Association between traumatic brain injuries and ketamine infusion side effects following combat injury.

INTRODUCTION: Ketamine is a vital component for acute pain management in emergency trauma care for both civilian and military hospitals. This preliminary analysis examined whether combat-injured US service members sustaining traumatic brain injuries (TBI) experienced increased odds of ketamine side effects compared with those without TBI. METHODS: This preliminary analysis included combat-injured service members, ages ≥18 years with documented pain scores during the 24 hours before and 48 hours after receiving an intravenous ketamine infusion at Walter Reed National Military Medical Center (WRNMMC) between 2007 and 2014. Logistic regression modeling examined the association between TBI and ketamine side effects (eg, hallucinations, nightmares, dysphoria, nausea, decreased oxygen saturation) during hospitalisation. RESULTS: Of the 77 patients, 62% presented with a documented TBI. Side effects were documented for 18.8% of those without TBI and 24.4% of those with TBI. Analyses were unable to find evidence against the null hypothesis with the current sample size, even when adjusting for injury characteristics and preinfusion opioid doses (adjusted OR=0.90 (95% CI 0.26 to 3.34), p=0.87). CONCLUSION: In this small sample of combat-injured service members, we were unable to detect a difference in ketamine-related side effects by documented TBI status. These hypothesis-generating findings support the need for future studies to examine the use of intravenous ketamine infusions for pain management, and subsequent care outcomes in patients who experience polytraumatic trauma inclusive of TBI.

Expansion of immature, nucleated red blood cells by transient low-dose methotrexate immune tolerance induction in mice.

Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.

Oral health behaviours of older Australian men: the Concord Health and Ageing in Men Project.

BACKGROUND: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of older Australian men. The aim of this paper is to describe the oral health behaviours and dental service use of CHAMP participants and explore associations between oral health behaviours with and general health status. METHOD: Information collected related to socio-demographics, general health, oral health service-use and oral health behaviours. Key general health conditions were ascertained from the health questionnaire and included physical capacity and cognitive status. RESULTS: Fifty-seven percent of the men reported visiting a dental provider at least once or more a year and 56.7% did so for a "dental check-up". Of those with some natural teeth, 59.3% claimed to brush their teeth at least twice or more a day. Most men (96%) used a standard fluoride toothpaste. Few participants used dental floss, tooth picks or mouth-rinses to supplement oral hygiene. Cognitive status and self-rated general health were associated with dental visiting patterns and toothbrushing behaviour. CONCLUSIONS: Most older men in CHAMP perform favourable oral health behaviours. Smoking behaviour is associated with less favourable dental visiting patterns, and cognitive status with toothbrushing behaviour.

Polyomaviruses of the skin: integrating molecular and clinical advances in an emerging class of viruses.

BACKGROUND: Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses that express tumour antigen proteins. Fourteen species of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous polyomavirus - Merkel cell polyomavirus (MCPyV) - six more species have been detected in the skin: trichodysplasia spinulosa-associated polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10 and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6 and HPyV7 have been definitively associated with diseases of the skin, most commonly in immunocompromised individuals. MCPyV is a predominant aetiology in Merkel cell carcinomas. TSPyV is one of the aetiological factors of trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to pruritic skin eruptions. The roles of HPyV9, HPyV10 and HPyV13 in pathogenesis, if any, are still unknown, but their molecular features have provided some insight into their functional biology. RESULTS: In this review, we summarize the known molecular mechanisms, clinical presentation and targeted therapies of each of the eight cutaneous HPyVs. CONCLUSIONS: We hope that heightened awareness and clinical recognition of HPyVs will lead to increased reports of HPyV-associated diseases and, consequently, a more robust understanding of how to diagnose and treat these conditions.

Clinicopathological Features of Cardiac Glycolipid Storage Disease in an Adult Pug.

A 12-year-old neutered male pug suffered cardiac arrest and died under general anaesthesia during diagnostic imaging for evaluation of exercise intolerance and respiratory crisis. Histopathological evaluation revealed two types of storage material, glycolipid and lipopigment, having differential distributions in multiple organs. The heart was most strikingly affected and other less affected tissues included the liver, brain, kidneys and skin. Cardiomyocytes were swollen with extensive sarcoplasmic vacuolation together with coalescing areas of myocardial fibrosis. Transmission electron microscopy revealed irregular myelin-like structures and complex concentric lamellar bodies dominating the sarcoplasm and displacing myofibrils. These findings were consistent with a lysosomal storage disease (LSD) as the cause of cardiac disease and death. The unique clinical presentation, histomorphology and ultrastructural features of the material suggested a glycolipid storage disease most closely resembling Anderson-Fabry (Fabry) disease in man. Fabry disease is a LSD that can present in later life and is characterized by loss of α-galactosidase A function and, often, accumulation of glycosphingolipids in tissues including the heart, kidneys, vascular endothelium and smooth muscle.

Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1).

Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.

Prevalence and severity of asthmatic symptoms in Grenadian school children: the Grenada National Asthma Survey.

OBJECTIVE: The goal of this study was to determine the prevalence of asthma in school children in the tri-island Caribbean nation of Grenada. SETTING, PARTICIPANTS AND OUTCOMES: This was a self-report study provided to the guardians of all primary school children between ages 6 and 7 throughout Grenada, Carriacou and Petite Martinique in 2013. Of the 2362 surveys provided, 1374 were returned, resulting in a response rate of 58.2%. Only responders listing birthdays between 1 January 2006 and 31 December 2007 were included in the analysis, resulting in 1165 qualifying responders. Asthma diagnosis was based on previous physician diagnosed asthma and/or self-reported presence of wheeze in the past 12 months (current wheeze). Severity of asthma, medication usage, environmental exposures, physician and emergency department visits were compared among respondents. RESULTS: The prevalence of wheezing in the past year was 30.5±1.8%, and of these 68.4% were previously diagnosed with asthma. Of the current wheeze participants, 39.9±9.2% reported moderate to severe asthma symptoms and increased exposure to cigarette smoke, excessive dust, burning brush and landfills. Carriacou and Petite Martinique, the two smaller islands, had a lower incidence of current wheeze (14.1±7.7%) and exposure rates to cigarette smoke and burning brush as compared to the larger, denser island of Grenada. Although 65.7% of respondents diagnosed with asthma reported taking medication, the number of annual doctor and emergency department visits were high (2.82 and 0.86, respectively). Respondents with the most severe asthma symptoms reported the most emergency department visits with an average of 1.05 visits annually, whereas respondents with moderate asthma symptoms had the most doctor visits with an average of 3.33 visits annually. CONCLUSIONS: This study indicates that the prevalence of childhood asthma in Grenada is very high and warrants policy consideration in public health and education to decrease its morbidity.

Retrospective cohort study evaluating exenatide twice daily and long-acting insulin analogs in a Veterans Health Administration population with type 2 diabetes.

AIM: This was a retrospective cohort study that evaluated the differences in glycated haemoglobin (HbA1c) and body mass index (BMI) in veterans with type 2 diabetes mellitus (T2DM), prescribed exenatide twice daily (BID) versus long-acting insulin analog (LAIA) two years after initiation in the United States (US) veteran population. MATERIALS AND METHODS: Patients were included if they were ≥ 18 years old with T2DM, and initiated exenatide BID or LAIA at the Veterans Health Administration between January 1, 2006 and December 31, 2010. Multivariate models were used to evaluate the changes in HbA1c and BMI between groups, controlling for potential confounders. Logistic regression was used to evaluate the odds of achieving ≥ 0.5% HbA1c reduction based on baseline HbA1c stratifications: low,<7%; moderate, 7% to<9%; and high,≥ 9%. RESULTS: A total of 446 exenatide BID and 51,531 LAIA patients met inclusion/exclusion criteria. On average, exenatide BID patients were significantly older (64 versus 60 years) with a higher BMI (37.8 versus 32.9 kg/m(2)). Baseline HbA1c was 8.2% and 8.8% for exenatide BID and LAIA patients, respectively (P<0.001); otherwise, patients were similar for all other characteristics. Exenatide BID treatment was significantly associated with a 0.32% (95%CI: 0.18-0.47%) greater reduction in HbA1c at two years compared with LAIA. Similar findings were observed for BMI reduction (0.68 kg/m(2); 95%CI: 0.42-0.95 kg/m(2)). Exenatide BID patients with moderate baseline HbA1c had significantly higher odds of achieving ≥ 0.5% HbA1c reduction compared with LAIA patients (OR=1.5; 95%CI: 1.2-2.0). CONCLUSIONS: Veterans treated with exenatide BID had significantly greater reduction in HbA1c and BMI compared with patients treated with LAIA patients two years after initiation.

