Ralph A. DeFronzo, MD, and colleagues recruited 602 adults with IGT to study whether pioglitazone (Actos, Takeda) could reduce the risk for type 2 diabetes. Patients were randomly assigned to pioglitazone, at 30 mg per day and increased to 45 mg per day after 1 month, or placebo for a mean 2.4 years.

After follow-up, the pioglitazone group had an annual incidence rate for type 2 diabetes of 2.1% vs. the placebo group’s 7.6%. The researchers calculated a hazard ratio for conversion to diabetes in the pioglitazone group of 0.28 (95% CI, 0.16-0.49). According to the researchers, the decreased rate of conversion to diabetes was “slightly larger than that observed with other thiazolidinediones (52% to 62%) and lifestyle modification (58%).”

Nearly half (48%) of the pioglitazone group converted from IFG to normal glucose tolerance compared with 28% of the placebo group (P<.001). In addition, compared with placebo, pioglitazone significantly reduced levels of fasting glucose (11.7 mg/dL vs. 8.1 mg/dL), 2-hour glucose (30.5 mg/dL vs. 15.6 mg/dL) and HbA1c (–0.04% vs. 0.2%).

Other positive findings associated with pioglitazone therapy included decreased diastolic blood pressure (20 mm Hg vs. 0 mm Hg), reduced carotid intima-media thickening rate (31.5%), increased HDL levels (7.35 mg/dL vs. 4.5 mg/dL) and improved serum levels of alanine aminotransferase and aspartate aminotransferase.

The number of patients lost to follow-up was “relatively high” in both groups; 90 patients assigned to pioglitazone and 71 assigned to placebo dropped out of the study.

Weight gain — one reason for withdrawal in both groups — was greater in patients assigned to pioglitazone (3.9 kg vs. 0.77 kg; P<.001). However, “the greater the weight gain, the greater the improvements in beta-cell function and insulin sensitivity and, thus, the greater the reduction in HbA1c,” the researchers wrote in the study. Edema was also more frequent in the pioglitazone group (12.9% vs. 6.4%; P=.007).

The incidence of fracture, which has been implicated as a cause for concern with the TZD drug class, was similar in both groups; all were related to trauma.

The researchers concluded that “treatment of 18 participants for 1 year prevented one case of diabetes. The influence of these effects on long-term diabetic complications remains to be determined.”

Disclosure: The study was supported by Takeda Pharmaceuticals. The researchers report various relevant financial disclosures; read the full study for details.

Source: Endocrine Today

Wikipedia Sperm penetrating an ovum during fertilization.

Sperm has been successfully grown in a test tube for the first time, a breakthrough technology that could eventually help cure male infertility, Japanese scientists said Thursday.

In the experiment, researchers at Yokohama City University were able to produce healthy, fertile offspring using the laboratory created sperm. Their findings can be found in the journal Nature.

“Until now, none of the attempts have been wholly successful, and when the sperm have been used, the pups born have not been healthy and have soon died,” said Dr. Allan Pacey, senior lecturer in andrology at the University of Sheffield, in northern England.

The next step is to reproduce the technique in humans as the technology will give new hope to men with low sperm counts or abnormal sperm.

“Until now, none of the attempts have been wholly successful, and when the sperm have been used, the pups born have not been healthy and have soon died,” said Dr. Allan Pacey, senior lecturer in andrology at the University of Sheffield, in northern England.

The findings could also be a boon for young male cancer patients. Because the technique also works when the tissue samples were frozen and thawed again, fertility in young boys could be preserved before they underwent chemotherapy and radiotherapy by freezing their sperm

Lung cancer close-up MOREDUN ANIMAL HEALTH LTD/SPL / Gettyimages

The study of how covalent marks on DNA and histones are involved in the origin and spread of cancer cells
is also leading to new therapeutic strategies.

Much of the current hype in epigenetics stems from the recognition of its role in human cancer. Yet, intriguingly, the first epigenetic change in human tumors—global genomic DNA hypomethylation—was reported way back in the early 1980s, at about the same time the first genetic mutation in an oncogene was discovered.¹ So why the delay in recognizing the importance of epigenetics in cancer?

