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https://www.readbyqxmd.com/read/28324831/primary-and-acquired-resistance-to-pd-1-pd-l1-blockade-in-cancer-treatment
#1
REVIEW
Qiaohong Wang, Xia Wu
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous...
March 18, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28324061/progesterone-protects-against-bpa-induced-arrhythmias-in-female-rat-cardiac-myocytes-via-rapid-signaling
#2
Jianyong Ma, Kui Hong, Hong-Sheng Wang
Bisphenol A (BPA) is an estrogenic endocrine disrupting chemical (EDC) that has a range of potential adverse health effects. Previously we showed that acute exposure to BPA promoted arrhythmias in female rat hearts through estrogen receptor rapid signaling. Progesterone (P4) and estrogen have antagonistic or complementary actions in a number of tissues and systems. In the current study, we examined the influence, and possible protective effect, of P4 on the rapid cardiac actions of BPA in female rat cardiac myocytes...
January 25, 2017: Endocrinology
https://www.readbyqxmd.com/read/28324055/substrate-metabolism-and-insulin-sensitivity-during-fasting-in-obese-human-subjects-impact-of-gh-blockade
#3
Morten Høgild Pedersen, Mads Vandsted Svart, Janne Lebeck, Martin Bidlingmaier, Hans Stødkilde-Jørgensen, Steen Bønløkke Pedersen, Niels Møller, Niels Jessen, Jens O L Jørgensen
Context: Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. GH secretion increases during fasting and GH causes insulin resistance. Objective: To study the metabolic effects of GH blockade during fasting in obese subjects. Subjects and Methods: Nine obese males were studied thrice in a randomized design: 1) After an overnight fast (Control), 2) After 72 h fasting (Fasting) and 3) After 72 h fasting with GH blockade (pegvisomant) (Fasting + GHA)...
January 18, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28324027/follistatin-targets-distinct-pathways-to-promote-brown-adipocyte-characteristics-in-brown-and-white-adipose-tissues
#4
Rajan Singh, Melissa Braga, Srinivasa T Reddy, Se-Jin Lee, Meher Parveen, Victor Grijalva, Laurent Vergnes, Shehla Pervin
We previously demonstrated that Fst expression is highest in brown adipose tissue (BAT) and skeletal muscle, but is also present at substantial levels in epididymal (Epi) and subcutaneous (SC) white adipose tissues (WAT). Fst promotes mouse brown preadipocyte differentiation and promotes browning during differentiation of mouse embryonic fibroblasts (MEFs). Fst-transgenic (Fst-Tg) mouse show significant increase in circulating Fst levels and increased brown adipose mass. BAT of Fst-Tg mice had increased expression of brown adipose-associated markers including uncoupling protein 1 (UCP1), PRDM16, PGC-1α and Glut4...
January 16, 2017: Endocrinology
https://www.readbyqxmd.com/read/28324021/endogenous-calcitonin-gene-related-peptide-regulates-lipid-metabolism-and-energy-homeostasis-in-male-mice
#5
Tian Liu, Akiko Kamiyoshi, Takayuki Sakurai, Yuka Ichikawa-Shindo, Hisaka Kawate, Lei Yang, Megumu Tanaka, Xian Xian, Akira Imai, Liuyu Zhai, Kazutaka Hirabayashi, Kun Dai, Keiya Tanimura, Teng Liu, Nanqi Cui, Kyoko Igarashi, Akihiro Yamauchi, Takayuki Shindo
Calcitonin gene-related peptide (CGRP) is a bioactive peptide produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is largely distributed in the cardiovascular and nervous systems, where it acts as a regulatory factor. CGRP is also expressed in organs and tissues involved in metabolic regulation, including white adipose tissue (WAT), where its function is largely unknown. In this study, we examined the effects of endogenous CGRP on metabolic function. When we administered a high-fat diet to CGRP knockout (CGRP-/-) and wild-type (WT) mice for 10 weeks, we observed that food intake did not differ between the two groups, but body weight and visceral fat weight were significantly lower in CGRP-/- mice...
