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https://www.readbyqxmd.com/read/28808818/first-in-human-study-of-the-epichaperome-inhibitor-pu-h71-clinical-results-and-metabolic-profile
#1
Giovanna Speranza, Larry Anderson, Alice P Chen, Khanh Do, Michelle Eugeni, Marcie Weil, Larry Rubinstein, Eva Majerova, Jerry Collins, Yvonne Horneffer, Lamin Juwara, Jennifer Zlott, Rachel Bishop, Barbara A Conley, Howard Streicher, Joseph Tomaszewski, James H Doroshow, Shivaani Kummar
Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments...
August 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28808027/de-novo-mutations-in-inhibitors-of-wnt-bmp-and-ras-erk-signaling-pathways-in-non-syndromic-midline-craniosynostosis
#2
Andrew T Timberlake, Charuta G Furey, Jungmin Choi, Carol Nelson-Williams, Erin Loring, Amy Galm, Kristopher T Kahle, Derek M Steinbacher, Dawid Larysz, John A Persing, Richard P Lifton
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28801522/vascular-niche-contribution-to-age-associated-neural-stem-cell-dysfunction
#3
Deana Marie Apple, Erzsebet Kokovay
Neural stem cells (NSCs) persist throughout life in the dentate gyrus and the ventricular-subventricular zone (V-SVZ), where they continuously provide new neurons and some glia. These cells are found in specialized niches that regulate quiescence, activation, differentiation, and cell fate choice. A key aspect of the regulatory niche is the vascular plexus, which modulates NSC behavior during tissue homeostasis and regeneration. During aging, NSCs become depleted and dysfunctional, resulting in reduced neurogenesis and poor brain repair...
August 11, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28798841/microfluidic-engineering-of-neural-stem-cell-niches-for-fate-determination
#4
Yachen Wang, Jingyun Ma, Na Li, Liang Wang, Liming Shen, Yu Sun, Yajun Wang, Jingyuan Zhao, Wenjuan Wei, Yan Ren, Jing Liu
Neural stem cell (NSC) transplantation has great therapeutic potential for neurodegenerative diseases and central nervous system injuries. Successful NSC replacement therapy requires precise control over the cellular behaviors. However, the regulation of NSC fate is largely unclear, which severely restricts the potential clinical applications. To develop an effective model, we designed an assembled microfluidic system to engineer NSC niches and assessed the effects of various culture conditions on NSC fate determination...
January 2017: Biomicrofluidics
https://www.readbyqxmd.com/read/28795331/cells-expressing-prominin-1-in-neonatal-murine-inferior-colliculus-differentiate-into-neurons-and-glia
#5
Haruka Okazaki, Akira Kanda, Seiji Kanda, Takaki Shimono, Yasutaka Yun, Yoshiki Kobayashi, Zeyun Wang, Hisashi Ooka, Kensuke Suzuki, Dan Bui Van, Koichi Tomoda, Hiroshi Iwai, Toshimasa Nishiyama
Inferior colliculus (IC) is a major center for the integration and processing of acoustic information from ascending auditory pathways. Damage to the IC as well as normal aging can impair auditory function. Novel strategies such as stem cell (SC)-based regenerative therapy are required for functional recovery because mature neural cells have a minimal regenerative capacity after an injury. However, it is not known if there are neural stem cells (NSCs) in the IC. Herein, we screened for NSCs by surface marker analysis using flow cytometry...
August 9, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28795171/the-crossroads-of-neural-stem-cell-development-and-tumorigenesis
#6
Odessa R Yabut, Samuel J Pleasure
Isolated brain tumors contain cells that exhibit stem cell features and a tissue microenvironment bearing remarkable similarities to the normal neurogenic niche. This supports the idea that neural stem (NSCs) or progenitor cells, and their progeny are the likely tumor cell(s) of origin. This prompted the investigation of the relationship between NSCs/progenitors and the initiation of tumorigenesis. These studies led to the identification of common signaling machineries underlying NSC development and tumor formation, particularly those with known roles in proliferation and cell fate determination...
December 2016: Opera Medica et Physiologica
https://www.readbyqxmd.com/read/28780091/production-performance-and-milk-fatty-acid-profile-in-grazing-dairy-cows-offered-ground-corn-or-liquid-molasses-as-the-sole-supplemental-nonstructural-carbohydrate-source
#7
A F Brito, K J Soder, P Y Chouinard, S F Reis, S Ross, M D Rubano, M D Casler
The objective of this study was to compare the effects of ground corn or liquid molasses fed as the sole supplemental nonstructural carbohydrate (NSC) source on production performance, milk fatty acid (FA) profile, grazing behavior, and N metabolism in grazing dairy cows. A strip-grazing management system was used, with cows offered a new strip of fresh herbage after each milking, resulting in approximately 16 h of access to pasture daily. Animals were fed a diet formulated to yield an 86:14 forage-to-concentrate ratio consisting [dry matter (DM) basis] of 74% mixed grass-legume herbage, 12% mixed-mostly legume baleage, 12% NSC source, and 2% mineral-vitamin premix...