In the 1980s epigenetics was a fledgling discipline, hampered by methodological limitations, while genetic knowledge of cancer was expanding exponentially. By the mid-1990s however, classical tumor suppressor genes, such as p16^INK4a, hMLH1, and VHL,² were shown to undergo a specific epigenetic hit (the inactivation of gene expression by CpG island hypermethylation), resulting in a major acceleration in the field. We now know that so-called “epigenetic changes” explain many hallmark features of malignant disease: these genes are deregulated not at the DNA level, but at the complexly packaged chromatin level, which ultimately results in cell dysfunction.

Epigenetics may be important for the cancer field, but what does the term really mean? Truth be told, it has many definitions, which have changed over the years as our knowledge has changed. Researchers studying this discipline recognize how bewildering such a nebulous term can be to nonexperts, and they get together from time to time to put forward better explanations and nomenclatures, but they usually come up empty-handed, or with recommendations that people do not remember. Thus, we have to go back to the classics. Waddington defined epigenetics in 1939 as “the causal interactions between genes and their products, which bring the phenotype into being.” Adrian Bird redefined the term as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.” I prefer a more concrete definition: the inheritance of patterns of DNA and RNA activity that do not depend on the naked nucleotide sequence. By “inheritance,” we mean a memory of such activity transmitted from one cell generation to the next (through mitosis), or from one organismal generation to the next during meiosis. Meiotic inheritance is perhaps more provocative, as there is still scant direct evidence of epigenetic inheritance from one generation to the next, but genomic imprinting is a good example: when it goes awry it can lead to diseases such as Prader-Willi syndrome.

Epigenetics today is not a purely speculative subject, as it was in Waddington’s time; it is based on a rapidly growing understanding of the chemical modifications that our genome and its regulatory proteins (the components of chromatin) undergo to control its functions. There are many modes of epigenetic control, including nucleosome positioning and noncoding-RNA–mediated regulation of gene expression (such as microRNAs). (See infographic: Epigenetics—A Primer) Nucleosome positioning refers to the constraints nucleosomes put on the DNA wrapped around their histone core, often affecting the accessibility of transcription factors and hence their ability to transcribe a gene. The best-studied epigenetic marks, however, are DNA methylation and histone modifications.

In humans, DNA methylation typically occurs at the cytosine base of DNA, within CpG dinucleotides. What is interesting is the existence of CpG-rich regions—“CpG islands”—that are associated with the 5’-end regulatory regions of almost all housekeeping genes as well as with half of tissue-specific genes. When these promoter CpG islands are methylated, the associated genes tend to be transcriptionally inactive. Indeed the correct expression of many tissue-specific, germline-specific, imprinted, and X-chromosome inactivated (in females) genes, as well as that of repetitive genomic sequences, relies largely on DNA methylation.

The other critical epigenetic marks are chemical modifications of the N-terminal tails of histone proteins. Histones, once considered mere DNA-packaging proteins, regulate the underlying DNA sequences through complex posttranslational modifications such as lysine acetylation, arginine and lysine methylation, or serine phosphorylation. It has been proposed that distinct combinations of modifications presented on histone tails form a “histone code” that regulates gene activity. This has prompted vigorous debate, with dissenters arguing that patterns of histone modification cannot really constitute a “code” that adheres to hard and fast rules, as in the case of the triplet codon rule that translates transcribed DNA sequences into protein. Nonetheless, for many epigenetic researchers this is a helpful perspective in trying to make sense of the numerous combinations of histone tail modifications.

A central question in epigenetics is how one genotype can give rise to different phenotypes. In an individual, it is clear that all tissues have the same genome, yet activity varies vastly from cell to cell. We now know that this is largely because the right epigenetic marks instruct specialized programs that distinguish, for example, a retinal cell from a myocyte, a T lymphocyte, or a skin epithelial cell sharing the same DNA sequence. Thus, defects in cloned animals could be explained by our inability to replicate exactly the epigenetic program that steered the course of development in the donor individual. Similarly, defects in babies conceived by in vitro fertilization could be attributable to imprinting variations leading to imprinted disorders. DNA methylation and histone modifications even seem to explain the different penetrance of diseases displayed in monozygotic twins, as first reported in one of our papers.³ This work has occasionally prompted inquiries from police or lawyers, asking whether we can assist in differentiating one identical twin from his or her sibling in court cases.