January 20, 2017: Endocrinology
https://www.readbyqxmd.com/read/28323959/insulin-and-glucagon-partners-for-life
#6
Jens Juul Holst, William Holland, Jesper Gromada, Young Lee, Roger H Unger, Hai Yan, Kyle W Sloop, Timothy J Kieffer, Nicolas Damond, Pedro L Herrera
In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused around the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment of diabetes. Among the most enlightening experimental results presented were findings from studies where glucagon receptor-deficient mice were administered streptozotocin to destroy pancreatic beta cells or had undergone diphtheria toxin-induced beta cell ablation...
January 31, 2017: Endocrinology
https://www.readbyqxmd.com/read/28320090/treatment-with-anti-programmed-cell-death-1-pd-1-antibody-restored-postoperative-cd8-t-cell-dysfunction-by-surgical-stress
#7
Zhirong Sun, Anrong Mao, Yun Wang, Yanjun Zhao, Jiawei Chen, Pingbo Xu, Changhong Miao
Millions of patients benefit from surgery and are exposed to surgical stress. However, ample studies suggest that surgical stress contributes to tumor recurrence or distant metastases. Surgical stress suppresses CD8+ T cells (CTL) function which is vital for eliminating the malignant cells. Anti-programmed cell death 1 (PD-1) therapy is an effective and safe treatment that increases survival rate of patients with multiple cancers, however, whether anti-PD-1 therapy is able to reverse the immunosuppression following surgery remains largely unknown...
March 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28319894/resolvin-d1-via-prevention-of-ros-mediated-shp2-inactivation-protects-endothelial-adherens-junction-integrity-and-barrier-function
#8
Rima Chattopadhyay, Somasundaram Raghavan, Gadiparthi N Rao
Resolvins are a novel class of lipid mediators that play an important role in the resolution of inflammation, although the underlying mechanisms are not very clear. To explore the anti-inflammatory mechanisms of resolvins, we have studied the effects of resolvin D1 (RvD1) on lipopolysaccharide (LPS)-induced endothelial barrier disruption as it is linked to propagation of inflammation. We found that LPS induces endothelial cell (EC) barrier disruption via xanthine oxidase (XO)-mediated reactive oxygen species (ROS) production, protein tyrosine phosphatase SHP2 inactivation and Fyn-related kinase (Frk) activation leading to tyrosine phosphorylation of α-catenin and VE-cadherin and their dissociation from each other affecting adherens junction (AJ) integrity and thereby increasing endothelial barrier permeability...
March 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/28319731/stimulating-cd27-to-quantitatively-and-qualitatively-shape-adaptive-immunity-to-cancer
#9
REVIEW
Timothy Nj Bullock
The capacity of the immune system to recognize and respond to tumors has been appreciated for over 100 years. However, clinical success has largely depended on the elucidation of the positive and negative regulators of effector cells after their activation via the antigen cell receptor. On the one hand, effector cells upregulate checkpoint molecules that are thought to play a role in limiting immunopathology. On the other, second and third waves of costimulation are often required to promote the expansion, survival and differentiation of effector cells...
March 16, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28316970/dgk-%C3%AE-a-checkpoint-in-cancer-mediated-immuno-inhibition-and-target-for-immunotherapy
#10
Elfriede Noessner
Immunotherapy is moving to the forefront of cancer treatments owing to impressive durable responses achieved with checkpoint blockade antibodies and adoptive T-cell therapy. Still, improvements are necessary since, overall, only a small percentage of patients benefit from current therapies. Here, I summarize evidence that DGK-α may represent an immunological checkpoint suppressing the activity of cytotoxic immunocytes in the tumor microenvironment. DGK-inhibitors can restore the antitumor function of tumor-suppressed adaptive and innate cytotoxic immunocytes...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28315922/superior-perioperative-analgesia-with-combined-femoral-obturator-sciatic-nerve-block-in-comparison-with-posterior-lumbar-plexus-and-sciatic-nerve-block-for-acl-reconstructive-surgery
#11
Metaxia Bareka, Michael Hantes, Eleni Arnaoutoglou, George Vretzakis
PURPOSE: The purpose of this randomized controlled study is to compare and evaluate the intraoperative and post-operative outcome of PLPS nerve block and that of femoral, obturator and sciatic (FOS) nerve block as a method of anaesthesia, in performing ACL reconstruction. METHODS: Patients referred for elective arthroscopic ACL reconstruction using hamstring autograft were divided in two groups. The first group received combined femoral-obturator-sciatic nerve block (FOS Group) under dual guidance, whereas the second group received posterior lumbar plexus block under neurostimulation and sciatic nerve block (PLPS Group) under dual guidance...
