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Tuesday, 23 September 2014

Posted by Tanaji Gude On 15:00

Police drove through Kroo Bay this morning, past the open sewers and snuffling pigs, yelling at people to go inside—largely to no avail. All the 14,000 residents of the shanty town in Freeport, Sierra Leone, had been ordered to stay indoors for three days, to try to stop the spread of Ebola.
Sierra Leone’s attempted lockdown is unprecedented: The whole country has been placed on house arrest and 20,000 volunteers have been recruited to help identify suspected Ebola carriers. “Some of the things we are asking you to do are difficult, but life is better than these difficulties,” President Ernest Bai Koroma said.

Nothing about controlling the spread of the virus has come easy. Yesterday, the bodies of eight people, part of a delegation of health officials and journalists, were found in a remote village in Guinea, apparently killed by people throwing rocks. Health workers around the region, including in Liberia and Sierra Leone, have been physically threatened by misinformed people who fear they are actually spreading the disease. In the midst of this widespread panic, the World Health Organization reports that more than 700 new cases were recorded this week; despite all efforts, the outbreak is still growing.
But a rare spot of good news came in the form of a diagnostic test that may help prevent future epidemics. Dr. William Karesh, Executive Vice President for Health and Policy at EcoHealth Alliance and a wildlife veterinarian who has studied Ebola in great apes for years, has discovered a method of detecting Ebola antibodies in feces. Up till now, detection methods in the wild relied on collecting blood or tissue from infected apes, one of the animal reservoirs for the disease. (The direct introduction to humans in this current outbreak is suspected to have come from fruit bats, not apes.) Since collecting poop is much easier than taking blood samples or carting carcasses out of the jungle, this technique can help scientists’ canvas larger areas and more accurately pinpoint hotspots likely to be at risk for future outbreaks.

Gorillas are actually even more susceptible to Ebola than humans, with a mortality rate approaching 95 percent. Over the last twenty years, Ebola outbreaks in apes have decimated populations; Karesh estimates some 25 percent of wild apes in the Congo have been killed by the virus. Karesh hopes his technique will help scientists detect Ebola in apes sooner.
This could help scientists better target susceptible populations for possible future vaccination campaigns. That day might not be too far away: although no vaccine currently exists, ‘orphan’ vaccines, originally developed for people but abandoned during the lengthy licensing process (this can happen for many reasons, including the discovery of harmful side effects) may protect apes against the virus. A study published in PNAS this spring suggests that one such vaccine, developed by the biotech company Integrated Bio therapeutics, prevents mice from developing the disease.

As Karesh says, "everything is linked to animals." If gorilla poop can create a road map for understanding how Ebola spreads, both vulnerable species and the human populations who surround them will benefit. 

Thursday, 11 September 2014

Posted by Tanaji Gude On 11:51

A blend of three monoclonal antibodies has completely protected monkeys against a lethal dose of Ebola virus. Unlike other post-infection therapies, the treatment works even at advanced stages of the disease.

The filo viruses known as Ebola virus and Marburg virus are among the most deadly of pathogens, with fatality rates of up to 90% (ref. 1). Early this year, a new strain of the Zaire species of Ebola virus emerged2 in the West African country of Guinea and quickly spread to Liberia, Sierra Leone and Nigeria. The outbreak persists despite the best efforts of local and international authorities, and is now the largest filo virus outbreak on record, with no end in sight. There are no licensed vaccines or post-exposure treatments against Ebola, so moving the most promising interventions forward is a matter of utmost urgency. In a paper published on Nature's website today, Qiu et al.3 report that rhesus monkeys can be completely protected from lethal Ebola infection using ZMapp — a blend of three monoclonal antibodies. Crucially, the treatment protected monkeys even when it was administered as late as 5 days after exposure to the virus, at a time when the animals were severely ill.

