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Reason for Old Age Found, Solution Possible Soon: Scientists

The scientists at Arizona State University have found a rare atomic level change at the enzyme telomerase that holds secrets as to how we grow old.

The telomerase is a naturally occurring enzyme that maintains telomeres and prevents them from shortening during cell division. Telomeres are found at the ends of human chromosomes and are stretches of DNA which protect the genetic data.

“Telomerase is crucial for telomere maintenance and genome integrity. Mutations that disrupt telomerase function have been linked to numerous human diseases that arise from telomere shortening and genome instability,” explained Julian Chen, a professor of chemistry and biochemistry at Arizona State.

The telomeres keep chromosome ends from fraying and sticking to each other, which would destroy or scramble our genetic information.

“This shortening process is associated with aging, cancer and a higher risk of death,” scientists noted.

“We are particularly excited about this research because it provides, for the first time, an atomic level description of the protein-RNA interaction in the vertebrate telomerase complex,” Chen added.

The scientists in collaboration with the Chinese Academy of Sciences in Shanghai had conducted the crucial research, which will be published in the journal Nature Structural and Molecular Biology.

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New class of antibiotics discovered

WASHINGTON: In a breakthrough, scientists have discovered a new class of antibiotics to fight deadly bacteria such as methicillin-resistant Staphylococcus aureus and other drug-resistant bacteria that threaten public health.

The new class, called oxadiazoles, was discovered by University of Notre Dame researchers led by Mayland Chang and Shahriar Mobashery in silico (by computer) screening and has shown promise in the treatment of MRSA in mouse models of infection.

Researchers who screened 1.2 million compounds found that the oxadiazole inhibits a penicillin-binding protein, PBP2a, and the biosynthesis of the cell wall that enables MRSA to resist other drugs.

The oxadiazoles are also effective when taken orally. This is an important feature as there is only one marketed antibiotic for MRSA that can be taken orally, researchers said.

MRSA has become a global public-health problem since the 1960s because of its resistance to antibiotics.

In the US alone, 278,000 people are hospitalised and 19,000 die each year from infections caused by MRSA, said researchers.

Only three drugs currently are effective treatments, and resistance to each of those drugs already exists.

The researchers have been seeking a solution to MRSA for years.

“Professor Mobashery has been working on the mechanisms of resistance in MRSA for a very long time,” Chang said.

“As we understand what the mechanisms are, we can devise strategies to develop compounds against MRSA,” said Chang.

“Mayland Chang and Shahriar Mobashery’s discovery of a class of compounds that combat drug resistant bacteria such as MRSA could save thousands of lives around the world. We are grateful for their leadership and persistence in fighting drug resistance,” said Greg Crawford, dean of the College of Science at the University of Notre Dame.

The research is published in the Journal of the American Chemical Society.

Breakthrough in lung cancer therapy

https://i1.wp.com/drugdiscovery.com/upimages/1376408358_lung-cancer-tumour_13912.jpgWASHINGTON —  A new study shows that a combination of drugs can be used in targeted therapy against a common type of lung cancer.

Lung adenocarcinomas, the most common genetic subtype of lung cancer which has long defied treatment with targeted therapies, has had its growth halted by a combination of two already-in-use drugs in laboratory and animal studies, setting the stage for clinical trials of the drugs on patients, researchers at Dana-Farber Cancer Institute in Boston, Massachusetts and other scientists report in a new study.

The study, published in the journal Cancer Discovery, describes a new tack in the treatment of lung adenocarcinomas which account for about 40 percent of all lung cancers that carry mutations in the gene KRAS.

While most efforts to target KRAS directly with drugs have not proved successful, the authors of the current study took a more circuitous approach, targeting KRAS’s accomplices, the genes that carry out its instructions rather than KRAS itself, reports Science Daily.

“About 30 percent of lung adenocarcinomas have mutations in KRAS which amount to nearly 30,000 of all patients diagnosed with lung cancer each year in the United States,” says the study’s senior author, David Barbie, MD, of the Lowe Centre for Thoracic Oncology at Dana-Farber and the Broad Institute of Harvard and Massachusetts Institute of Technology.

“That represents the single biggest subset of lung cancer patients, if grouped by the mutations within their tumour cells. Unfortunately, there has not been a reliable way of striking at the genetic mechanism that causes these cells to proliferate.”

Mutations in KRAS cause cancer cells to grow and divide in a wildly disordered way. The lack of drugs able to block KRAS safely has led investigators to look for ways of stifling its effects “downstream”  by interfering with the signals it sends to other genes.

