Posts Tagged ‘california’

New mouse model points to therapy for liver disease

Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.

“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”

The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.

“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine.

The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.

Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.

“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

source : http://www.sciencedaily.com/releases/2014/08/140818134912.htm

Prostate cancer diagnosis improves with MRI technology

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, MD, MHS, the UC San Diego Health System urologic oncologist who, along with Christopher Kane, MD, chair of the Department of Urology and Karim Kader, MD, PhD, urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

Lopez is thankful he will be able to celebrate his 58th wedding anniversary with his wife.

“Life is going on as normal,” said Lopez. “This is the wave of the future. I see this new technology as the way to save thousands of lives. I commend Dr. Parsons for taking the lead in San Diego in this area.”

For patients, the only added step to the prostate examination is the addition of MRI imaging which occurs in a separate visit in advance of the biopsy exam. Working with David Karow, MD, PhD, a UC San Diego Health System radiologist, Parsons uses sophisticated new tools and software — DynaCAD for Prostate with the UroNav fusion biopsy system — to combine the MRI with real-time, ultrasound-guided biopsy images in the clinic resulting in what he calls a 3D road map of the prostate.

“The MRI-guided prostate biopsy will enhance the patient experience by reducing the number of false-positive biopsies and resulting in earlier diagnosis when cancer is present,” said Parsons.

source : http://www.sciencedaily.com/releases/2014/08/140812133501.htm

Tumor suppressor mutations alone don’t explain deadly cancer: Biomarker for head and neck cancers identified

The study, published online August 3 in the journal Nature Genetics, shows that high mortality rates among head and neck cancer patients tend to occur only when mutations in the tumor suppressor gene coincide with missing segments of genetic material on the cancer genome’s third chromosome.

The link between the two had not been observed before because the mutations co-occur in about 70 percent of head and neck tumors and because full genetic fingerprints of large numbers of cancer tumors have become available only recently.

“These two genetic malfunctions are not two separate stab wounds to the body,” said co-senior author Trey Ideker, PhD, chief of the Division of Genetics. “One exposes the Achilles tendon and the other is a direct blow to it.”

To patients with these cancers, the study’s results mean that there may be therapeutic value in testing tumors for the two genetic identifiers, known as a TP53 mutation (short for tumor protein 53) and a 3p deletion (short for deletions of genetic information on the short arm “p” of the third chromosome).

TP53 plays a key role in regulating cell growth, detecting and fixing DNA, and directing cell apoptosis (death) if the DNA damage is irreparable. Because of this, the TP53 protein is sometimes called the “guardian of the genome.”

The study’s findings suggest that if both markers are present, treatment should be intensified. If only one mutation is present, treatment might be de-intensified because the TP53 mutation alone is less deadly than previously thought. The latter would have immediate benefits in reducing deaths caused by complications related to medical care.

“We are in the early stages of being able to personalize head and neck cancer treatments based on the tumor’s actual biology, the same as what’s done with breast cancers,” said co-senior author Quyen Nguyen, MD, PhD, associate professor of Otolaryngology-Head and Neck Surgery. “In the past, treatments have been based largely on the size and location of the tumor. Now, we know that some large tumors may respond to less aggressive treatment while some small tumors may need intensified treatment. This will have a huge impact for patients.”

The study analyzed the complete genomic signatures of 250 cases of squamous cell head and neck cancer extracted from The Cancer Genome Atlas, a repository of sequenced cancer genomes for more than 20 different types of human cancers maintained by the National Institutes of Cancer. All of the tumors were from patients younger than 85 years of age.

Of these, 179 had both mutations; 50 had one of the two mutations; and 22 had neither mutation. Comparisons with patient outcome data showed that half of patients with both mutations would likely die of cancer within 2 years, while 66 percent of patients with one or neither mutation would be expected to live five years or more. These survival statistics were independent of the patients’ clinical cancer stage.

Besides causing cervical cancer, the human papilloma virus (HPV) is implicated in the growing epidemic of head and neck cancers in otherwise healthy adults. It is believed that the virus can co-opt the activity of TP53, affecting cells in much the same way as a TP53 mutation but without causing a mutation. For this reason, the analysis examined HPV-positive and HPV-negative tumors separately.

One of the study’s more compelling discoveries is that among HPV-positive tumors, the most aggressive cancer cases were also highly linked to the presence of 3p deletions.

“Our findings raise fundamental questions about the role of TP53 in cancer and suggest that some of the deleterious health effects of TP53 mutations might actually be due to something else going on in the third chromosome,” said lead author Andrew Gross, a graduate student in the Bioinformatics and Systems Biology Program.

Co-authors include Ryan K. Orosco, John P. Shen, Hannah Carter, Matan Hofree, Michel Choueiri, Charles S. Coffey, Scott M. Lippman and Ezra E. Cohen, UC San Diego; Ann Marie Egloff and Jennifer R. Grandis, University of Pittsburg; and Neil Hayes, University of North Carolina.

Funding for the study was provided, in part, by the National Institutes of Health (grants P50 GM085764, P41 GM103504 and U24 CA184427), Burroughs Welcome Fund and The American Cancer Society.

source : http://www.sciencedaily.com/releases/2014/08/140803193126.htm