August 2, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28776671/%C3%AE-asarone-inhibited-cell-growth-and-promoted-autophagy-via-p53-bcl-2-bclin-1-and-p53-ampk-mtor-pathways-in-human-glioma-u251-cells
#8
Nanbu Wang, Qinxin Zhang, Laiyu Luo, Baile Ning, Yongqi Fang
Glioma is the most common type of primary brain tumor and has an undesirable prognosis. Autophagy plays an important role in cancer therapy, but it's effect is still not definite. P53 is an important tumor suppressor gene and protein that is closely to autophagy. Our aim was to study the effect of β-asarone on inhibiting cell proliferation in human glioma U251 cells and to detect the effect of the inhibition on autophagy through the P53 signal pathway. For cell growth, the cells were divided into four groups: the model, β-asarone, temozolomide (TMZ) and co-administration groups...
August 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28771534/neural-stem-cell-mediated-recovery-is-enhanced-by-chondroitinase-abc-pretreatment-in-chronic-cervical-spinal-cord-injury
#9
Hidenori Suzuki, Christopher S Ahuja, Ryan P Salewski, Lijun Li, Kajana Satkunendrarajah, Narihito Nagoshi, Shinsuke Shibata, Michael G Fehlings
Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury...
2017: PloS One
https://www.readbyqxmd.com/read/28766845/neural-stem-cell-therapy-aiming-at-better-functional-recovery-after-spinal-cord-injury
#10
REVIEW
Yicheng Zhu, Naohiro Uezono, Tetsuro Yasui, Kinichi Nakashima
Injury to the spinal cord causes transection of axon fibers and neural cell death, resulting in disruption of the neural network and severe functional loss. Reconstruction of the damaged neural circuits was once considered to be hopeless as the adult mammalian central nervous system has very poor ability to regenerate. For this reason, there is currently no effective therapeutic treatment for spinal cord injury (SCI). However, with recent developments in stem cell research and cell culture technology, regenerative therapy using neural stem cell (NSC) transplantation has rapidly been developed, and this therapeutic strategy makes it possible to rebuild the destroyed neural circuits...
August 2, 2017: Developmental Dynamics: An Official Publication of the American Association of Anatomists
https://www.readbyqxmd.com/read/28766159/what-is-the-difference-in-morphologic-features-of-the-thoracic-pedicle-between-patients-with-adolescent-idiopathic-scoliosis-and-healthy-subjects-a-ct-based-case-control-study
#11
Bo Gao, Wenjie Gao, Chong Chen, Qinghua Wang, Shaochun Lin, Caixia Xu, Dongsheng Huang, Peiqiang Su
BACKGROUND: Describing the morphologic features of the thoracic pedicle in patients with adolescent idiopathic scoliosis is necessary for placement of pedicle screws. Previous studies showed inadequate reliability owing to small sample size and heterogeneity of the patients surveyed. QUESTIONS/PURPOSES: To use CT scans (1) to describe the morphologic features of 2718 thoracic pedicles from 60 female patients with Lenke Type 1 adolescent idiopathic scoliosis and 60 age-, sex-, and height-matched controls; and (2) to classify the pedicles in three types based on pedicle width and analyze the distribution of each type...
August 1, 2017: Clinical Orthopaedics and related Research
https://www.readbyqxmd.com/read/28763058/a-novel-preventive-therapy-for-paclitaxel-induced-cognitive-deficits-preclinical-evidence-from-c57bl-6-mice
#12
P Huehnchen, W Boehmerle, A Springer, D Freyer, M Endres
Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg(-1) paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l(-1), which was sevenfold higher compared with the neocortex...
August 1, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28748452/single-cell-transcriptomics-reveals-gene-signatures-and-alterations-associated-with-aging-in-distinct-neural-stem-progenitor-cell-subpopulations
#13
Zhanping Shi, Yanan Geng, Jiping Liu, Huina Zhang, Liqiang Zhou, Quan Lin, Juehua Yu, Kunshan Zhang, Jie Liu, Xinpei Gao, Chunxue Zhang, Yinan Yao, Chong Zhang, Yi E Sun
Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside...
July 26, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28744001/an-intrinsic-mechanism-controls-reactivation-of-neural-stem-cells-by-spindle-matrix-proteins
#14
Song Li, Chwee Tat Koe, Su Ting Tay, Angie Lay Keng Tan, Shenli Zhang, Yingjie Zhang, Patrick Tan, Wing-Kin Sung, Hongyan Wang
The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly. However, intrinsic mechanisms that reactivate Drosophila larval neural stem cells (NSCs) to exit from quiescence are not well established. Here we show that the spindle matrix complex containing Chromator (Chro) functions as a key intrinsic regulator of NSC reactivation downstream of extrinsic insulin/insulin-like growth factor signalling. Chro also prevents NSCs from ire-entering quiescence at later stages...