Since the discovery of Ebola virus (Fig. 1) in 1976, researchers have been actively developing treatments to combat infection. Studies over the past decade have found that modulators of blood coagulation4, 5, an antisense oligonucleotide called AVI-6002 (ref. 6) and a vaccine7 based on vesicular stomatitis virus (VSV) all afforded partial protection of monkeys against Ebola when administered within an hour of virus exposure. The VSV-based vaccine was used in 2009 to treat a laboratory worker in Germany shortly after she was accidentally pricked with a needle possibly contaminated by an Ebola-infected animal8. The worker survived, but it is unclear whether this was because she had not been exposed to Ebola or because the vaccine protected her.

Subsequent advances have been made in developing treatments that can completely protect monkeys against Ebola. These include small 'interfering' RNAs (known as TKM-Ebola9) and various combinations of antibodies10, 11, 12. But these treatments need to be administered within 2 days of exposure to the virus. So although these approaches were highly important and can be used to treat known exposures, the need for treatments that protect at later times after infection was paramount.

Further development and improvement of the antibody-based strategies led to a cocktail of monoclonal antibodies13 that protected 43% of monkeys when given as late as 5 days after Ebola exposure — a time at which the clinical signs of disease are apparent. Another therapy that combines monoclonal antibodies with interferon-α (a protein that stimulates an antiviral response) provides almost complete protection of macaques when given 3 days after exposure14, at which point the virus can be detected but clinical signs are only just beginning to be seen in some animals.

Quintal. now report ZMapp, an antibody therapy that does not require interferon-α, and which was developed by two collaborating teams of researchers who had worked on some of the previously reported antibody treatments. ZMapp was made by testing different combinations of chimaeric monoclonal antibodies (in which fragments of human antibodies are attached to antibody fragments from mice). The optimal formulation contains two antibodies from a previously reported blend14 and a third from a different cocktail13.

To test the therapy, Quintal. administered a lethal dose of Ebola virus to three groups of six animals, and then treated them with three doses of ZMapp. The first group received therapy at 3, 6 and 9 days post-infection; the second group at 4, 7 and 10 days; and the third group at 5, 8 and 11 days. Remarkably, all the animals survived, and were found to have undetectable viral loads by 21 days after infection. It should be noted that the authors used the Kikwit variant of the virus in these experiments, because the Guinean strain from the current West African outbreak was not available in time for this part of their study. However, they went on to show that ZMapp inhibits replication of the Guinean strain in cell culture.

The development of ZMapp and its success in treating monkeys at an advanced stage of Ebola infection is a monumental achievement. On this basis, the treatment has been used in the current Ebola outbreak to treat several patients on compassionate grounds15. Of these, two US health-care workers have recovered — but whether ZMapp had any effect is unknown, because at the time of writing, about 45% of patients in this outbreak survive without treatment16. As of 26 August, two other patients treated with ZMapp have not survived, but this might be because the treatment was initiated too late in the course of the disease.

The diversity of strains and species of Ebola and Marburg viruses remain an obstacle for all candidate treatments. Lethal disease in humans is caused by three different species of Ebola virus (Sudan, Bundibugyo and Zaire) and two genetically distinct lineages of Marburg virus. Treatments that protect against one species of Ebola — Zaire, in the case of ZMapp — will probably not protect against a different species of the virus, and might not protect against a different strain within a species.

Although the need for treatments for filo virus infections is unquestionable, the most effective way to manage and control future outbreaks might be through preventive vaccines, some of which have been tailored to protect against multiple species and strains. During outbreaks, single-injection vaccines are needed to ensure rapid use and protection. At least five preventive vaccines have been shown to completely protect monkeys against Ebola and Marburg infection17. But only VSV-based vaccines have been reported to completely protect monkeys against Ebola (Zaire) virus after a single injection18 — notably, the wild-type virus, rather than a cultured variant that has also been used in research, and which produces slower disease progression in macaques.

