Project Work in Medical Biochemistry and Microbiology 2013/2014 - Uppsala University, Sweden

Project Work in Medical Biochemistry and Microbiology 2013/2014 - Uppsala University, Sweden

Early tumor response from stereotactic radiosurgery predicts outcome

The response of a patient with metastatic brain tumors to treatment with stereotactic radiosurgery in the first six-to-twelve weeks can indicate whether follow-up treatments and monitoring are necessary, according to research conducted at the University of North Carolina School of Medicine.

          The study of 52 patients with metastatic brain legions, found that the tumors whose sizes decreased significantly after treatment with stereotactic radiosurgery (SRS) did not resume growth or require additional treatment. The research, conducted by a team led by Matthew G. Ewend, MD, chair of the UNC Department of Neurosurgery and member of the UNC Lineberger Comprehensive Cancer Center, could reduce the need to continually monitor patients who respond well to SRS.

 The volume of the tumors over time was measured to see the outcome, based on what happened in the beginning, what would happen long term.It was that tumors that did not shrink in the beginning were more likely later to be correlated to a patient having a neurological problem or needing steroids. If they did shrink, they were more likely to stay under control long term."

The advent of SRS systems allows physicians to target tumors with precise, high-dose beams of radiation. While the technique is in widespread use, current practice requires repeated check-ups to determine its effectiveness. The results of this study indicate that this monitoring may only be necessary for patients who do not respond favorably within the first six to twelve weeks after SRS treatment.

 few MRIs  scans are necessary afterwards for a good response.

Between 20 and 40 percent of adults with cancer develop brain tumors, which metastasize from cancers elsewhere in the body. The number of brain tumors treated by physicians has increased, as better treatments for the cancers that spawn them increase patient survival. Because of the systemic nature of these cancers, the survival implications of positive early response depend largely on how patients respond to therapy for their initial cancer.

"This is not in a vacuum. Even if you control the brain disease, they can still die of their other disease. With better control of the brain disease, the patients have a better chance of living longer, but it will take both improvements in systemic therapy and brain therapy," said Dr. Ewend.

The UNC study included patients with lung, breast, melanoma and renal cell cancers. It builds on prior research that indicated a similar response in patients with clear cell renal cancer. Dr. Ewend said that future research will need to increase the number of patients to reinforce the results and determine what factors influence positive early response. One possibility for future research is to determine the genetic factors behind tumor response, which will allow researchers to develop a genetic test to help predict a patient's outcome.

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Story Source:

The above story is based on materials provided by University of North Carolina School of Medicine. Note: Materials may be edited for content and length.

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Journal Reference: Suzanne R. Sharpton, Eric K. Oermann, Dominic T. Moore, Eric Schreiber, Riane Hoffman, David E. Morris, Matthew G. Ewend. The Volumetric Response of Brain Metastases After Stereotactic Radiosurgery and Its Post-treatment Implications. Neurosurgery, 2014; 74 (1): 9 DOI: 10.1227/NEU.0000000000000190

DIFFERENT CANCER SAME MUTATION

 

An astounding variety of genetic abnormalities can cause healthy cells to turn cancerous. Few of these are shared among cancers of the same tissue, and fewer still are shared among cancers of different tissues. Nevertheless, scientists searching for such common genetic needles in an array of cancer.

“For the first time we have been able to analyze, across the board, large numbers of tumor samples . . . and also systematically look across different tumor types,” said Chris Sander, chair of the computational biology program at the Memorial Sloan-Kettering Cancer Center in New York, and senior author on one of the new papers. The main aim was to learn about principles of cancer biology that might not have been obvious from previous studies examining one tumor type in isolation.

“TCGA is all about analyzing each tumor type separately,” said Josh Stuart, a professor of biomolecular engineering at the University of California, Santa Cruz, who was not involved in either study. ON every time a new experiment is carried out in cancer, we always wanted to compare it to the previous one and it has been analyzed that there is some kind of  similarities.

One benefit of looking at cancer samples from all tissue types is that the pool of data becomes larger, offering more statistical power. .