“The next step will be to take these results to the clinic where the combination can be tested on lung cancer patients,” says Wong.

“We’re in the process of developing a clinical trial. Because KRAS mutations are also common in colon and pancreatic cancer, we’re hopeful that trials will be organised for these patients as well.”

New class of antibiotics can treat drug-resistant tuberculosis

LungsScientists have discovered a “promising” new class of antibiotics that could treat drug-resistant strains of tuberculosis (TB).

Researchers from St Jude Children’s Research Hospital in US said the drugs increased survival of mice infected with TB and were effective against drug-resistant strains of TB. The antibiotics, called spectinamides, were created by changing the chemical structure of an existing antibiotic, spectinomycin, which does not work against TB. In multiple trials of mice with both active and chronic

TB infections, researchers found that one version of the new drug – an analog known as 1599 – was as good as or better than current TB drugs at reducing levels of the bacteria in the lungs of mice.

In addition, 1599 caused no serious side effects.

“This study demonstrates how classic antibiotics derived from natural products can be redesigned to create semi-synthetic compounds to overcome drug resistance,” said corresponding author Richard Lee, a member of the St Jude Department of Chemical Biology and Therapeutics. The new class of antibiotics works against TB by disrupting the function of a part of the cell known as the ribosome, which is responsible for protein synthesis. To do that, the spectinamides bind to a particular site on ribosomes that is not shared by other TB drugs. That allows the drug to be used in combination with other medications.

For this study, researchers used an approach called structure-based design to re-engineer how spectinomycin binds to the ribosome.

To guide their design efforts, scientists used a 3-D model that provided an atomic-level view of spectinomycin bound to the tuberculosis ribosome.

The research reported on the first 20 of the more than 120 spectinomycin derivatives that have resulted from the effort. The list includes 1599 and two other analogs tested

against TB in mice, researchers said.

The three analogs not only bound the ribosome tightly, but they were more successful at avoiding a TB resistance mechanism called efflux.

The TB bacteria use efflux pumps as a strategy to remove drugs and other threats from the cell before they can work against the bacteria. Efflux pumps, however, did not protect TB against spectinamides, researchers said.

The drugs were also effective against multi-drug-resistant strains of TB growing in the laboratory. The strains had been isolated from patients with the disease.

The study is published in the journal Nature Medicine.

Scientists urge caution on antibiotic alternatives

The new treatments are intended to enable the patient to tolerate disease, and buy the immune system valuable time to get rid of the infection naturally

New types of drugs intended for use in place of antibiotics have been given a cautious welcome by scientists at the Universities of Liverpool and Edinburgh.

Researchers have been probing the long-term effectiveness of drugs being developed by the pharmaceutical industry. These work by limiting the symptoms caused by a bug or virus in the body, rather than killing it outright.

Becoming resistant

These treatments are designed to avoid the problem of infections becoming resistant to treatment, which has become widespread with antibiotics.

This approach is intended to enable the patient to tolerate disease, and buy the immune system valuable time to get rid of the infection naturally.

“Antibiotic resistance is a serious issue and these alternatives offer hope in solving the problem”

Researchers at the Universities of Liverpool and Edinburgh created a mathematical model to discover how drugs that limit the damage caused by disease could affect how infections spread and evolve.

They found that for infections where the symptoms are not linked to the spread of disease, these drugs may prevent disease from evolving too quickly. They will be useful over longer periods of time.

However, parasitologist, Dr Andy Fenton, from Liverpool’s Institute of Integrative Biology cautions that people given damage limitation treatments may appear healthy, but carry high levels of infection and so may be more likely to pass on disease. In addition, people with lesser symptoms could remain undiagnosed and add to the spread of disease.

Cautious

“Antibiotic resistance is a serious issue and these alternatives offer hope in solving the problem,” he said.

“However we should be cautious as it’s possible that in some cases these drugs may cause disease to spread.”

The study, ‘Limiting Damage during Infection: Lessons from Infection Tolerance for Novel Therapeutics’, was published in PLoS Biology. Read it here

Stem cells: Living adult tissue transformed back into embryo state

https://astronlife.files.wordpress.com/2013/09/062fc-004_tile_zooboing-com_cells.jpgThe living tissue inside an animal has been regressed back into an embryonic state for the first time, Spanish researchers say.

They believe it could lead to new ways of repairing the body, for example after a heart attack.

However, the study published in the journal Nature, showed the technique led to tumours forming in mice.

Stem cell experts said it was a “cool” study, but would need to be much more controlled before leading to therapies.

When an egg is first fertilised, it has the potential to develop into every tissue in the human body, from brain cells to skin.

