Archive for the ‘Cardiology’ Category

Sabotage as therapy: Aiming lupus antibodies at vulnerable cancer cells

The findings were published recently in Nature‘s journal Scientific Reports.

The study, led by James E. Hansen, M.D., assistant professor of therapeutic radiology at Yale School of Medicine, found that cancer cells with deficient DNA repair mechanisms (or the inability to repair their own genetic damage) were significantly more vulnerable to attack by lupus antibodies.

“Patients with lupus make a wide range of autoantibodies that attack their own cells and contribute to the signs and symptoms associated with lupus. Some of these antibodies actually penetrate into cell nuclei and damage DNA, and we suspected that we may be able to harness the power of these antibodies for use in targeted cancer therapy,” Hansen said.

The genetic code that determines how a cell develops is written in DNA. Damage to this code can cause a cell to malfunction, die, or transform into a cancer cell. Normal cells are equipped to repair damaged DNA and preserve the genetic code, but many cancer cells have defective DNA repair machinery and accumulate genetic mutations.

This difference between normal cells and certain cancer cells creates an opportunity to develop therapies that damage DNA and only kill cancer cells that cannot repair the damage. However, DNA is sequestered inside cell nuclei, where delivery of therapies can be challenging. Yale Cancer Center researchers are finding that naturally occurring lupus antibodies just may be a solution to this problem.

“Lupus antibody-based cancer therapy is an emerging new concept, and I believe we are just seeing the tip of the iceberg in terms of the potential of this approach,” said Hansen.

The researchers previously found that a lupus antibody called 3E10 inhibits DNA repair and sensitizes cancer cells to DNA damage, and they have now found that the DNA-damaging lupus antibody 5C6 is toxic to DNA repair-deficient cancer cells.

“Now that we know that more than one lupus antibody has a selective effect on cancer cells, I am confident that additional lupus autoantibodies with even greater therapeutic potential await discovery,” Hansen said.

source : http://www.sciencedaily.com/releases/2014/09/140902151302.htm

Increase seen in use of double mastectomy, although not associated with reduced death

Randomized trials have demonstrated similar survival for patients with early-stage breast cancer treated with breast-conserving surgery and radiation or with mastectomy. However, previous data show increasing use of mastectomy, and particularly bilateral mastectomy (removal of both breasts) among U.S. patients with breast cancer. Evidence for a survival benefit with this procedure appears limited to rare patient subgroups. “Because bilateral mastectomy is an elective procedure for unilateral breast cancer [in one breast] and may have detrimental effects in terms of complications and associated costs as well as body image and sexual function, a better understanding of its use and outcomes is crucial to improving cancer care,” according to background information in the article.

Allison W. Kurian, M.D., M.Sc., of the Stanford University School of Medicine, Stanford, Calif., and colleagues used data from the California Cancer Registry from 1998 through 2011 to compare the use of and rate of death after bilateral mastectomy, breast-conserving therapy with radiation, and unilateral mastectomy (removal of one breast).

The analyses included 189,734 patients. The researchers found that the rate of bilateral mastectomy increased from 2.0 percent in 1998 to 12.3 percent in 2011, an annual increase of 14.3 percent. The increase in bilateral mastectomy rate was greatest among women younger than 40 years: the rate increased from 3.6 percent in 1998 to 33.0 percent in 2011, increasing by 17.6 percent annually. Use of unilateral mastectomy declined in all age groups

Bilateral mastectomy was more often used by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute-designated cancer center; in contrast, unilateral mastectomy was more often used by racial/ethnic minorities and those with public/Medicaid insurance.

Compared with breast-conserving surgery with radiation, bilateral mastectomy was not associated with a mortality difference, whereas unilateral mastectomy was associated with higher mortality.

“In a time of increasing concern about overtreatment, the risk-benefit ratio of bilateral mastectomy warrants careful consideration and raises the larger question of how physicians and society should respond to a patient’s preference for a morbid, costly intervention of dubious effectiveness,” the authors write.

“These results may inform decision-making about the surgical treatment of breast cancer.”

Editorial: Contralateral Prophylactic Mastectomy: Is It a Reasonable Option?

In an accompanying editorial, Lisa A. Newman, M.D., M.P.H., of the University of Michigan, Ann Arbor, discusses the issues involved with the use of contralateral prophylactic mastectomy (risk-reducing mastectomy for the unaffected breast).

