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https://www.readbyqxmd.com/read/28922848/aggressive-behavior-in-silent-subtype-iii-pituitary-adenomas-may-depend-on-suppression-of-local-immune-response-a-whole-transcriptome-analysis
#1
Timothy E Richardson, Zhong-Jian Shen, Mohammed Kanchwala, Chao Xing, Alexander Filatenkov, Ping Shang, Samuel Barnett, Zahidur Abedin, James S Malter, Jack M Raisanen, Dennis K Burns, Charles L White, Kimmo J Hatanpaa
Silent subtype III pituitary adenomas (SS-3) are clinically nonfunctional adenomas that are more aggressive in terms of invasion and risk of recurrence than their conventional null cell counterparts. We previously showed that these tumors can be distinguished by immunohistochemistry based on the identification of a markedly enlarged and fragmented Golgi apparatus. To understand the molecular correlates of differential aggressiveness, we performed whole transcriptome sequencing (RNAseq) on 4 SS-3 and 4 conventional null cell adenomas...
October 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28922790/the-balance-between-cytotoxic-t-cell-lymphocytes-and-immune-checkpoint-expression-in-the-prognosis-of-colon-tumors
#2
Laetitia Marisa, Magali Svrcek, Ada Collura, Etienne Becht, Pascale Cervera, Kristell Wanherdrick, Olivier Buhard, Anastasia Goloudina, Vincent Jonchère, Janick Selves, Gerard Milano, Dominique Guenot, Romain Cohen, Chrystelle Colas, Pierre Laurent-Puig, Sylviane Olschwang, Jérémie H Lefèvre, Yann Parc, Valérie Boige, Côme Lepage, Thierry André, Jean-François Fléjou, Valentin Dérangère, François Ghiringhelli, Aurélien de Reynies, Alex Duval
Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI)...
January 1, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28922786/relapse-free-survival-as-a-surrogate-for-overall-survival-in-the-evaluation-of-stage-ii-iii-melanoma-adjuvant-therapy
#3
Stefan Suciu, Alexander M M Eggermont, Paul Lorigan, John M Kirkwood, Svetomir N Markovic, Claus Garbe, David Cameron, Srividya Kotapati, Tai-Tsang Chen, Keith Wheatley, Natalie Ives, Gaetan de Schaetzen, Achmad Efendi, Marc Buyse
Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials. Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included...
January 1, 2018: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#4
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 18, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28921644/clinical-pharmacology-considerations-for-the-development-of-immune-checkpoint-inhibitors
#5
Jennifer Sheng, Shivani Srivastava, Kinjal Sanghavi, Zheng Lu, Brian J Schmidt, Akintunde Bello, Manish Gupta
Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921468/inflammasomes-in-the-gut-mucosal-homeostasis
#6
Xiaomin Yao, Guangxun Meng
Inflammasomes are critical checkpoints in inflammation. The activation of inflammasome can cause a series of inflammatory responses including maturation of interleukin (IL)-1β and IL-18 and a specialized form of cell death called pyroptosis. Since its identification in the early 2000s, inflammasomes have been implicated to play multifaceted roles in varied pathological and physiological conditions, especially in the mucosal compartments including the gut. Maintaining gut mucosal homeostasis has always been a remarkable challenge for the host due to both the vast mucosal surface that is exposed to the outside and the enormous amount of local microbiota...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28921056/oxidative-stress-in-atherosclerosis
#7
REVIEW
Ajoe John Kattoor, Naga Venkata K Pothineni, Deepak Palagiri, Jawahar L Mehta
PURPOSE OF REVIEW: Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury...
September 18, 2017: Current Atherosclerosis Reports
https://www.readbyqxmd.com/read/28920954/p38-mapk-mk2-dependent-phosphorylation-controls-cytotoxic-ripk1-signalling-in-inflammation-and%C3%A2-infection
#8
Manoj B Menon, Julia Gropengießer, Jessica Fischer, Lena Novikova, Anne Deuretzbacher, Juri Lafera, Hanna Schimmeck, Nicole Czymmeck, Natalia Ronkina, Alexey Kotlyarov, Martin Aepfelbacher, Matthias Gaestel, Klaus Ruckdeschel
Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38(MAPK)/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1-dependent apoptosis and necroptosis...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28920952/mk2-phosphorylation-of-ripk1-regulates-tnf-mediated-cell-death
#9
Yves Dondelinger, Tom Delanghe, Diego Rojas-Rivera, Dario Priem, Tinneke Delvaeye, Inge Bruggeman, Franky Van Herreweghe, Peter Vandenabeele, Mathieu J M Bertrand
TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis...
