. "PARPi are hugely exciting new drugs which are especially effective in women with BRCA mutations—but unfortunately, as with many other treatments, it is common for cancer cells to eventually develop resistance, ” comments co-researcher Stephen Pettitt, Ph.D., staff scientist in cancer genomics at the ICR. “Our study has discovered one of the reasons why resistance to PARPi such as olaparib might occur. Testing for the mutations we have identified could offer even more personalized treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib should be used." The ICR team, together with colleagues in the U.K., U.S., and Bulgaria, report on their findings in Nature Communications, in a paper entitled “Genome-Wide and High-Density CRISPR-Cas9 Screens Identify Point Mutations in PARP1 Causing PARP Inhibitor Resistance.” The PARP enzyme PARP1 acts as DNA damage sensor, which attaches to and coordinates the repair of single- or double-stranded breaks in DNA. Drugs that target PARP1 and PARP2 cause the death of cancer cells that already have defects in genes, such as the tumor suppressors BRCA1 or BRCA2, because this double deficit in repair mechanisms is effectively lethal to the cells. Studies have shown that as well as blocking the catalytic activity of PARP1, most clinical PARPi cause cytotoxicity by trapping PARP1 where it binds to DNA at the sites of DNA damage. To try and understand the mechanisms of PARPi toxicity in even greater detail, the ICR researchers developed genome-wide, high-density CRISPR-Cas9 “tag-mutate-enrich” mutagenesis screens. The approach involved generating mutations in specific sections of the PARP1 gene, and tagging the mutated proteins so that the effects on cancer cell response to drug therapy could be tracked. Using this method the team could generate and identify near full-length mutant forms of PARP1 that cause resistance to PARPi both in vitro and in tumor-bearing animal models. Mice with PARP1-mutant tumors were more resistant to therapy with talazoparib, whereas the drug delayed tumor growth and increased survival in control animals. Specific mutations in the DNA-binding region of the PARP1 gene were found to disrupt the ability of the enzyme protein to bind to DNA, and so prevented PARPi from trapping them at the site of DNA damage. Interestingly, even mutations at sites on the PARP1 gene that are not known to be directly involved with DNA binding caused PARPi resistance, suggesting that they may also prevent PARP1 trapping. Further analyses suggested that these mutations may affect amino acids that are involved in hydrogen-bonding interactions that act to bridge the DNA-binding and catalytic domains of the protein, which could ultimately impact on PARP1 trapping. “Our genetic screens also uncovered several clusters of mutations that suggest that regions of PARP1 outside the DNA-binding domain can influence trapping, observations that are consistent with inter-domain interactions being critical for PARP1 binding and activation, ” the authors state. More surprisingly, some cancer cells with mutant BRCA1 were resistant to PARP1 inhibitors, even when the enzyme couldn't carry out DNA repair. The team's analyses suggested that some residual BRCA1 function may be retained in these cells, which is enough to support cell survival even when PARP1 is mutated. “Our experiments also showed that PARP1 mutation can be tolerated in certain BRCA1 mutant, PARPi-sensitive tumour cells, ” the researchers comment. “This suggests that PARP1 trapping still underlies the increased cytotoxicity of PARPi in these tumour cells but that some residual BRCA1 function allows these cells to tolerate PARP1 mutations.…” In parallel with their screening studies, the researchers analyzed cells from an ovarian cancer patient who had developed olaparib resistance. They identified a specific mutation in the patient's PARP1 gene that meant the enzyme could still be recruited to sites of DNA damage, but didn’t bind well to the DNA, so wasn’t trapped by the drug. “…we also observed a PARP1 mutation that abolished trapping in a patient with de novo resistance to olaparib, suggesting that such mutations can arise in patients and could potentially contribute to resistance.” The team says that the finding that PARP1 mutations outside of the DNA-binding domains can still influence PARP1 trapping, and so PARPi resistance “…reinforces the importance of trapped PARP1 as a cytotoxic DNA lesion and suggests that PARP1 mutations are also tolerated in cells with a pathogenic BRCA1 mutation where they result in distinct sensitivities to chemotherapeutic drugs compared to other mechanisms of PARPi resistance.” They further suggest that their "tag-mutate-enrich” approach could, in principle, be used to generate full-length mutants of any gene associated with a particular disease. “This could be employed in the analysis of other resistance mutations observed in patients being treated with targeted therapies in order to annotate likely drivers and passengers of resistance." "The evolution of cancers into drug-resistant forms is a major challenge we face in getting cancer treatments to work, ” states Dr. Lord. “Studies like this can tell us how and why drug resistance occurs, and give us new ways of predicting the likely response to new-style targeted drugs. We hope our research will help doctors use the best drug right from the outset, respond quickly to early signs of resistance, and work out the best ways to combine treatments to overcome drug resistance. Charles Swanton, Ph.D., Cancer Research UK's chief clinician, adds, “This ambitious study using state-of-the-art molecular technologies shows new ways in which tumors become resistant to PARPi, a family of drugs discovered and developed by Cancer Research UK–funded scientists. Importantly, this resistance may influence the success of future treatment options, so increasing our understanding of how resistance occurs means we may be able to design even better therapies and predict how well a patient may respond to future treatment." "Studies like this, which build on the development of PARPi as a brand new treatment option for some women with breast cancer, could help take us a step closer to an even more personalized approach to treating the disease, " noted Baroness Delyth Morgan, chief executive at Breast Cancer Now, which partly funded the study. “It is vital that we understand exactly how and when cancer cells begin to adapt to and resist treatment, so that we can remain one step ahead of often elusive cancer cells.”
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