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https://www.readbyqxmd.com/read/28107736/crystal-structures-binding-interactions-and-adme-evaluation-of-brain-penetrant-n-substituted-indazole-5-carboxamides-as-subnanomolar-selective-monoamine-oxidase-b-and-dual-mao-a-b-inhibitors
#1
Nikolay T Tzvetkov, Hans-Georg Stammler, Beate Neumann, Silvia Hristova, Liudmil Antonov, Marcus Gastreich
The pharmacological and physicochemical analysis of structurally optimized N-alkyl-substituted indazole-5-carboxamides, developed as potential drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD) and other neurological disorders, is reported. Recent efforts have been focused on the development of subnanomolar potent, selective MAO-B (N1-alkyl-substituted compounds 12a-14a and 15) and dual active MAO-A/B (N2-methylated compounds 12b-14b) inhibitors with nanomolar potency towards MAO-B and moderately active against MAO-A enzyme, respectively...
January 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28107628/constructing-fast-carrier-tracks-into-flexible-perovskite-photodetectors-to-greatly-improve-responsivity
#2
Xiaoming Li, Dejian Yu, Jun Chen, Yue Wang, Fei Cao, Yi Wei, Ye Wu, Lin Wang, Ying Zhu, Zhiguo Sun, Jianping Ji, Yalong Shen, Handong Sun, Haibo Zeng
Intrinsically high mobility and large absorption coefficient endow inorganic halide perovskites (IHPs) with great promise for high-performance photodetectors (PDs), which, however, are being hindered by the low carrier extraction and transport efficiency of the solution assembled films. Here, we report on a general strategy to enhance the film conductivity of perovskites that conductive nanonets were constructed with carbon nanotubes (CNTs) to provide fast carriers tracks. As a result, the CsPbBr3 nanosheet/CNT composite films exhibit high conductivity and the advantages are demonstrated by the high performances of corresponding planar PDs...
January 20, 2017: ACS Nano
https://www.readbyqxmd.com/read/28107610/tonsil-derived-mesenchymal-stem-cells-t-mscs-prevent-th17-mediated-autoimmune-response-via-regulation-of-the-programmed-death-1-programmed-death-ligand-1-pd-1-pd-l1-pathway
#3
Ji-Yon Kim, Minhwa Park, Yu-Hee Kim, Kyung-Ha Ryu, Kyung Ho Lee, Kyung-Ah Cho, So-Youn Woo
Our knowledge of the immunomodulatory role of mesenchymal stem cells (MSCs) in both the innate and adaptive immune systems has dramatically expanded, providing great promise for treating various autoimmune diseases. However, the contribution of MSCs to Th17 dominant immune disease, such as psoriasis and its underlying mechanism remains elusive. In this study, we demonstrated that human palatine tonsil-derived MSCs (T-MSCs) constitutively express both the membrane-bound and soluble forms of programmed death-ligand 1 (PD-L1), which enables T-MSCs to be distinguished from MSCs originating from other organs (i...
January 20, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28107571/increased-pd-l1-expression-in-breast-and-colon-cancer-stem-cells
#4
Yanheng Wu, Mingshui Chen, Peihong Wu, Chen Chen, Zhi Ping Xu, Wenyi Gu
Here we report the expression of programmed cell death ligand 1/2 (PD-L1/L2) in breast and colon cancer stem cells (CSCs). The stemness of these cells was confirmed by their surface markers. Using flow cytometry analysis we demonstrated that PD-L1 expression was higher in CSCs of both cancers compared to non-stem like cancer cells. Consistent with this, detection of cellular PD-L1 proteins by Western blot assay also showed increased PD-L1 protein in CSCs. In contrast, only trance amounts of PD-L2 were detected in CSCs of both cancers...
January 20, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28107186/the-combination-of-pd-l1-expression-and-decreased-tumor-infiltrating-lymphocytes-is-associated-with-a-poor-prognosis-in-triple-negative-breast-cancer
#5
Hitomi Mori, Makoto Kubo, Rin Yamaguchi, Reiki Nishimura, Tomofumi Osako, Nobuyuki Arima, Yasuhiro Okumura, Masayuki Okido, Mai Yamada, Masaya Kai, Junji Kishimoto, Yoshinao Oda, Masafumi Nakamura
This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors (P = 0...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28106982/a-novel-iron-ii-preferring-dopamine-agonist-chelator-as-potential-symptomatic-and-neuroprotective-therapeutic-agent-for-parkinson-s-disease
#6
Banibrata Das, Ashoka Kandegedara, Liping Xu, Tamara Antonio, Timothy L Stemmler, Maarten E A Reith, Aloke K Dutta
Parkinson's disease (PD) is a progressive neurodegenerative disorder and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron (II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (-)-12 (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D2/D3 receptors indicate potent agonist activity of (-)-12. The molecule displayed an efficient preferential iron (II) chelation properties along with potent in vivo activity in a reserpinized PD animal model...