That flexibility is lost as an embryo develops. However, transforming adult tissues back into an embryonic-like state may lead to treatments that can regenerate a weakened heart, or the light-sensing cells in the eye or even the brain after a stroke.

‘Thought impossible’

The transformation has been done in a laboratory, by treating skin samples with a mix of chemicals or genetic modification.

Now scientists at the Spanish National Cancer Research Centre in Madrid have achieved the same results inside an animal.

“It is a surprising result, this was not expected, most of us thought that it would be impossible,” lead researcher Prof Manuel Serrano told the BBC.

The research group used mice genetically modified to switch on, when they were given a specific drug, production of four chemicals shown to reverse a tissue’s destiny in the laboratory.

Tissues were successfully transformed back into an embryonic state, but without further direction they rapidly developed into tumours.

Speaking on Science In Action on the BBC World Service, Prof Serrano said: “Of course this is not what we want for regenerative medicine.

“We want to turn back the clock in a controlled manner and this is something we have to work out in the future.

“We have to find conditions where we reprogramme only partially so that they acquire a plastic state and repair the tissue.”

‘Monumental task’

Prof Robin Ali, from the Institute of Ophthalmology in London, is using stem cell technology to rebuild the retina to restore sight. He said the “ultimate goal” would be some treatment that could regenerate the back of the eye, “but that is a long way off”.

He added: “This is a really elegant study with important implications for the field.

“It will be a monumental task to prove this is safe, as what you’re doing is innately dangerous, but it is exciting as it’s potentially a new strategy for regenerative medicine.” 

“To me the interesting thing was the evidence that the cells correspond to an earlier stage of development.

“If we can repeat that with human cells, it would be incredibly useful and could have important research implications, such as understanding the placenta and how to help maintain a pregnancy.”

Prof Chris Mason, a stem cell scientist at University College London, said: “Overall it’s very cool and potentially very exciting, but it has massive issues in terms of control.”

Instead he thought techniques that transformed cells in the body directly into the desired tissue would be better than going via stem cells.

“It’s like a tree, instead of going down from a branch to the root and back up to a different branch, maybe we’ll be able to jump from branch to branch.”

One pill for all heart problems

HeartCHANDIGARH: How often do you forget to pop that pill to control your shooting blood pressure? Or skip the aspirin tablet that could have prevented a stroke at night? Not anymore.

For the first time, doctors and researchers have come up with a single pill for all cardiovascular diseases (CVD), including high blood pressure and vulnerability to stroke, doing away with the pain of popping multiple pills to keep your heart healthy. Trials for this new pill – called the polypill – across Europe and India have proved successful, according to a study published on Wednesday in the Journal of the American Medical Association.

As many as 28 Indian institutes, including AIIMS, PGIChandigarh and George Institute for Global Health-India worked together as part of the study, planned by London’s Imperial College. The formulation for the drug was done by Dr Reddy’s Laboratories.

“Most patients with high BP require multiple drugs to keep it under control. This raises the problem of compliance over a prolonged period as patients often forget to take some of the pills. In India, compliance to multiple pills for CVD is as low as 10%. Polypill will take care of it,” said Dr Vivekanand Jha, executive director of George Institute for Global Health-India.

While studies have shown that patients with CVD do not take recommended medications in the long-term, the use of fixed-dose combinations (FDCs) like a polypill improves adherence to a large extent. The study showed adherence rate increasing by 20% with use of the polypill, a combination of aspirin, statin (cholesterol lowering drugs), and two blood pressure-lowering agents.

Funded by the European Commission’s Seventh Framework Program, the study has shown evidence, for the first time, about the risks and benefits of the single pill.

As many as 2,004 people, in the mean age of 62 and with high risk of CVD, initially participated in the study in India and across Europe between July 2010 and July 2011.

he trial follow-up concluded in July 2012. Previous trials have assessed short-term effects. At the end of the study on 1921 of the participants, conducted for an average 15 months, it was found that 829 (86.3%) of the 961 participants who were administered the polypill continued with it. In comparison, only 621 (64.7%) of the 960 participants continued with multiple pills as prescribed. But the study showed one limitation: If any of its components led to some adverse effect, the polypill had to be discontinued.

The study involved the Imperial College, London’s International Centre for Circulatory Health, The George Institute for Global Health-India, Centre for Chronic Disease Control, New Delhi, Royal College of Surgeons in Ireland, Dublin; Julius Center for Health Sciences and Primary Care, Utrech; Public Health Foundation of India, New Delhi and The George Institute for Global Health, Sydney.