An epigenetic mutant-mouse strain illustrates how even diet can alter phenotype via an epigenetic mechanism: a DNA methylation variant mouse (agouti strain) changes fur color depending on the levels of methyl donors obtained through its diet, and the trait is heritable to the next generation. These discoveries actually restore some credibility to Lamarck’s discredited hypothesis of the inheritance of acquired traits, which has long been regarded as the antithesis of neo-Darwinian genetic theory.

Many cancer scientists have gotten aboard the epigenetic bandwagon since new, user-friendly PCR- and sequencing-based technologies have been developed. The list of tumor suppressor genes shown to undergo epigenetic inactivation has consequently grown long in the last few years. And in addition to the candidate-gene approach, array-based techniques have also detected on the order of 300 epigenetically modified genes in cancers, using expression arrays combined with DNA demethylating treatments or direct DNA methylation microarrays. (See graphic below.)

Epigenetic disruption of the “dark genome”—the 90% of our genome that does not code for messenger RNA and proteins—is a very exciting finding that looks to be extremely relevant in cancer etiology. MicroRNAs with growth-inhibitory functions, such as miR-124a and miR-34b/c, undergo epigenetic inactivation because the sequences surrounding their respective transcription start sites become hypermethylated.⁴ Overall, the emerging picture shows that distinctive cancer-associated patterns of CpG island hypermethylation are tumor type-specific and contribute decisively to the origin and development of human cancer.

 

INFOGRAPHIC: Click to view full image

Lucy Reading-Ikkanda

Besides providing a better understanding of cancer at the molecular level, what hope does epigenetics bring to applied cancer research? Epigenetics has already revealed useful diagnostic (GSTP1 in prostate cancer) and prognostic biomarkers. This has been an eye-opener for oncologists and hematologists, as transformed cells with specific hypermethylation patterns on certain genes have turned out to be reliable biomarkers for particular types and stages of cancer. The best example is the aberrant DNA methylation of the GSTP1 gene, almost exclusively observed in prostate cancer, which seems to be a valuable biomarker for indicating the disease and a malignant transformation prognosis in older males with high levels of prostate-specific antigen. The fact that these epigenetic markers can be detected in all types of biological fluids and biopsies⁵ in a background of many normal cells makes them very promising tools for disease screening and monitoring. With the advent of genome-wide methodologies, researchers are currently working on typing whole aberrant DNA methylation fingerprints. Such expression microarray signatures could, in the future, serve as potential prognostic tools, which could indicate time to progression or overall survival. This research is being done in breast cancer; however, clinical application is still years away.

Another invaluable use of epigenetic markers is in the prediction of responses to particular chemotherapy agents. The proof of principle was provided by the DNA repair enzyme MGMT, which, when the gene’s promoter region was hypermethylated at its CpG island, predicted that treatment with alkylating agents such as carmustine or temozolomide in gliomas would generate a good therapeutic response.⁶ This is because MGMT repairs the lesions caused by these drugs, and if the enzyme is not there, as in cancer cells, the DNA damage is permanent and the cell dies.

Potential treatment strategies for breast cancer in carriers of mutated BRCA1, the classical tumor suppressor gene, have been boosted by pharmacoepigenetics—the study of epigenetic variants that affect the response to drug therapies. The population of mutated BRCA1 carriers is low; thus, the discovery that BRCA1 can exist as an epimutant when hypermethylated has increased the pool of individuals affected by this high-risk, cancer-causing aberration. This is accelerating the development of the use of PARP (poly [ADP-ribose] polymerase) inhibitors, known to have a good response in BRCA1 tumors.⁷

Histone modification patterns are also altered in human tumors. In particular, levels of histone H4 lysine 20 trimethylation (H4K20me3) and histone H4 lysine 16 monoacetylation (H4K16ac) are severely disturbed in cancer cells⁸ both globally and at particular loci. Comparing absolute results between laboratories, however, is proving troublesome, since the central technique—chromatin immunoprecipitation—has more interindividual and interlaboratory variation than the usual DNA methylation assays, and depends largely on the quality of the antibodies used. Thus the community is not yet at a stage where it can use altered histone modification profiles found in cancer as biomarkers. Researchers are, however, finding an increasing number of histone modifier genes disrupted in many cancers, opening the door to small-molecule drug development targeted against aberrant histone modifiers. This is particularly applicable to hematological malignancies and sarcomas, in which translocations that generate fusion proteins involving histone methyltransferases and histone acetyltransferases are common. The approach is also relevant for the gene amplification of histone demethylases in solid tumors.