September 18, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28920006/dosing-immunotherapy-combinations-analysis-of-3-526-patients-for-toxicity-and-response-patterns
#10
Mina Nikanjam, Harsh Patel, Razelle Kurzrock
Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28920005/the-frequency-of-neoantigens-per-somatic-mutation-rather-than-overall-mutational-load-or-number-of-predicted-neoantigens-per-se-is-a-prognostic-factor-in-ovarian-clear-cell-carcinoma
#11
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919997/increased-infiltration-and-tolerised-antigen-specific-cd8-tem-cells-in-tumor-but-not-peripheral-blood-have-no-impact-on-survival-of-hcmv-glioblastoma-patients
#12
M Bahador, A Gras Navarro, M A Rahman, M Dominguez-Valentin, S Sarowar, E Ulvestad, G Njølstad, S A Lie, E K Kristoffersen, E Bratland, M Chekenya
Human cytomegalovirus (HCMV) antigens in glioblastoma (GBM) present opportunities for personalised immunotherapy. However, their presence in GBM tissue is still under debate, and evidence of their impact on functional immune responses and prognosis is sparse. Here, we investigated the presence of pp65 (UL83) and immediate early 1 (IE-1) HCMV antigens in a cohort of Norwegian GBM patients (n = 177), using qPCR, immunohistochemistry, and serology. HCMV status was then used to investigate whether viral antigens influenced immune cell phenotype, infiltration, activation and patient survival...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919992/molecular-and-clinical-characterization-of-tim-3-in-glioma-through-1-024-samples
#13
Guanzhang Li, Zheng Wang, Chuanbao Zhang, Xing Liu, Jinquan Cai, Zhiliang Wang, Huimin Hu, Fan Wu, Zhaoshi Bao, Yanwei Liu, Liang Zhao, Tingyu Liang, Fan Yang, Ruoyu Huang, Wei Zhang, Tao Jiang
Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma. Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919987/programmed-death-ligand-1-pd-l1-expression-influences-the-immune-tolerogenic-microenvironment-in-antiretroviral-therapy-refractory-kaposi-s-sarcoma-a-pilot-study
#14
Salvinia Mletzko, David J Pinato, Rebecca C Robey, Alessia Dalla Pria, Peter Benson, Nesrina Imami, Mark Bower
Upregulation of programmed death ligand 1 (PD-L1) is a mechanism of immune escape utilized by a variety of tumors. PD-L1 expression in tumor cells or in the surrounding infiltrate correlates with clinical responsiveness to novel therapies targeting the PD-1/PD-L1 immune checkpoint. In the context of HIV-1 infection, Kaposi's sarcoma (KS) is largely responsive to restoration of immunity following combination antiretroviral therapy (cART), but there is a subset that is not. We hypothesized that this subset of cART-refractory KS may utilize the PD-L1 pathway of immune escape...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919986/immune-biomarkers-for-prognosis-and-prediction-of-responses-to-immune-checkpoint-blockade-in-cutaneous-melanoma
#15
REVIEW
Nicolas Jacquelot, Jonathan M Pitt, David P Enot, Maria Paula Roberti, Connie P M Duong, Sylvie Rusakiewicz, Alexander M Eggermont, Laurence Zitvogel
Existing clinical, anatomopathological and molecular biomarkers fail to reliably predict the prognosis of cutaneous melanoma. Biomarkers for determining which patients receive adjuvant therapies are needed. The emergence of new technologies and the discovery of new immune populations with different prognostic values allow the immune network in the tumor to be better understood. Importantly, new molecules identified and expressed by immune cells have been shown to reduce the antitumor immune efficacy of therapies, prompting researchers to develop antibodies targeting these so-called "immune checkpoints", which have now entered the oncotherapeutic armamentarium...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919706/profile-of-pembrolizumab-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma-design-development-and-place-in-therapy
#16
REVIEW
Sulsal Haque, Mahender Yellu, Jaskirat Randhawa, Nooshin Hashemi-Sadraei
Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide, and despite advances in cytotoxic, surgical and radiation techniques, outcomes are still poor in those with both locally advanced and metastatic diseases. The need for development of better therapeutics along with a greater understanding of the relationship between the immune system and malignancies has led to a new therapeutic modality, immune modulators, particularly checkpoint inhibitors in HNSCC. It is now well recognized that HNSCC circumvents crucial pathways utilized by the immune system to escape surveillance...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28919440/structural-insight-into-blm-recognition-by-topbp1
#17
Luxin Sun, Yuhao Huang, Ross A Edwards, Sukmin Yang, Andrew N Blackford, Wojciech Niedzwiedz, J N Mark Glover
Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5...
September 1, 2017: Structure
https://www.readbyqxmd.com/read/28918995/cutaneous-adverse-events-of-targeted-therapies-for-hematolymphoid-malignancies
#18
REVIEW
Julia D Ransohoff, Bernice Y Kwong
The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies...
July 14, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28918779/-acutely-induced-diabetes-mellitus-in-a-63-year-old-female-after-treatment-with-ipilimumab-for-metastatic-melanoma
#19
Line Bisgaard Jørgensen, Knud Yderstræde
Immune checkpoint inhibitors have improved survival rate in patients with advanced melanoma, but also have the potential to induce several adverse events. We report on a 63-year-old woman who had advanced melanoma and was admitted with diabetic ketoacidosis, which had occurred upon treatment with ipilimumab. On admission, the C-peptide level was low, and the HbA1c concentration was 50 mmol/l indicating a rapid onset of the disease. The patient had also been diagnosed with thyroiditis. Diabetes mellitus is a rare and serious side effect of treatment with ipilimumab, and we recommend being aware of this due to the rapid course...
September 11, 2017: Ugeskrift for Laeger
https://www.readbyqxmd.com/read/28917596/response-rate-to-chemotherapy-after-immune-checkpoint-inhibition-in-metastatic-urothelial-cancer
#20
Bernadett Szabados, Nick van Dijk, Yen Zhi Tang, Michiel van der Heijden, Akhila Wimalasingham, Alfonso Gomez de Liano, Simon Chowdhury, Simon Hughes, Sarah Rudman, Mark Linch, Thomas Powles
Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described (n=28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1...
September 13, 2017: European Urology
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