Antibody therapies and several other strategies mentioned here should ultimately be included in an arsenal of interventions for controlling future Ebola outbreaks. Although ZMapp in particular has been administered for compassionate use, the next crucial step will be to formally assess its safety and effectiveness. Testing the latter is clearly difficult, because intentional infection of human subjects in clinical trials is not possible. US regulations, however, could allow the treatment to be licensed for widespread use on the basis of safety testing in humans and efficacy testing in animals. In the long run, the manufacture of ZMapp could require investment in infrastructure for making monoclonal antibodies at an industrial scale — assuming that funding is available to pay the production costs.

Wednesday, 10 September 2014

Posted by Tanaji Gude On 12:52
A new spin-out company from King's College London, has developed a new dental technique that allows a decayed tooth to effectively repair and heal itself without the need for drills, needles or fillings. This breakthrough procedure, which uses electrical stimulation to help teeth "remineralise", could be available as early as 2017.
With 2.3 billion sufferers annually, dental caries is one of the most common preventable diseases globally. Tooth decay normally develops in stages – starting as a microscopic defect where minerals leach out of a tooth. Minerals continue to move in and out of the tooth in a natural cycle, but when too much mineral is lost, the enamel is undermined and the tooth is said to have developed a caries lesion (which can later become a physical cavity). Dentists normally treat caries in a tooth by drilling to remove the decay and then filling the tooth with a material such as amalgam or composite resin.
Reminova Ltd takes a different approach – one that re-builds the tooth and heals it without the need for drills, needles or amalgam. By accelerating the natural process by which calcium and phosphate minerals re-enter the tooth to repair a defect, the device boosts the tooth's natural repair process. Dentistry has been trying to harness this process for the last few decades, but the new breakthrough by King's means the method could soon be in use at the dentist's chair.
The two-step method developed by Reminova first prepares the damaged part of the enamel outer layer of the tooth. It then uses a tiny electric current to "push" minerals (such as calcium and phosphate) into the tooth to repair the damaged site. The defect is remineralised in a painless process that requires no drills, no injections and no filling materials. Electric currents are already used by dentists to check pulp or nerves in a tooth; the new device uses a far smaller current than that currently used on patients and which cannot be felt by the patient. This technique, known as Electrically Accelerated and Enhanced Remineralisation (EAER), could be brought to market by 2017.

Professor Nigel Pitts from the Dental Institute at King's College London said: "The way we treat teeth today is not ideal – when we repair a tooth by putting in a filling, that tooth enters a cycle of drilling and re-filling as, ultimately, each 'repair' fails. Not only is our device kinder to the patient and better for their teeth, it's expected to be at least as cost-effective as current dental treatments. Along with fighting tooth decay, our device can also be used to whiten teeth."
Kit Malt house, Chair of Med City and London's Deputy Mayor for Business and Enterprise: "It's brilliant to see the really creative research taking place at King's making its way out of the lab so quickly and being turned into a new device that has the potential to make a real difference to the dental health and patient experience of people with tooth decay.

"Increasing the rate at which we can turn great ideas into successful medical and healthcare companies is one of the key aims of MedCity, and will have huge benefits for the UK's health and well-being, as well as its economy."

Posted by Tanaji Gude On 12:43
 New research has uncovered the structure of one of the most important and complicated proteins    in cell division – a fundamental process in life and the development of cancer.
A team from The Institute of Cancer Research in London and the Medical Research Council Laboratory of Molecular Biology in Cambridge has produced the first detailed 3D images of the anaphase-promoting complex (APC/C). Mapping this gigantic protein in unprecedented detail will transform scientists’ understanding of exactly how cells copy their chromosomes and divide, and could reveal binding sites for future cancer drugs.
The APC/C performs a wide range of vital tasks associated with mitosis, the process during which a cell copies its chromosomes and pulls them apart into two separate cells. Mitosis is used in cell division by all animals and plants. Discovering its structure could ultimately lead to new treatments for cancer, which hijacks the normal process of cell division to make thousands of copies of harmful cancer cells.
In the study, which was funded by Cancer Research UK, the researchers reconstituted human APC/C, using a combination of electron microscopy and imaging software to visualize it at a resolution of less than a manometer (one billionth of a meter). The resolution was so fine that it allowed them to see the secondary structure – the set of basic building blocks which combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 sub-units of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same research team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped at all, until now. Each of the APC/C’s sub-units bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes – including the initiation of DNA replication, the segregation of chromosomes along protein ‘rails’ called spindles, and the ultimate splitting of one cell into two, called cytokinesis. Disrupting each of these processes could selectively kill cancer cells, or stop them dividing.