A strong selling point for epigenetic cancer research is the fact that epigenetically inactivated genes can conceivably be reactivated with the right drugs, while genetic changes are irreversible. To date, a few pharmacological compounds directed toward epigenetic enzymes have shown promise in treating leukemias and lymphoma. These include DNA demethylating agents (5-azacytidine and 5-aza-2’-deoxycytidine) and histone deacetylase inhibitors (i.e. suberoyl anilide bishydroxamide, SAHA⁹). Although their exact antitumor mechanism has not been completely elucidated, most of them cause programmed cell death and, at current doses, show limited toxicity in patients. The translation of these advances in hematological malignancies to solid tumors is slow, and it will be critical for ongoing studies to identify markers of good response to epigenetic drugs. New compounds continue to be developed in preclinical research, targeting other histone modifiers, such as the class of histone deacetylases called sirtuins. Researchers are on the lookout for more specific DNA demethylating agents that do not change normal DNA methylation.

Cancer epigenetics is an exciting field as we continue to discover new types of epigenetic marks and levels of epigenetic control. Recent examples include the newly discovered 5-hydroxymethylcytosine modification; the chemical modification of RNA; the existence of important regulatory regions outside the minimal promoter, such as CpG island shores and enhancers; the role of chromatin remodeling factors that move nucleosomes around using ATP; and, most importantly, the epigenetic layers present in the noncoding RNA genome. The widespread use of high-throughput technologies will in a short time, I am sure, produce comprehensive cancer epigenomes to study and employ in the better management of oncology patients. Glimpses can already be seen in the publication of, for example, small-epigenome characterization¹⁰ and whole-genome DNA methylation analyses.¹¹

F1000 Member Manel Esteller is Director of the Cancer Epigenetics and Biology Program of the Bellvitge Institute for Biomedical Research (IDIBELL) in Barcelona and leader of the Cancer Epigenetics Group.

Source: the Scientist

Dr Daphne Austin explains her logic on BBC Radio 5 live: “There is sufficient evidence to suggest that we’re [currently] doing more harm than good.

“Are we confident that we are providing the care that they need right through?” Dr Austin asks presenter Victoria Derbyshire.

“We need to have a better debate about this.”

Industry analysts widely expect Benlysta, one the most closely watched medicines of the year, to secure the Food and Drug Administration’s blessing by Thursday.

Annual global sales may top $3 billion in 2015, according to Thomson Reuters consensus forecasts. The company will split Benlysta profits with British partner GlaxoSmithKline Plc.

The drug’s approval will turn Human Genome from money-losing biotech to an industry star and takeover target.

“You’re going to have revenue for a long time from this product. You’re going to become one of the big boys,” said Avik Roy, an analyst at Monness Crespi Hardt. He predicts peak annual sales of more than $5 billion in 2019.

Human Genome shares have soared with hopes for Benlysta. Investors had largely written off the drug after early data were mixed. Shares fell below 50 cents in March 2009 but jumped later that year when the first encouraging Benlysta data was released.

On Monday, Human Genome shares were up 0.5 percent to $25.70 in afternoon trading on Nasdaq.

(To see a graphic of Human Genome’s share price, click on http://r.reuters.com/syj48r )

Shares may gain about $2 on a positive FDA ruling, RBC Capital Markets analyst Michael Yee said. FDA approval will attract investors who avoided the shares when Benlysta’s fate remained uncertain, he said.

Clearance has been expected since an advisory panel recommended the drug in a 13-2 vote last November. In December, the FDA delayed a final decision by three months.

Investors now want to see if regulators endorse Benlysta for a wide range of lupus patients or urge some limits.