[Nutritional status in patients with recurrent glioblastoma]. / Évaluation du statut nutritionnel chez les patients présentant un glioblastome en récidive.

INTRODUCTION: Nutritional status is a major clinical parameter in multiple cancers. Indeed, nutritional status is a prognostic factor and a predictor of response and toxicity to treatments in breast and lung cancers for instance. To our knowledge, in patients suffering from malignant primary brain tumors, nutritional status has been poorly investigated. METHODS: Nutritional status of 26 glioblastoma patients relapsing after a first line of treatment was studied. The body mass index (BMI), the prognostic inflammatory and nutritional index (PINI) and the instant nutritional score (INS) were assessed. RESULTS: The BMI was abnormal in 12 patients, two were malnourished while 10 were overweight. The BMI was not correlated to age of patients. Overweight status did not impact patient survival but it was associated with reduced performance status. The PINI was abnormal in three patients. Finally, the INS was abnormal in 24 patients, noted 2 (n=22) or 4 (n=4). CONCLUSIONS/DISCUSSION: Our results were not in favor of systematic nutritional support in patients with recurrent glioblastoma after a first line of treatment. Being overweight does not influence prognosis but may influence performance status. Steroid therapy and chemotherapy (inducing sodium and water retention and lymphopenia) weaken the relevance of BMI and INS for nutritional assessment in patients with recurrent glioblastoma. Further studies using additional nutritional tests in larger, independent and prospective cohorts of patients are warranted to obtain more details.

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.

AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. CONCLUSIONS/INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.

RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice.

OBJECTIVE: To investigate the impact of reduced adipocyte fatty acid-binding protein 4 (FABP4) in control of body weight, glucose and lipid homeostasis in diet-induced obese (DIO) mice. METHODS: We applied RNA interference (RNAi) technology to generate FABP4 germline knockdown mice to investigate their metabolic phenotype. RESULTS: RNAi-mediated knockdown reduced FABP4 mRNA expression and protein levels by almost 90% in adipocytes of standard chow-fed mice. In adipocytes of DIO mice, RNAi reduced FABP4 expression and protein levels by 70 and 80%, respectively. There was no increase in adipocyte FABP5 expression in FABP4 knockdown mice. The knockdown of FABP4 significantly increased body weight and fat mass in DIO mice. However, FABP4 knockdown did not affect plasma glucose and lipid homeostasis in DIO mice; nor did it improve their insulin sensitivity. CONCLUSION: Our data indicate that robust knockdown of FABP4 increases body weight and fat mass without improving glucose and lipid homeostasis in DIO mice.

Monocyte chemoattractant protein-1 in the choroid plexus: a potential link between vascular pro-inflammatory mediators and the CNS during peripheral tissue inflammation.

During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of cerebrospinal fluid (CSF) production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the small inducible cytokine A2 (SCYA2) gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCP-1 protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared with other rat CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the nuclear factor-kappa B (NF-kappaB) signaling cascade including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and inhibitor of kappa B alpha (IkappaBalpha) in choroid tissue. Given that we also detected increased levels of MCP-1 protein by ELISA, we sought to identify potential downstream targets of MCP-1 and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding endothelial leukocyte adhesion molecule 1 (E-selectin), a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during peripheral tissue inflammation, likely initiated by blood-borne inflammatory mediators, which may modify events in CNS.

Randomized clinical trial to determine the effect of nasogastric drainage on tracheal acid aspiration following oesophagectomy.

BACKGROUND: The aim of this study was to investigate tracheal acid aspiration after oesophagectomy and to determine whether it is influenced by nasogastric (NG) drainage. METHODS: Thirty-four patients undergoing oesophagectomy were randomized to one of three methods of NG drainage: a single-lumen tube with free drainage and 4-hourly aspiration, a sump-type tube on continuous suction drainage, or no NG tube. A tracheal pH probe was used to collect information on acid aspiration for 48 h after surgery. A pH < 5.5 was considered abnormal (normal pH 6.8-7.2). Total time with tracheal pH < 5.5, number of reflux episodes and longest reflux time were compared between groups. RESULTS: There was significant and persistent tracheal acid aspiration in all patients. Patients with a sump-type tube had a significantly shorter total time with tracheal pH < 5.5 than those in the other groups (sump-type tube versus single-lumen tube, P = 0.0069; sump-type tube versus no tube, P = 0.0071). Patients randomized to no NG tube experienced more respiratory complications after surgery than those who had either single-lumen or sump-type tubes (seven of 12 versus four of 22 patients; P = 0.023). Insertion of a NG tube was necessary in the first week after surgery in seven of 12 patients in this group. CONCLUSION: Routine NG drainage after oesophagectomy is necessary. A sump-type NG tube is better at preventing tracheal acid aspiration and may reduce the incidence of respiratory complications.