Professor David Barford, who led the study as Professor of Molecular Biology at The Institute of Cancer Research, London: “It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature. We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis, and ultimately lead to the discovery of new cancer drugs.”

Professor Paul Workman, Interim Chief Executive of The Institute of Cancer Research, London: “The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research. The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”
Dr. Kat Arney, Science Information Manager at Cancer Research UK: “Figuring out how the fundamental molecular ‘nuts and bolts’ of cells work is vital if we’re to make progress understanding what goes wrong in cancer cells and how to tackle them more effectively. Revealing the intricate details of biological shapes is a hugely important step towards identifying targets for future cancer drugs.”

Posted by Tanaji Gude On 12:31
 For the first time, researchers have demonstrated proof-of-concept that the HIV virus can be eliminated from the DNA of human cell cultures. Although years away from clinical application, this breakthrough has been described as an important step forward in the search for a cure.

The HIV-1 virus has proved to be tenacious – inserting its genome permanently into victims' DNA, forcing patients to take a lifelong drug regimen to control the virus and prevent a fresh attack. Now, a team of Temple University School of Medicine researchers has designed a way to "snip out" the integrated HIV-1 genes for good.
"This is one important step on the path toward a permanent cure for AIDS," says Kamel Khalili, PhD. He and colleague, Wenhui Hu, led the work which marks the first successful attempt to eliminate latent HIV-1 virus from human cells. "It's an exciting discovery – but it's not yet ready to go into the clinic. It's a proof-of-concept that we're moving in the right direction," added Dr. Khalili.
In a study published yesterday by the Proceedings of the National Academy of Sciences (PNAS), Dr. Khalili and colleagues detail how they created molecular tools to delete the HIV-1 proviral DNA. When deployed, a combination of DNA-snipping enzyme called a nuclease and targeting strand of RNA called a guide RNA (gRNA) hunt down the viral genome and excise the HIV-1 DNA. From there, the cell's own gene repair machinery takes over – soldering the loose ends of the genome back together – resulting in virus-free cells.

"Since HIV-1 is never cleared by the immune system, removal of the virus is required in order to cure the disease," said Khalili, whose work focuses on the neuropath genesis of viral infections. The same technique could theoretically be used against a variety of viruses, he said. The research shows that these molecular tools also hold promise as a therapeutic vaccine; cells armed with the nuclease-RNA combination proved impervious to HIV infection.

Worldwide, over 35 million people have HIV, including more than 1 million in the United States. Every year, another 50,000 Americans contract the virus, according to the U.S. Centers for Disease Control and Prevention.
Although highly active antiretroviral therapy (HAART) has controlled HIV-1 for infected people in the developed world for the last 15 years, the virus can rage again with any interruption in treatment. Even when HIV-1 replication is well controlled with HAART, the lingering HIV-1 presence has longer-term health consequences. "The low level replication of HIV-1 makes patients more likely to suffer from diseases usually associated with aging," Khalili said. These include cardiomyopathy – a weakening of the heart muscle – bone disease, kidney disease, and neurocognitive disorders. "These problems are often exacerbated by the toxic drugs that must be taken to control the virus," he added.
His team based the two-part HIV-1 editor on a system that evolved as a bacterial defense mechanism to protect against infection, Khalili said. His lab engineered a 20-nucleotide strand of guide RNA to target the HIV-1 DNA and paired it with Cas9 (to induce strand breaks in DNA). The gRNA targets the control region of the gene called the long terminal repeat (LTR). LTRs are present on both ends of the HIV-1 genome. By targeting both LTRs, the Cas9 snips out the 9,709-nucleotides that comprise the HIV-1 genome. To avoid any risk of the gRNA accidentally binding with part of the patient's genome, the researchers selected nucleotide sequences that do not appear in any coding sequences of human DNA, thereby avoiding off-target effects and subsequent cellular DNA damage.

