New lead on deadly pancreatic cancer

Mouse model reveals mechanism of potential therapy for lethal tumours.

cancer cellA clinical trial run in both mice and humans has examined a new way to attack pancreatic cancer.STEVE GSCHMEISSNER / SCIENCE PHOTO LIBRARY

There are currently no effective weapons against pancreatic ductal adenocarcinoma, for which death usually follows diagnosis by just months.

But scientists have stumbled across an unexpected way to break through the cancer’s formidable defences in clinical trials involving humans and, unusually, mice. Their results are published today in Science1.

Robert Vonderheide, an immunologist at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia, and his team activated immune cells that chewed holes in the protective shell, or stroma, that the pancreatic cancer builds around itself, and attacked the tumour cells.

Surprisingly, the immune cells involved were not the usual suspects — sophisticated anti-tumour T cells — but more primitive cells called macrophages.

“This opens up a fresh set of possibilities for seeking new treatments,” says Terry Van Dyke, head of the Mouse Cancer Genetics Program at the National Cancer Institute in Frederick, Maryland, who was not involved in the study. “It’s a clear indication that activating macrophages will be efficacious.”

Breaking the barrier

It is the unusually tough stroma surrounding pancreatic ductal adenocarcinomas that is responsible for the disease’s poor prognosis. Not only is it almost entirely impenetrable to drugs, but it also becomes enmeshed with white blood cells that prevent the immune system from launching its own attack on the cancer.

Others have designed molecular strategies to attack the stroma in the hope of facilitating drug access, and these are currently being tested in the clinic. But the stromal assault by Vonderheide’s team occurred inadvertently.

The authors’ original intention was to try to counteract the stroma’s immunosuppressive actions by activating the protein CD40. This protein activates many types of immune cell, although it is best known for its ability to activate anti-tumour T cells. And it was on these that the scientists focused their attention, expecting the activated T cells to slip through the stroma and target the cancer.

They carried out a clinical trial on 21 patients with inoperable pancreatic cancer who were being treated with gemcitabine, the standard chemotherapy drug for the disease. They gave the patients additional injections of an experimental CD40-activating antibody.

On average, the 21 patients survived several weeks longer than would have been expected without the antibody treatment, and four patients exhibited temporary regression of their tumours. The authors examined biopsies from two of the shrunken tumours under the microscope and found them stuffed with macrophages but devoid of T cells.

“Even before the patient trial had finished, we realised that the therapy was looking successful, but perhaps not for the reasons we had imagined,” says Vonderheide.

Antibody action

To establish the underlying mechanism, the scientists turned to mice that had been genetically engineered to develop a cancer similar to human pancreatic ductal adenocarcinoma. They were able to repeat the human trial in the animals, with a full set of controls, and subject them to more detailed and invasive examinations.

They treated one set of animals with gemcitabine and a mouse version of the CD40-activating antibody, and other sets with gemcitabine alone, antibody alone or no drugs. Tumours regressed in 30% of mice treated with the antibody — whether or not they had also received gemcitabine. “It was also a surprise to find that gemcitabine itself was not contributing much to the therapeutic effect,” says Vonderheide.

The authors then took a close look at how the immune systems of the mice, and their tumours, had responded to CD40 activation.

“The antibody did actually cause T cells to be activated, but for some reason they remained in lymph nodes and didn’t migrate to the tumours,” says Vonderheide. Instead, they found activated macrophages swarming into tumours, he says — and also hanging around the stroma, which started to curl inwards and break down.

“This discovery could never have been made without using a mouse model of the cancer to dissect out the mechanism in detail,” says Van Dyke, who recently moved to the National Cancer Institute to start a big translational medicine programme that will similarly match patient and mouse clinical trials in several cancers. Many such efforts are springing up around the world, including a large programme at Harvard in Cambridge, Massachusetts, launched with US stimulus money.

