University of Utah researchers and their colleagues have identified the gene that is mutated in a hereditary form of a rare neuroendocrine tumor called paraganglioma (PGL). The gene, called hSDH5, is required for activation of an enzyme complex that plays a critical role in the chemical reactions that take place within cells to convert biochemical energy into usable energy. This study is published in the journal Science

Paragangliomas are rare, generally benign tumors that arise from cells called glomus cells, which are located along blood vessels and play a role in regulating blood pressure and blood flow. Approximately 25 percent of paragangliomas are hereditary. Of the four familial PGL syndromes, three forms have previously been associated with mutations in genes of the succinate dehydrogenase (SDH) complex, an enzyme complex involved in the ability of cells to extract energy from nutrients.

Studies in Yeast

“Defects in mitochondria, the power sources of the cell, have been implicated in a variety of human disorders, including cancer,” says Jared Rutter, PhD, associate professor of biochemistry at the University of Utah School of Medicine, investigator at the University’s Huntsman Cancer Institute, and lead author of the study. “Because it is incredibly difficult to perform in-depth studies in humans, we decided to use a much simpler model system, the yeast Saccharomyces cerevisiae, in order to study mitochondrial functions before going back to humans and determining whether what we learned in yeast was also relevant to humans. Following this strategy, we first characterized a mitochondrial protein called Sdh5 in yeast and then moved on to study its potential role in human disease.”

Sdh5 is a mitochondrial protein that is highly conserved, meaning that it has remained largely unchanged throughout the course of evolution and likely performs similar essential cellular functions in both yeast and humans. Rutter and his colleagues discovered that, in yeast, the Sdh5 protein is needed for the SDH complex to function normally. They also found that Sdh5 is required for activation of another protein called Sdh1 that is also part of the SDH complex.

Studies in Humans

“The amino acid sequence of yeast Sdh5 is 44 percent identical to its human counterpart, which we’ve named hSDH5. This gave us some confidence that the Sdh5 functions we discovered in yeast would also be carried out by human hSdh5,” explains Rutter. “Previous genetic studies have shown that the hereditary paragangliomas PGL1, PGL3, and PGL4 are associated with mutations causing loss of SDH activity. Although the gene for PGL2 had not been identified, we knew that it was located on the same chromosome as the hSDH5 gene.”

Rutter and his colleagues sequenced the hSDH5 gene in three individuals with PGL2 from a previously described Dutch lineage. They identified a single DNA nucleotide change which resulted in a mutation in the most conserved region of the protein. Of the 45 individuals within the affected lineage who inherited the mutation, 33 have developed PGL2, providing strong evidence that hSDH5 is the PGL2 gene. The seven individuals who inherited the mutation from their mothers are unaffected, suggesting an inheritance pattern that is specific to the parent of origin.

The researchers also discovered that, as in yeast, the inactivation of hSDH5 dramatically impaired the activity of the SDH complex, which was decreased by approximately 95% in tumors from three patients with PGL2.

Implications on Genetic Testing

The identification of hSDH5 as the PGL2 gene has potential clinical implications for patients with familial PGL syndromes. Genetic testing is suggested for the management of PGL, even when it does not seem to be inherited, in order to identify individuals who are at risk for developing tumors.

“Individuals with familial PGLs tend to be affected at a younger age with tumors at multiple sites,” says Rutter. “Including hSDH5 in DNA screening will allow for more comprehensive genetic testing, as well as earlier detection and treatment.”

Huaixiang Hao, a graduate student in Rutter’s laboratory, conducted the majority of the experiments in this study. Other study contributors include Oleh Khalimonchuk, Ph.D. and Dennis Winge, Ph.D. in the department of medicine at the University of Utah and Joshua Schiffman, M.D. and Brandon Bentz, M.D. from Huntsman Cancer Institute. Noah Dephoure, Ph.D. and Steven Gygi, Ph.D. from Harvard Medical School, as well as a number of Dutch scientists, were also involved in the study.

Source:
Kathy Wilets

University of Utah Health Sciences

Topical Treatment Improves Wound Healing

A group led by Dr. Yasunori Okada at Keio University in Tokyo, Japan has demonstrated that matrix metalloproteinases (MMPs) are instrumental in wound healing. Their report can be found in the August 2009 issue of The American Journal of Pathology.

