Cancer cells have long been known to have higher rates of the energy-generating metabolic pathway known as glycolysis. This enhanced glycolysis, a phenomenon known as the Warburg effect, is thought to allow cancer cells to survive the oxygen-deficient conditions they experience in the centre of solid tumours. A study reveals how damaged cells normally switch off glycolysis as they shut down and shows that defects in this process may contribute to the early stages of tumour development.
Various stresses can cause cells to cease proliferating and enter an inactive state known as ‘senescence’ that prevents their transformation into tumour cells. In 2005, Hiroshi Kondoh and colleagues found that cells normally limit glycolysis as they enter senescence and that increasing the levels of the glycolytic enzyme PGAM can prevent cells from exiting the cell cycle. PGAM is increased in many tumours, stimulating glycolysis and other important pathways. But how cells regulate PGAM has been unclear.
Working at Kyoto University in Japan, Kondoh and colleagues followed up on their previous work and found that, in response to DNA damage or oncogene expression, PGAM was degraded, thereby inhibiting glycolysis as the cells entered senescence. The enzyme Mdm2 targeted PGAM for degradation in response to these senescence-inducing stresses.
‘Mdm2 can clearly, in some cases, act as a tumor suppressor by destabilizing PGAM,’ says Kondoh. Recent studies have emphasized the importance of PGAM as a therapeutic target for cancer management. Identifying the modulators of PGAM stability might open up new avenues for intervention. EurekAlert

Finnish healthcare company Biohit Oyj and Randox Laboratories have signed a licensing agreement which gives Randox the worldwide licensing rights for GastroPanel developed by Biohit. GastroPanel is a simple, non-invasive blood test for the diagnosis and screening of gastric disorders. GastroPanel test reliably detects H. pylori infection and damage or dysfunction of the stomach mucosa (atrophic gastritis), leading to acid-free stomach. According to the latest studies, non-acid stomach is a remarkable risk factor for gastric and esophageal cancer. GastroPanel is a non-invasive blood test that reliably identifies both healthy and unhealthy stomachs as well as helps to prioritize patients for further examinations. According to Biohit Oyj CEO Semi Korpela, “The combination of GastroPanel reagents with Randox analysers opens up new distribution possibilities for both companies”. Dr. Peter FitzGerald CBE, Managing Director of Randox, comments “The addition of the Biohit GastroPanel will add significantly to the range of diagnostic products we offer. Our ability to deliver these biomarkers to healthcare providers using our Biochip Array systems will enable diagnosis of gastric disorders in patients with dyspepsia ensuring appropriate further investigation and treatment and contribute to a reduction in healthcare costs. The GastroPanel will be offered in Randox analysers used in hospitals and reference laboratories through our global distribution network in 145 countries.”

A research team from Weill Cornell Medical College and The Rockefeller University has identified a bacterium it believes may trigger multiple sclerosis (MS), a chronic, debilitating disorder that damages myelin forming cells in the brain and spinal cord.
Their study is the first to identify the bacterium, Clostridium (C.) perfringens type B, in humans.
The scientists say their study is small and must be expanded before a definitive connection between the pathogen and MS can be made, but they also say their findings are so intriguing that they have already begun to work on new treatments for the disease.
‘This bacterium produces a toxin that we normally think humans never encounter. That we identified this bacterium in a human is important enough, but the fact that it is present in MS patients is truly significant because the toxin targets the exact tissues damaged during the acute MS disease process,’ say the study’s first author, K. Rashid Rumah, an MD/PhD student at Weill Cornell Medical College, and the study’s senior investigator, Dr. Timothy Vartanian, professor of neurology and neuroscience at Weill Cornell Medical College and director of the Judith Jaffe Multiple Sclerosis Center at New York-Presbyterian Hospital/Weill Cornell Medical Center.
‘While it is clear that new MS disease activity requires an environmental trigger, the identity of this trigger has eluded the MS scientific community for decades,’ Dr. Vartanian says. ‘Work is underway to test our hypothesis that the environmental trigger for MS lays within the microbiome, the ecosystem of bacteria that populates the gastrointestinal tract and other body habitats of MS patients.’
The study describes discovery of C. perfringens type B in a 21-year-old woman who was experiencing a flare-up of her MS.
The woman was part of the Harboring the Initial Trigger for MS (HITMS) observational trial launched by Dr. Vartanian and K. Rashid Rumah, who works both with Dr. Vartanian and with co-author Dr. Vincent Fischetti at The Rockefeller University.
C. perfringens, found in soil, is one of the most common bacteria in the world. It is divided into five types. C. perfringens type A is commonly found in the human gastrointestinal tract and is believed to be largely harmless.
C. perfringens types B and D carry a gene (epsilon toxin) that emits a protoxin — a non-active precursor form of the toxin — which is turned into the potent ‘epsilon’ toxin within the intestines of grazing animals. The epsilon toxin travels through the blood to the brain, where it damages brain blood vessels and myelin, the insulation protecting neurons, resulting in MS-like symptoms in the animals. While the D subtype has only been found in two people, based on prior studies by other investigators, the B subtype had never been found in humans.
Nevertheless, Rumah and the research team set out to see if subtypes B or D exist in humans and if they are associated with MS. They tested banked blood and spinal fluid from both MS patients and healthy controls for antibody reactivity to the epsilon toxin. Investigators found that levels of epsilon toxin antibodies in MS patients were 10 times higher than in the healthy controls — the blood of only one out of 100 control participants showed an immune reaction to the toxin.
The team also examined stool samples from both MS patients and healthy controls enrolled in the HITMS clinical study, and found that 52 percent of healthy controls carried the A subtype compared to 23 percent of MS patients. ‘This is important because it is believed that the type A bacterium competes with the other subtypes for resources, so that makes it potentially protective against being colonised by epsilon toxin secreting subtypes and developing MS,’ say Rumah and Vartanian.
The search by investigators for evidence of C. perfringens type B paid off in the case of a young MS patient. Co-author Dr. Jennifer Linden, a microbiologist at Weill Cornell Medical College, isolated the actual bacterium from the patient’s stool.
The authors suspect that once a human is infected with C. perfringens type B or D, the pathogen usually lives in the gut as an endospore, a seed-like structure that allows some bacteria to remain dormant for long periods. ‘The human gastrointestinal tract is host to approximately 1,000 different bacterial species, but is not a hospitable environment for C. perfringens type B or D, so it does not grow well there. It hibernates in a protective spore. When it does grow, we anticipate it generates a small quantity of epsilon toxin, which travels through the blood into the brain,’ Dr. Vartanian says. ‘We believe the bacterium’s growth is episodic, meaning the environmental trigger is always present, and it rears its ugly head from time to time.’
He says researchers do not know how humans are infected with C. perfringens type B or D, but they are studying potential routes of exposure. The scientists are also in the first stages of investigating potential treatments against the pathogen. Weill Cornell Medical College