“Despite a lot of effort, only one new drug, erlotinib, has been approved by the Food and Drug Administration in the last decade for metastatic pancreatic cancer, and that only prolongs life by two weeks,” says Vonderheide. “Maybe our discovery will lead to new ideas about how to manipulate the immune system for best therapeutic effect.”

source: nature oncology

Bone Marrow Histopathology in POEMS Syndrome: A Distinctive Combination of Plasma Cell, Lymphoid and Myeloid Findings

POEMS is an uncommon syndromic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell dyscrasia and skin changes. There are few descriptions of the bone marrow pathology of POEMS; therefore peripheral blood smears and bone marrow aspirates and biopsies from 87 patients (143 total, 67 pre-treatment, 76 post-treatment cases) with POEMS were studied. Plasma cell clonality was analyzed by flow cytometry, immunohistochemistry and/or in-situ hybridization. Monotypic plasma cells were detected in 44 pre-treatment cases (66%); the majority of expressed lambda light chain (91%). The monotypic plasma cells were typically present in a background of increased polytypic plasma cells. Lymphoid aggregates were found in 33 (49%) pre-treatment cases and in most cases were rimmed by plasma cells (97%). Megakaryocyte hyperplasia (36 cases) and clusters (62 cases) were frequent, however none of 43 cases tested had the JAK2V617F mutation. In summary, we have identified a novel constellation of features that should trigger POEMS syndrome as part of the differential diagnosis. The constellation of lambda restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates and megakaryocytic hyperplasia in a bone marrow is highly suggestive of this diagnosis, especially in the context of a peripheral neuropathy.

source: oncostat

MIT scientist announces first “practical” artificial leaf


Rather than using nuclear, wind, or fossil fuel power, homes of the future might be powered by leaves – artificial ones, that is, designed to mimic the process by which plants draw energy from the sun.

The latest breakthrough comes from Daniel Nocera (pictured), a chemist at the Massachusetts Institute of Technology, Cambridge, Massachusetts, who has unveiled a prototype solar-powered device the size of a playing card that can break water down into hydrogen and oxygen – valuable fuels for producing electricity via fuel cells.

Previously Nocera had developed a catalyst that could do so with the low-voltage output from a solar cell, a major breakthrough in and of itself, since normally electrolysis (the process of breaking water into hydrogen and oxygen with electricity) requires higher voltage than can easily be produced with solar cells. But Nocera’s new “artificial leaf” combines the a the solar cell and the electrolysis unit into one piece by chemically painting the catalyst onto a solar cell and immersing it in water.

“We could put it in a bottle of water, hold it up to the sun, and you would start seeing hydrogen and oxygen bubbles coming off,” Nocera said at a press conference today at a meeting of the American Chemical Society, in Anaheim, California.

The chemistry is complex but is similar “from a systems engineering sense” to the manner in which leaves generate energy from sunlight. In plants, the energy of incoming sunlight is first used to produce electrons and positive charges within the leaf. These are then used to split water into oxygen and hydrogen (the latter being trapped as carbohydrates, rather than released into the air). “Whether you realize it or not, leaves are buzzing with electricity,” Nocera says. “They just don’t’ have any wires.”

In his artificial leaf, a silicon chip, similar to those used in conventional solar cells, produces electrons and positively charged holes. Then catalysts on the chip use this low-voltage current to produce oxygen and hydrogen – one gas on each side of the chip.

It’s not a new concept. The first such device was made in 1998 by John Turner, of the U.S. National Renewable Energy Laboratory in Boulder, Colorado. “But it used “really expensive materials,” Nocera says. “Things like NASA would use.”

His new device, on the other hand, uses abundant cheap materials, “The word here is practical,” he says.

But it’s still a few years from commercialization. “There’s got to be some tricky engineering to collect the gases as they’re coming off the silicon,” he says. “We don’t know how to do that yet.”

Meanwhile, however, his catalyst is under development as a way to power third world houses with fuel cells, fed by conventional solar panels. “By the end of 2011, we’re going to have prototypes of that on the ground, probably in India.” Nocera is reported to have struck a deal with India’s sprawling Tata group which is interested in the technology, though the details have not been disclosed.

The latest version of Nocera’s technology is of commercial interest because, by integrating the catalyst with the chips, it dispenses with the need for traditional solar panels. That, he says, will cut costs considerably, by eliminating wires, etc. “The price of the silicon of a solar panel isn’t much,” he says. “A lot of the cost is the wiring. What this does is get rid of all that.”

“The real goal here,” he adds, “is giving energy to the poor” – especially, he notes, in rural Africa, India, and China.

Even better, he adds, the device doesn’t need ultrapure water. “You can use nature water sources, which is a big deal in parts of the world where it’s costly to have to use pure water.”