March 18, 2017: Knee Surgery, Sports Traumatology, Arthroscopy: Official Journal of the ESSKA
https://www.readbyqxmd.com/read/28315150/radioiodination-and-preclinical-evaluation-of-4-benzyl-1-3-125-i-iodobenzylsulfonyl-piperidine-as-a-breast-tumor-imaging-tracer-in-mouse
#12
Masoud Sadeghzadeh, Behrouz Alirezapour, Ghorban Ali Charkhlooie, Maryam Keshavarz Baghery, Amir Khorouti
OBJECTIVE: 4-Benzyl-1-(3-iodobenzylsulfonyl)piperidine, 4-B-IBSP, has shown high-binding affinity to both sigma (σ) receptors in our previous work. In current study, radiolabeling and preclinical evaluation of 4-benzyl-1-(3-[(125)I]-iodobenzylsulfonyl)piperidine, 4-B-[(125)I]IBSP, in human ductal breast carcinoma (T47D) cells and in breast adenocarcinoma-bearing BALB/c mice are described. METHODS: Radioiodination of this new σ ligand was performed by a palladium-catalyzed stannylation approach followed by oxidative iododestannylation reaction using Iodo-Gen...
March 17, 2017: Annals of Nuclear Medicine
https://www.readbyqxmd.com/read/28314848/effects-of-late-sodium-current-blockade-on-ventricular-refibrillation-in-a-rabbit-model
#13
Mohammed Ali Azam, Nima Zamiri, Stéphane Massé, Marjan Kusha, Patrick F H Lai, Govind K Nair, Nigel S Tan, Christopher Labos, Kumaraswamy Nanthakumar
BACKGROUND: After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na(+) current to inactivate leads to intracellular Ca(2+) dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na(+) current, on ventricular refibrillation. METHODS AND RESULTS: Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes...
March 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28314298/multi-omics-profiling-of-patients-with-melanoma-treated-with-nivolumab-in-project-hope
#14
Shusuke Yoshikawa, Yoshio Kiyohara, Masaki Otsuka, Ryota Kondou, Chizu Nonomura, Haruo Miyata, Akira Iizuka, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Masatoshi Kusuhara, Takashi Sugino, Tohru Mochizuki, Ken Yamaguchi, Yasuto Akiyama
BACKGROUND: Project HOPE (High-tech Omics-based Patient Evaluation) has been in progress since 2014 and uses whole-exome sequencing (WES) and gene expression profiling (GEP). Among a total of 1,685 patients with cancer, 13 with melanoma were registered and characterized using multi-omics analyses to investigate specific biomarkers in responders to programmed cell death-1 (PD-1) blockade. MATERIALS AND METHODS: The patients with melanoma comprised of six males and seven females, and their mean age was 68 years...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28306559/immunotherapy-a-new-treatment-paradigm-in-bladder-cancer
#15
Nicole N Davarpanah, Akira Yuno, Jane B Trepel, Andrea B Apolo
PURPOSE OF REVIEW: T-cell checkpoint blockade has become a dynamic immunotherapy for bladder cancer. In 2016, atezolizumab, an immune checkpoint inhibitor, became the first new drug approved in metastatic urothelial carcinoma (mUC) in over 30 years. In 2017, nivolumab was also approved for the same indication. This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy...