“The need for patients to be accurately informed regarding safe and oncologically acceptable treatment options is indisputable. The dense fog of complex emotions that accompanies a new cancer diagnosis can impair the ability to process this information. Patients should be encouraged to allow the intensity of these immediate reactions to subside before committing to mastectomy prematurely. Physicians should not permit excessive treatment delays to compromise outcomes, but the initial few weeks surrounding the diagnosis are more effectively utilized by time invested in patient education and procedures that contribute to comprehensive treatment planning as opposed to hastily coordinating impulsive, irreversible surgical plans.”

source : http://www.sciencedaily.com/releases/2014/09/140902171150.htm

‘K-to-M’ Histone Mutations: How Repressing Repressors May Drive Tissue-Specific Cancers

In 2012, investigators from multiple research institutions studying the sequence of the genome from cancer patients rocked the “chromatin world” when they independently reported that mutations in the gene that encodes histone H3.3 occurred in aggressive pediatric brain tumors. This finding was stunning, as researchers had never before associated histone mutations with any disease, much less a deadly tumor. What followed was a race by cancer researchers worldwide to discover how histone mutations might promote tumorigenesis.

Now a paper from a laboratory at the Stowers Institute of Medical Research reports the first animal model created to assess the molecular effects of two different histone H3.3 mutations in the fruit fly Drosophila. The study from a team led by Investigator Ali Shilatifard, Ph.D. published in the August 29, 2014 issue of Science, strongly suggests that these mutations actually could drive cancer and identifies interacting partners and pathways that could be targeted for the treatment of cancer.

Molecular biologists categorize these mutations as “K-to-M,” because a normal lysine residue (symbolized by K) in the protein is replaced by methionine (M) through mutations in the DNA sequence. In pediatric tumors, K-to-M mutations occurred at lysine residue 27 (K27) of histone H3.3. Researchers suggested that the presence of even a small population of these damaged proteins in the nucleus muffled a large repressor complex called PRC2. Normally, PRC2 acts as an enzyme to decorate histone lysines with one or more methyl groups, which silences gene expression by squeezing associated DNA into an impenetrable coil.

“Previously scientists knew that mutations in methylating enzymes like PRC2 occur in some cancers,” says Shilatifard. “What was surprising here was finding that mutation in one of the copies of the histone H3 gene, one of the proteins that PRC2 modifies, is associated with cancer. To figure out how that happened, we were interested in developing an in vivo model for the process in systems that we can study.”

The team first engineered a version of histone H3.3 that mimicked the K27-to-M mutation and then inserted that construct into embryonic fly tissues to produce the damaged protein in a living fruit fly. Using antibodies that recognize methylated lysines, they discovered that a dose of the mutant protein was sufficient to decrease global methylation of normal histone H3.3 proteins at K27, just as loss of the PRC2 repressor would. When the group engineered a similar K-to-M mutant at lysine 9 (K9), they saw similar results. This analysis of the H3K27 and H3K9 mutants confirmed in vivo that K-to-M mutations in histone H3.3 repress a key repressor, PRC2, but did not nail down how this happened.

“One question was whether a single amino acid change like this could alter the way histone H3.3 interacts with other proteins,” says Marc Morgan, Ph.D., a co-first author of the paper, “The mutant could be either losing or gaining something.” To determine which, the group collaborated with the Stowers Proteomics Center to compare factors binding to normal histone H3.3 versus the K-to-M mutants using mass spectrometry.

That analysis revealed that the presence of mutant histones globally dampens histone interactions with some of the usual repressor suspects. But in what Morgan calls an “Aha!” moment, they detected promiscuous association of a demethylase called KDM3B with the histone H3K9 mutant. “This suggests that these mutations inappropriately pull a demethylating enzyme onto chromatin, which then erases methylation marks in histones around it,” Morgan says.

Loss of methylation marks could allow expression of nearby genes. To confirm this, the group employed a Drosophila staining trick that allows experimenters to visualize how repressed genes are affected in entire tissues. The expression of KDM3B demethylase derepressed the gene expression in tissues such as salivary glands, just like the expression of the H3K9 mutant. This supports the idea that K-to-M mutations recruit a demethylase (like KDM3B) to demethylate chromatin on the K9 residue of H3.3 proteins in the neighborhood, where it likely uncoils chromatin to allow activation of genes that should be silenced.

This outcome could cause cancer in numerous ways. “One possibility might be that oncogenes that are usually silenced by methylation of residue 9 might be derepressed in the presence of the mutation,” says Hans-Martin Herz, Ph.D., a co-first author of the paper. But Herz is cautious in interpreting these findings, simply because, unlike the K27 mutations, mutations at residue K9 are not yet reported to be associated with cancer.

Intriguingly, other researchers recently reported a different K-to-M mutation (at residue 36 of histone H3.3) in chondroblastoma, a bone cancer sub-type. Why K-to-M mutations are so specific to a particular cancer is unknown, but Shilatifard says there can be little doubt that they play a central rather than a bystander role in tumorigenesis. “Uncharacterized K-to-M mutations may occur in other cancers,” he says. “Our work allows us to identify the molecular players involved in chromatin signaling in Drosophila and then apply those findings to human cells.”

source : http://www.sciencedaily.com/releases/2014/08/140829103216.htm