Wound healing is the complex process of regenerating dermal and epidermal tissue after skin injury. MMPs, which can degrade proteins, are essential in breaking down wounded tissues to allow for wound healing; however, the specific function of individual MMPs in wounded tissues requires further study.

Using mouse models that lacked individual MMPs, Hattori et al noted that wound closure in MMP-deficient mice was significantly delayed compared with normal mice. Both MMPs examined played key roles in movement of skin cells, and one contributed to new blood vessel growth as well. Topical treatment with MMPs increased the rate of wound healing in these mice, providing a possible therapeutic strategy for treating delayed wound healing.

Dr. Okada and colleagues “have provided the first evidence of the importance of MMP-9 and MMP-13 on cutaneous wound healing by demonstrating that [mice that lack either] MMP-9, MMP-13, or both MMP-9/13 exhibit a significant delay in macroscopic wound closure and histological re-epithelialization. … [Their data] suggest the possible treatment of delayed wound healing by the application of the MMPs or inducers of the MMPs.”

Hattori N, Mochizuki S, Kishi K, Nakajima T, Takaishi H, D’Armiento J, Okada Y: MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing. Am J Pathol 2009, 175: 533-546

FUT-175 Complements Experimental Autoimmune Encephalomyelitis (EAE)

Dr. Feng Lin and colleagues at Case Western Reserve University in Cleveland, OH have discovered that the complement inhibitor FUT-175 delays EAE onset. They present these findings in the August 2009 issue of The American Journal of Pathology.

Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune response attacks the central nervous system (CNS), causing physical and cognitive disability. Complement, molecules involved in clearing infection, may enhance this misguided immune response.

Li et al therefore examined the effects of FUT-175, a drug with few clinical side effects that prevents the functions of complement, on the development of EAE, a mouse model of MS. They found that FUT-175 prevented production of activated complement and inhibited specific immune responses with little non-specific toxicity. FUT-175 treatment delayed EAE disease onset and decreased the severity of disease. Thus, FUT-175 may be a novel candidate to treat autoimmune diseases such as MS.

This study by Li et al “provide[s] further insight into how to most effectively apply … complement inhibitors for treating T cell-mediated diseases.”

Li Q, Nacion K, Bu H, Lin F: The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis. Am J Pathol 2009, 175: 661-667

New Target for Tumor Angiogenesis Inhibition

Researchers led by Dr. Horace DeLisser at the University of Pennsylvania School of Medicine in Philadelphia, PA have found that loss of PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1) inhibits tumor angiogenesis. They report their data in the August 2009 issue of The American Journal of Patholog

Tags: Case Western Reserve University, Mmps, Western Reserve University

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Elekta Receives FDA 510 (k) Clearance For Monaco VMAT Treatment Planning Solution

Posted by: admin in Prescription Cancer Drugs on August 05th, 2009

Elekta (STO:EKTAB) has received FDA 510(k) clearance for the VMAT (Volumetric Modulated Arc Therapy) enhancement to Monaco®, treatment planning solution.

Monaco treatment planning system, introduces a set of tools to make the treatment planning process easier, more straightforward and clinically reliable. For the clinicians this gives the flexibility and control needed for complex treatment. For the clinic administrator it provides reduced planning time and increased clinical throughput.

“We are extremely proud and very pleased to receive clearance to add this VMAT technique to Monaco in the U.S. market,” said Rob Cessac, Product Manager for Elekta CMS Software. “Our continued support and development of leading approaches to cancer treatment promises to create a positive future for clinicians and patients.”

The biologically-based Monaco IMRT (Intensity Modulated Radiotherapy) treatment planning system features constrained optimization and dose calculation algorithms and help reduce the time needed to optimize IMRT plans.

Monaco has been available for use clinically for the past two years for step-and-shoot IMRT planning. The product was developed in cooperation with Eberhard Karls University Tuebingen in Germany. For the latest Monaco with VMAT news, visit http://www.elekta.com.

Source
Elekta

Tags: Clinicians, Imrt, S Market

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