March 16, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28304152/reprogramming-of-histone-methylation-controls-the-differentiation-of-monocytes-into-macrophages
#16
Qi-Fan Zheng, Hui-Min Wang, Zhan-Feng Wang, Jin-Yang Liu, Qi Zhang, Li Zhang, Yuan-Hua Lu, Han You, Guang-Hui Jin
Subset heterogeneity of the mononuclear phagocyte system (MPS) is controlled by defined transcriptional networks and programs; however, the dynamic establishment of programs that control broad, orchestrated expression of transcription factors (TFs) during the progression of monocyte-into-phagocyte (MP) differentiation remains largely unexplored. By using chromatin immunoprecipitation assays, we show the extensive trimethylation of histone H3 lysine 4 (H3K4me3) as well as histone H3 lysine 27 (H3K27me3) occupancy with broad footprints at the promoters of MP differentiation-related TFs, such as HOXA and FOXO genes, KLF4, IRF8 and others...
March 17, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28303624/effect-of-eplerenone-in-patients-with-heart-failure-and-reduced-ejection-fraction-potential-effect-modification-by-abdominal-obesity-insight-from-the-emphasis-hf-trial
#17
Arnaud Olivier, Bertram Pitt, Nicolas Girerd, Zohra Lamiral, Jean-Loup Machu, John J V McMurray, Karl Swedberg, Dirk J van Veldhuisen, Timothy J Collier, Stuart J Pocock, Patrick Rossignol, Faiez Zannad, Anne Pizard
AIMS: An excessive production of aldosterone influences outcome in patients with heart failure (HF) and in obese patients. Findings from laboratory studies suggest that chronic aldosterone blockade maybe more beneficial in abdominally obese HF-prone rats. In the current study, we investigated if the clinical response to a mineralocorticoid receptor antagonist in mildly symptomatic HF patients varied by abdominal obesity. METHODS AND RESULTS: A total of 2587 NYHA class II, reduced ejection fraction HF (HFrEF) patients enrolled in the EMPHASIS-HF trial were randomly assigned to eplerenone and placebo...
March 16, 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28303006/short-course-high-dose-rifampicin-achieves-wolbachia-depletion-predictive-of-curative-outcomes-in-preclinical-models-of-lymphatic-filariasis-and-onchocerciasis
#18
Ghaith Aljayyoussi, Hayley E Tyrer, Louise Ford, Hanna Sjoberg, Nicolas Pionnier, David Waterhouse, Jill Davies, Joanne Gamble, Haelly Metugene, Darren A N Cook, Andrew Steven, Raman Sharma, Ana F Guimaraes, Rachel H Clare, Andrew Cassidy, Kelly L Johnston, Laura Myhill, Laura Hayward, Samuel Wanji, Joseph D Turner, Mark J Taylor, Stephen A Ward
Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18-24 months post-treatment...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302645/pd-l1-on-tumor-cells-is-sufficient-for-immune-evasion-in-immunogenic-tumors-and-inhibits-cd8-t-cell-cytotoxicity
#19
Vikram R Juneja, Kathleen A McGuire, Robert T Manguso, Martin W LaFleur, Natalie Collins, W Nicholas Haining, Gordon J Freeman, Arlene H Sharpe
It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity...
March 16, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28302482/fap-positive-fibroblasts-induce-immune-checkpoint-blockade-resistance-in-colorectal-cancer-via-promoting-immunosuppression
#20
Lingling Chen, Xiangting Qiu, Xinhua Wang, Jian He
Immune checkpoint blockades that significantly prolonged survival of melanoma patients have been less effective on colorectal cancer (CRC) patients. Growing evidence suggested that fibroblast activation protein-alpha (FAP) on cancer associate fibroblasts (CAFs) has critical roles in regulating antitumor immune response by inducing tumor-promoting inflammation. In this study, we explored the roles of FAP in regulating the tumor immunity and immune checkpoint blockades resistance in CRC experimental systems. We found that CAFs with high FAP expression could induce immune checkpoint blockade resistance in CRC mouse model...
March 13, 2017: Biochemical and Biophysical Research Communications
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