The editing process was successful in a number of cell types that can harbor HIV-1 – including microglia and macrophages, as well as in T-lymphocytes. "T-cells and monocytic cells are the main cell types infected by HIV-1, so they are the most important targets for this technology," Dr. Khalili said.
The HIV-1 eradication approach faces several significant challenges before the technique is ready for patients, Dr. Khalili said. The researchers must devise a method to deliver the therapeutic agent to every single infected cell. Finally, because HIV-1 is prone to mutations, treatment may need to be individualized for each patient's unique viral sequences.
"We are working on a number of strategies so we can take the construct into preclinical studies," Dr. Khalili said. "We want to eradicate every single copy of HIV-1 from the patient. That will cure AIDS. I think this technology is the way we can do it."

Last week, a report by the United Nations claimed that AIDS could be brought under control by 2030.
Posted by Tanaji Gude On 12:19
 Researchers from the University of Bradford have devised a simple blood test that can be used to diagnose whether people have cancer or not.

The test will enable doctors to rule out cancer in patients presenting with certain symptoms – saving time, and preventing costly and unnecessary invasive procedures such as colonoscopies and biopsies being carried out. Alternatively, it could be a useful aid for investigating patients who are suspected of having a cancer that is currently hard to diagnose.

Early results have shown the method gives a high degree of accuracy diagnosing cancer and pre-cancerous conditions from the blood of patients with melanoma, colon cancer and lung cancer. The Lymphocyte Genome Sensitivity (LGS) test looks at white blood cells and measures the damage caused to their DNA when subjected to different intensities of ultraviolet light (UVA), which is known to damage DNA. The results of the empirical study show a clear distinction between the damage to the white blood cells from patients with cancer, with pre-cancerous conditions and from healthy patients.
The research was led by Professor Diana Anderson, from the University’s School of Life Sciences, who says: “White blood cells are part of the body’s natural defense system. We know that they are under stress when they are fighting cancer or other diseases, so I wondered whether anything measurable could be seen if we put them under further stress with UVA light. We found that people with cancer have DNA which is more easily damaged by ultraviolet light than other people, so the test shows the sensitivity to damage of all the DNA – the genome – in a cell.”
The study looked at blood samples taken from 208 individuals. Ninety-four healthy individuals were recruited from staff and students at the University and 114 blood samples were collected from patients referred to specialist clinics within Bradford Royal Infirmary prior to their diagnosis and treatment. The samples were coded, anonymity, randomized and then exposed to UVA light through five different depths of agar. 
UVA damage was observed in the form of DNA fragments being pulled in an electric field towards the positive end of the field, causing a comet-like tail. During the LGS test, the longer the tail the more DNA damage, and the measurements correlated to those patients who were ultimately diagnosed with cancer (58), those with pre-cancerous conditions (56) and those who were healthy (94).

“These are early results completed on three different types of cancer and we accept that more research needs to be done; but these results so far are remarkable,” said Prof. Anderson. "Whilst the numbers of people we tested are, in epidemiological terms, quite small, in molecular epidemiological terms, the results are powerful. We’ve identified significant differences between the healthy volunteers, suspected cancer patients and confirmed cancer patients of mixed ages at a statistically significant level of P<0.001. This means that the possibility of these results happening by chance is 1 in 1000. We believe that this confirms the test’s potential as a diagnostic tool.”

