ONCOLOGY: Loss of the breast cancer gene BRCA1 in the absence of genetic mutations is controlled by the protein HOXA9

Women with BRCA1 genetic mutations that prevent their BRCA1 protein from being expressed or functioning properly are predisposed to develop breast and ovarian cancers. BRCA1 expression is also often reduced in breast tumors from women who do not have predisposing genetic mutations and the reason for this is not known. However, Valerie Weaver and colleagues, at the University of California, San Francisco, have now generated data that provide an explanation for the loss of BRCA1 expression in sporadic human breast tumors in the absence of BRCA1 genetic modifications by analyzing human breast cancer tissue and cell lines. Specifically, they generate several lines of evidence to indicate that the protein HOXA9 restricts breast tumor aggression by inducing BRCA1 expression and infer that the frequently observed downregulation of the HOXA9 gene in sporadic human breast cancers leads to loss of BRCA1 expression in the absence of BRCA1 genetic modifications.

TITLE: HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype

IMMUNOLOGY: A NOD(1) to antibacterial host defense via type I IFNs

Type I IFNs are immune molecules that have a central role in antiviral host defense. New research, performed by a team of researchers at the National Institutes of Health, Bethesda, and Kyoto University Graduate School of Medicine, Japan, has now shown that their production can be triggered by stimulation of the protein NOD1 and that this contributes to protection against the bacterium Helicobacter pylori in mice.

The protein NOD1 is found inside the epithelial cells that line the various body cavities, including the intestines and stomach. It functions to sense specific microbial components, responding by triggering an inflammatory immune response. In this study, which was led by Warren Strober and Tomohiro Watanabe, stimulating NOD1 in human epithelial cells was unexpectedly found to activate a signaling pathway that leads to the production of type I IFNs. While detailed analysis uncovered the molecules in the pathway, the physiologic significance of this pathway was revealed by the observation that mice lacking the receptor for type I IFNs and mice in which the signaling pathway was inhibited showed increased susceptibility to H. pylori infection. These data expand our knowledge of the role of both NOD1 and type I IFNs in host defense.

TITLE: NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway

HEMATOLOGY: Setting the story straight: HDL does not regulate blood clotting

HDL cholesterol is considered good cholesterol and its levels in the blood correlate inversely with hardening of the arteries, a condition that is a major cause of heart attack and stroke. Previous studies have indicated a role for HDL as a regulator of blood clotting (blood coagulation). Specifically, it was found that HDL helped the anticoagulant protein APC degrade the blood clotting protein FVa. However, a team of researchers, led by Björn Dahlbäck, at Lund University, Sweden, has now isolated HDL from human plasma using a different purification technique and found that HDL does not have the ability to perform this function, rather this property of HDL is instead caused by contaminating negatively charged phospholipid membranes.

TITLE: Reevaluation of the role of HDL in the anticoagulant activated protein C system in humans

HEMATOLOGY: Linking Treg immune cells to graft-versus-host-disease

Treatment for a number of leukemias, lymphomas, and other medical conditions is transplantation with bone marrow cells that can generate all blood cells from a genetically nonidentical individual (a process known as allogeneic hematopoietic stem cell transplantation [HSCT]). Despite treatment with immunosuppressive drugs, some patients go on to develop graft-versus-host-disease (GVHD), a condition in which immune cells derived from the transplanted cells attack and destroy the recipient's body. This is one of the most common and clinically important problems affecting long-term HSCT survivors and it is associated with a relative deficiency in immune cells known as Tregs in the blood. Jerome Ritz and colleagues, at the Dana-Farber Cancer Institute, Boston, have now determined that Treg deficiency occurs in patients in which the number of immune cells known as CD4+ T cells takes a long time to rebound following HSCT.

TITLE: Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

NEPHROLOGY: New player in salt retention by the kidney

It is important that the amount of salt we consume is matched by the amount released by our kidneys into the urine. This is because the amount of salt in our body determines how much fluid is retained, and too much salt in our body means excess fluid is retained and blood pressure rises. One cause of high blood pressure is abnormal retention of sodium, the component of salt responsible for regulating fluid levels, by the kidney. Drugs that block sodium transport systems in the kidney are used to treat disease states such as high blood pressure caused by abnormal renal sodium retention. Although drugs known as thiazides have been used to treat high blood pressure for many years, data indicate that not all the sodium transport mechanisms in the kidney targeted by thiazides have been identified. However, Dominique Eladari and colleagues, at INSERM U872, France, have now determined in mice that thiazides target the protein SLC4A8 and that this is an ion exchanger that mediates thiazide-sensitive sodium retention in a region of the kidney known as the cortical collecting ducts.

TITLE: The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice

Source:
Karen Honey
Journal of Clinical Investigation