Read new research paper from CWRUmedicine Hematology Oncology on Human beta-defensin-2 expression

“Expression of human beta-defensin-2 in intratumoral vascular endothelium and in endothelial cells induced by transforming growth factor beta”
Peptides 2010 Feb
Kawsar HI, Ghosh SK, Hirsch SA, Koon HB, Weinberg A, Jin G.

Human beta-defensin-2 (hBD-2) is a small cationic peptide originally identified from psoriatic skin lesions as an antimicrobial agent of the innate immune system. The expression of hBD-2 is believed to be induced exclusively in epithelial cells by microbial components and certain proinflammatory cytokines, such as interleukin-1 beta (IL-1 beta). In this study, we report, for the first time, that hBD-2 is expressed in vascular endothelial cells associated with oral squamous cell carcinoma (OSCC) and Kaposi’s sarcoma lesions, but not in that of normal stroma. Expression of hBD-2 in vascular endothelial cells was further substantiated by in vitro experiments using cultured human umbilical vein endothelial cells (HUVECs). Transforming growth factor beta1 (TGF beta 1) and IL-1 beta, two well-known tumorigenic inflammatory mediators, induce hBD-2 transcript and peptide expression in HUVECs. However, TGF beta 1 does not stimulate hBD-2 expression in oral epithelial cells. In addition, proinflammatory cytokines and microbial reagents do not induce the expression of hBD-1 and hBD-3 in HUVECs. Since hBD-2 has been shown to modulate migration, proliferation, and tube formation of HUVECs in vitro and participate in immune cell trafficking, its expression in vascular endothelial cells located within malignant lesions may play a role in tumor angiogenesis and cancer metastasis.

Read the full article on CWRUmedicine.org

Read about “Gab2 Promotes Hematopoietic Stem Cell Maintenance & Self-Renewal with STAT5”

BACKGROUND ::
Grb2-associated binding (Gab) adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol-3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs). Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5), a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner.

METHODOLOGY & PRINCIPAL FINDINGS ::
To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit(+)Lin(-)Sca-1(+) (KLS) cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background. Fetal liver cells isolated from homozygous STAT5 mutant mice lacking Gab2 showed significant reduction in HSC number (KLS CD150(+)CD48(-)), reduced HSC survival, and dramatic loss of self-renewal potential as measured by serial transplantation.

CONCLUSIONS & SIGNIFICANCE ::
These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non-redundant with STAT5. Furthermore, important synergy between STAT5 and Gab2 was observed in HSC self-renewal, which might be exploited to optimize stem cell-based therapeutics.

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Read about “Direct detection and quantification of abasic sites for in vivo studies of DNA damage & repair”

Use of chemotherapeutic agents to induce cytotoxic DNA damage and programmed cell death is a key strategy in cancer treatments. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway resulted in formation of abasic or apurinic/apyrimidinic (AP) sites, and blockage of AP sites led to a significant enhancement of drug sensitivity due to reduction of DNA base excision repair. Since a number of chemotherapeutic agents also induce formation of AP sites, monitoring of these sites as a clinical correlate of drug effect will provide a useful tool in the development of DNA-targeted chemotherapies aimed at blocking abasic sites from repair. Here we report an imaging technique based on positron emission tomography (PET) that allows for direct quantification of AP sites in vivo. For this purpose, positron-emitting carbon-11 has been incorporated into methoxyamine ([(11)C]MX) that binds covalently to AP sites with high specificity. The binding specificity of [(11)C]MX for AP sites was demonstrated by in vivo blocking experiments. Using [(11)C]MX as a radiotracer, animal PET studies have been conducted in melanoma and glioma xenografts for quantification of AP sites. Following induction of AP sites by temozolomide, both tumor models showed significant increase of [(11)C]MX uptake in tumor regions in terms of radioactivity concentration as a function of time, which correlates well with conventional aldehyde reactive probe (ARP)-based bioassays for AP sites.