A scientist team examined DNA copy number alterations—common features in cancer—at roughly 1.5 million loci across the genome. They found approximately 200,000 copy number alterations in total, which worked out to about 39 alterations per cancer sample.

To determine which of these alterations might be causing cancer, the researchers looked for only those that recurred across various cancer types. By doing so, they whittled down the 200,000 or so loci to just 140. Only 35 of these loci contained known oncogenes or tumor suppressor genes, meaning the remaining 105 contained new cancer-causing candidates to investigate.

Another scientist  team—which studied gene mutations and DNA methylation changes in addition to copy number alterations—similarly whittled down many thousands of such genetic aberrations to just 479 that were recurrent across multiple cancer types.

The team then asked which of these 479 genetic events occurred in each cancer sample, paving the way for new categories of cancer based on the particular constellations of aberrations they possessed. Interestingly, the team found that cancers with abundant single gene mutations tended not to have many copy number alterations and vice versa.

The two team  come to in conclusion is that they have a spectrum of tumors that are driven by copy number abnormalities  and then another set of tumors that are driven primarily by a series of mutational events. The two papers provided a very cogent argument that these are two of the major driving events.

Beyond learning more about the mechanisms behind the disease’s origins, such cancer studies might lead to a new kind of clinical trial. Sander described such studies as basket or matrix trials, in which patients with different tumor types—for example, breast, ovarian, or colorectal—but similar constellations of genetic alterations, would be treated with the same drug or drugs.

 It’s possible that the same mutation in different cancer types could indicate different responses to drugs.

REFERNCE-

G. Ciriello et al., “Emerging landscape of oncogenic signatures across human cancers,” Nature Genetics, doi:10.1038/ng.2762, 2013.

T. I. Zack et al., “Pan-cancer patterns of somatic copy number alteration,” Nature Genetics,doi:10.1038/ng.2760, 2013.

HOW VITAMIN D HELPS PREVENT LUNG CANCER?
Increasing vitamin D may now be a matter of life or death, as recent studies have shown that it may play a vital role in the fight against lung cancer. To date, lung cancer is one of the three most common cancers that kill men and women in developed countries with a statistic of one million deaths every year.
Researchers from the University of California at San Diego discovered a correlative relationship between higher rates of lung cancer and less exposure to the sun.
Cancer and vitamin D
The study compared data from national and international databases and compared the lung cancer rates in 111 countries. It found a correlation with smoking, lung cancer and significant lower UVB exposure. Although the current study focused only on lung cancer, research conducted on other cancers have pointed to the fact that most cancer cases are seen in subjects living far from the equator, suggesting that lower levels of vitamin D also account for a high risk of colon and other cancers.
Traditionally, vitamin D was thought to be mostly responsible for bone health and was the medical answer to the rickets phenomenon decades ago. More recent findings have shown that the body has cells and tissues which contain vitamin D receptors necessary for its proper functioning, spurring a lot of interest in the potential of what it can do. The fact that it has just been discovered to prevent a spectrum of chronic diseases, cancer included, has stimulated a debate about whether it is the answer to the cancer problem that has plagued the world.
What is vitamin D?
Curiously, vitamin D is not a vitamin but a hormone that, as earlier mentioned, affects a lot of physiological processes.
The body needs sufficient sun exposure to produce vitamin D . It can even be stored in the skin until the time when body needs it again. Strangely, it is impossible to get an overdose from sun exposure since the body has a mechanism that controls the amount it needs.
Getting vitamin D from dietary sources may not be enough, as there are not many foods naturally containing vitamin D. This leaves supplementation, which can be an option for those who may not get enough sun exposure.
Vitamin D controls cancer cells
The likely explanation for this is that vitamin D locally controls genes that help keep cancer at bay by keeping cellular proliferation in check. It has also been suggested that it can induce cell death and regeneration, reducing the potential for malignant cells to survive. Once it has done its job, it initiates its own destruction to guarantee that it does not enter circulation to influence calcium metabolism.
Andreas Moritz, a practitioner of alternative medicine and author of "Cancer is not Disease - It's a Survival Mechanism," describes cancer as the body's healing attempt when all other measures of self-preservation have failed. According to him, the reason the body allows some of its cells to become abnormal is because it attempts to heal itself. Thus, blocking its healing attempt can destroy the body while supporting it in its healing mechanisms can save it.
. The present treatment of cancer involves procedures such as chemotherapy, invasive procedure and use of pharmaceuticals. This narrow-minded focus on finding a cure practically ignores other options which have been around far longer than conventional medicine - such as the concept of a nutritional cure.
A look at the current trend in cancer treatments has seen such debilitating side effects in a patient's quality of life that it may appear to hasten a patient's decline rather improve his or her health. A patient may as well not undergo chemotherapy, as his chances of surviving without the procedure may well be higher than when he is undergoing treatment.
Nutritional care, on the other hand, seeks to work with the body's needs by providing the necessary vitamins and minerals needed to properly function. It is actually the natural way of keeping the body in balance and the best way to prevent diseases. In the event that the body's system is compromised due to illness, the body's immune system may be strengthened by taking food that naturally boost its immune system.
REFERENCE--
NATURAL NEWS JOURNAL
Learn more: http://www.naturalnews.com/035282_vitamin_D_lung_cancer_prevention.html#ixzz2fvBkc5oj