Turner agrees. If the process works, he says, it’s a good candidate for meeting the U.S. Department of Energy’s ‘SunShot’ initiative for developing solar power at investment costs of $1 per watt or less. And they may also be a “path forward” toward a carbon-free hydrogen economy, he says.

source: nature

Virus-eater’ discovered in Antarctic lake

First of the parasitic parasites to be discovered in a natural environment points to hidden diversity.


Viruses from Organic lake, including the virophage (bottom left) and its prey (top).From reference 1

A genomic survey of the microbial life in an Antarctic lake has revealed a new virophage — a virus that attacks viruses. The discovery suggests that these life forms are more common, and have a larger role in the environment, than was once thought.

An Australian research team found the virophage while surveying the extremely salty Organic Lake in eastern Antarctica. While sequencing the collective genome of microbes living in the surface waters, they discovered the virus, which they dubbed the Organic Lake Virophage (OLV).

The OLV genome was identified nestling within the sequences of phycodnaviruses — a group of giant viruses that attack algae. Evidence of gene exchange, and possible co-evolution, between the two suggests that OLV preys on the phycodnavirus. Although OLV is the dominant virophage in the lake, the work suggests others might be present.

By killing phycodnaviruses, the OLV might allow algae to thrive. Ricardo Cavicchioli, a microbiologist at the University of New South Wales in Sydney, Australia, and his colleagues found that mathematical models of the Organic Lake system that took account of the virophage’s toll on its host showed lower algal mortality and more blooms during the lake’s two ice-free summer months.

“Our work reveals not only an amazing diversity in microbial life in this lake, but also how little we understand about the complexity of the biological functions at work,” says Cavicchioli. The findings are published in the Proceedings of the National Academies of Science1.

Giant killer

Another virophage described this month has similar ecological effects. The marine Mavirus attacks the giant Cafeteria roenbergensis virus, which preys on Cafeteria roenbergensis, one of the world’s most widespread species of zooplankton2.

“The Mavirus is able to rescue the infected zooplankton — which, in a way, confers immunity from infection,” says Curtis Suttle, a marine microbiologist at the University of British Columbia in Vancouver, Canada, and leader of the team that discovered the Mavirus.

“We unknowingly had Mavirus in culture with our Cafeteria system since the early 1990s,” says Suttle. But the virophage was not identified until the Cafeteria genome was sequenced.

The Mavirus genome is similar to DNA sequences called eukaryotic transposons, which insert themselves within the genomes of multicellular organisms such as plants and animals. These ‘jumping genes’ may be descended from a virophage, says Suttle. “One can imagine evolutionary pressure for hosts to somehow cultivate virophages to protect themselves from infection by giant viruses,” he says.

French Sputnik

The first virophage, dubbed Sputnik, was discovered in a water-cooling tower in Paris in 20083.

“We have been waiting for others to find virophages, to confirm our discovery wasn’t an artefact,” says Christelle Desnues, a microbiologist at the National Centre of Scientific Research in Marseilles, France, and a member of the team that described Sputnik. She now anticipates “an exponential discovery of virophages”.

The hosts of all three known virophages belong to a group of giant viruses known as nucleocytoplasmic large DNA viruses (NCLDV). “NCLDV viruses have large and complex genomes that allow them to incorporate the smaller virophages, something smaller viruses may not be able to do,” says Desnues.

The OLV was discovered when Cavicchioli’s graduate student, Sheree Yau, noticed that some of the sequences from microbes in Organic Lake were similar to those encoding Sputnik’s protein shell. Mavirus has similar sequences, so the trend might help to identify other virophages.

OLV, or virophages like it, may be widespread. The gene for its protein shell matches sequences already found in a host of other aquatic environments, including nearby Ace Lake in Antarctica, a saline lagoon in the Galapagos, an oceanic upwelling zone near the Galapagos, an estuary in New Jersey, and a freshwater lake in Panama.

The high number of matches reflects the fact that the OLV is the first virophage to be found in its natural environment, says Federico Lauro, also a molecular biologist at the University of New South Wales and a co-author of the paper.

Organic Lake, formed 6,000 years ago when sea levels were higher, is a natural laboratory, says Lauro. “These marine-derived lakes are great labs to work in because they are isolated, yet dynamic systems.”

source: nature

Osteoarthritis of the Hip or Knee Raises Mortality Risk

Excess all-cause mortality was observed in OA patients.

