Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.

We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL

The proangiogenic capacity of polymorphonuclear neutrophils delineated by microarray technique and by measurement of neovascularization in wounded skin of CD18-deficient mice

Growing evidence supports the concept that polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. We employed an oligonucleotide microarray technique to gain further insight into the molecular mechanisms underlying the proangiogenic potential of human PMN. In addition to 18 known angiogenesis-relevant genes, we detected the expression of 10 novel genes, namely midkine, erb-B2, ets-1, transforming growth factor receptor-beta(2) and -beta(3), thrombospondin, tissue inhibitor of metalloproteinase 2, ephrin A2, ephrin B2 and restin in human PMN freshly isolated from the circulation. Gene expression was confi rmed by the RT-PCR technique. In vivo evidence for the role of PMN in neovascularization was provided by studying neovascularization in a skin model of wound healing using CD18-deficient mice which lack PMN infi ltration to sites of lesion. In CD18-deficient animals, neo- vascularization was found to be signifi cantly compromised when compared with wild- type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation mediated angiogenesis which may be a consequence of the broad spectrum of proangiogenic factors expressed by these cells. Copyright (c) 2006 S. Karger AG, Basel

Effect of synbiotic supplementation in children and adolescents with cystic fibrosis: a randomized controlled clinical trial

BACKGROUND/OBJECTIVES:Cystic fibrosis (CF) is characterized by excessive activation of immune processes. The aim of this study was to evaluate the effect of synbiotic supplementation on the inflammatory response in children/adolescents with CF. SUBJECTS/METHODS:A randomized, placebo-controlled, double-blind, clinical-trial was conducted with control group (CG, n = 17), placebo-CF-group (PCFG, n = 19), synbiotic CF-group (SCFG, n = 22), PCFG negative (n = 8) and positive (n = 11) bacteriology, and SCFG negative (n = 12) and positive (n = 10) bacteriology. Markers of lung function (FEV1), nutritional status [body mass index-for age (BMI/A), height-for-age (H/A), weight-for-age (W/A), upper-arm fat area (UFA), upper-arm muscle area (UMA), body fat (%BF)], and inflammation [interleukin (IL)-12, tumor necrosis factor-alpha (TNF-α), IL-10, IL-6, IL-1β, IL-8, myeloperoxidase (MPO), nitric oxide metabolites (NOx)] were evaluated before and after 90-day of supplementation with a synbiotic. RESULTS:No significance difference was found between the baseline and end evaluations of FEV1 and nutricional status markers. A significant interaction (time vs. group) was found for IL-12 (p = 0.010) and myeloperoxidase (p = 0.036) between PCFG and SCFG, however, the difference was not maintained after assessing the groups individually. NOx diminished significantly after supplementation in the SCFG (p = 0.030). In the SCFG with positive bacteriology, reductions were found in IL-6 (p = 0.033) and IL-8 (p = 0.009) after supplementation. CONCLUSIONS: Synbiotic supplementation shown promise at diminishing the pro-inflammatory markers IL-6, IL-8 in the SCFG with positive bacteriology and NOx in the SCFG in children/adolescents with CF

Hypertensive Cardiotoxicity in Cancer Treatment-Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies-Epidemiology, Incidence, and Pathophysiology

Cardiotoxicity is the umbrella term for cardiovascular side effects of cancer therapies. The most widely recognized phenotype is left ventricular dysfunction, but cardiotoxicity can manifest as arrhythmogenic, vascular, myocarditic and hypertensive toxicities. Hypertension has long been regarded as one of the most prevalent and modifiable cardiovascular risk factors in the general population, but its relevance during the cancer treatment journey may be underestimated. Hypertensive cardiotoxicity occurs de novo in a substantial proportion of treated cancer patients. The pathology is incompletely characterized—natriuresis and renin angiotensin system interactions play a role particularly in conventional treatments, but in novel therapies endothelial dysfunction and the interaction between the cancer and cardiac kinome are implicated. There exists a treatment paradox in that a significant hypertensive response not only mandates anti-hypertensive treatment, but in fact, in certain cancer treatment scenarios, hypertension is a predictor of cancer treatment efficacy and response. In this comprehensive review of over 80,000 patients, we explored the epidemiology, incidence, and mechanistic pathophysiology of hypertensive cardiotoxicity in adjunct, conventional chemotherapy, and novel cancer treatments. Conventional chemotherapy, adjunct treatments, and novel targeted therapies collectively caused new onset hypertension in 33–68% of treated patients. The incidence of hypertensive cardiotoxicity across twenty common novel therapies for any grade hypertension ranged from 4% (imatinib) to 68% (lenvatinib), and high grade 3 or 4 hypertension in <1% (imatinib) to 42% (lenvatinib). The weighted average effect was all-grade hypertension in 24% and grade 3 or 4 hypertension in 8%

