News from the Journal of Clinical Investigation: April 1, 2011

Ulcerative colitis is an inflammatory bowel disease that puts patients at high risk of developing, but the mechanism that explains the link between the two diseases is not fully understood. The enzyme heparanase is overexpressed in most human, and functions to modulate the interaction of tumor cells with the extracellular environment, promoting a series of events that allow cancer progression. Patients with ulcerative colitis have been shown to have high levels of heparanase in the colon, but if this enzyme plays a role in the pathogenesis of UC or its progression to cancer is not known.In the new research, a group led by Hang Nguyen Thi Thu, at Emory University in Atlanta, Georgia, has studied the role of CD98 in CRC using mouse models in which the molecule can be deleted or over-expressed in particular in L ‘ intestines. They found that the overexpression of CD98 promoted cell proliferation and production of proinflammatory molecules, thereby increasing the inflammatory response associated colitis and the promotion of tumorigenesis. In contrast, deletion of CD98 rendered mice resistant to inflammation induced by the CRC.

TITLE: Suppression of the dual-specificity phosphatase-2 by hypoxia increases drug resistance and malignancy of cancer in humans and mice

Expression of a peptide is TFF1 in gastric epithelial cells is lost in most human gastric cancer. They found that TFF1 normally suppresses NF-kB-mediated inflammation and loss of TFF1 leads to activation of NF kB and tumor formation in mice. The researchers believe that these results help to define the sequence of events in the progression of gastric cancer, and explain the link between TFF1 loss and the inflammation that leads to the development of cancer.

In this work, Dean Li and colleagues at the University of Utah in Salt Lake City, has investigated the role of training Pdcd10 CCM generating a mouse model in which the gene could be conditionally deleted. Furthermore, they found that the CCM were launched when the mice were killed according to the two copies of each of these three genes, a condition called loss of heterozygosity. The researchers believe that these results suggest that effective treatment requires the identification of causal mutations in each patient CCM.

Three genes, two mechanisms, a disease: an understanding of cerebral cavernous malformations

is one of the most common cancers, although not all causes are known, there is a strong link between chronic inflammation, as occurs in cases of ulcerative colitis, and the development of CRC. One of the proteins upregulated intestinal inflammation is called CD98, this protein is thought to contribute to the control of signaling pathways that regulate cell division, survival, and other functions. Interestingly, CD98 is upregulated in many human cancers, but it is unclear what role in the pathogenesis of cancer.

In this work, Claire Lewis and colleagues at the University of Sheffield Medical School, Sheffield, United Kingdom, found that in a mouse model, treatment with a VDA promoted the recruitment of MET. MET recruitment inhibit or reduce the population of cells in mice significantly improved the response to treatment VDA. The researchers believe that this study suggests that the objective pharmacological SPECT may improve the therapeutic efficacy of ADV in the treatment of solid tumors.

In addition, an overview is given of the mission of the JRC and its implementation, scientific activities and relations with the outside world. It covers the entrance to the JRC in the different phases of the policy cycle: the anticipation and policy formulation, implementation and evaluation.

Infection with a given bacterial species can have very variable, depending on the strain. Group A streptococci , for example, can cause, flesh-eating bacteria syndrome, or a simple colonization without symptoms. This variation is thought to be related to slight variations in the DNA sequence of the bacteria, so-called single nucleotide polymorphisms that alter the functions of proteins that the bacteria produce. However, the role of these SNPs in the pathogenesis is not fully known

In this work, Israel Vlodavsky and colleagues at the Rappaport Faculty of Medicine, Haifa, Israel and the Hadassah-Hebrew University Medical Center in Jerusalem, Israel, studied a mouse model of UC associated cancer. They found that heparanase activated immune cells to help maintain a state of chronic inflammation of the intestine, and promote the expression of the enzyme continues. The researchers believe their findings suggest that heparanse is an interesting therapeutic for the treatment of UC and the prevention of colon cancer.

TITLE: The loss of TFF1 is associated with activation of NF-B-mediated inflammation and gastric cancer in mice and humans

In this article, Scott Summers and his colleagues at Duke University, NUS, Singapore, has studied the link between TLR4 signaling and ceramide in the development of insulin resistance in mice. They found that TLR4 signaling promoted the synthesis of ceramide, and that this was necessary for saturated fatty acids induce insulin resistance. The researchers believe this finding helps to explain the mechanism of insulin resistance, and can help identify new therapeutic targets for the disease.

As solid tumors grow, they need new blood vessels to maintain their supply of oxygen and nutrients. So, stop vascular agents have been studied as potential therapies, and have been shown to promote tumor regression in humans and in mouse models. However, the blood vessels that remain on the margins after treatment to regrow and re-vascularize the tumor, limiting the clinical efficacy of the VDA treatment.

The intestine is colonized by bacteria that can help promote good digestion and also by species that may be pathogenic. Therefore, it is important that the immune system to distinguish between these two, so that the inflammatory response to invasive species can be controlled. However, little is known about how these antibodies have been created, or their specificity. In this work, Hedda Wardemann and his colleagues at the Max Planck Institute in Berlin, Germany, studied antigens to intestinal cells of these residents react in the B samples from human patients. They found that most of these B cells produce antibodies directed against antigens unique, suggesting that arises from the specific immune response to intestinal bacteria. Above all, the researchers believe that these results help us understand the immune responses that occur in patients with inflammatory bowel disease.

Three genes have been linked to familial cases of CCM, in all, patients are found to have loss of function of a single copy gene . Although two of these genes, called KRIT1 and CCM2 are known to operate in the development of the heart and blood vessels, the function of the third gene, called Pdcd10, is unknown. The molecular mechanisms leading to the formation of CCM are not fully understood, and at present no medical treatment is available for these patients.

In this work, James Musser and his colleagues at the Research Institute of Methodist Hospital in Houston, Texas, has studied the effects of SNP in RopB on the virulence of the strains by sequencing of the gene in many different strains. They found that only amino acid changes within RopB could significantly alter the global gene expression profiles and modify the virulence of the strains. They believe that this helps to explain how a small change in the genome of a species can influence the virulence of a given strain. The researchers hope that their method could be adapted to the study of other pathogenic bacteria, and could provide information to guide the development of new therapies.

TITLE: Mutations in two distinct genetic pathways cause cerebral cavernous malformations in mice

Muscle, liver and other tissues of blood sugar in response the hormone insulin. Insulin resistance, which is associated, is a condition in which tissues do not respond to insulin signals, which often leads to cardiovascular disease. Insulin resistance in muscle is thought to be related to exposure to saturated fatty acids, which are converted into molecules called ceramides can inhibit insulin signaling.

TITLE: a circuit that powers heparanase promotes chronic inflammatory colitis associated with tumorigenesis in mice

TITLE: simple substitution of natural amino acids in a regulatory protein gene expression changes and the virulence of Streptococcus

Dual-specificity phosphatase are negative regulators of intracellular signaling pathway. In the new research, Shaw-Jenq Tsai and colleagues at the National Cheng Kung University in Taiwan, found that DUSP2 expression is lost in many cancers, and that this effect is due to transcriptional repression of HIF. The researchers believe their results to identify DUSP2 as a vital link between hypoxia and tumor progression, and suggest that it may represent a promising new therapeutic target.

TITLE: TIE2 expressing macrophages limit the therapeutic efficacy of interrupting vascular combretastatins agent A4 phosphate in mice

Gastric cancer is a leading cause of cancer deaths. Infection with the bacterium H.

pylori was identified as a risk factor for stomach cancer, but the molecular pathogenesis has not been fully defined.

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