Cancer Study Reveals Potential Drug Targets

   (NIH) - 1/31/2014 - Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. They also discovered that, at the molecular level, some subtypes of bladder cancer — also known as urothelial carcinoma — resemble subtypes of breast, head and neck and lung cancers, suggesting similar routes of development.
   The researchers’ findings provide important insights into the mechanisms underlying bladder cancer, which is estimated to cause more than 15,000 deaths in the United States in 2014. TCGA is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.
   “TCGA Research Network scientists continue to unravel the genomic intricacies of many common and often intractable cancers, and these findings are defining new research directions and accelerating the development of new cancer therapies,” NIH Director Francis Collins said.
   In this study, published online Jan. 29, 2014 in Nature, investigators examined bladder cancer that invades the muscle of the bladder, the deadliest form of the disease. The current standard treatments for muscle-invasive bladder cancer include surgery and radiation combined with chemotherapy. There are no recognized second-line therapies — second choices for treatments when the initial therapy does not work — and no approved targeted agents for this type of bladder cancer. Approximately 72,000 new cases of bladder cancer will be diagnosed in the United States in 2014.
   “This project has dramatically improved our understanding of the molecular basis of bladder cancers and their relationship to other cancer types,” said lead author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston. “In the long run, the potential molecular targets identified may help us to personalize therapy based on the characteristics of each patient’s tumor.”
   “The real excitement about this project is that we now have a menu of treatment and research directions to pursue,” said Seth Lerner, M.D., professor and chair in urologic oncology at Baylor College of Medicine in Houston, and one of the senior authors of the paper. “The field is poised to use this information to make new advances toward therapies for a very-difficult-to-treat form of bladder cancer.”   
   The research team analyzed DNA, RNA and protein data generated from the study of 131 muscle-invasive bladder cancer from patients who had not yet been treated with chemotherapy. The scientists found recurrent mutations in 32 genes, including nine that were not previously known to be significantly mutated. They discovered mutations in the TP53 gene in nearly half of the tumor samples, and mutations and other aberrations in the RTK/RAS pathway (which is commonly affected in cancers) in 44 percent of tumors. TP53 makes the p53 tumor suppressor protein, which helps regulate cell division. RTK/RAS is involved in regulating cell growth and development.
   The investigators also showed that genes that regulate chromatin — a combination of DNA and protein within a cell’s nucleus that determines how genes are expressed — were more frequently mutated in bladder cancer than in any other common cancer studied to date. These findings suggest the possibility of developing therapies to target alterations in chromatin remodeling.
   Overall, the researchers identified potential drug targets in 69 percent of the tumors evaluated. They found frequent mutations in the ERBB2, or HER2, gene. The researchers also identified recurring mutations as well as fusions involving other genes such as FGFR3 and in the PI3-kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.
   Because the HER2 gene and its encoded protein, HER2 — which affects cell growth and development — are implicated in a significant portion of breast cancers, scientists would like to find out if new agents under development against breast cancer can also be effective in treating subsets of bladder cancer patients.
   “We’ve organized our medical care around the affected organ system,” Dr. Lerner said. “We have thought of each of these cancers as having its own characteristics unique to the affected organ. Increasingly, we are finding that cancers cross those lines at the molecular level, where some individual cancers affecting different organs look very similar. As targeted drug agents go through preclinical and clinical development, we hope that rather than treating 10 percent of breast cancers or 5 percent of bladder cancers, it eventually will make sense to treat multiple cancer types where the target is expressed.” The same theme runs through TCGA’s Pan-Cancer project, which is aimed at identifying genomic similarities across cancer types, with the goal of gaining a more global understanding of cancer behavior and development.
   “It is increasingly evident that there are genomic commonalities among cancers that we can take advantage of in the future,” NHGRI Director Eric Green said. “TCGA is providing us with a repertoire of possibilities for developing new cancer therapeutics.”
   The scientists also uncovered a potential viral connection to bladder cancer. It is known that animal papilloma viruses can cause bladder cancer. In a small number of cases, DNA from viruses — notably, from HPV16, a form of the virus responsible for cervical cancer — was found in bladder tumors. This suggests that viral infection can contribute to bladder cancer development.
   Tobacco is a major risk factor for bladder cancer; more than 70 percent of the cases analyzed in this study occurred in former or current smokers. However, the analysis did not identify major molecular differences between the tumors that developed in patients with or without a history of smoking.
   “The definitive molecular portrait of bladder cancer by the TCGA Network has uncovered a promising array of potential therapeutic targets that provides a blueprint for investigations into the activity of existing and novel therapeutic agents in this cancer,” said Louis Staudt, M.D., Ph.D., director, NCI Center for Cancer Genomics.
Reference
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. Online January 29, 2014. DOI: 10.1038/nature12965.