Little is known about causes of death in people with hip or knee osteoarthritis (OA). In this population-based cohort study, investigators assessed all-cause and disease-specific mortality in 1163 patients (age, 35) with symptomatic, x-ray–confirmed hip or knee OA who were seen in general practices in southwest England.

After median follow-up of 14 years, excess all-cause mortality was observed in patients with OA compared with the general population. Similarly, excess cardiovascular-, cancer-, and dementia-associated mortality was observed in OA patients compared with the general population. Several baseline characteristics of OA patients were associated independently with higher all-cause mortality: advanced age, male sex (hazard ratio, 1.6), diabetes (HR, 2.0), cancer (HR, 2.3), cardiovascular disease (HR, 1.4), and walking disability (HR, 1.5). In fact, mortality rose with increasing severity of walking disability.

Comment: In this study, patients with hip or knee OA had higher risk for death than did the general population. The authors speculate that less physical activity, smoldering inflammation, and use of nonsteroidal anti-inflammatory drugs (and resultant higher cardiovascular risk) might account for the elevated risk. Although these results suggest that patients with OA should be more physically active, the pain and disability of OA and practical issues such as the costs of joining a gym make this difficult for many patients.

Source:Journal Watch General Medicine


Atorvastatin Linked to Small Increase in Risk for Type 2 Diabetes

Atorvastatin seems to carry a “slight increase in the risk” for new-onset type 2 diabetes, according to an analysis of three large trials published in the Journal of the American College of Cardiology.

Researchers were responding to a 2010 Lancet meta-analysis, which found a small but measurable risk for new-onset diabetes after all statin use. The current analysis focuses on atorvastatin’s effects in the TNT, IDEAL, and SPARCL trials. It found that atorvastatin, when compared with placebo in the SPARCL trial, carries a higher risk for diabetes. In the other trials, there was a slightly increased risk when an 80-mg dose was compared with lower doses (10-mg atorvastatin in TNT, 20-mg simvastatin in IDEAL), but the differences did not achieve statistical significance.

The JACC authors conclude (as did the authors of the Lancet meta-analysis) that the benefits of statins “far outweigh the risks.”

source: JACC

Prostaglandin D2 and adenosine as endogenous somnogens

Prostaglandin D2 (PGD2) is the most potent endogenous sleep-promoting substance thus far reported. We have extensively studied its action mechanism at the molecular level. PGD2 is produced by lipocalin-type PGD synthase, which is dominantly localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain; and it is secreted into the cerebrospinal fluid and stimulates DP1 receptors localized in the arachnoid membrane of the ventral surface from the basal forebrain to the hypothalamus to increase the extracellular concentration of adenosine as a paracrine sleep-promoting molecule. Adenosine diffuses into the brain parenchyma, suppresses cholinergic arousal neurons in the basal forebrain via adenosine A1 receptors, activates sleep-active neurons in the ventrolateral preoptic area via adenosine A2A receptors, and concomitantly suppresses the histaminergic arousal center in the tuberomammillary nucleus through GABAergic and galaninergic inhibitory projections. Administration of an inhibitor of lipocalin-type PGD synthase (SeCl4), an antagonist of DP1 receptors (ONO-4127Na) or an antagonist of adenosine A2A receptors (caffeine) results in sleep inhibition in rats and mice, indicating that the PGD2–adenosine system is crucial for the maintenance of physiological sleep.

source: Sleep and Biological Rhythms

What are the mechanisms activating the sleep-active neurons located in the preoptic area?

The purpose of this review is to outline the mechanisms responsible for the induction and maintenance of slow-wave sleep (SWS, also named non–rapid eye movement or non-REM sleep). The latest hypothesis on the mechanisms by which cortical activity switches from an activated state during waking to a synchronised state during SWS is presented. It is proposed that the activated cortical state during waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic and hypocretin systems located at different subcortical levels. In contrast, the neurons inducing SWS are mainly localized in the ventrolateral preoptic (VLPO) and median preoptic nuclei. These neurons use the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The notion that the switch from waking to SWS is due to the inhibition of the waking systems by the VLPO sleep-active neurons is introduced. At the onset of sleep, the sleep neurons are activated by the circadian clock localized in the suprachiasmatic nucleus and a powerful hypnogenic factor, adenosine, which progressively accumulates in the brain during waking.

source: Sleep and Biological Rhythms


Are All Statins the Same : Focus on the Efficacy and Tolerability of Pitavastatin

da Silva PM – Pitavastatin, the latest addition to the statin family, produces potent and consistent beneficial effects on lipids, is well tolerated, and has a favorable pharmacokinetic profile. The combination of a potent decrease in total and low-density lipoprotein (LDL) cholesterol levels and increase in high-density lipoprotein (HDL) cholesterol levels suggest that pitavastatin may produce substantial cardiovascular protection.

