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Rag da Silva, C P Churchward, A V Karlyshev, O Eleftheriadou, A K Snabaitis, M R Longman, A Ryan, R Griffin
BACKGROUND AND PURPOSE: The level of cell surface expression of the meningococcal vaccine antigen, Factor H binding protein (FHbp) varies between and within strains and this limits the breadth of strains that can be targeted by FHbp-based vaccines. The molecular pathway dictating expression of FHbp at the cell surface, including its lipidation, sorting to the outer membrane and export, and the potential regulation of this pathway have not been investigated until now. This knowledge will aid our evaluation of FHbp vaccines...
October 26, 2016: British Journal of Pharmacology
Li Cheng, Jun Zhang, Xin-Yi Li, Li Yuan, Yan-Fang Pan, Xiao-Rong Chen, Tian-Ming Gao, Jian-Tian Qiao, Jin-Shun Qi
Amyloid β protein (Aβ) plays a critical role in pathogenesis of Alzheimer's disease (AD). Our previous studies indicated that the sequence 31-35 in Aβ molecule is an effective active center responsible for Aβ neurotoxicity in vivo and in vitro. In the present study, we prepared a novel antibody specifically targeting the sequence 31-35 of amyloid β protein, and investigated the neuroprotection of the anti-Aβ31-35 antibody against Aβ1-42 -induced impairments in neuronal viability, spatial memory, and hippocampal synaptic plasticity in rats...
October 26, 2016: Hippocampus
Carrie D Patnode, Michelle L Henninger, Caitlyn A Senger, Leslie A Perdue, Evelyn P Whitlock
Importance: Although 80% of infants in the United States start breastfeeding, only 22% are exclusively breastfed up to around 6 months as recommended by a number of professional organizations. Objective: To systematically review the evidence on the benefits and harms of breastfeeding interventions to support the US Preventive Services Task Force in updating its 2008 recommendation. Data Sources: MEDLINE, PubMed, Cumulative Index for Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and PsycINFO for studies published in the English language between January 1, 2008, and September 25, 2015...
October 25, 2016: JAMA: the Journal of the American Medical Association
Jacques Klein, Arachk de Górski, Daniel Benamran, Jean-Paul Vallee, Thomas De Perrot, Gregory J Wirth, Christophe E Iselin
INTRODUCTION: The study aimed to evaluate 3 different modalities of transrectal ultrasound (TRUS)-guided prostate biopsies (PBs; 2D-, 3D- and targeted 3D-TRUS with fusion to MRI - T3D). Primary end point was the detection rate of prostate cancer (PC). Secondary end point was the detection rate of insignificant PC according to the Epstein criteria. PATIENTS AND METHODS: Inclusion of 284 subsequent patients who underwent 2D-, 3D- or T3D PB from 2011 to 2015. All patients having PB for initial PC detection with a serum prostate-specific antigen value ≤20 ng/ml were included...
October 27, 2016: Urologia Internationalis
Anders Fytagoridis, Mattias Åström, Jennifer Samuelsson, Patric Blomstedt
BACKGROUND: The caudal zona incerta (cZi) and posterior subthalamic area (PSA) are an emerging deep brain stimulation (DBS) target for essential tremor (ET). OBJECTIVES: To evaluate the efficacy of tremor control in relation to the anatomical locations of stimulation fields in 50 patients with ET and DBS of the cZi. METHODS: A total of 240 contacts were evaluated separately with monopolar stimulation, and amplitudes were optimized for improvement of tremor and hand function...
October 27, 2016: Stereotactic and Functional Neurosurgery
Peter Sandner, Peter Berger, Christoph Zenzmaier
Fibrotic diseases cause high rates of morbidity and mortality, and their incidence increases with age. Despite intense research and development efforts, effective and well-tolerated antifibrotic treatments are scarce. Transforming growth factor-β signaling, which is widely considered the most important profibrotic factor, causes a pro-oxidant shift in redox homeostasis and a concomitant decrease in nitric oxide (NO) signaling. The NO/cyclic guanosine monophosphate (cGMP) signaling cascade plays a pivotal role in the regulation of cell and organ function in whole-body hemostasis...
