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https://www.readbyqxmd.com/read/28494868/interferon-receptor-signaling-pathways-regulating-pd-l1-and-pd-l2-expression
#1
Angel Garcia-Diaz, Daniel Sanghoon Shin, Blanca Homet Moreno, Justin Saco, Helena Escuin-Ordinas, Gabriel Abril Rodriguez, Jesse M Zaretsky, Lu Sun, Willy Hugo, Xiaoyan Wang, Giulia Parisi, Cristina Puig Saus, Davis Y Torrejon, Thomas G Graeber, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Robert Damoiseaux, Roger S Lo, Antoni Ribas
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter...
May 9, 2017: Cell Reports
https://www.readbyqxmd.com/read/28374786/targeted-agents-and-immunotherapies-optimizing-outcomes-in-melanoma
#2
REVIEW
Jason J Luke, Keith T Flaherty, Antoni Ribas, Georgina V Long
Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints...
April 4, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28298179/preparation-of-peptide-mhc-and-t-cell-receptor-dextramers-by-biotinylated-dextran-doping
#3
Michael T Bethune, Begoña Comin-Anduix, Yu-Hsien Hwang Fu, Antoni Ribas, David Baltimore
Peptide-major histocompatibility complex (pMHC) multimers enable the detection, characterization, and isolation of antigen-specific T-cell subsets at the single-cell level via flow cytometry and fluorescence microscopy. These labeling reagents exploit a multivalent scaffold to increase the avidity of individually weak T-cell receptor (TCR)-pMHC interactions. Dextramers are an improvement over the original streptavidin-based tetramer technology because they are more multivalent, improving sensitivity for rare, low-avidity T cells, including self/tumor-reactive clones...
March 1, 2017: BioTechniques
https://www.readbyqxmd.com/read/28247156/orbitofrontal-overactivation-in-reward-processing-in-borderline-personality-disorder-the-role-of-non-suicidal-self-injury
#4
Daniel Vega, Pablo Ripollés, Àngel Soto, Rafael Torrubia, Joan Ribas, Jose Antonio Monreal, Juan Carlos Pascual, Raymond Salvador, Edith Pomarol-Clotet, Antoni Rodríguez-Fornells, Josep Marco-Pallarés
Borderline Personality Disorder (BPD) is a disabling and difficult-to-treat mental disease. One of its core features is a significant difficulty in affect regulation, which is often accompanied by Non-Suicidal Self-Injury (NSSI). It is suggested that this type of behavior elicits positive emotions and mitigates emotional distress, and therefore can ultimately be reinforced and promoted. In spite of the high prevalence of NSSI behaviors (also in non-BPD samples), their role in modulating reward-related processes has not yet been investigated in BPD patients...
February 28, 2017: Brain Imaging and Behavior
https://www.readbyqxmd.com/read/28187290/primary-adaptive-and-acquired-resistance-to-cancer-immunotherapy
#5
REVIEW
Padmanee Sharma, Siwen Hu-Lieskovan, Jennifer A Wargo, Antoni Ribas
Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients...
February 9, 2017: Cell
https://www.readbyqxmd.com/read/28147313/mapk-pathway-inhibition-induces-met-and-gab1-levels-priming-braf-mutant-melanoma-for-rescue-by-hepatocyte-growth-factor
#6
Sean Caenepeel, Keegan Cooke, Sarah Wadsworth, Guo Huang, Lidia Robert, Blanca Homet Moreno, Giulia Parisi, Elaina Cajulis, Richard Kendall, Pedro Beltran, Antoni Ribas, Angela Coxon, Paul E Hughes
Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28129544/genomic-and-transcriptomic-features-of-response-to-anti-pd-1-therapy-in-metastatic-melanoma
#7
Willy Hugo, Jesse M Zaretsky, Lu Sun, Chunying Song, Blanca Homet Moreno, Siwen Hu-Lieskovan, Beata Berent-Maoz, Jia Pang, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Shirley Lomeli, Xiangju Kong, Mark C Kelley, Jeffrey A Sosman, Douglas B Johnson, Antoni Ribas, Roger S Lo
No abstract text is available yet for this article.
January 26, 2017: Cell
https://www.readbyqxmd.com/read/28114250/new-combination-strategies-using-programmed-cell-death-1-programmed-cell-death-ligand-1-checkpoint-inhibitors-as-a-backbone
#8
Siwen Hu-Lieskovan, Antoni Ribas
The discovery of immune checkpoints and subsequent clinical development of checkpoint inhibitors have revolutionized the field of oncology. The durability of the antitumor immune responses has raised the hope for long-term patient survival and potential cure; however, currently, only a minority of patients respond. Combination strategies to help increase antigen release and T-cell priming, promote T-cell activation and homing, and improve the tumor immune microenvironment, all guided by predictive biomarkers, can help overcome the tumor immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of patients...