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Read about “Non-Hodgkin’s lymphoma in the elderly”

The expansion of older population segments and the continuous increase in the incidence of non-Hodgkin’s lymphoma (NHL) makes this group of neoplasms an important and growing problem. Older NHL patients have increased risk of therapy-related toxicity as a result of age-related physiological changes and frequent co-morbidities. A functional assessment of the elderly patient is necessary to determine the likelihood of tolerating and responding to therapy. The comprehensive geriatric assessment (CGA) is one multidisciplinary tool that has been applied successfully to older cancer patients and aids in identification of subjects who will or will not benefit from anti-neoplastic treatment. Although indolent lymphomas present more frequently at advanced stage, randomized trials do not show better outcomes with early therapy, supporting close observation until specific therapeutic indications arise. Use of the monoclonal antibody rituximab as a single agent or in combination with chemotherapy improves survival and has become the standard of care in first-line treatment. Radioimmunoconjugates, bendamustine, and other monoclonal antibodies as well as novel targeted agents also are active against indolent lymphomas. Diffuse large B-cell lymphoma is an aggressive but potentially curable disease. Several trials performed exclusively in elderly patients have demonstrated improved response rates and survival with the addition of rituximab to CHOP (cyclophosphamide, doxorubicin [adriamycin], vincristine, prednisone) chemotherapy in the front-line setting. Salvage chemotherapy followed by autologous haematopoietic cell transplant (autoHCT) has been shown to have better failure-free and overall survival in randomized trials involving younger patients. Highly selected individuals up to age 70 years may attain long-term survival benefit from autoHCT, although transplant-related mortality is higher than in younger patients.

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Dr. Afshin Dowlati discusses a new way to predict effectiveness of chemotherapy

Doctors often have trouble knowing who might respond to certain cancer treatments. “We kind of give chemotherapy and wish for a good result,” says Dr. Afshin Dowlati. That could change.

Dowlati led a study that revealed lung cancer patients with low levels of a molecule that controls cellular interaction have twice the chance of responding to chemotherapy than those with high levels. Those levels can also predict how likely a patient is to live a year after diagnosis. The difference could help patients decide whether to try chemotherapy, drugs or pursue alternative therapies, Dowlati says.

Learn more at CWRUmedicine.org

ASH 2010 Scholar Award Winner Marvin Nieman, PhD

The American Society of Hematology (ASH) announces the 2010 recipients of its Scholar Awards. The program is designed to support hematologists who have chosen a career in research by providing partial salary or other support during that critical period required for completion of training and achievement of status as an independent investigator.

The awards are made possible through grants from the corporate community, individual donors, foundations, and funds committed by the Society. The awards are for two years at $50,000 per year for fellows and $75,000 per year for junior faculty

The 2010 Scholar Basic Research Junior Faculty Award Winner is Marvin Nieman, PhD

Video Health Tip :: Dr Stanton Gerson discusses Colon Cancer

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New test developed by CWRUmedicine researchers may reduce colon cancer

Colon cancer is the second most deadly cancer in the U.S. despite being the most preventable. The American Gastroenterological Association (AGA) recently announced concern that people will neglect colon cancer screening during this economic climate.

Screening is recommended in both sexes over age 50 and earlier if a patient has a family history of this disease. However, some people put it off due to fear of having a colonoscopy, which can be both invasive and expensive. As more people lose health insurance coverage, the high cost of this procedure may lead many more people to forego screening.

Sanford Markowitz, MD, CWRUmedicine oncologist and colon cancer researcher of the University Hospitals Ireland Cancer Center at University Hospitals Case Medical Center, has developed a less expensive, non-invasive test for this disease.

About the test:

• The non-invasive test detects DNA markers for colon cancer using a stool sample that is taken at home
• The DNA Stool Test is available now at the doctor’s office, or can be easily ordered by the doctor
• Although the test isn’t covered by insurance, the cost is significantly lower
• Patients with negative results will not need to commit time and money to having a colonoscopy; patients with positive results will move forward with  colonoscopy to provide more information
• It is 80 percent effective and while colonoscopy is still the most effective test, it is not useful if patients are avoiding it altogether
• The American Cancer Society added the test to its screening guidelines last year

Learn more at CWRUmedicine.org

Watch & learn about DNA Screening for Colon Cancer

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CWRUmedicine’s Channel.flv (5335 KB)

It is estimated that colon cancer will kill 50,000 people in the United States this year. But found early, that number could be lowered substantially. So why do so many still die from it? The answer and the solution can be found in a medical laboratory at Case Western Reserve Department of Medicine in Cleveland, Ohio.
View more videos on CWRUmedicine YouTube Channel

CWRUmedicine’s Marvin T. Nieman, Ph.D. awarded The American Society of Hematology 2010 Scholar Award

The program is designed to support hematologists who have chosen a career in research by providing partial salary or other support during that critical period required for completion of training and achievement of status as an independent investigator.

The awards are for two years at $50,000 per year for fellows and $75,000 per year for junior faculty.

Read more at CWRUmedicine.org