“These new findings dispel several myths about the polypill. Despite the use of older medications and fixed doses, the polypill group improved blood pressure and cholesterol levels simply because those surevyed took recommended medications more regularly,” said Prof D Prabhakaran, executive director of the Centre for Chronic Disease Control.

Parliamentary panel on clinical trials seeks action against PATH

New Delhi: A Parliamentary standing committee says the government should act against a US-based non-profit for allegedly violating Indian laws while conducting clinical trials on hundreds of women and children in Gujarat and Andhra Pradesh—an allegation that is rejected by the American group.
The committee also made grave allegations of impropriety against the Indian Council of Medical Research (ICMR), the nation’s apex body for the formulation, coordination and promotion of biomedical research, and the drugs controller general of India (DCGI).
PATH carried out phase IV trials of human papilloma virus (HPV) vaccine for cervical cancer as part of a study in 2009. Phase IV safety surveillance is designed to detect any rare or long-term adverse effects over a larger patient population and longer time period than was possible during earlier phases of clinical trials.
During the trials, PATH administered Merck Ltd’s Gardasil vaccine on 108 girls aged 9-15, and GlaxoSmithKline Plc.’s Cervarix vaccine on 162 women aged 18-35. The study was suspended and an inquiry committee formed in April 2010 following the deaths of seven of those who were administered the vaccines.
However, after analysing the seven deaths—five from the Gardasil group and two from the Cervarix group—no common pattern to the deaths was found to suggest these were caused by the vaccines.
In its report presented to the Rajya Sabha on Friday, the committee urged the government to look into the roles of DCGI and ICMR for allegedly turning a blind eye to “irregularities” in the conduct of the trials.
PATH made a strong defence of its actions.
“We believe that by following the guidance provided by ICMR, as well as two state governments and three ethical review committees, we designed a project that met or exceeded the country’s existing regulatory standards for demonstration projects while providing the greatest health benefit to Indian women,” said Amy MacIver, director of media relations at PATH, in a statement issued on Friday.
But the parliamentary committee was scathing about ICMR, saying: “In their over-enthusiasm to act as a willing facilitator to the machinations of PATH, they have transgressed into the domain of other agencies which deserves the strongest condemnation and strictest action against them.”
It also questioned ICMR’s decision to promote the vaccines for inclusion in the Universal Immunization Programme even before an independent study on their utility and rationale was undertaken.
ICMR dismissed the committee’s criticism. “We have already conducted an inquiry on the deaths of the girls and no link was found between the deaths and the vaccine. The report was submitted to the ministry of health in 2010,” said Dr. Tanvir Kaur at the non-communicable diseases division of ICMR.
“The studies carried out by PATH were definitely not clinical trials,” she added.
The parliamentary panel also took on DCGI, saying it played a “questionable role”. Although DCGI initially maintained that clinical trial rules must be enforced, it stayed silent while the rules and regulations were violated, the panel said.
DCGI chief G.N. Singh responded, “Clinical trial regulations in India were not strict four years ago, but now we have a highly regulated regime.”
“We are taking the recommendations of the standing committee report in the right stride and will work on the suggestions. Such problems should not arise in the future,” said Singh, who heads the Central Drugs Standard Control Organization (CDSCO) as the DCGI.
The panel alleged that many of the consent forms for the tests had thumb impressions for signatures, or had been signed by hostel wardens. Obtaining informed consent from people participating in such drug studies is essential for clinical trials. In case of minors, forms are to be signed by parents or guardians.
The panel also raised the issue of including vulnerable and tribal populations in the trials, and the lack of preparedness to deal with adverse events.
The PATH statement said, “At the time of its review, ICMR determined the project was a post-licensure observational study and not a clinical trial.”
“The demonstration projects in India, Peru, Uganda and Vietnam generated important new evidence on the best ways to introduce HPV vaccines and are informing the work of governments across Africa, Asia, and Latin America to help prevent cervical cancer deaths,” PATH said.
The panel asked the ministry of health and family welfare to promptly report PATH’s alleged violations to the World Health Organization and UNICEF (the UN agency for children), and suggested that the National Human Rights Commission also look into the reported violations.
“It is shocking to see how an American organization used surreptitious methods to establish itself in India, performed trials on hundreds of women and children in our country with so many violations, and two of our government agencies rushed to help this organization,” said Dr. Chandra M. Gulhati, editor of Monthly Index of Medical Specialities.
India approved 475 clinical trials for “new chemical entities” not used as drugs elsewhere in the world between January 2005 and June 2012, according to documents submitted by DCGI in the Supreme Court.
The documents said 11,972 adverse effects, excluding deaths, were reported in the period, with 506 of these being directly attributable to the trials. They put deaths from trials at 2,644 in the past five years.
In a 3 January ruling, the apex court revoked the powers of the Indian drug regulator to approve trials for new chemical entities, placing the responsibility on the health secretary, who was asked to personally vet all approvals.
On 26 July, the Supreme Court directed the Union government to come up with a new regulatory regime for clinical trials that reflects the concerns of all stakeholders.
The National Institutes of Health (NIH), part of the US department of health and human services, cancelled about 40 ongoing clinical trials in India after the health ministry tightened regulatory norms for trials, Mint reported in July.
The health ministry amended the Drugs and Cosmetics Act with new provisions for regulation and ethical supervision of trials; compensation of trial subjects, and mandatory accreditation of all stakeholders, including institutional review boards, research institutions, sponsors and contract research organizations.