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

"I really should've gone to the doctor": older adults and family caregivers describe their experiences with community-acquired pneumonia

BACKGROUND: Responding to acute illness symptoms can often be challenging for older adults. The primary objective of this study was to describe how community-dwelling older adults and their family members responded to symptoms of community-acquired pneumonia (CAP). METHODS: A qualitative study that used face-to-face semi-structured interviews to collect data from a purposeful sample of seniors aged 60+ and their family members living in a mid-sized Canadian city. Data analysis began with descriptive and interpretive coding, then advanced as the research team repeatedly compared emerging thematic categories to the raw data. Searches for disconfirming evidence and member checking through focus groups provided additional data and helped ensure rigour. RESULTS: Community-acquired pneumonia symptoms varied greatly among older adults, making decisions to seek care difficult for them and their family members. Both groups took varying amounts of time as they attempted to sort out what was wrong and then determine how best to respond. Even after they concluded something was wrong, older adults with confirmed pneumonia continued to wait for days, to over a week, before seeking medical care. Participants provided diverse reasons for this delay, including fear, social obligations (work, family, leisure), and accessibility barriers (time, place, systemic). Several older adults and family members regretted their delays in seeking help. CONCLUSION: Treatment-seeking delay is a variable, multi-phased decision-making process that incorporates symptom assessment plus psychosocial and situational factors. Public health and health care professionals need to educate older adults about the potential causes and consequences of unnecessary waits. Such efforts may reduce the severity of community-acquired pneumonia upon presentation at clinics and hospitals, and that, in turn, could potentially improve health outcomes

In vitro bioactivity of titanium-doped bioglass

Previous studies have suggested that incorporating relatively small quantities of titanium dioxide into bioactive glasses may result in an increase in bioactivity and hydroxyapatite formation. The present work therefore investigated the in vitro bioactivity of a titanium doped bioglass and compared the results with 45S5 bioglass. Apatite formation was evaluated for bioglass and Ti-bioglass in the presence and absence of foetal calf serum. Scanning electron microscopy (SEM) images were used to evaluate the surface development and energy dispersive X-ray measurements provided information on the elemental ratios. X-ray diffraction spectra confirmed the presence of apatite formation. Cell viability was assessed for bone marrow stromal cells under direct and indirect contact conditions and cell adhesion was assessed using SEM

The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX-2 through an IKKγ/NF-κB-dependent pathway

The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells

Three Saturn-mass planets transiting F-type stars revealed with TESS and HARPS: TOI-615b, TOI-622b, and TOI-2641b

While the sample of confirmed exoplanets continues to grow, the population of transiting exoplanets around early-type stars is still limited. These planets allow us to investigate the planet properties and formation pathways over a wide range of stellar masses and study the impact of high irradiation on hot Jupiters orbiting such stars. We report the discovery of TOI-615b, TOI-622b, and TOI-2641b, three Saturn-mass planets transiting main sequence, F-type stars. The planets were identified by the Transiting Exoplanet Survey Satellite (TESS) and confirmed with complementary ground-based and radial velocity observations. TOI-615b is a highly irradiated (∼1277 F) and bloated Saturn-mass planet (1.69-0.06+0.05 RJup and 0.43-0.08+0.09 MJup) in a 4.66 day orbit transiting a 6850 K star. TOI-622b has a radius of 0.82-0.03+0.03 RJup and a mass of 0.30-0.08+0.07 MJup in a 6.40 day orbit. Despite its high insolation flux (∼600 F), TOI-622b does not show any evidence of radius inflation. TOI-2641b is a 0.39-0.04+0.02 MJup planet in a 4.88 day orbit with a grazing transit (b = 1.04-0.06+0.05) that results in a poorly constrained radius of 1.61-0.64+0.46 RJup. Additionally, TOI-615b is considered attractive for atmospheric studies via transmission spectroscopy with ground-based spectrographs and JWST. Future atmospheric and spin-orbit alignment observations are essential since they can provide information on the atmospheric composition, formation, and migration of exoplanets across various stellar types