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https://www.readbyqxmd.com/read/29342325/the-neuromuscular-complications-of-immune-checkpoint-inhibitor-therapy
#1
REVIEW
Noah A Kolb, Christopher R Trevino, Waqar Waheed, Fatemeh Sobhani, Kara K Landry, Alissa A Thomas, Mike Hehir
Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however the unbridling of the immune system may induce a variety of immune related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI related immune diseases...
January 17, 2018: Muscle & Nerve
https://www.readbyqxmd.com/read/29342309/prognostic-power-of-a-tumor-differentiation-gene-signature-for-bladder-urothelial-carcinomas
#2
Qianxing Mo, Fotis Nikolos, Fengju Chen, Zoe Tramel, Yu-Cheng Lee, Kazukuni Hayashi, Jing Xiao, Jianjun Shen, Keith Syson Chan
Background: Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas. Methods: Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome...
January 12, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29342300/metastatic-joint-involvement-or-inflammatory-arthritis-a-conundrum-with-immune-checkpoint-inhibitor-related-adverse-events
#3
Jemima Albayda, Clifton O Bingham, Ami A Shah, Ronan J Kelly, Laura Cappelli
No abstract text is available yet for this article.
January 12, 2018: Rheumatology
https://www.readbyqxmd.com/read/29342242/meiotic-spindle-formation-in-mammalian-oocytes-implications-for-human-infertility
#4
Suk Namgoong, Nam-Hyung Kim
In the final stage of oogenesis, mammalian oocytes generate a meiotic spindle and undergo chromosome segregation to yield an egg that is ready for fertilization. Herein, we describe the recent advances in understanding the mechanisms controlling formation of the meiotic spindle in metaphase I (MI) and metaphase II (MII) in mammalian oocytes, and focus on the differences between mouse and human oocytes. Unlike mitotic cells, mammalian oocytes lack typical centrosomes that consist of two centrioles and the surrounding pericentriolar matrix proteins (PCM), which serve as microtubule-organizing centers (MTOCs) in most somatic cells...
January 12, 2018: Biology of Reproduction
https://www.readbyqxmd.com/read/29341936/rheumatic-manifestations-among-cancer-patients-treated-with-immune-checkpoint-inhibitors
#5
REVIEW
Merav Lidar, Eitan Giat, Daniela Garelick, Yuval Horowitz, Howard Amital, Yael Steinberg-Silman, Jacob Shachter, Ronnie Shapira-Frommer, Gal Markel
BACKGROUND: The use of immune checkpoint inhibitors (ICI) has grown incessantly since they were first approved in 2014. These monoclonal antibodies inhibit T cell activation, yielding a dramatic tumor response with improved survival. However, immunotherapy is frequently hampered by immune adverse events (iAE) such as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently, rheumatic side effects were only infrequently reported. Aim To describe the rheumatic manifestations encountered among patients treated with ICIs in a large tertiary cancer center in Israel METHODS: The cancer center's patient registry was screened for patients who had ever been treated with ipilimumab, pembrolizumab and/or nivolumab with relevant data gathered from clinical charts...
January 13, 2018: Autoimmunity Reviews
https://www.readbyqxmd.com/read/29340837/exacerbation-of-autoimmune-hemolytic-anemia-induced-by-the-first-dose-of-programmed-death-1-inhibitor-pembrolizumab-a-case-report
#6
Kenta Ogawa, Jiro Ito, Daichi Fujimoto, Mari Morita, Yuko Yoshizumi, Koichi Ariyoshi, Keisuke Tomii, Nobuyuki Katakami
Immune checkpoint inhibitors (ICIs) have demonstrated efficacy against various types of cancers. In addition to immune-related adverse events (irAEs) induced by ICIs, exacerbation of baseline autoimmune disease has been occasionally reported. This is the first report of autoimmune hemolytic anemia (AIHA) exacerbated by pembrolizumab. An 82-year-old Japanese male was diagnosed with lung adenocarcinoma 2 years ago. The patient had chronic anemia with positive direct and indirect Coombs test prior to initiating pembrolizumab therapy at a nearby hospital...