January 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28106569/cerebellar-volume-and-executive-function-in-parkinson-disease-with-and-without-freezing-of-gait
#7
Peter S Myers, Marie E McNeely, Jonathan M Koller, Gammon M Earhart, Meghan C Campbell
BACKGROUND: Freezing of gait (FOG) affects approximately 50% of people with Parkinson Disease (PD), impacting quality of life and placing financial and emotional strain on the individual and caregivers. People with PD and FOG have similar deficits in motor adaptation and cognition as individuals with cerebellar lesions, indicating the cerebellum may play a role in FOG. OBJECTIVE: To examine potential differences in cerebellar volumes and their relationships with cognition between PD with (FOG+) and without FOG (FOG-)...
January 17, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28106568/physical-therapy-versus-a-general-exercise-programme-in-patients-with-hoehn-yahr-stage-ii-parkinson-s-disease-a%C3%A2-randomized-controlled-trial
#8
Savina Dipasquale, Roberto Meroni, Francesco Sasanelli, Ivan Messineo, Daniele Piscitelli, Cecilia Perin, Cesare Maria Cornaggia, Cesare G Cerri
BACKGROUND AND OBJECTIVE: Several studies suggest that general exercise (GE) and physical therapy programmes (PT) improve the outcomes of Parkinson's disease (PD) patients; however, the available data do not allow a determination of which treatment is more effective. Our study aims to compare the effects of physiotherapy and general exercise in Parkinson's disease. METHODS: Design and setting: Randomized controlled trial -general hospital outpatient clinic. The participants were patients with Hoehn Yahr stage II PD...
January 17, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28106567/fractional-anisotropy-and-mean-diffusion-as-measures-of-dopaminergic-function-in-parkinson-s-disease-challenging-results
#9
Niklas Lenfeldt, Johan Eriksson, Björn Åström, Lars Forsgren, Susanna Jakobson
BACKGROUND: Diffusion tensor imaging (DTI) has been purported as an imaging technique to assess dopaminergic degeneration in Parkinson's disease. OBJECTIVE: To test if fractional anisotropy (FA) and mean diffusion (MD) in the basal ganglia as measured by DTI correlates with dopaminergic function as measured by dopamine transporter (DAT) and dopamine D2-receptor (D2R) SPECT. METHODS: One-hundred and eleven patients with Parkinson's disease (71±10 years) and thirty-one controls (68±7 years) performed DTI, DAT and D2R SPECT at baseline and four follow-ups (1-year: 89 patients/zero controls; 3-year: 72/11; 5-year: 48/17; and 8-year: 13/13)...
January 17, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28106566/cerebral-amyloid-burden-and-hoehn-and-yahr-stage-3-scoring-in-parkinson-disease
#10
Vikas Kotagal, Nicolaas I Bohnen, Martijn L T M Müller, Kirk A Frey, Roger L Albin
BACKGROUND: Progression to Hoehn and Yahr (HY) stage 3 marks the transition to advanced disease staging and disability in Parkinson disease (PD). OBJECTIVE/METHODS: We conducted a case-control study of 36 PD subjects at HY stage 2.5 or 3, with groups matched for gender, age, and disease duration. Positron Emission tomography (PET) imaging included dihydrotetrabenazine [11C]DTBZ and Pittsburgh Compound B [11C]PiB. RESULTS: Subjects with HY 2...
January 17, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28106099/nesfatin-1-protects-dopaminergic-neurons-against-mpp-mptp-induced-neurotoxicity-through-the-c-raf-erk1-2-dependent-anti-apoptotic-pathway
#11
Xiao-Li Shen, Ning Song, Xi-Xun Du, Yong Li, Jun-Xia Xie, Hong Jiang
Several brain-gut peptides have been reported to have a close relationship with the central dopaminergic system; one such brain-gut peptide is nesfatin-1. Nesfatin-1 is a satiety peptide that is predominantly secreted by X/A-like endocrine cells in the gastric glands, where ghrelin is also secreted. We previously reported that ghrelin exerted neuroprotective effects on nigral dopaminergic neurons, which implied a role for ghrelin in Parkinson's disease (PD). In the present study, we aim to clarify whether nesfatin-1 has similar effects on dopaminergic neurons both in vivo and in vitro...
January 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28105978/simultaneous-transplantation-of-fetal-ventral-mesencephalic-tissue-and-encapsulated-genetically-modified-cells-releasing-gdnf-in-a-hemi-parkinsonian-rat-model-of-parkinson-s-disease
#12
Alberto Perez-Bouza, Stefano Di, Stefanie Seiler, Morten Meyer, Lukas Andereggen, Alexander Huber, Raphael Guzman, Hans R
Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat model of PD we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor or mocktransfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior and 2, 4, 6 and 9 weeks post-transplantation...
