Genetic polymorphisms linked to susceptibility to malaria

The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature

Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family, which inhibits cell apoptosis by sequestering pro-apoptotic proteins Bim and Bid. Mcl-1 overexpression has been associated with progression in leukemia and some solid tumors including prostate cancer (PCa). However, the regulatory mechanism for Mcl-1 expression in PCa cells remains elusive.</p> <p>Results</p> <p>Immunohistochemical analyses revealed that Mcl-1 expression was elevated in PCa specimens with high Gleason grades and further significantly increased in bone metastasis, suggesting a pivotal role of Mcl-1 in PCa metastasis. We further found that vascular endothelial growth factor (VEGF) is a novel regulator of Mcl-1 expression in PCa cells. Inhibition of endogenous Mcl-1 induced apoptosis, indicating that Mcl-1 is an important survival factor in PCa cells. Neuropilin-1 (NRP1), the "co-receptor" for VEGF₁₆₅isoform, was found to be highly expressed in PCa cells, and indispensible in the regulation of Mcl-1. Intriguingly, VEGF₁₆₅promoted physical interaction between NRP1 and hepatocyte growth factor (HGF) receptor c-MET, and facilitated c-MET phosphorylation <it>via </it>a NRP1-dependent mechanism. VEGF₁₆₅induction of Mcl-1 may involve rapid activation of Src kinases and signal transducers and activators of transcription 3 (Stat3). Importantly, NRP1 overexpression and c-MET activation were positively associated with progression and bone metastasis in human PCa specimens and xenograft tissues.</p> <p>Conclusions</p> <p>This study demonstrated that Mcl-1 overexpression is associated with PCa bone metastasis. Activation of VEGF₁₆₅-NRP1-c-MET signaling could confer PCa cells survival advantages by up-regulating Mcl-1, contributing to PCa progression.</p

PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells

BACKGROUND: Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. CONCLUSIONS/SIGNIFICANCE: Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis

Reproducible Research Practices and Transparency across the Biomedical Literature

<div><p>There is a growing movement to encourage reproducibility and transparency practices in the scientific community, including public access to raw data and protocols, the conduct of replication studies, systematic integration of evidence in systematic reviews, and the documentation of funding and potential conflicts of interest. In this survey, we assessed the current status of reproducibility and transparency addressing these indicators in a random sample of 441 biomedical journal articles published in 2000–2014. Only one study provided a full protocol and none made all raw data directly available. Replication studies were rare (<i>n</i> = 4), and only 16 studies had their data included in a subsequent systematic review or meta-analysis. The majority of studies did not mention anything about funding or conflicts of interest. The percentage of articles with no statement of conflict decreased substantially between 2000 and 2014 (94.4% in 2000 to 34.6% in 2014); the percentage of articles reporting statements of conflicts (0% in 2000, 15.4% in 2014) or no conflicts (5.6% in 2000, 50.0% in 2014) increased. Articles published in journals in the clinical medicine category versus other fields were almost twice as likely to not include any information on funding and to have private funding. This study provides baseline data to compare future progress in improving these indicators in the scientific literature.</p></div

Characteristics of assessed articles.

<p>Characteristics of assessed articles.</p

Articles in the clinical medicine journal category versus other journal categories.

<p>Articles in the clinical medicine journal category versus other journal categories.</p

Distribution of funding overall (A) or among publically funded articles (B).

<p>Distribution of funding overall (A) or among publically funded articles (B).</p

Trends in presence of statements of conflicts of interest.

<p>Trends in presence of statements of conflicts of interest.</p