October 27, 2016: Gerontology
Zhe Li, Jian-Guo Zhang, Yan Ye, Xiaoping Li
BACKGROUND: Accurate implantation of a depth electrode into the brain is of the greatest importance in deep brain stimulation (DBS), and various stereotactic systems have been developed for electrode implantation. However, an updated analysis of depth electrode implantation in the modern era of DBS is lacking. OBJECTIVE: This study aims at providing an updated review on targeting accuracy of DBS electrode implantation by analyzing contemporary DBS electrode implantation operations from the perspective of precision engineering...
October 27, 2016: Stereotactic and Functional Neurosurgery
Aakash Garg, Deepti Virmani, Sahil Agrawal, Chirag Agarwal, Abhishek Sharma, Giulio Stefanini, John B Kostis
Heart failure with a preserved ejection fraction (HFpEF) is increasingly prevalent and a leading cause of morbidity and mortality worldwide. HFpEF has a complex pathophysiology, with recent evidence suggesting that an interaction of cardiovascular and noncardiovascular comorbidities (e.g. obesity, hypertension, diabetes, coronary artery disease, and chronic kidney disease) induces an inflammatory state that eventually leads to myocardial structural and functional alterations. Current ACCF/AHA guidelines suggest incorporation of biomarkers along with clinical and imaging tools to establish the diagnosis and disease severity in heart failure (HF)...
October 27, 2016: Cardiology
Kate Bunton, Brad H Story
OBJECTIVE: The goal of the Arizona Child Acoustic Database project was to obtain a large set of acoustic recordings, primarily vowels, collected from a cohort of children over a critical period of growth and development. METHOD: Data was recorded longitudinally from 63 children between the ages of 2;0 and 7;0 at 3-month intervals. The protocol included individual American English vowels and diphthongs, nonsense multi-vowel transitions, word level multi-vowel sequences (e...
October 27, 2016: Folia Phoniatrica et Logopaedica
Tsung-Yan Chen, Ting-Tse Lin, Mu-Yang Hsieh, Lin Lin, Chung-Wei Yang, Shao-Yuan Chuang, Po-Hsun Huang, Chih-Cheng Wu
BACKGROUND: Arteriovenous fistula (AVF) thrombosis is a relevant cause of morbidity in hemodialysis (HD) patients. The number of circulating endothelial progenitor cells (EPCs) has been identified as a surrogate marker for vascular repair and health. Deficiency of EPCs has been demonstrated in dialysis patients to be associated with vascular events. Nonetheless, their role in thrombosis of AVFs remains unknown. METHODS: From January 2010 to May 2013, 147 HD patients with dysfunctional AVFs were enrolled...
October 27, 2016: American Journal of Nephrology
Musaffe Tuna, Christopher I Amos
Approximately 18% of all human cancers have a viral etiology, and human papillomavirus (HPV) has been identified as one of the most prevalent viruses that plays causative role in nearly all cervical cancers and, in addition, in subset of head and neck, anal, penile and vulvar cancers. The recent introduction of next generation sequencing (NGS) and other 'omics' approaches have resulted in comprehensive knowledge on the pathogenesis of HPV-driven tumors. Specifically, these approaches have provided detailed information on genomic HPV integration sites, disrupted genes and pathways, and common and distinct genetic and epigenetic alterations in different human HPV-associated cancers...
October 23, 2016: Oncotarget
Ying Xiong, Li Liu, Jiajun Wang, Wei Xi, Yu Xia, Qi Bai, Yang Qu, Qilai Long, Jiejie Xu, Jianming Guo
BACKGROUND: Chemokine (C-C motif) ligand 21 (CCL21), a ligand of the chemokine (C-C motif) receptor 7, has recently been identified as an immuno-based anti-cancer molecule for its dendritic cells and T lymphocytes chemoattractant function. The aim of this study was to investigate prognostic values of CCL21 expression in metastatic renal cell carcinoma patients treated with targeted therapy. METHODS: This study included 111 patients with metastatic renal cell carcinoma receiving targeted therapy...
