Increased risk of bone fractures in hemodialysis patients treated with proton pump inhibitors in real world: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Long-term treatment with Proton Pump Inhibitors (PPIs) is associated with an increased risk of fractures in the general population. PPIs are widely prescribed to dialysis patients but to date no study specifically tested, by state-of-art statistical methods, the relationship between PPIs use and fractures in this patient-population. This study aimed to assess whether PPIs use is associated with bone fractures (i.e. hip fractures and fractures other than hip fractures) in a large international cohort of hemodialysis patients. We considered an observational prospective cohort of 27097 hemodialysis patients from the DOPPS study. Data analysis was performed by the Fine & Gray method, considering the competitive risk of mortality, as well as by a cause-specific hazards Cox model dealing death as a censoring event and matching patients according to the prescription time. Out of 27,097 hemodialysis patients, 13,283 patients (49%) were on PPI treatment. Across the follow-up (median:19\u2009months), 3.8 bone fractures x 100 person-years and 1.2 hip fractures x 100 person-years occurred. In multiple Cox models, considering the competitive risk of mortality, the incidence rate of bone (SHR: 1.22, 95% CI: 1.10-1.36, P\u2009<\u20090.001) and hip fractures (SHR: 1.35, 95% CI: 1.13-1.62, P = 0.001) was significantly higher in PPI treated than in PPI untreated patients. These findings held true also in multiple, cause-specific, hazards Cox models matching patients according to the prescription time (bone fractures, HR: 1.47, 95% CI: 1.23-1.76, P\u2009<\u20090.001, hip fractures (HR: 1.85, 95% CI: 1.37-2.50, P\u2009<\u20090.001). The use of PPIs requires caution and a careful evaluation of risks/benefits ratio in hemodialysis patients

Guidelines for the use and interpretation of assays for monitoring autophagy (2nd edition)

In 2008 we published the first set of guidelines for standardiz- ing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new tech- nologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in differ- ent organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes..

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions

Characterization of TEM1/endosialin in human and murine brain tumors

<p>Abstract</p> <p>Background</p> <p><it>TEM1/endosialin </it>is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of <it>TEM1/endosialin </it>in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.</p> <p>Methods</p> <p><it>In situ </it>hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize <it>TEM1/endosialin </it>expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in <it>TEM1/endosialin </it>expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown <it>in vitro</it>. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude <it>TEM1/endosialin </it>knockout (KO) and wildtype (WT) mice.</p> <p>Results</p> <p><it>TEM1/endosialin </it>was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated <it>TEM1/endosialin </it>expression in 79% of tumors. Robust <it>TEM1/endosialin </it>expression occurred in 31% of glioblastomas (grade IV astroctyomas). <it>TEM1/endosialin </it>expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. <it>In vitro</it>, <it>TEM1/endosialin </it>was upregulated in human endothelial cells cultured in matrigel. Vascular <it>Tem1/endosialin </it>was induced in intracranial U87MG GBM xenografts grown in mice. <it>Tem1/endosialin </it>KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although <it>Tem1/endosialin </it>KO tumors were significantly more vascular than the WT counterparts.</p> <p>Conclusion</p> <p><it>TEM1/endosialin </it>was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of <it>TEM1/endosialin </it>did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of <it>TEM1/endosialin </it>and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.</p

Viral-mediated oncolysis is the most critical factor in the late-phase of the tumor regression process upon vaccinia virus infection

<p>Abstract</p> <p>Background</p> <p>In principle, the elimination of malignancies by oncolytic virotherapy could proceed by different mechanisms - e.g. tumor cell specific oncolysis, destruction of the tumor vasculature or an anti-tumoral immunological response. In this study, we analyzed the contribution of these factors to elucidate the responsible mechanism for regression of human breast tumor xenografts upon colonization with an attenuated vaccinia virus (VACV).</p> <p>Methods</p> <p>Breast tumor xenografts were analyzed 6 weeks post VACV infection (p.i.; regression phase) by immunohistochemistry and mouse-specific expression arrays. Viral-mediated oncolysis was determined by tumor growth analysis combined with microscopic studies of intratumoral virus distribution. The tumor vasculature was morphologically characterized by diameter and density measurements and vessel functionality was analyzed by lectin perfusion and extravasation studies. Immunological aspects of viral-mediated tumor regression were studied in either immune-deficient mouse strains (T-, B-, NK-cell-deficient) or upon cyclophosphamide-induced immunosuppression (MHCII⁺-cell depletion) in nude mice.</p> <p>Results</p> <p>Late stage VACV-infected breast tumors showed extensive necrosis, which was highly specific to cancer cells. The tumor vasculature in infected tumor areas remained functional and the endothelial cells were not infected. However, viral colonization triggers hyperpermeability and dilatation of the tumor vessels, which resembled the activated endothelium in wounded tissue. Moreover, we demonstrated an increased expression of genes involved in leukocyte-endothelial cell interaction in VACV-infected tumors, which orchestrate perivascular inflammatory cell infiltration. The immunohistochemical analysis of infected tumors displayed intense infiltration of MHCII-positive cells and colocalization of tumor vessels with MHCII⁺/CD31⁺vascular leukocytes. However, GI-101A tumor growth analysis upon VACV-infection in either immunosuppressed nude mice (MHCII⁺-cell depleted) or in immune-deficient mouse strains (T-, B-, NK-cell-deficient) revealed that neither MHCII-positive immune cells nor T-, B-, or NK cells contributed significantly to VACV-mediated tumor regression. In contrast, tumors of immunosuppressed mice showed enhanced viral spreading and tumor necrosis.</p> <p>Conclusions</p> <p>Taken together, these results indicate that VACV-mediated oncolysis is the primary mechanism of tumor shrinkage in the late regression phase. Neither the destruction of the tumor vasculature nor the massive VACV-mediated intratumoral inflammation was a prerequisite for tumor regression. We propose that approaches to enhance viral replication and spread within the tumor microenvironment should improve therapeutical outcome.</p

Gene therapy: the end of the rainbow?

The increased understanding of the molecular basis of oral cancer has led to expectations that correction of the genetic defects will lead to improved treatments. Nevertheless, the first clinical trials for gene therapy of oral cancer occurred 20 years ago, and routine treatment is still not available. The major difficulty is that genes are usually delivered by virus vectors whose effects are weak and temporary. Viruses that replicate would be better, and the field includes many approaches in that direction. If any of these are effective in patients, then gene therapy will become available in the next few years. Without significant advances, however, the treatment of oral cancer by gene therapy will remain as remote as the legendary pot of gold at the end of the rainbow

Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas

Local recurrence of glioblastomas is a major cause of patient mortality after definitive treatment. This review discusses the roles of the chemokine stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4 (CXCR4) in affecting the sensitivity of glioblastomas to irradiation. Blocking these molecules prevents or delays tumour recurrence after irradiation by inhibiting the recruitment of CD11b+ monocytes/macrophages that participate in revascularising the tumour. We review the literature pertaining to the mechanism by which revascularisation occurs following tumour irradiation using experimental models. Areas of interest and debate in the literature include the process by which endothelial cells die after irradiation and the identity/origin of the cells that reconstitute the tumour blood vessels after injury. Understanding the processes that mediate tumour revascularisation will guide the improvement of clinical strategies for preventing recurrence of glioblastoma after irradiation

Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations

Biological Effects of a De Novo Designed Myxoma Virus Peptide Analogue: Evaluation of Cytotoxicity on Tumor Cells

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