Three Businessmen Indicted On Fraud Charges

    ST. LOUIS, MO — 1/19/2014 - Three St. Louis-area businessmen recently surrendered to authorities on two separate indictments alleging bank fraud against Excel Bank, which failed in 2012 after receiving $4,000,000 in capital from the Treasury Department through the Troubled Asset Relief Program (TARP).
   According to the indictments, William Glasgow owned dozens of rental properties as part of his real estate business, Glasgow Realty, and did business with Excel Bank, the holding company of which was Investors Financial Corporation of Pettis County, Missouri. The indictment states that Glasgow had two loans on his rental properties, which he received by falsifying documentation.
   In a separate unrelated indictment, James Crews and Michael Hilbert are alleged to have engaged in the real estate business, doing business through various entities including Crews Corporation, Hillcrew Properties, Merz Properties, Eagle Group, and Marathon RE. They owned dozens of rental properties in the St. Louis area and are alleged to have defrauded Excel Bank by submitting numerous draw requests for hundreds of thousands of dollars in escrow funds set aside for improvements to those properties.
   William Glasgow, Town & Country, Missouri, was indicted by a federal grand jury on two felony counts of bank fraud. In a separate unrelated indictment, James Crews, Wentzville, Missouri; and Michael Hilbert, St. Charles, Missouri, were indicted the same day on two felony counts each of bank fraud. The indictments were returned December 11, 2013, but remained sealed until the defendants appeared in federal court for arraignment on Jan. 10 in St. Louis.
   If convicted, each count of bank fraud carries a maximum penalty of 30 years in prison and/or fines up to $1 million. In determining the actual sentences, a judge is required to consider the U.S. Sentencing Guidelines, which provide recommended sentencing ranges.
  The case was investigated by the Office of the Special Inspector General for the Troubled Asset Relief Program and the Federal Bureau of Investigation. Assistant United States Attorney Tom Albus is handling the case for the U.S. Attorney’s Office.
   Defendants are presumed innocent until proven guilty.
   Source: Federal Bureau of Investigation

