Renal cell carcinoma harboring somatic TSC2 mutations in a child with methylmalonic acidemia

Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence.     

Fodrin and band 4.1 in a plasma membrane-associated fraction of human neutrophils

Erythrocytes possess a well-characterized submembranous filamentous network which interacts with transmembrane glycoproteins and is composed primarily of spectrin, ankyrin, band 4.1, and short actin filaments. An analogous structure was recently described in platelets. Human polymorphonuclear leukocytes (PMNs) were examined for the presence and plasma membrane association of similar proteins. Isolated PMNs, free of contamination with erythrocytes or platelets, were disrupted by nitrogen cavitation and separated into subcellular organelles on a discontinuous Percoll gradient. Detergent lysates of plasma membrane vesicles, but not azurophilic or specific granules, contained insoluble actin filaments and associated proteins. Immunoblots of detergent-insoluble plasma membrane fractions contained proteins recognized by antibodies to brain fodrin and erythrocyte band 4.1, whereas blots probed with antibodies to erythrocyte spectrin and ankyrin were negative. Fodrin and band 4.1 were not detected in granule fractions, but some fodrin was present in the cytosol. The association of proteins related to fodrin and band 4.1 with the plasma membrane suggests that PMNs contain a submembranous skeleton structurally analogous to that of erythrocytes and platelets. The specific function of these proteins and their structural organization in human PMNs await further study.     

Rac-dependent monocyte chemoattractant protein-1 production is induced by nutrient deprivation

Under ischemic conditions, the vessel wall recruits inflammatory cells. Human aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments have been performed in the presence of nutrient deprivation (ND). We hypothesized that ND rather than hypoxia mediates endothelial MCP-1 production during ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species (ROS) are involved in this process. ND was generated by shifting HAECs from 10% to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND, peaking at 18 hours. MCP-1 production was increased over a similar time frame, but peaked later at 24 hours. These effects were blocked by treatment with antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production were enhanced by RacV12 (constitutively active) in the absence of ND, and were inhibited by RacN17 (dominant-negative) adenoviral transduction under ND, suggesting that the small G-protein Rac1 is required. In conclusion, ND, an important component of ischemia, is sufficient to induce MCP-1 production by HAECs, and such production requires a functional Rac1, redox-dependent pathway.     

Follow-up of Australian aboriginal patients following open-heart surgery in Western Australia

BACKGROUND: To date there has been only one published report pertaining to the outcomes following open-heart surgery in Australian aboriginal patients. METHODS: The records of 57 consecutive aboriginal patients who underwent open-heart surgery at our institution over a 6-year period were retrospectively reviewed. Attempts were made to contact the patient by telephone, by letter, through their listed next of kin, general practitioners, community nurse or through the aboriginal liaison officer. RESULTS: There were 38 males and 19 females. Forty-five patients had coronary artery bypass grafting, 10 had isolated valve procedures while 2 had a combined operation. Mechanical prostheses were used for all valve replacements. There was a high incidence of diabetes, hypertension, hypercholesterolemia and smoking. There was one hospital death. Follow-up ranged from 6 months to 6 years with a mean of 3.09 years. Forty-four of the 56 (78.6%) hospital survivors were contactable while 21.4% were not contactable. There were two late deaths. Of the coronary patients who could be contacted, only 79% were taking Aspirin and a similar number Statin. 23% patients had recurrence of angina. There were five episodes of anticoagulation related complications in three patients. Only 44% of the patients were conversant with anticoagulation. CONCLUSIONS: The follow-up of the aboriginal patients was disappointing. The compliance with the medications was sub-optimal. There was a high incidence of recurrence of angina and anticoagulation related complications. The results raise concern about the use of mechanical prosthesis in these patients.     

Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras

Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by which Ras induces cellular transformation is, however, not fully elucidated. We present here evidence that oncogenic Ras suppresses the expression of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN), and this action of oncogenic Ras is mediated by the Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway via up-regulation of c-Jun. Jun(+/+) cells undergo cellular transformation by oncogenic Ras, and restoration of wild-type PTEN, but not a phosphate-defective mutant of PTEN, induces apoptosis in these cells. Conversely, in Jun(-/-) cells, oncogenic Ras neither suppresses PTEN nor causes transformation, but rather it induces PTEN-dependent apoptosis. An apoptotic response to oncogenic Ras in Jun(-/-) cells can be prevented by suppressing PTEN expression. These findings imply that oncogenic Ras suppresses the apoptotic gene PTEN via the Raf-MEK-ERK-c-Jun pathway to induce antiapoptosis and cellular transformation. Together, our findings identify a novel molecular interface between the oncogenic and tumor suppressor pathways that regulates cellular transformation and survival.     

眼部用药对老年人的全身影响

老年人使用眼药的情况是很普遍的,这些药物可能具有严重的全身影响,特别是在老年病人。这在医源性疾病的鉴别诊断中应予以考虑。文献报道的这个问题并非仅限于老龄人群,尽管大多数病人属于老年。眼药滴入球结膜囊中,除少量流出或吞下外,大部分均经由结膜毛细血管、鼻粘膜及咽部直接进入血液循环,其吸收量之大可足以产生副作用。由于老年人常常使用多种药物,因而与其他药物产生药物相互作用的可能性亦是存在的。现根据眼部用药的不良反应所涉及的主要