July 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28743088/chitosan-derived-co-spheroids-of-neural-stem-cells-and-mesenchymal-stem-cells-for-neural-regeneration
#15
Hao-Wei Han, Shan-Hui Hsu
Chitosan has been considered as candidate biomaterials for neural applications. The effective treatment of neurodegeneration or injury to the central nervous system (CNS) is still in lack nowadays. Adult neural stem cells (NSCs) represents a promising cell source to treat the CNS diseases but they are limited in number. Here, we developed the core-shell spheroids of NSCs (shell) and mesenchymal stem cells (MSCs, core) by co-culturing cells on the chitosan surface. The NSCs in chitosan derived co-spheroids displayed a higher survival rate than those in NSC homo-spheroids...
July 18, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28735382/combined-medication-of-antiretroviral-drugs-tenofovir-disoproxil-fumarate-emtricitabine-and-raltegravir-reduces-neural-progenitor-cell-proliferation-in-vivo-and-in-vitro
#16
Peipei Xu, Yingchun Wang, Zhao Qin, Lisha Qiu, Min Zhang, Yunlong Huang, Jialin C Zheng
The application of combination antiretroviral therapy has greatly reduced the death rate from AIDS. However, up to 50% of patients on combination antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND), which is associated with residual neuroinflammation and oxidative injury in the brain. Neural stem cells (NSCs) and progenitors play a vital role in repairing neuronal injuries. Therefore, we hypothesize that combination antiretroviral therapy may adversely affect NSCs/progenitors, contributing to the increasing prevalence of HAND...
July 22, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28728023/persistent-expression-of-vcam1-in-radial-glial-cells-is-required-for-the-embryonic-origin-of-postnatal-neural-stem-cells
#17
Xiao-Ling Hu, Guo Chen, Sanguo Zhang, Jiangli Zheng, Jun Wu, Qing-Ran Bai, Yue Wang, Ji Li, Huanhuan Wang, Han Feng, Jia Li, Xicai Sun, Qijun Xia, Fan Yang, Jing Hang, Chang Qi, Timothy N Phoenix, Sally Temple, Qin Shen
During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs...
July 19, 2017: Neuron
https://www.readbyqxmd.com/read/28725041/a-screen-for-novel-hepatitis-c-virus-rdrp-inhibitor-identifies-a-broad-spectrum-antiviral-compound
#18
Abhilasha Madhvi, Smita Hingane, Rajpal Srivastav, Nishant Joshi, Chandru Subramani, Rajagopalan Muthumohan, Renu Khasa, Shweta Varshney, Manjula Kalia, Sudhanshu Vrati, Milan Surjit, C T Ranjith-Kumar
Hepatitis C virus (HCV) is a global pathogen and infects more than 185 million individuals worldwide. Although recent development of direct acting antivirals (DAA) has shown promise in HCV therapy, there is an urgent need for the development of more affordable treatment options. We initiated this study to identify novel inhibitors of HCV through screening of compounds from the National Cancer Institute (NCI) diversity dataset. Using cell-based assays, we identified NSC-320218 as a potent inhibitor against HCV with an EC50 of 2...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720530/downregulation-of-protein-phosphatase-2a-by-apolipoprotein-e-implications-for-alzheimer-s-disease
#19
Veena Theendakara, Dale E Bredesen, Rammohan V Rao
The apolipoprotein E ε4 allele is the single most important genetic risk factor associated with Alzheimer's disease (AD). Tau phosphorylation and hyperphosphorylation is an underlying feature of AD and is regulated by specific kinases and phosphatases. Among phosphatases, protein phosphatase 2A (PP2A) is the principal tau dephosphorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including among others decreased protein levels of PP2A, decreased mRNA and protein levels of the catalytic subunit PP2AC and variable regulatory B subunits and reduced methylation of the catalytic subunit, all of which results in disruption of the PP2A phosphatase activity...
July 15, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28715630/misfolded-sod1-accumulation-and-mitochondrial-association-contribute-to-the-selective-vulnerability-of-motor-neurons-in-familial-als-correlation-to-human-disease
#20
Salah Abu-Hamad, Joy Kahn, Marcel F Leyton-Jaimes, Jonathan Rosenblatt, Adrian Israelson
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, with a 10% genetic linkage, of which 20% of these cases may be attributed to mutations in superoxide dismutase (SOD1). Specific mutations in SOD1 have been associated with disease duration, which can be highly variable ranging from a life expectancy of 3 to beyond 10 years. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles disrupting their function or forms insoluble toxic aggregates...
July 31, 2017: ACS Chemical Neuroscience
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