January 20, 2017: Cell Transplantation
https://www.readbyqxmd.com/read/28105616/-interpretation-of-the-updates-of-nccn-2017-version-1-0-guideline-for-colorectal-cancer
#13
Gong Chen
The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting...
January 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28105370/interstitial-nephritis-in-melanoma-patients-secondary-to-pd-1-checkpoint-inhibitor
#14
Julia Escandon, Stephanie Peacock, Asaad Trabolsi, David B Thomas, Ayman Layka, Jose Lutzky
BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases. CASE PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28105368/clinical-and-immunologic-correlates-of-response-to-pd-1-blockade-in-a-patient-with-metastatic-renal-medullary-carcinoma
#15
Kathryn E Beckermann, Pradeep C Jolly, Ju Y Kim, Jennifer Bordeaux, Igor Puzanov, W Kimryn Rathmell, Douglas B Johnson
BACKGROUND: Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in adolescent and young adults, typically in association with sickle cell trait. RMC exhibits rapid disease progression, frequent metastases at diagnosis, and dismal clinical outcomes. Currently available therapies, including cisplatin-based combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies demonstrate either transient responses or minimal activity. Therefore, further molecular characterization and additional treatment strategies are urgently needed in this aggressive disease...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28105229/programmed-cell-death-1-correlates-with-the-occurrence-and-development-of-mg63-osteosarcoma
#16
Fuyou Zhao, Qiong Wu, Xiusong Dai, Yumei Li, Huaiyong Gan, Ri Wang, Jie Lv, Yuqing Chen
The aim of the present study was to investigate the effect of programmed cell death 1 (PD-1) on osteosarcoma (OD) stem cells and T cells, and to determine their correlation. OS stem cells were sorted and identified from OS MG63 cells. Flow cytometry was used to detect the PD-1 expression of the OS tumor stem cell membrane surface. The expression of PD-1 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). MTT was used to detect the effect of PD-1 signals on T-cell proliferation. The results indicated that the cancer cells (cultured in DMEM medium containing 10% fetal bovine serum) exhibited clear proliferation within 1 week of cell culture, which showed their strong proliferation and aggressive ability...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28104537/correlation-between-classic-driver-oncogene-mutations-in-egfr-alk-or-ros1-and-22c3-pd-l1-%C3%A2-50-expression-in-lung-adenocarcinoma
#17
Deepa Rangachari, Paul A VanderLaan, Meghan Shea, Xiuning Le, Mark S Huberman, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: Targeted somatic genomic analysis (EGFR, ALK and ROS1) and PD-L1 tumor proportion score (TPS) by immunohistochemistry (IHC) are used for selection of 1(st)-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported. METHODS: We retrospectively probed the first 71 lung adenocarcinoma-patient pairs from our institution analyzed for PD-L1 IHC using the clone 22C3 pharmDx kit and evaluated co-occurrence of genomic aberrations along with clinical-pathologic characteristics...
January 16, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28104397/pink1-alleviates-myocardial-hypoxia-reoxygenation-injury-by-ameliorating-mitochondrial-dysfunction
#18
Yang Li, Liangxian Qiu, Xiping Liu, Zhiwen Hou, Bo Yu
PTEN inducible kinase-1 (PINK1) mutant induces mitochondrial dysfunction of cells, resulting in an inherited form of Parkinson's disease. However its exact role in the cardiomyocytes is unclear. The present study examined the function of PINK1 in hypoxia-reoxygenation (H/R) induced H9c2 cell damage and its potential mechanism. The H/R model in H9c2 cells was established by 6 h of hypoxia and 12 h of reoxygenation. The CCK8 and LDH assay indicated that the cell viability was obviously reduced after H/R. The expression of PINK1 was decreased in H/R-induced H9c2 cells compared with control group...
January 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28104279/effect-of-inhibition-of-fatty-acid-amide-hydrolase-on-mptp-induced-dopaminergic-neuronal-damage
#19
J M Viveros-Paredes, R E Gonzalez-Castañeda, A Escalante-Castañeda, A R Tejeda-Martínez, F Castañeda-Achutiguí, M E Flores-Soto
INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)...
January 16, 2017: Neurología: Publicación Oficial de la Sociedad Española de Neurología
https://www.readbyqxmd.com/read/28104251/efficacy-safety-and-pharmacokinetics-of-natalizumab-in-japanese-multiple-sclerosis-patients-a-double-blind-randomized-controlled-trial-and-open-label-pharmacokinetic-study
#20
Takahiko Saida, Jun-Ichi Kira, Shuji Kishida, Takashi Yamamura, Yukiko Sudo, Kazutaka Ogiwara, J T Tibung, Nisha Lucas, Meena Subramanyam
BACKGROUND: Natalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. METHODS: This multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B)...
January 2017: Multiple Sclerosis and related Disorders
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