Lupus is a debilitating and potentially fatal disease that has proved hard to treat. It causes the immune system to attack the body’s own tissue and organs, leading to arthritis, kidney damage, chest pain, fatigue, skin rashes and other problems. The organ damage can be fatal.

An estimated 5 million people worldwide have the disease. Current drugs often fail to help or cause harsh side effects, such as severe bone loss from steroids.

In company-funded studies, more patients given Benlysta saw symptoms improve compared with current standard care, which typically includes immunosuppressant drugs such as Roche’s CellCept and steroids such as prednisone.

CLAMOR FOR NEW OPTIONS

Supporters on the FDA advisory panel said lupus patients needed a new option even though Benlysta did not help everyone and some experts described the drug’s benefits as mild.

The FDA likely will clear Benlysta for “a pretty broad population of moderate to severe” lupus patients, Yee said. The agency probably will require the prescribing instructions to note the drug has not been widely studied in black patients or people with severe kidney disease, he said.

The discovery doubles the number of gene regions linked to the development of coronary atherosclerosis, which the authors note is the most common cause of death globally.

“I’ve been waiting my entire life to see the names of these genes,” study co-author Dr. Thomas Quertermous, a professor in cardiovascular medicine at Stanford University in Palo Alto, Calif., said in a Stanford news release. “We are making huge progress, but there is much work left to do.”

Meanwhile, Quertermous said, “these new discoveries will allow scientists worldwide to eventually better understand the root causes of coronary atherosclerosis, possibly leading to important new drug therapies that may profoundly reduce the risk of having a heart attack.”

The findings stem from an analysis of data collected by more than 150 researchers participating in 14 genomic studies conducted all over the world, including the United States, Iceland, Canada, and Great Britain.

Quertermous and his colleagues report their observations in the March 6 online issue of Nature Genetics. He and his Stanford colleagues reported no conflicts of interest; GlaxoSmithKline supported two of the studies.

• MORE:Heart stories, video, and more

To get a better understanding of the genetic underpinnings of heart disease, the authors reviewed the genetic profiles of more than 22,000 men and women, all of European descent and all heart disease patients. In addition, they examined the genetic profiles of another 60,000 healthy individuals.

After poring through enormous quantities of genetic code — a process that Quertermous described as being “like looking for a change in one letter in one word in the Encyclopedia Britannica” — the research consortium finally settled on 13 gene regions linked to atherosclerosis risk.

“With such information we should be able to better identify people at high risk early on in life and quickly take the steps to neutralize that excess risk by strongly recommending lifestyle and pharmacological therapies that we already know substantially reduce risk,” a study co-author, Dr. Themistocles (Tim) Assimes, an assistant professor of medicine at Stanford, noted in the news release.

“(But) although we are inching closer to that day, we will probably need to reliably identify many more variants predisposing to heart attacks over the next few years before it becomes useful to perform this genetic profiling in a doctor’s office,” he cautioned.

Feb. 22, 2011 — Combining a standard noninvasive test that measures electrical activity in the brain with a high-tech computer analysis may help determine the risk of autism spectrum disorder in infants, according to a new study.

In the study, a computer program that assists in evaluating brainwave data from an electroencephalogram (EEG) was used to determine the way nerve cells communicate with one another in infants. Using the data generated, researchers were able to predict which 9-month-old infants have a high risk of autism with 80% accuracy.

“Electrical activity produced by the brain has a lot more information than we realized,” says researcher William Bosl, PhD, of Children’s Hospital Boston, in a news release. “Computer algorithms can pick out patterns in those squiggly lines that the eye can’t see.”

These results are only preliminary, but researchers say the technique could lead to less invasive and much earlier determination of autism risk by picking up subtle differences in brain organization and activity.

Autism is typically diagnosed through extensive behavioral testing at 2-3 years of age.

Checking for Autism Risk

In the study, published in BMC Medicine, researchers compared EEGs from 79 infants aged 6 to 24 months. Forty-six of the infants were considered at high risk for autism because they had an older sibling with the behavioral disorder.

The babies wore helmet-like caps studded with electrodes on their scalps to measure electrical activity while they watched a research assistant blowing bubbles. The tests were repeated, when possible, at 6, 9, 12, 18, and 24 months of age.