Our understanding of the biological processes that cause cancer is limited. UV light and smoking are two well-understood cancer-causing processes. Exposure to either of these processes causes distinguishable patterns of genetic damage, or ‘signatures’, on the genome that can lead to cancer. All cancer-causing processes leave their own distinct imprint or signature, on the genomes of cancer cells.
The APOBEC family of genes control enzymes that are believed to have evolved in humans to fight off viral infections. Scientists have speculated that these enzymes are responsible for a very distinct signature of mutations that is present in approximately half of all cancer types. Therefore, understanding the cancer-causing process behind this common genetic signature is pivotal for disease control and prevention.
The team studied the genomes of breast cancers in patients with a specific inherited deletion in two of these APOBEC genes. They found that these cancer genomes had a much greater prevalence of the distinct mutational signature that is thought to be driven by the APOBEC family of genes.
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‘The increased frequency of this common cancer signature in breast cancer patients with APOBEC gene abnormalities supports our theory that these enzymes play a role in generating this mutational signature,’ says Dr Serena Nik-Zainal, first author from the Wellcome Trust Sanger Institute.
This genetic deletion is found on chromosome 22 where the APOBEC genes, APOBEC3A and APOBEC3B, sit next to each other. Women with this genetic deletion have previously been reported to be more susceptible to breast cancer.
The team examined 923 samples of breast cancer from women from across the world and found more than 140 people with either one or two copies of the deletion on each chromosome. Breast cancer in women with the deletion had a much greater quantity of mutations of this particular genetic signature.
However, the mutational activity of the APOBEC genes appears to be a double-edged sword. This genetic deletion is much more prevalent in some populations than others: it is found in only 8 per cent of Europeans, but is present in 93 per cent of the population of Oceania. Although this deletion increases risk of cancer development, it also seems to provide a currently unknown advantage in populations where it is more common. Wellcome Trust Sanger Iinstitute

A team of researchers has brought new clarity to the picture of how gene-environmental interactions can kill nerve cells that make dopamine. Dopamine is the neurotransmitter that sends messages to the part of the brain that controls movement and co-ordination. Their discoveries include identification of a molecule that protects neurons from pesticide damage.

‘For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death,’ says Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study.

Until now, the link between pesticides and Parkinson’s disease was based mainly on animal studies and epidemiological research that demonstrated an increased risk of disease among farmers, rural populations, and others exposed to agricultural chemicals.

In the new study, Lipton, along with Rajesh Ambasudhan, Ph.D., research assistant professor in the Del E. Webb Center, and Rudolf Jaenisch, M.D., founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology (MIT), used skin cells from Parkinson’s patients that had a mutation in the gene encoding a protein called alpha-synuclein. Alpha-synuclein is the primary protein found in Lewy bodies—protein clumps that are the pathological hallmark of Parkinson’s disease.

Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then ‘corrected’ the alpha-synuclein mutation in other cells. Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson’s disease, called A9 dopamine-containing neurons—thus creating two sets of neurons—identical in every respect except for the alpha-synuclein mutation.

‘Exposing both normal and mutant neurons to pesticides—including paraquat, maneb, or rotenone—created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death,’ said Frank Soldner, M.D., research scientist in Jaenisch’s lab and co-author of the study.

‘In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels,’ said Scott Ryan, Ph.D., researcher in the Del E. Webb Center and lead author of the paper.

Having access to genetically matched neurons with the exception of a single mutation simplified the interpretation of the genetic contribution to pesticide-induced neuronal death. In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway—called MEF2C-PGC1alpha—that normally protects neurons that contain dopamine. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected the nerve cells from the pesticides.

‘Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect of free radicals on the pathway,’ said Ambasudhan. ‘One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson’s.’ Sanford-Burnham Medical Research Institution