UNMASKING THE ROLE OF MAST CELLS IN DENGUE


Immune cells called mast cells can hinder rather than help the body's response to dengue virus, which suggests that mast cell products could be used as biomarkers to identify severe forms of the disease.

Every year, millions of people become infected with dengue virus: a mosquito-borne pathogen that poses an increasingly serious threat to global health. While the majority of individuals either experience no symptoms or mild dengue fever—a flu-like illness with headache, rash, and muscle and joint pain—a small percentage go on to develop a life-threatening condition called dengue hemorrhagic fever (DHF). This can result in hemorrhage, shock, organ failure and even death (World Health Organization, 1997).DHF is marked by the leakage of plasma proteins and fluid out of capillaries so that the blood becomes more concentrated. This vascular leakage is accompanied by a decrease in the number of platelets—cell fragments that help the blood to clot—and abnormalities in liver function. At present, there is neither a vaccine nor any specific therapy for severe dengue infection, and progress on both these fronts has been hampered by an incomplete understanding of disease pathogenesis. Now, in recent research by, Soman Abraham of Duke University and co-workers from the National University of Singapore reveals a pathogenic role for immune cells called mast cells in the response to dengue infection (St John et al., 2013). The study also reveals a potential biomarker that could identify patients at risk of DHF, as well as novel therapeutic targets.

Mast cells are part of the innate immune system—the body’s first line of defense against pathogens—and reside in tissues surrounding blood vessels and lymphatic vessels. They can be activated by the binding of specific antibodies to receptors on their surface, and can also recognize pathogens and inflammatory proteins directly. Mast cells contain large numbers of granules, which are enriched in substances such as histamine, tryptase, chymase and tumor necrosis factor, and within seconds of the mast cells being activated, these substances are released in a process called degranulation. The activated mast cells also begin to synthesize leukotrienes, prostaglandins, cytokines, and other inflammatory mediators. The release of these substances/mediators increases the permeability of blood vessels and recruits immune cells to the site of the infection. It also leads to activation of various non-immune cells, such as smooth muscle cells and mucous glands, which help to remove allergens and pathogens from the body.

Several lines of evidence are consistent with a protective role for mast cells in the host response to pathogens (Abraham and St John, 2010). Dengue virus is known to infect mast cells, particularly in the presence of pre-existing antibodies from an earlier infection (King et al., 2000). Mast cells also contribute to immunosurveillance, responding to dengue virus by activating host anti-viral responses and releasing signaling molecules that recruit additional immune cells (St John et al., 2011). By contrast, other recent work suggests that mast cells may sometimes have a pathogenic role. When infected with dengue virus in vitro, they trigger activation of endothelial cells (Brown et al., 2011). These line the inside of blood vessels and their activation can promote inflammation and blood clotting. Moreover, levels of certain mast cell proteins are elevated in patients with DHF compared to those with milder dengue fever (Furuta et al., 2012).