  • Pitavastatin is approved as adjunctive therapy to diet to reduce elevated levels of total cholesterol, LDL cholesterol, apolipoprotein (Apo) B, and triglycerides and to increase levels of HDL cholesterol in adult patients with primary hyperlipidemia or mixed dyslipidemia.
  • Pitavastatin undergoes minimal metabolism by cytochrome P450 (CYP) enzymes and, therefore, has a low propensity for drug-drug interactions with drugs metabolized by CYP enzymes or the CYP3A4 substrate grapefruit juice.
  • In clinical trials, pitavastatin potently and consistently reduced serum levels of total, LDL, and non-HDL cholesterol, and triglycerides in patients with primary hypercholesterolemia where diet and other non-pharmacological measures were inadequate.
  • Mean reductions from baseline in serum total and LDL cholesterol and triglyceride levels were 21-32%, 30-45%, and 10-30%, respectively.
  • A consistent trend towards increased HDL cholesterol levels of 3–10% was seen.
  • Long-term extension studies show that the beneficial effects of pitavastatin are maintained for up to 2 years.
  • Pitavastatin produces reductions from baseline in serum total and LDL cholesterol levels to a similar extent to those seen with the potent agent atorvastatin and to a greater extent than those seen with simvastatin or pravastatin.
  • Studies comparing pitavastatin and atorvastatin have shown no significant differences in the favorable effects on lipid parameters, although pitavastatin was consistently associated with trends towards increased HDL cholesterol levels.
  • Pitavastatin produces beneficial effects on lipids in patients with type 2 diabetes mellitus and metabolic syndrome without deleterious effects on markers of glucose metabolism, such as fasting blood glucose levels or proportion of glycosylated hemoglobin.
  • Pitavastatin appears to exert a number of beneficial effects on patients at risk of cardiovascular events independent of lipid lowering.
  • In the JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) study, pitavastatin was non-inferior to atorvastatin at reducing plaque volume in patients with ACS undergoing percutaneous coronary intervention.
  • Beneficial effects, including favorable effects on the size and composition of atherosclerotic plaques, improvements in cardiovascular function, and improvements in markers of inflammation, oxidative stress, and renal function, have been demonstrated in a number of small studies.
  • Pitavastatin is generally well tolerated in hyperlipidemic patients with or without type 2 diabetes, with the most common treatment-related adverse events being musculoskeletal or gastrointestinal in nature.
  • Increases in plasma creatine kinase levels were seen in <5% of pitavastatin recipients and the incidence of myopathy or rhabdomyolysis was extremely low.

source: American journal of cardiovascular drugs

What Can Medical Education Learn From the Neurobiology of Learning?

The last several decades have seen a large increase in knowledge of the underlying biological mechanisms that serve learning and memory. The insights gleaned from neurobiological and cognitive neuroscientific experimentation in humans and in animal models have identified many of the processes at the molecular, cellular, and systems levels that occur during learning and the formation, storage, and recall of memories. Moreover, with the advent of noninvasive technologies to monitor patterns of neural activity during various forms of human cognition, the efficacy of different strategies for effective teaching can be compared. Considerable insight has also been developed as to how to most effectively engage these processes to facilitate learning, retention, recall, and effective use and application of the learned information. However, this knowledge has not systematically found its way into the medical education process. Thus, there are considerable opportunities for the integration of current knowledge about the biology of learning with educational strategies and curricular design. By teaching medical students in ways that use this knowledge, there is an opportunity to make medical education easier and more effective. The authors present 10 key aspects of learning that they believe can be incorporated into effective teaching paradigms in multiple ways. They also present recommendations for applying the current knowledge of the neurobiology of learning throughout the medical education continuum.

source: Association of American Medical Colleges