October 23, 2016: Oncotarget
Siham Bibi, Yanyan Zhang, Caroline Hugonin, Mallorie Depond Mangean, Liang He, Ghaith Wedeh, Jean-Marie Launay, Sjoerd Van Rijn, Thomas Würdinger, Fawzia Louache, Michel Arock
Systemic mastocytosis are rare neoplasms characterized by accumulation of mast cells in at least one internal organ. The majority of systemic mastocytosis patients carry KIT D816V mutation, which activates constitutively the KIT receptor. Patient with advanced forms of systemic mastocytosis, such as aggressive systemic mastocytosis or mast cell leukemia, are poorly treated to date. Unfortunately, the lack of in vivo models reflecting KIT D816V+ advanced disease hampers pathophysiological studies and preclinical development of new therapies for such patients...
October 22, 2016: Oncotarget
Yiqing Pan, Yue Liu, Li Wang, Feng Xue, Yanqin Hu, Ran Hu, Chen Xu
Sertoli cells create a local tolerogenic microenvironment to maintain testicular immune privilege especially through the formation of a blood-testis barrier (BTB). However, the molecular mechanisms underlying the immune modulation function and BTB dynamics of Sertoli cells remained elusive. MAP phosphatase (MKP)-1 acts as a crucial negative regulator of the inflammatory response. Nevertheless, the role of MKP-1 in regulating Sertoli cells has not been elucidated. In this study, we have for the first time uncovered distinct cellular localization of MKP-1 in the cells at different stages of mouse testis, and the level of MKP-1 expression was significantly up-regulated by LPS-induced acute testis inflammation...
October 22, 2016: Oncotarget
Shalini Singh Yadav, Jinyi Li, Jennifer A Stockert, James O'Connor, Bryan Herzog, Cordelia Elaiho, Matthew D Galsky, Ashutosh Kumar Tewari, Kamlesh Kumar Yadav
Several promising targeted-therapeutics for prostate cancer (PCa), primarily affecting the androgen receptor (AR) and the PI3K/AKT/mTOR-pathway, are in various phases of development. However, despite promise, single-agent inhibitors targeting the two pathways have not shown long-term benefits, perhaps due to a complex compensatory cross talk that exists between the two pathways. Combination therapy has thus been proposed to maximize benefit. We have carried out a systematic study of two-drug combination effect of MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor) and RAD001 (mTOR inhibitor) using various PCa cell lines...
October 20, 2016: Oncotarget
Bo Yang, Shiming Zhang, Zhihao Wang, Chunxu Yang, Wen Ouyang, Fuxiang Zhou, Yunfeng Zhou, Conghua Xie
β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive. Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degradation...
October 22, 2016: Oncotarget
Shyam Nyati, Areeb Chator, Katerina Schinske, Brandon S Gregg, Brian Dale Ross, Alnawaz Rehemtulla
The sterile alpha motif and leucine zipper containing kinase ZAK (AZK, MLT, MLK7), is a MAPK-kinase kinase (MKKK). Like most MAPKKKs which are known to activate the c-Jun. amino-terminal kinase (JNK) pathway, ZAK has been shown to participate in the transduction of Transforming growth factor-β (TGF-β)-mediated non-canonical signaling. A role for ZAK in SMAD-dependent, canonical TGF-β signaling has not been previously appreciated. Using a combination of functional genomics and biochemical techniques, we demonstrate that ZAK regulates canonical TGFβRI/II signaling in lung and breast cancer cell lines and may serve as a key node in the regulation of TGFBR kinase activity...
October 23, 2016: Translational Oncology
Hriday Bera, Sridevi Chigurupati
Thymidine phosphorylase (TP, EC, an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexpression of many angiogenic factors such as matrix metalloproteases (MMPs), interleukins (ILs), vascular endothelial growth factor (VEGF) etc., resulting in promotion of angiogenesis and cancer metastasis. In addition, overshooting TP level protects tumour cells from apoptosis and helps cell survival...
October 17, 2016: European Journal of Medicinal Chemistry
Ju Hui Jeong, Yong Jin Oh, Yunmee Lho, Sun You Park, Kwang-Hyeon Liu, Eunyoung Ha, Young Ho Seo
The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50 = 50...
October 18, 2016: European Journal of Medicinal Chemistry
Timothy J Ritchie, Simon J F Macdonald
The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities...
October 15, 2016: European Journal of Medicinal Chemistry
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