January 2017: Cancer Journal
https://www.readbyqxmd.com/read/28039162/infiltration-of-cd8-t-cells-and-expression-of-pd-1-and-pd-l1-in-synovial-sarcoma
#9
Theodore S Nowicki, Ryan Akiyama, Rong Rong Huang, I Peter Shintaku, Xiaoyan Wang, Paul C Tumeh, Arun Singh, Bartosz Chmielowski, Christopher Denny, Noah Federman, Antoni Ribas
Tumors expressing programmed death ligand 1 (PD-L1) interact with the corresponding negative-signal generating immune receptor on the surface of CD8 T cells, PD-1, thereby suppressing antitumor activity. Therapeutics blocking this interaction have shown promise in various cancers by restoring functional antitumor T-cell activity. We explored the degree of PD-L1, PD-1, and CD8 expression in a retrospective analysis of 29 clinical synovial sarcoma samples. Quantitative immunohistochemistry and multiplex immunofluorescence were used to determine relative quantification of CD8(+) and PD-1(+) T cells and PD-L1 expression within the intratumor area and the interface between the tumor and the surrounding nontumor tissue (i...
February 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27903604/what-does-pd-l1-positive-or-negative-mean
#10
Antoni Ribas, Siwen Hu-Lieskovan
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response...
December 12, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak1-2-mutations
#11
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung T Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway...
February 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27864013/factors-predictive-of-response-disease-progression-and-overall-survival-after-dabrafenib-and-trametinib-combination-treatment-a-pooled-analysis-of-individual-patient-data-from-randomised-trials
#12
Georgina V Long, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Stephen R Lane, Carmen Mak, Philippe Legenne, Keith T Flaherty, Michael A Davies
BACKGROUND: Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF(V600E)-mutant or BRAF(V600K)-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma...
December 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27863197/programmed-death-ligand-1-expression-and-response-to-the-anti-programmed-death-1-antibody-pembrolizumab-in-melanoma
#13
Adil I Daud, Jedd D Wolchok, Caroline Robert, Wen-Jen Hwu, Jeffrey S Weber, Antoni Ribas, F Stephen Hodi, Anthony M Joshua, Richard Kefford, Peter Hersey, Richard Joseph, Tara C Gangadhar, Roxana Dronca, Amita Patnaik, Hassane Zarour, Charlotte Roach, Grant Toland, Jared K Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S Peter Kang, Scot Ebbinghaus, Omid Hamid
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27650277/a-phase-i-dose-escalation-study-of-tak-733-an-investigational-oral-mek-inhibitor-in-patients-with-advanced-solid-tumors
#14
Alex A Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey A Sosman, Anna Pavlick, Grace K Dy, Xiaofei Zhou, Esha Gangolli, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bózon
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1...
February 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/27648299/jun-dependency-in-distinct-early-and-late-braf-inhibition-adaptation-states-of-melanoma
#15
Bjoern Titz, Anastasia Lomova, Allison Le, Willy Hugo, Xiangju Kong, Johanna Ten Hoeve, Michael Friedman, Hubing Shi, Gatien Moriceau, Chunying Song, Aayoung Hong, Mohammad Atefi, Richard Li, Evangelia Komisopoulou, Antoni Ribas, Roger S Lo, Thomas G Graeber
A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27622011/combined-treatment-with-dabrafenib-and-trametinib-with-immune-stimulating-antibodies-for-braf-mutant-melanoma
#16
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27596353/health-related-quality-of-life-in-the-randomised-keynote-002-study-of-pembrolizumab-versus-chemotherapy-in-patients-with-ipilimumab-refractory-melanoma
#17
Dirk Schadendorf, Reinhard Dummer, Axel Hauschild, Caroline Robert, Omid Hamid, Adil Daud, Alfons van den Eertwegh, Lee Cranmer, Steven O'Day, Igor Puzanov, Jacob Schachter, Christian Blank, April Salama, Carmen Loquai, Janice M Mehnert, Darcy Hille, Scot Ebbinghaus, S Peter Kang, Wei Zhou, Antoni Ribas
BACKGROUND: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument...
November 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27589875/response-to-programmed-cell-death-1-blockade-in-a-murine-melanoma-syngeneic-model-requires-costimulation-cd4-and-cd8-t-cells
#18
Blanca Homet Moreno, Jesse M Zaretsky, Angel Garcia-Diaz, Jennifer Tsoi, Giulia Parisi, Lidia Robert, Katrina Meeth, Abibatou Ndoye, Marcus Bosenberg, Ashani T Weeraratna, Thomas G Graeber, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAF(V600E)-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAF(V600E) mutation and PTEN loss (BRAF(V600E)/PTEN(-/-))...
October 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27537535/cancer-research-in-the-21st-century
#19
James S Economou, Dennis J Slamon, Antoni Ribas, Michael E Phelps
No abstract text is available yet for this article.
October 2016: Annals of Surgery
https://www.readbyqxmd.com/read/27533633/the-efficacy-of-anti-pd-1-agents-in-acral-and-mucosal-melanoma
#20
Alexander N Shoushtari, Rodrigo R Munhoz, Deborah Kuk, Patrick A Ott, Douglas B Johnson, Katy K Tsai, Suthee Rapisuwon, Zeynep Eroglu, Ryan J Sullivan, Jason J Luke, Tara C Gangadhar, April K S Salama, Varina Clark, Clare Burias, Igor Puzanov, Michael B Atkins, Alain P Algazi, Antoni Ribas, Jedd D Wolchok, Michael A Postow
BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials...
November 15, 2016: Cancer
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