Food restriction normalizes chylomicron remnant metabolism in murine models of obesity as assessed by a novel stable isotope breath test.

Evidence is increasing that defective metabolism of postprandial remnants of triglyceride-rich lipoproteins contributes to atherogenesis. In obesity, postprandial lipemia is increased by mechanisms that are not currently established. In the present study, a recently developed (13)CO(2) breath test was used to assess the metabolism of chylomicron remnants (CR) in obese mice. Six murine obese models ob/ob, fat/fat, New Zealand Obese (NZO), db/db, gold thioglucose (GTG)-treated and agouti (A(y)) were studied. All obese mice were hyperphagic and their breath test metabolism was markedly impaired (P < 0.01) compared with control, nonobese mice. The breath test was also impaired (P < 0.01) in all obese mice except A(y) mice after 24-h food deprivation. However, after restriction to the food intake of paired control mice for 6 wk, the breath test in all obese mice improved to values of control, nonobese mice. The obese NZO, fat/fat and ob/ob mice had significant (P < 0.02) weight loss when food restricted, whereas A(y), GTG, and db/db mice did not. In all obese mice, plasma cholesterol levels decreased (P < 0.02) after the 6-wk period of food restriction. Plasma triglyceride levels significantly decreased (P < 0.02) in NZO, GTG and db/db mice, but not in other obese mice. Plasma glucose levels were significantly decreased (P < 0.02) after the 6-wk period in the obese mice except for the A(y) and NZO mice; levels were greater in food-restricted db/db mice. Although some of the obese models such as db/db were diabetic, our data suggest that the defective breath test was independent of diabetes because all obese and diabetic models responded similarly to food restriction. Impaired hepatic catabolism of CR was excluded as a cause of the abnormal breath tests. In summary, the impairment (P < 0.05) in remnant metabolism as assessed by the breath test in obese mice was corrected by food restriction, associated with improvements in plasma glucose, triglyceride and cholesterol levels.

Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak.

Tek/Tie-2 is an endothelial cell (EC)-specific receptor tyrosine kinase that plays a critical role in angiogenesis via its regulation by the angiopoietin family of growth factor ligands. Angiopoietin-1 (Ang1) can promote EC migration; however, the signaling mechanisms underlying this process remain elusive. Here we demonstrate that Dok-R/Dok-2 can associate with Tek in ECs following Ang1 stimulation, resulting in tyrosine phosphorylation of Dok-R and the subsequent recruitment of Nck and the p21-activating kinase (Pak/Pak1) to the activated receptor. Ang1-mediated migration is increased upon Dok-R overexpression and this requires a functional Nck binding site on Dok-R. Localization of this Dok-R-Nck-Pak complex to the activated Tek receptor at the cellular membrane is coincident with activation of Pak kinase. The ability of Dok-R to bind Nck is required for maximal activation of Pak and overexpression of Pak results in increased Ang1-mediated cell motility. Our study outlines a novel signaling pathway underlying Ang1-driven cell migration that involves Dok-R and its recruitment of Nck and the subsequent activation of Pak.

BioGlue surgical adhesive for thoracic aortic repair during coagulopathy: efficacy and histopathology.

BACKGROUND: We hypothesized that induction of coagulopathy in sheep would model clinical needle hole and surgical bleeding from synthetic graft anastomoses, and that a new tissue bioadhesive (BioGlue) would control postoperative blood loss during surgical repair of the thoracic aorta. METHODS: Sheep were anticoagulated with aspirin and heparin. A bypass was made using end-to-side anastomoses of a graft to a partially occluded descending thoracic aorta. Experimental anastomoses (EXP, n = 9) were treated with BioGlue, and control anastomoses (CON, n = 5) were treated with Surgicel to gain intraoperative hemostasis. RESULTS: EXP animals exhibited significantly reduced postsurgical bleeding (CON median 955 mL versus EXP median 470 mL, p < 0.003), a reduced rate of blood loss over the first 2 postoperative hours (CON median 210 mL/hr versus EXP median 92.5 mL/hr, p < 0.006), and over the entire recovery period (CON median 158 mL/hr versus EXP median 86 mL/hr, p < 0.05), and reduced total blood loss (CON mean 1,497 +/- 691 mL versus EXP mean 668 +/- 285 mL, p < 0.008). On histologic examination of tissues explanted after 3 months, BioGlue was relatively inert and demonstrated a minimal inflammatory response. CONCLUSIONS: The use of BioGlue significantly reduced the volume and rate of postsurgical bleeding in a coagulopathic sheep model for thoracic aortic operations. Histopathologically, BioGlue generated only a minimal inflammatory response. This new surgical tissue bioadhesive should prove extremely beneficial for coagulopathic patients undergoing thoracic aortic or vascular procedures.

Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches.

The ultimate target of anti-angiogenic drugs is the genetically stable, activated endothelial cell of a newly forming tumor blood vessel, rather than the genetically unstable tumor cell population per se. This led to the notion that acquired resistance to such drugs may not develop as readily, if at all. While there is some evidence that this lack of resistance development may be the case for some direct-acting angiogenesis inhibitors, it is becoming apparent that resistance can develop over time to many types of angiogenesis inhibitors including, possibly, some direct inhibitors, especially when used as monotherapies. Possible mechanisms for such acquired or induced resistance include: (i) redundancy of pro-angiogenic growth factors when the drug used targets a single such growth factor or its cognate endothelial cell-associated receptor tyrosine kinase; (ii) the anti-apoptotic/pro-survival function of growth factors such as VEGF, which, in high local concentrations, can antagonize the pro-apoptotic effects of various angiogenesis inhibitors; (iii) epigenetic, transient upregulation, or induction, of various anti-apoptotic effector molecules in host-endothelial cells; and (iv) heterogeneous vascular dependence of tumor cell populations. It is suggested that long-term disease control with anti-angiogenic drugs can be best achieved by judicious combination therapy. In this regard, the great molecular diversity of anti-angiogenic drug targets, in contrast to chemotherapy, makes this a particularly attractive therapeutic option, especially when approved, commercially available drugs considered to have anti-angiogenic effects are used in such combination treatment strategies.

Somatic control over the germline stem cell lineage during Drosophila spermatogenesis.

Stem cells divide both to produce new stem cells and to generate daughter cells that can differentiate. The underlying mechanisms are not well understood, but conceptually are of two kinds. Intrinsic mechanisms may control the unequal partitioning of determinants leading to asymmetric cell divisions that yield one stem cell and one differentiated daughter cell. Alternatively, extrinsic mechanisms, involving stromal cell signals, could cause daughter cells that remain in their proper niche to stay stem cells, whereas daughter cells that leave this niche differentiate. Here we use Drosophila spermatogenesis as a model stem cell system to show that there are excess stem cells and gonialblasts in testes that are deficient for Raf activity. In addition, the germline stem cell population remains active for a longer fraction of lifespan than in wild type. Finally, raf is required in somatic cells that surround germ cells. We conclude that a cell-extrinsic mechanism regulates germline stem cell behaviour.

Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has been shown to act as an endothelial cell mitogen as well as a vascular permeability factor. Several recent reports have also implicated VEGF as a major survival factor for endothelial cells during angiogenesis and vasculogenesis along with other growth factors such as bFGF and angiopoietin-1. VEGF has been shown to mediate this additional function, at least in part through the induction of bcl-2 and the activation of the PI3 kinase-Akt/PKB signaling pathway. We report here that VEGF can also mediate the induction/upregulation of members of a newly discovered family of antiapoptotic proteins, namely the Inhibitors of Apoptosis (IAP), in vascular endothelial cells. We show that VEGF(165) leads to the induction of XIAP (2.9-fold) and survivin (19.1-fold) protein in human umbilical vein endothelial cells (HUVECs). In contrast, bFGF had little effect on XIAP expression, but produced approximately a 10-fold induction on survivin. VEGF-dependent upregulation of survivin could be prevented by cell cycle arrest in the G1 and S phases. These findings implicate that the survival and mitotic functions of VEGF in an angiogenic context may be more intrinsically related than previously anticipated. Moreover, they also raise the possibility of therapeutically targeting XIAP or survivin in antiangiogenic therapy as a means of suppressing tumor growth, in addition to directly targeting tumor cells which express these survival proteins.