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https://www.readbyqxmd.com/read/27925177/t-cell-diversification-reflects-antigen-selection-in-the-blood-of-patients-on-immune-checkpoint-inhibition-and-may-be-exploited-as-liquid-biopsy-biomarker
#1
Nuray Akyüz, Anna Brandt, Alexander Stein, Simon Schliffke, Thorben Mährle, Julia Quidde, Eray Goekkurt, Sonja Loges, Thomas Haalck, Christopher Ford, Anne Marie Asemissen, Benjamin Thiele, Janina Radloff, Toni Thenhausen, Artus Krohn-Grimberghe, Carsten Bokemeyer, Mascha Binder
Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next-generation T- and B-cell immunosequencing (TCRß/IGH)...
December 7, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27924752/predictive-biomarkers-for-checkpoint-inhibitor-based-immunotherapy
#2
REVIEW
Geoffrey T Gibney, Louis M Weiner, Michael B Atkins
The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Durable responses can be seen in patients with melanoma and other malignancies. Although monotherapy with PD-1 or PD-L1 agents are typically well tolerated, the risk of immune-related adverse events increases with combination regimens. The development of predictive biomarkers is needed to optimise patient benefit, minimise risk of toxicities, and guide combination approaches. The greatest focus has been on tumour-cell PD-L1 expression...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27924751/neurological-sequelae-of-cancer-immunotherapies-and-targeted-therapies
#3
REVIEW
Wolfgang Wick, Anne Hertenstein, Michael Platten
Neurological complications of cancer and of anticancer treatments can be substantially disabling to patients, especially with classic chemotherapies. As a rare but important complication, targeted therapies might also result in similar unwanted effects, partly because inhibition of VEGF is a common downstream effect. Therapeutic antibodies, such as the CD20-depleting antibody rituximab, and underlying haematological malignancies, can induce long-lasting cellular immunosuppression, predisposing patients to opportunistic CNS infections, such as progressive multifocal leukoencephalopathy, where treatment-induced recovery can result in severe reconstitution of immune inflammatory syndromes of the central nervous system...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27923825/rational-selection-of-syngeneic-preclinical-tumor-models-for-immunotherapeutic-drug-discovery
#4
Suzanne I S Mosely, John E Prime, Richard C A Sainson, Jens-Oliver Koopmann, Dennis Y Q Wang, Danielle M Greenawalt, Miika J Ahdesmaki, Rebecca Leyland, Stefanie Mullins, Luciano Pacelli, Danielle Marcus, Judith Anderton, Amanda Watkins, Jane Coates Ulrichsen, Philip Brohawn, Brandon W Higgs, Matthew McCourt, Hazel Jones, James A Harper, Michelle Morrow, Viia Valge-Archer, Ross Stewart, Simon J Dovedi, Robert W Wilkinson
Murine syngeneic tumor models are critical to novel immuno-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We employed array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles...
December 6, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27923550/treatment-design-and-rationale-for-a-randomized-trial-of-cisplatin-and-etoposide-plus-thoracic-radiotherapy-followed-by-nivolumab-or-placebo-for-locally-advanced-non-small-cell-lung-cancer-rtog-3505
#5
David E Gerber, James J Urbanic, Corey Langer, Chen Hu, I-Fen Chang, Bo Lu, Benjamin Movsas, Robert Jeraj, Walter J Curran, Jeffrey D Bradley
Radiation Therapy Oncology Group (RTOG) 3505 is a randomized phase 3 study of concurrent chemoradiation followed by immune checkpoint inhibitor therapy or placebo in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with surgically unresectable stage 3 NSCLC will receive thoracic radiotherapy to 60 Gy with concurrent cisplatin 50 mg/m(2) intravenously (I.V.) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) I.V. on days 1 to 5 and days 29 to 33. Between 4 and 12 weeks after completion of concurrent chemoradiation, eligible patients will be randomized to the anti-programmed death 1 (PD-1) monoclonal antibody nivolumab 240 mg I...