‘Female sperm’ and ‘male eggs’ may be possible

Researchers have suggested that it may be possible in the future to create sperm from women and eggs from men – a feat, that if achieved, could revolutionise infertility treatments.

Katsuhiko Hayashi of Kyoto University in Japan and his senior professor Mitinori Saitou used skin cells from mice to create primordial germ cells or PGCs. PGCs are the common precursor of both male and female sex cells.

These cells were then developed into both sperm and eggs. Scientists used these to create live-births via in vitro fertilisation.

The technique offers numerous possibilities for reproductive medicine. It may allow infertile women to have babies by creating eggs from their skin cells, and also make it possible for sperm and eggs cells to be created from either males or females, ‘The Independent’ reported.

In the technique, pluripotent stem cells were extracted from early-stage embryos and somatic cells, and were then converted into PGCs using signalling molecules.

These germ cells were transplanted into the ovaries and testes of living mice to develop. Once these cells were mature they were extracted and used to fertilise one another in vitro.

The initial research took place in October last year, with researchers claiming that the live-births were merely a ‘side effect’ of the research to demonstrate that the creation of PGCs had been successful.

Other researchers have replicated the production of PGCs but could not succeed in producing live births. The scientists involved also have many other hurdles to overcome including the production of ‘fragile’ and ‘misshapen’ eggs, wrote David Cyranoski in ‘Scientific American’.

The Japanese team is now working on monkey embryos and believe they could repeat the mouse work in monkeys within 5-10 years, with the creation of human PGCs following shortly after.

While making PGCs for infertility treatment will be a huge jump, many scientists are urging caution as embryonic stem cells frequently pick up chromosomal abnormalities, genetic mutations and epigenetic irregularities during culture.

Hayashi has also said that a viable infertility treatment could be 10 or even 50 years in the future.

“My impression is that it is very far away. I don’t want to give people unfeasible hope,” he said.

Gall bladder, uterine cancer on the rise

Cervical cancer in women is decreasing, while uterine and gall bladder cancer is on the rise at least in major metropolitan cities, suggests India’s latest cancer statistics without providing any explanation for the observed trend.

According to the population based cancer registry prepared by the Indian Council of Medical Research (ICMR), actual reported cases of cervical cancer declined between 2009 and 2011 in Bangalore, Bhopal, Chennai, Delhi and Mumbai. Decline was seen in Assam, Mizoram and Thiruvananthapuram, too. Uterine cancers,  are on the rise in Bangalore, Chennai, Delhi and Mumbai in the same period. In Bangalore, the number of cases increased by 7.4 per cent between 1986 and 2009, whereas the rise was 7.3 per cent between 2005 and 2010 in Mumbai, compared to 1.7 per cent increase between 1982 and 2004.

“There is a declining trend in cervical cancer and increase in uterus and gall bladder cancer cases in some cities. We don’t know the reason yet,” said V M Katoch, director-general of ICMR. In the country, breast and cervical cancer remain the two most common cancers in women.

Among men, cancer of the lung, mouth, oesophagus and stomach are common. Cancers of the tongue, rectum, liver, lung, prostate, brain, non-Hodgkin’s lymphoma and a type of leukaemia have shown statistically significant increase.Cancer of the gall bladder in women is increasing in Chennai, Bangalore and Bhopal. In Delhi, the hike is seen in men, whereas in Mumbai, it went up both in men and women. Lung cancer among women, too, had increased in the four metros.

The new statistics come from collation of data from 28 population based cancer registries, covering 7.45 per cent of the population. As many as 250 centres contributed to the database, which was approved by ICMR’s top science advisory panel last week.

This is the third report from the ICMR registry with the addition of new sites.

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