The EEGs were then interpreted using modified multiscale entropy (mMSE), which measures the randomness of a signal.

The results showed that the greatest difference in brain activity patterns between the high-risk group and the comparison group of infants was at 9 months of age.

But there was a gender difference that researchers say they can’t yet explain. The method’s accuracy at picking out babies at risk for autism was greatest for girls at 6 months and for boys at 12 and 18 months.

Researchers say patterns in brain electrical activity can give many clues about how the brain is wired and how the connections between neurons in each part of the brain are functioning and organized.

“Many neuroscientists believe that autism reflects a ‘disconnection syndrome,’ by which distributed populations of neurons fail to communicate efficiently with one another,” says researcher Charles A. Nelson, PhD, research director of the Developmental Medicine Center at Children’s Hospital Boston, in the release. “The current paper supports this hypothesis by suggesting that the brains of infants at high risk for developing autism exhibit different patterns of neural connectivity.”

Gradual hearing loss is a common symptom of aging, but in some people it may also be an early sign of Alzheimer's disease.

Gradual hearing loss is a common symptom of aging, but in some people it may also be an early sign of Alzheimer’s disease or other types of dementia, a new study suggests.

The risk of dementia appears to rise as hearing declines. Older people with mild hearing impairment — those who have difficulty following a conversation in a crowded restaurant, say — were nearly twice as likely as those with normal hearing to develop dementia, the study found. Severe hearing loss nearly quintupled the risk of dementia.

Health.com: 25 signs and symptoms of Alzheimer’s Disease

It’s unclear why the loss of hearing and mental function might go hand in hand. Brain abnormalities may contribute independently to both conditions, but it’s also possible that hearing problems can help bring on dementia, the researchers say. Hearing loss may lead to social isolation (which itself has been linked to dementia), for instance, or it may interfere with the brain’s division of labor.

“The brain might have to reallocate resources to help with hearing at the expense of cognition,” says the lead researcher, Frank R. Lin, M.D., an ear surgeon at Johns Hopkins Hospital in Baltimore. That may explain in part why straining to hear conversations over background noise in a loud restaurant can be mentally exhausting for anyone, hard of hearing or not, he adds.

The findings suggest that poor hearing is a “harbinger of impending dementia,” says George Gates, M.D., a hearing expert at the University of Washington in Seattle, who was not involved in the new study but whose own research has demonstrated a link between the two conditions.

“We listen with our ears but hear with our brains,” Gates says. “It is simply not possible to separate audition and cognition.”

Health.com: 9 foods that may help save your memory

In the study, which appears in the Archives of Neurology, Lin and his colleagues followed more than 600 dementia-free adults between the ages of 36 and 90 for an average of 12 years. A little less than 30 percent of the study participants had some hearing loss at the start of the study.

Overall, 9 percent of the participants went on to develop Alzheimer’s disease or another form of dementia. Mild, moderate, and severe hearing loss were associated with a two-fold, three-fold, and five-fold higher risk of later dementia, respectively, in comparison to normal hearing.

People with moderate hearing loss generally struggle to communicate even in quiet settings, and those with severe hearing loss are near deaf.

Lin says that hearing loss has an enormous impact on the lives of his patients and their family members. “Yet because it is such a slow and insidious process, it is often left ignored and untreated.”

Whether hearing aids or other treatments (such as cochlear implants) can help stave off dementia is the “50 billion dollar question,” Lin adds. Thirty million Americans currently have impaired hearing and 1 in 30 are predicted to suffer from dementia by 2050, so if those treatments prove to be helpful, their impact would be felt widely.

Health.com: Aging workforce means dementia on the job could rise

There is no cure for dementia, and there are no surefire ways of preventing it. Gates isn’t optimistic that restoring hearing can affect the course of dementia. However, if treatments and prevention strategies for dementia do become available in the future, he says, hearing loss could play an important role in early detection.

Lin and his colleagues have begun researching the effect of hearing aids on the risk of dementia. “Whether or not it can help dementia, we don’t know yet,” he says. “But in the meantime, there’s no reason not to take your hearing loss seriously and pursue some type of treatment.”

Copyright Health Magazine 2010