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Results of Celebrity Features, Observed Homophily, and Reverence about Consumer-Celebrity Para-Social Connection along with Manufacturer Attitude.
CONCLUSIONS We suggest that DF exclusively suppresses GM-CSF-producing Th1 cells in both animal and human CD4+ T cells through an IFN-γ-dependent pathway. These findings indicate that DF has a better therapeutic effect on patients with Th1-dominant immunophenotype. However, future longitudinal study to validate this finding in MS is needed. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.The Arabidopsis (Arabidopsis thaliana) root epidermis consists of a position-dependent pattern of root-hair cells and non-hair cells. Underlying this cell-type patterning is a network of transcription factors including a central MYB-bHLH-WD40 complex containing WEREWOLF (WER), GLABRA 3/ENHANCER OF GLABRA 3 (GL3/EGL3), and TRANSPARENT TESTA GLABRA 1 (TTG1). In this study, we used a genetic enhancer screen to identify apum23-4, a mutant allele of the ribosome biogenesis factor (RBF) gene PUMILIO 23 (APUM23), which caused prospective root-hair cells to instead adopt the non-hair cell fate. We discovered that this cell fate switch relied on MYB23, a MYB protein encoded by a WER target gene and acting redundantly with WER. In the apum23-4 mutant, MYB23 exhibited ectopic expression that was WER-independent and instead required ANAC082, a recently identified ribosomal stress response mediator. We examined additional RBF mutants that produced ectopic non-hair cells and determined that this cell fate switch is generally linked to defects in ribosome biogenesis. Further, the flagellin peptide flg22 triggers the ANAC082-MYB23-GL2 pathway. Taken together, our study provides a molecular explanation for root epidermal cell fate switch in response to ribosomal defects and, more generally, it demonstrates a novel regulatory connection between stress conditions and cell fate control in plants. © 2020 American Society of Plant Biologists. All rights reserved.How the membrane trafficking system spatially organizes intracellular activities and intercellular signaling networks is not well understood in plants. The TRAnsport Protein Particle (TRAPP) complexes play key roles in selective delivery of membrane vesicles to various subcellular compartments in yeast and animals, but are not characterized in plants. Here we interrogate TRAPP complexes in Arabidopsis. Affinity purification of a core subunit AtTRS33 followed by quantitative mass spectrometry identified fourteen interacting proteins; including homologues of all thirteen TRAPP components in yeast and mammals and a novel protein we named TRAPP-interacting plant protein (TRIPP), which is conserved in multi-cellular photosynthetic organisms. Proteomic and molecular analyses showed that TRIPP specifically associates with the TRAPPII complex through binary interactions with two TRAPPII-specific subunits. TRIPP co-localizes with a subset of TRS33 compartments and trans-Golgi network markers in a TRS33-dependent manner. Loss-of-function tripp mutation caused dwarfism, sterility, partial photomorphogenesis in the dark, reduced polarity of the auxin transporter PIN2, incomplete cross wall formation and altered localization of a TRAPPII-specific component. Our study demonstrates that plants possess at least two distinct TRAPP complexes similar to metazoans, and identifies TRIPP as a novel plant-specific component of the TRAPPII complex with important functions in trafficking, plant growth and development. © 2020 American Society of Plant Biologists. All rights reserved.Phytochromes are red (R) and far-red (FR) light photoreceptors in plants, and PHYTOCHROME-INTERACTING FACTORS (PIFs) are a group of bHLH family transcription factors that play central roles in repressing photomorphogenesis. Here, we report that MYB30, an R2R3-MYB family transcription factor, acts as a negative regulator of photomorphogenesis in Arabidopsis. We show that MYB30 preferentially interacts with the Pfr (active) forms of the phytochrome A and phytochrome B holoproteins (phyA, phyB), and that MYB30 levels are induced by phyA and phyB in the light. Irbinitinib clinical trial It was previously shown that phytochromes induce rapid phosphorylation and degradation of PIFs upon R light exposure. Our current data indicate that MYB30 promotes PIF4 and PIF5 protein reaccumulation under prolonged R light irradiation by directly binding to their promoters to induce their expression, and by inhibiting the interaction of PIF4 and PIF5 with the Pfr form of phyB. In addition, our data indicate that MYB30 also interacts with PIFs, and that they act additively to repress photomorphogenesis. In summary, our study demonstrates that MYB30 negatively regulates Arabidopsis photomorphogenic development by acting to promote PIF4 and PIF5 protein accumulation under prolonged R light irradiation, thus providing new insights into the complicated but delicate control of PIFs in plants' responses to their dynamic light environment. © 2020 American Society of Plant Biologists. All rights reserved.In 2015, the UK government published the National Strategic Defence and Security Review (SDSR) 2015, which laid out their vision for the future roles and structure of the UK Armed Forces. SDSR 2015 envisaged making broader use of the Armed Forces to support missions other than warfighting. One element of this would be to increase the scale and scope of defence engagement (DE) activities that the UK conducts overseas. DE activities traditionally involve the use of personnel and assets to help prevent conflict, build stability and gain influence with partner nations as part of a short-term training teams. This paper aimed to give an overview of the Specialist Infantry Group and its role in UK DE. It will explore the reasons why the SDSR 2015 recommended their formation as well as an insight into future tasks. © Author(s) (or their employer(s)) 2020. link2 No commercial re-use. See rights and permissions. Published by BMJ.PURPOSE After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenibfor hepatocellular carcinoma (HCC).On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of NOS3 and ANGPT2 polymorphisms in HCC patients treated with sorafenib [NCT02786342]. EXPERIMENTAL DESIGN This prospective multicenter study was conducted at 10 centres in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression free survival (PFS), while secondary outcomes included overall survival (OS) and disease-control rate (DCR). RESULTS 165 patients were enrolled between March2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS(5.9 vs 2.4 months, HR 0.43, p=0.0007) and OS(15.7 vs 8.6 months, HR 0.38, p less then 0.0001) compared to TT genotype.There was no statistically significant association betweenANGPT2 rs55633437 TT/GT genotypes and PFS(2.4 vs 5.7 months, HR 1.93, p=0.0833) and OS(15.1 vs 13.0 months, HR 2.68, p=0.55) when compared to the other genotype. Following adjustment for clinical covariates,multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR 0.50, p=0.0128)and OS (HR 0.29, p=0.0041). CONCLUSIONS The INNOVATE study met the primary endpoint, confirming that advanced HCC patients with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients. Copyright ©2020, American Association for Cancer Research.PURPOSE Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune-stimulation, which may potentiate anti-PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC. EXPERIMENTAL DESIGN This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin ineligible patients. Patients received radiotherapy concurrently with 3 cycles of pembrolizumab 200mg q3 weeks followed by 3 adjuvant cycles. The primary endpoint was a PFS of >16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling. RESULTS Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated twenty-four month PFS and OS rates were 71% (95% CI 49-84) and 75% (51-88). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells. CONCLUSIONS Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets. Copyright ©2020, American Association for Cancer Research.PURPOSE Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. MATERIALS AND METHODS In two prospective phase 1 studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12 and 9 patients, respectively. CRS (grade 1/2) was reversible in 8 patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. CONCLUSIONS This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. link3 We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC. Copyright ©2020, American Association for Cancer Research.PURPOSE In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41. EXPERIMENTAL DESIGN Eligible patients had a baseline pre-adjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter® Breast Cancer 360™ gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base two. To screen for candidate genes and meta-gene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization. RESULTS Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early- stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens.
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