Professor Anderson believes that if the LGS proves to be a useful cancer diagnostic test, it would be a highly valuable addition to the more traditional investigative procedures for detecting cancer. A clinical trial is currently underway at Bradford Royal Infirmary. This will investigate the effectiveness of the LGS test in correctly predicting which patients referred by their GPs with suspected colorectal cancer would, or would not, benefit from a colonoscopy – currently the preferred investigation method. The University of Bradford has filed patents for the technology and a spin-out company, Oncascan, has been established to commercialize the research.
Posted by Tanaji Gude On 12:04

Fully autonomous weapons, or “killer robots,” would jeopardize basic human rights, whether used in wartime or for law enforcement, Human Rights Watch said in a report released yesterday, on the eve of the first multilateral meeting on the subject at the United Nations.

The 26-page report, “Shaking the Foundations: The Human Rights Implications of Killer Robots,” is the first report to assess in detail the risks posed by these weapons during law enforcement operations – expanding the debate beyond the battlefield. Human Rights Watch found that fully autonomous weapons threaten rights and principles under international law as fundamental as the right to life, the right to a remedy, and the principle of dignity.
“In policing, as well as war, human judgment is critically important to any decision to use a lethal weapon,” said Steve Goose, arms division director. “Governments need to say no to fully autonomous weapons for any purpose and to preemptively ban them now, before it is too late.”
International debate over fully autonomous weapons has previously focused on their potential role in armed conflict and questions over whether they would comply with international humanitarian law, also called the laws of war. Human Rights Watch, in this new report, examines the potential impact of fully autonomous weapons under human rights law, which applies during peacetime as well as armed conflict.

Nations must adopt a preemptive international ban on these weapons, which could identify and fire on targets without meaningful human intervention, Human Rights Watch said. Countries are pursuing ever-greater autonomy in weapons, and precursors already exist.
The release of the report, co-published with Harvard Law School’s International Human Rights Clinic, coincides with the first ever multilateral meeting on the weapons. Many of the 117 countries that joined the Convention on Conventional Weapons will attend the meeting of experts on lethal autonomous weapons systems at the United Nations in Geneva this week. Members of the convention agreed at their annual meeting in November 2013 to begin work on the issue in 2014.
Human Rights Watch believes the agreement to work on these weapons in the Convention on Conventional Weapons forum could eventually lead to new international law prohibiting fully autonomous weapons. The convention preemptively banned blinding lasers in 1995.
Human Rights Watch is a founding member and coordinator of the Campaign to Stop Killer Robots. This coalition of 51 nongovernmental organizations in two dozen countries calls for a preemptive ban on the development, production, and use of fully autonomous weapons.
Human Rights Watch issued its first report on the subject, “Losing Humanity: The Case against Killer Robots,” back in November 2012. In April 2013, Christ of Hens – UN special reporter on extrajudicial, summary or arbitrary executions – issued a report citing a range of objections to the weapons, and called for all nations to adopt national moratorium and begin international discussions about how to address them.
Fully autonomous weapons could be prone to killing people unlawfully because these weapons could not be programmed to handle every situation, Human Rights Watch found. According to robot experts, there is little prospect that these weapons would possess human qualities, such as judgment, that facilitate compliance with the right to life in unforeseen situations.
Fully autonomous weapons would also undermine human dignity, Human Rights Watch said. These inanimate machines could not understand or respect the value of life, yet they would have the power to determine when to take it away.
Serious doubts exist about whether there could be meaningful accountability for the actions of a fully autonomous weapon. There would be legal and practical obstacles to holding anyone – a superior officer, programmer, or manufacturer – responsible for a robot’s actions. Both criminal and civil law are ill suited to the task, Human Rights Watch found.
“The accountability gap would weaken deterrence for future violations,” said Bonnie Docherty, senior researcher in the arms division at Human Rights Watch and lecturer at the Harvard clinic as well as author of the report. “It would be very difficult for families to obtain retribution or remedy for the unlawful killing of a relative by such a machine.”

The human rights impacts of killer robots compound a host of other legal, ethical, and scientific concerns – including the potential for an arms race, prospect of proliferation, and questions about their ability to protect civilians adequately on the battlefield or the street, Human Rights Watch found.