January 16, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29340115/hypermutation-and-microsatellite-instability-in-gastrointestinal-cancers
#7
REVIEW
Kizuki Yuza, Masayuki Nagahashi, Satoshi Watanabe, Kazuaki Takabe, Toshifumi Wakai
Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29340034/prexasertib-a-cell-cycle-checkpoint-kinases-1-and-2-inhibitor-increases-in-vitro-toxicity-of-parp-inhibition-by-preventing-rad51-foci-formation-in-brca-wild-type-high-grade-serous-ovarian-cancer
#8
Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn, Jung-Min Lee
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339767/regulatory-t-cells-trigger-effector-t-cell-dna-damage-and-senescence-caused-by-metabolic-competition
#9
Xia Liu, Wei Mo, Jian Ye, Lingyun Li, Yanping Zhang, Eddy C Hsueh, Daniel F Hoft, Guangyong Peng
Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29339738/dna-methyltransferase-inhibition-upregulates-mhc-i-to-potentiate-cytotoxic-t-lymphocyte-responses-in-breast-cancer
#10
Na Luo, Mellissa J Nixon, Paula I Gonzalez-Ericsson, Violeta Sanchez, Susan R Opalenik, Huili Li, Cynthia A Zahnow, Michael L Nickels, Fei Liu, Mohammed N Tantawy, Melinda E Sanders, H Charles Manning, Justin M Balko
Potentiating anti-tumor immunity by inducing tumor inflammation and T cell-mediated responses are a promising area of cancer therapy. Immunomodulatory agents that promote these effects function via a wide variety of mechanisms, including upregulation of antigen presentation pathways. Here, we show that major histocompatibility class-I (MHC-I) genes are methylated in human breast cancers, suppressing their expression. Treatment of breast cancer cell lines with a next-generation hypomethylating agent, guadecitabine, upregulates MHC-I expression in response to interferon-γ...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29339539/the-hippo-pathway-component-taz-promotes-immune-evasion-in-human-cancer-through-pd-l1
#11
Helena J Janse van Rensburg, Taha Azad, Min Ling, Yawei Hao, Brooke Snetsinger, Prem Khanal, Lori M Minassian, Charles H Graham, Michael J Rauh, Xiaolong Yang
The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional co-activator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumour microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2) and large tumour suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines...
January 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29339440/repurposing-tin-mesoporphyrin-as-an-immune-checkpoint-inhibitor-shows-therapeutic-efficacy-in-preclinical-models-of-cancer
#12
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339410/maintenance-of-genome-integrity%C3%A2-by-mi2-homologs-chd-3-and-let-418-in%C3%A2-caenorhabditis-elegans
#13
Carolyn A Turcotte, Solomon A Sloat, Julia A Rigothi, Erika Rosenkranse, Alexandra L Northrup, Nicolas P Andrews, Paula M Checchi
Meiotic recombination depends upon the tightly coordinated regulation of chromosome dynamics and is essential for the production of haploid gametes. Central to this process is the formation and repair of meiotic double-stranded breaks (DSBs), which must take place within the constraints of a specialized chromatin architecture. Here, we demonstrate a role for the nucleosome remodeling and deacetylase (NuRD) complex in orchestrating meiotic chromosome dynamics in Caenorhabditis elegans. Our data reveal that the conserved Mi2 homologs Chromodomain helicase DNA binding protein (CHD-3) and its paralog LET-418 facilitate meiotic progression by ensuring faithful repair of DSBs through homologous recombination...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29339377/robust-antitumor-responses-result-from-local-chemotherapy-and-ctla-4-blockade
#14
Charlotte E Ariyan, Mary Sue Brady, Robert H Siegelbaum, Jian Hu, Danielle M Bello, Jamie Green, Charles Fisher, Robert A Lefkowitz, Katherine S Panageas, Melissa Pulitzer, Marissa Vignali, Ryan Emerson, Christopher Tipton, Harlan Robins, Taha Merghoub, Jianda Yuan, Achim Jungbluth, Jorge Blando, Padmanee Sharma, Alexander Y Rudensky, Jedd D Wolchok, James P Allison
Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a non-inflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29339375/tusc2-immunogene-synergizes-with-anti-pd1-through-enhanced-proliferation-and-infiltration-of-natural-killer-cells-in-syngeneic-kras-mutant-mouse-lung-cancer-models
#15
Ismail M Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veerabhadran Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji, Jack A Roth
Expression of the multikinase inhibitor encoded by tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29339209/extratumoral-pd-1-blockade-does-not-perpetuate-obesity-associated-inflammation-in-esophageal-adenocarcinoma
#16
Karen C Galvin, Melissa J Conroy, Suzanne L Doyle, Margaret R Dunne, Ronan Fahey, Emma Foley, Katie E O'Sullivan, Derek G Doherty, Justin G Geoghegan, Narayanasamy Ravi, Cliona O'Farrelly, John V Reynolds, Joanne Lysaght
Checkpoint inhibitors, such as anti-PD-1 (Programmed death-1), are transforming cancer treatment for inoperable or advanced disease. As the incidence of obesity-associated malignancies, including esophageal adenocarcinoma (EAC) continue to increase and treatment with checkpoint inhibitors are being FDA approved for a broader range of cancers, it is important to assess how anti-PD-1 treatment might exacerbate pre-existing inflammatory processes at other sites. Outside the EAC tumor, the omentum and liver were found to be enriched with substantial populations of PD-1 expressing T cells...