To begin to decipher the pathogenic role of mast cells, St John et al. injected dengue virus under the skin of the mouse ear. Local activation of mast cells (degranulation) and signs of capillary leakage were observed in the mice, which suggests that mice can be used to study dengue virus.

To delineate the role of mast cells in systemic dengue infection, the Duke-NUS team then introduced a clinical isolate of dengue virus directly into the mouse abdominal cavity. This induced a number of responses similar to those seen in patients with DHF, and which are consistent with increased vascular permeability. The mice also showed evidence of the virus in their bloodstream, as well as viral replication in the liver and spleen—the two primary organs affected in humans—and expressed a marker for mast cell activation, MCPT1. Similar findings were obtained in immunocompromised mice in which dengue virus can replicate more efficiently over a longer period. By contrast, genetically modified mice that were deficient in mast cells did not show vascular leakage in response to dengue virus, but began to do so when they were supplied with mast cells. Moreover, treatment with clinically approved mast-cell stabilizing compounds inhibited both mast cell activation and vascular leakage, in normal as well as immunocompromised mice.

To verify the mouse data, levels of chymase—the human equivalent of mouse MCPT1—were measured in a cohort of infected adults. The early clinical presentation of dengue fever and DHF are similar, but St John et al. found that chymase levels were consistently elevated in DHF patients compared to those with dengue fever. These findings point to a role for chymase (or mast cell activation) in the blood vessel pathology associated with dengue infection, and suggest that it could be a useful biomarker for DHF. Further studies are required to investigate the sensitivity, specificity, and predictive value of the test at various time points, and to determine whether it would also work in children.

The work of St John, Abraham and co-workers has revealed mast cells to be another deleterious player in dengue pathogenesis, despite their previously reported protective function. However, the factors that determine whether the mast cell response is beneficial or harmful are still unclear. The type and location of infected cells is likely to be important as different groups of mast cells can release distinct mediators. Whether the cells are activated by the virus itself or by pre-existing antibodies could also influence the response outcome, as could viral dosage. Lastly, the activity of other immune system components could influence the response of mast cells, as could the patient's genetic background and whether they have allergies.

Download figureOpen in new tabDownload powerpointFigure 1.

The response of mast cells to dengue virus can be beneficial or detrimental. When a mosquito injects dengue virus (brown hexagons) into the skin, the viruses are detected by specific antibodies (green) or unidentified receptors (blue) on the surface of resting (i.e., non-activated) mast cells. These can then trigger an anti-viral response (left) by releasing the contents of their granules (degranulation) and by upregulating intracellular anti-viral molecules (RIG-I and MDA5). The activated mast cells also secrete signaling molecules called chemokines, which recruit other immune cells including natural killer cells (NK), natural killer T cells (NKT) and T cells, which help to clear the virus. However, if local control mechanisms fail, the virus will enter the bloodstream and be carried to other organs (right). This activates the mast cells in these organs so that they undergo degranulation, releasing ready-made proteases such as chymase and tryptase, and synthesizing inflammatory mediators (leukotrienes and vascular endothelial cell growth factor [VEGF]). These increase the permeability of capillaries, leading to vascular leakage. Mast cells in these organs can also be activated by endogenous inflammatory mediators (such as C3a and C5a) that help the body to remove pathogens. Blocking mast cells (or their mediators) with drugs such as cromolyn, ketotifen and montelukast reduces pathogenic vascular leakage, but might also hamper viral clearance. Anti-mast cell therapy could thus be a double-edged sword.

Medications that block mast cells or their mediators have long been used to treat allergy and asthma, albeit with modest efficacy (Boushey, 2012). However, the use of these drugs in dengue infection must wait until we have a better understanding of how mast cells are regulated. It will be essential to find out how we can block vascular leakage without impeding viral clearance, and achieve overall control of infection without triggering an unwanted immune reaction. Nevertheless, the work of St John et al. offers new hope that it will be possible to treat or prevent DHF using readily available drugs, just as soon as we can identify which patients will benefit, and when

- See more at: http://elife.elifesciences.org/content/2/e00767#sthash.lyHMNldy.dpuf
REFERENCE----
IMMUNOLOGY eLife journal