Study: Cognitive Training Shows Staying Power

   (NIH) - 1/16/2014 - Training to improve cognitive abilities in older people lasted to some degree 10 years after the training program was completed, according to results of a randomized clinical trial supported by the National Institutes of Health.
   The findings showed training gains for aspects of cognition involved in the ability to think and learn, but researchers said memory training did not have an effect after 10 years.
   The report, from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, appears in the January 2014 issue of the Journal of the American Geriatrics Society. The project was funded by the National Institute on Aging (NIA) and the National Institute of Nursing Research (NINR), components of the NIH.
   “Previous data from this clinical trial demonstrated that the effects of the training lasted for five years,” said NIA Director Richard J. Hodes, M.D. “Now, these longer term results indicate that particular types of cognitive training can provide a lasting benefit a decade later. They suggest that we should continue to pursue cognitive training as an intervention that might help maintain the mental abilities of older people so that they may remain independent and in the community.”
   “ACTIVE is an important example of intervention research aimed at enabling older people to maintain their cognitive abilities as they age,” NINR Director Patricia Grady said. “The average age of the individuals who have been followed over the last 10 years is now 82. Given our nation’s aging population, this type of research is an increasingly high priority.”
   The original 2,832 volunteers for the ACTIVE study were divided into three training groups — memory, reasoning and speed-of-processing — and a control group. The training groups participated in 10 60- to 70-minute sessions over five to six weeks, with some randomly selected for later booster sessions. The study measured effects for each specific cognitive ability trained immediately following the sessions and at one, two, three, five and 10 years after the training.
   The investigators were also interested in whether the training had an effect on the participants’ abilities to undertake some everyday and complex tasks of daily living. They assessed these using standardized measures of time and efficiency in performing daily activities, as well as asking the participants to report on their ability to carry out everyday tasks ranging from preparing meals, housework, finances, health care, using the telephone, shopping, travel and needing assistance in dressing, personal hygiene and bathing.
   At the end of the trial, all groups showed declines from their baseline tests in memory, reasoning and speed of processing. However, the participants who had training in reasoning and speed of processing experienced less decline than those in the memory and control groups. Results of the cognitive tests after 10 years show that 73.6 percent of reasoning-trained participants were still performing reasoning tasks above their pre-trial baseline level compared to 61.7 percent of control participants, who received no training and were only benefiting from practice on the test. This same pattern was seen in speed training: 70.7 percent of speed-trained participants were performing at or above their baseline level compared to 48.8 percent of controls. There was no difference in memory performance between the memory group and the control group after 10 years.
   Participants in all training groups said they had less difficulty performing the everyday tasks compared with those in the control group. However, standard tests of function conducted by the researchers showed no difference in functional abilities among the groups.
   “The speed-of-processing results are very encouraging,” said Jonathan W. King, Ph.D., program director for cognitive aging in the Division of Behavioral and Social Research at NIA and co-author. “The self-reported improvements in daily function are interesting, but we do not yet know whether they would truly allow older people to live independently longer; if they did, even a small effect would be important, not only for the older adults, but also for family members and others providing care.”
   The ACTIVE study followed healthy, community-dwelling older adults from six cities — Baltimore; Birmingham, Ala.; Boston; Detroit; State College, Pa.; and Indianapolis. The participants averaged 74 years of age at the beginning of the study and 14 years of education, 76 percent were female, 74 percent were white and 26 percent were African-American. The 10-year follow-up was conducted with 44 percent of the original sample between April 1998 and October 2010.
   The ACTIVE study was conducted by the following investigators:
  • George W. Rebok, Ph.D., Johns Hopkins University, Baltimore
  • Karlene Ball, Ph.D., University of Alabama at Birmingham
  • Michael Marsiske, Ph.D., University of Florida, Gainesville
  • John N. Morris, Ph.D., and Richard N. Jones, Sc.D., Hebrew Senior Life, Boston
  • Sharon L. Tennstedt, Ph.D., New England Research Institutes, Watertown, Mass.
  • Frederick W. Unverzagt, Ph.D., Indiana University School of Medicine, Indianapolis
  • Sherry L. Willis, Ph.D., University of Washington, Seattle
   The National Institute of Nursing Research (NINR) supports basic and clinical research that develops the knowledge to build the scientific foundation for clinical practice, prevent disease and disability, manage and eliminate symptoms caused by illness, and enhance end-of-life and palliative care. See: http://www.ninr.nih.gov. For more information on research, aging, and health, go to http://www.nia.nih.gov.

ACLU Appeals Dismissal of NSA-Related Suit

   (ACLU) - 1/5//2014 - The American Civil Liberties Union and the New York Civil Liberties Union filed a notice of appeal on January 2 in their federal lawsuit challenging the constitutionality of the NSA’s mass call-tracking program. Last Friday, the district court dismissed the case, ACLU v. Clapper, ruling that the program was constitutional and did not exceed the authority provided in the Patriot Act.
   "We believe that the NSA’s call-tracking program violates both statutory law and the Constitution, and we look forward to making our case in the appeals court,"  ACLU Deputy Legal Director Jameel Jaffer said. Jaffer is one of the two ACLU attorneys who argued the case in November.
   "The government has a legitimate interest in tracking the associations of suspected terrorists, but tracking those associations does not require the government to subject every citizen to permanent surveillance. Further, as the president’s own review panel recently observed, there’s no evidence that this dragnet program was essential to preventing any terrorist attack. We categorically reject the notion that the threat of terrorism requires citizens of democratic countries to surrender the freedoms that make democracies worth defending."
   The ACLU anticipates that the Second Circuit Court of Appeals will set an expedited briefing schedule and that it will hear oral argument in the spring.
   The recent ruling by U.S. District Judge William H. Pauley III conflicted with the December 16 decision in a similar lawsuit in Washington, Klayman v. Obama, in which U.S. District Judge Richard J. Leon found the NSA program to be likely unconstitutional. The Justice Department has 60 days to file an appeal. A federal court in San Francisco is currently considering a third case, First Unitarian Church of Los Angeles v. NSA, filed by the Electronic Frontier Foundation.
  The ACLU is a customer of Verizon Business Network Services, which, as revealed in The Guardian, received a secret order from the Foreign Intelligence Surveillance Court compelling the company to turn over "on an ongoing daily basis" phone call details such as whom calls are placed to and from, and when those calls are made. The lawsuit argues that the government’s blanket seizure of the ACLU’s phone records compromises the organization’s ability to carry out its work and to engage in legitimate communications with clients, journalists, advocacy partners, whistleblowers, and others.
   The appeal is available at: aclu.org/national-security/aclu-v-clapper-notice-appeal

The Arms Debate

Not All American's Have the Right to Bear Arms

Photo by Steve Rensberry (c) 2018