January 12, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29339161/a-new-genetically-engineered-mouse-model-of-choroid-plexus-carcinoma
#17
Salsabiel El Nagar, Frederique Zindy, Charlotte Moens, Luc Martin, Damien Plassard, Martine F Roussel, Thomas Lamonerie, Nathalie Billon
Choroid plexus carcinomas (CPCs) are highly malignant brain tumours predominantly found in children and associated to poor prognosis. Improved therapy for these cancers would benefit from the generation of animal models. Here we have created a novel mouse CPC model by expressing a stabilised form of c-Myc (MycT58A) and inactivating Trp53 in the choroid plexus of newborn mice. This induced aberrant proliferation of choroid plexus epithelial cells, leading to aggressive tumour development and death within 150 days...
January 12, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29339141/-immunotherapy-in-renal-cell-carcinoma-a-booming-clinical-research
#18
N Baize, P Bigot
CONTEXT: Nivolumab, an anti-PD1 immune control point inhibitor, is the first treatment that has improved the overall survival of patients after first-line metastatic renal cell carcinoma in 2015. Over the past two years, a large number of trials on these treatments and the interest of associations are being evaluated. OBJECTIVE: In this article, we propose to summarize the clinical development of checkpoint inhibitors to assess the direction of clinical research in this area...
January 12, 2018: Progrès en Urologie
https://www.readbyqxmd.com/read/29338610/cns-side-effects-of-immune-checkpoint-inhibitors-preclinical-models-genetics-and-multimodality-therapy
#19
Gwendolyn J McGinnis, Jacob Raber
Following cancer treatment, patients often report behavioral and cognitive changes. Novel cancer immunotherapeutics have the potential to produce sustained cancer survivorship, meaning patients will live longer with the side effects of treatment. Given the role of inflammatory pathways in mediating behavioral and cognitive impairments seen in cancer, we aim in this review to discuss emerging evidence for the contribution of immune checkpoint blockade to exacerbate these CNS effects. We discuss ongoing studies regarding the ability of immune checkpoint inhibitors to reach the brain and how treatment responses to checkpoint inhibitors may be modulated by genetic factors...
September 2017: Immunotherapy
https://www.readbyqxmd.com/read/29338609/chemotherapy-induced-immunomodulation-in-non-small-cell-lung-cancer-a-rationale-for-combination-chemoimmunotherapy
#20
Hua Zheng, Masha Zeltsman, Marjorie G Zauderer, Takashi Eguchi, Raj G Vaghjiani, Prasad S Adusumilli
Spurred by the survival benefits seen with the use of checkpoint blockade in non-small-cell lung cancer (NSCLC), there has been a growing interest in the potential applications of immunotherapy. Despite this, the objective response rate for single-agent immunotherapy remains ≤20% in patients with advanced NSCLC. A combinatorial approach that utilizes both chemotherapy and immunotherapy is a potential strategy to increase antitumor efficacy. Accumulating evidence has shown that the immunomodulatory effects of chemotherapeutic agents can be exploited in a combinational approach...
September 2017: Immunotherapy
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