October 26, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/27923055/a-novel-rrm3-function-in-restricting-dna-replication-via-an-orc5-binding-domain-is-genetically-separable-from-rrm3-function-as-an-atpase-helicase-in-facilitating-fork-progression
#6
Salahuddin Syed, Claus Desler, Lene J Rasmussen, Kristina H Schmidt
In response to replication stress cells activate the intra-S checkpoint, induce DNA repair pathways, increase nucleotide levels, and inhibit origin firing. Here, we report that Rrm3 associates with a subset of replication origins and controls DNA synthesis during replication stress. The N-terminal domain required for control of DNA synthesis maps to residues 186-212 that are also critical for binding Orc5 of the origin recognition complex. Deletion of this domain is lethal to cells lacking the replication checkpoint mediator Mrc1 and leads to mutations upon exposure to the replication stressor hydroxyurea...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27923043/clonal-evolutionary-analysis-during-her2-blockade-in-her2-positive-inflammatory-breast-cancer-a-phase-ii-open-label-clinical-trial-of-afatinib-vinorelbine
#7
Gerald Goh, Ramona Schmid, Kelly Guiver, Wichit Arpornwirat, Imjai Chitapanarux, Vinod Ganju, Seock-Ah Im, Sung-Bae Kim, Arunee Dechaphunkul, Jedzada Maneechavakajorn, Neil Spector, Thomas Yau, Mehdi Afrit, Slim Ben Ahmed, Stephen R Johnston, Neil Gibson, Martina Uttenreuther-Fischer, Javier Herrero, Charles Swanton
BACKGROUND: Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27922818/age-related-changes-in-the-gene-expression-profile-of-antigen-specific-mouse-cd8-t-cells-can-be-partially-reversed-by-blockade-of-the-btla-cd160-pathways-during-vaccination
#8
Noor Dawany, Elizabeth M Parzych, Louise C Showe, Hildegund Cj Ertl
We analyzed gene expression profiles of young and aged mouse CD8(+) T cells specific for the nucleoprotein (NP) of influenza A/PR8/34 virus. CD8(+) T cells were stimulated either by the NP antigen expressed in its native form or fused into the herpes virus (HSV)-1 glycoprotein D (gD) protein, which blocks signaling through the immunoinhibitory B and T lymphocyte attenuator (BTLA) and CD160 pathways. We show that NP-specific CD8(+) T cells from aged mice exhibit numerous differences in gene expression compared to NP-specific CD8(+) T cells from young mice, including a significant reduction of expression in genes involved in T cell receptor (TcR) and CD28 signaling...
November 9, 2016: Aging
https://www.readbyqxmd.com/read/27922816/the-progeroid-gene-bubr1-regulates-axon-myelination-and-motor-function
#9
Chan-Il Choi, Ki Hyun Yoo, Syed Mohammed Qasim Hussaini, Byeong Tak Jeon, John Welby, Haiyun Gan, Isobel A Scarisbrick, Zhiguo Zhang, Darren J Baker, Jan M van Deursen, Moses Rodriguez, Mi-Hyeon Jang
Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant...
September 12, 2016: Aging
https://www.readbyqxmd.com/read/27922697/regulation-of-pd-l1-expression-in-a-high-grade-invasive-human-oral-squamous-cell-carcinoma-microenvironment
#10
Mariko Hirai, Hiroko Kitahara, Yutaka Kobayashi, Koroku Kato, George Bou-Gharios, Hiroyuki Nakamura, Shuichi Kawashiri
Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients...
December 2, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27922280/ganetespib-for-small-cell-lung-cancer
#11
Deepa S Subramaniam, Eiran A Warner, Giuseppe Giaccone
Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC)...
December 6, 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27921007/long-term-response-to-nivolumab-and-acute-renal-failure-in-a-patient-with-metastatic-papillary-renal-cell-carcinoma-and-a-pd-l1-tumor-expression-increased-with-sunitinib-therapy-a-case-report
#12
Juan Ruiz-Bañobre, Urbano Anido, Ihab Abdulkader, José Antúnez-López, Rafael López-López, Jorge García-González
INTRODUCTION: Papillary renal cell carcinoma (PRCC), which represents around 20% of renal cell carcinomas, is a heterogeneous disease that includes different tumor types with several clinical and molecular phenotypes. Nivolumab, a fully human IgG4 programed cell death protein 1 immune checkpoint inhibitor antibody, has shown not only an overall survival advantage when compared to everolimus but also a relatively good side-effect profile among patients with previously treated advanced or metastatic renal cell carcinoma...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27920706/ipilimumab-induced-enteritis-without-colitis-a-new-challenge
#13
Marcus Messmer, Sunita Upreti, Yaman Tarabishy, Nikhilesh Mazumder, Reezwana Chowdhury, Mark Yarchoan, Matthias Holdhoff
INTRODUCTION: Ipilimumab is an immune checkpoint inhibitor targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA4), approved to treat metastatic melanoma. It was the first therapy shown to prolong survival in a large, randomized clinical trial. However, immune-related adverse events are common and can be severe. Enterocolitis is a common adverse event with ipilimumab, but enteritis without colitis has not been previously described. CASE REPORT: An 83-year-old man presented to our hospital with grade 3 diarrhea for 5 days...
September 2016: Case Reports in Oncology
https://www.readbyqxmd.com/read/27920704/autoimmune-hemolytic-anemia-as-a-complication-of-nivolumab-therapy
#14
Amruth R Palla, Devin Kennedy, Hossain Mosharraf, Donald Doll
Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al...
September 2016: Case Reports in Oncology
https://www.readbyqxmd.com/read/27920468/immune-checkpoint-therapy-for-pancreatic-cancer
#15
REVIEW
Henrik Johansson, Roland Andersson, Monika Bauden, Sarah Hammes, Stefan Holdenrieder, Daniel Ansari
Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy...
November 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27919707/autoimmune-cardiotoxicity-of-cancer-immunotherapy
#16
Feixiong Cheng, Joseph Loscalzo
Contemporary immunotherapies (e.g., immune checkpoint inhibitors), which enhance the immune response to cancer cells, improve clinical outcomes in several malignancies. A recent study reported the cases of two patients with metastatic melanoma who developed fatal myocarditis during ipilimumab and nivolumab combination immunotherapy; these examples highlight the risk of unbridled activation of the immune system.
December 2, 2016: Trends in Immunology
https://www.readbyqxmd.com/read/27919216/topoisomerase-ii-inhibitors-and-poisons-and-the-influence-of-cell-cycle-checkpoints
#17
Nicholas D Arcy, Brian Gabrielli
Interactions between the decatenation checkpoint and Topoisomerase II (TopoII) are vital for maintaining integrity of the genome. Agents that target this enzyme have been in clinical use in cancer therapy for over 30 years with great success. The types of compounds that have been developed to target TopoII are broadly divided into poisons and catalytic inhibitors. The TopoII poisons are in clinical use as anti-cancer therapies, although in common to most chemotherapeutic agents, they display considerable normal tissue toxicity...
December 5, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27918464/checkpoints-to-the-brain-directing-myeloid-cell-migration-to-the-central-nervous-system
#18
REVIEW
Meredith Harrison-Brown, Guo-Jun Liu, Richard Banati
Myeloid cells are a unique subset of leukocytes with a diverse array of functions within the central nervous system during health and disease. Advances in understanding of the unique properties of these cells have inspired interest in their use as delivery vehicles for therapeutic genes, proteins, and drugs, or as "assistants" in the clean-up of aggregated proteins and other molecules when existing drainage systems are no longer adequate. The trafficking of myeloid cells from the periphery to the central nervous system is subject to complex cellular and molecular controls with several 'checkpoints' from the blood to their destination in the brain parenchyma...
December 2, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27917363/future-therapy-for-hepatitis-b-virus-role-of-immunomodulators
#19
REVIEW
Edward A Pham, Ryan B Perumpail, Benjamin J Fram, Jeffrey S Glenn, Aijaz Ahmed, Robert G Gish
Although currently available therapies for chronic hepatitis B virus infection can suppress viremia and provide long-term benefits for patients, they do not lead to a functional cure for most patients. Advances in our understanding of the virus-host interaction and the recent remarkable success of immunotherapy in cancer offer new and promising strategies for developing immune modulators that may become important components of a total therapeutic approach to hepatitis B, some of which are now in clinical development...
2016: Current Hepatology Reports
https://www.readbyqxmd.com/read/27916276/a-surveillance-mechanism-ensures-repair-of-dna-lesions-during-zygotic-reprogramming
#20
Sabrina Ladstätter, Kikuë Tachibana-Konwalski
Sexual reproduction culminates in a totipotent zygote with the potential to produce a whole organism. Sperm chromatin reorganization and epigenetic reprogramming that alter DNA and histone modifications generate a totipotent embryo. Active DNA demethylation of the paternal genome has been proposed to involve base excision and DNA repair-based mechanisms. The nature and consequence of DNA lesions generated during reprogramming are not known. Using mouse genetics and chemical biology, we discovered that Tet3-dependent zygotic reprogramming generates paternal DNA lesions that are monitored by a surveillance mechanism...
November 21, 2016: Cell
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