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https://www.readbyqxmd.com/read/28808226/atr-inhibition-facilitates-targeting-of-leukemia-dependence-on-convergent-nucleotide-biosynthetic-pathways
#1
Thuc M Le, Soumya Poddar, Joseph R Capri, Evan R Abt, Woosuk Kim, Liu Wei, Nhu T Uong, Chloe M Cheng, Daniel Braas, Mina Nikanjam, Peter Rix, Daria Merkurjev, Jesse Zaretsky, Harley I Kornblum, Antoni Ribas, Harvey R Herschman, Julian Whitelegge, Kym F Faull, Timothy R Donahue, Johannes Czernin, Caius G Radu
Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms...
August 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28756137/survival-of-patients-with-advanced-metastatic-melanoma-the-impact-of-novel-therapies-update-2017
#2
REVIEW
Selma Ugurel, Joachim Röhmel, Paolo A Ascierto, Keith T Flaherty, Jean Jacques Grob, Axel Hauschild, James Larkin, Georgina V Long, Paul Lorigan, Grant A McArthur, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Claus Garbe
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma...
July 27, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28738052/collaborative-care-in-melanoma-the-essential-role-of-the-nurse%C3%A2
#3
John M Kirkwood, Antoni Ribas
This article provides perspective from medical oncologists on the importance of this supplement from the Melanoma Nursing Initiative. The authors (a) delineate the challenges inherent in addressing adverse event (AE) management with newer melanoma therapies, particularly in the community setting; (b) illustrate how advanced practice providers with extensive clinical trial experience in melanoma are in a key position to set the agenda and educate colleagues on best practices in AE management; and
August 1, 2017: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/28729151/standard-dose-pembrolizumab-in-combination-with-reduced-dose-ipilimumab-for-patients-with-advanced-melanoma-keynote-029-an-open-label-phase-1b-trial
#4
Georgina V Long, Victoria Atkinson, Jonathan S Cebon, Michael B Jameson, Bernie M Fitzharris, Catriona M McNeil, Andrew G Hill, Antoni Ribas, Michael B Atkins, John A Thompson, Wen-Jen Hwu, F Stephen Hodi, Alexander M Menzies, Alexander D Guminski, Richard Kefford, Benjamin Y Kong, Babak Tamjid, Archana Srivastava, Anna J Lomax, Mohammed Islam, Xinxin Shu, Scot Ebbinghaus, Nageatte Ibrahim, Matteo S Carlino
BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1...
July 17, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28692921/exploring-the-relationship-between-non-suicidal-self-injury-and-borderline-personality-traits-in-young-adults
#5
Daniel Vega, Rafael Torrubia, Àngel Soto, Joan Ribas, Joaquim Soler, Juan Carlos Pascual, Antoni Rodríguez-Fornells, Josep Marco-Pallarés
Non-suicidal self-injury (NSSI) is highly prevalent during late adolescence and young adulthood. There is some evidence of a link between NSSI and Borderline Personality Disorder (BPD), but little is known about the association between BPD traits and the various functions that maintain NSSI. The main purpose of this study was to explore the association between borderline personality traits and NSSI functions in a sample of college students. We also compared NSSI functions in college students who engaged in NSSI to those in an age-matched sample of BPD patients...
July 4, 2017: Psychiatry Research
https://www.readbyqxmd.com/read/28652246/mapk-signaling-and-inflammation-link-melanoma-phenotype-switching-to-induction-of-cd73-during-immunotherapy
#6
Julia Reinhardt, Jennifer Landsberg, Jonathan L Schmid-Burgk, Bartomeu Bibiloni Ramis, Tobias Bald, Nicole Glodde, Dorys Lopez-Ramos, Arabella Young, Shin Foong Ngiow, Daniel Nettersheim, Hubert Schorle, Thomas Quast, Waldemar Kolanus, Dirk Schadendorf, Georgina V Long, Jason Madore, Richard A Scolyer, Antoni Ribas, Mark J Smyth, Paul C Tumeh, Thomas Tüting, Michael Hölzel
Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28650338/ifn-%C3%AE-related-mrna-profile-predicts-clinical-response-to-pd-1-blockade
#7
Mark Ayers, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R Kaufman, Andrew Albright, Jonathan D Cheng, S Peter Kang, Veena Shankaran, Sarina A Piha-Paul, Jennifer Yearley, Tanguy Y Seiwert, Antoni Ribas, Terrill K McClanahan
Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed therapy response has not been rigorously evaluated...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28648698/three-year-pooled-analysis-of-factors-associated-with-clinical-outcomes-across-dabrafenib-and-trametinib-combination-therapy-phase-3-randomised-trials
#8
Dirk Schadendorf, Georgina V Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà, John B A G Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Michael A Davies, Ying Zhang, Mathilde Kaper, Bijoyesh Mookerjee, Jeffrey J Legos, Keith T Flaherty, Caroline Robert
AIM: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit...
June 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28646893/clinical-features-of-serous-retinopathy-observed-with-cobimetinib-in-patients-with-braf-mutated-melanoma-treated-in-the-randomized-cobrim-study
#9
Luis de la Cruz-Merino, Lorenza Di Guardo, Jean-Jacques Grob, Alfredo Venosa, James Larkin, Grant A McArthur, Antoni Ribas, Paolo A Ascierto, Jeffrey T R Evans, Antonio Gomez-Escobar, Giulio Barteselli, Susan Eng, Jessie J Hsu, Anne Uyei, Brigitte Dréno
BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF (V600)-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed...
June 24, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28609660/snapshot-immune-checkpoint-inhibitors
#10
Gabriel Abril-Rodriguez, Antoni Ribas
Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). A better understanding of the molecular mechanisms underlying checkpoint blockade therapies will facilitate the design of novel strategies to treat and prevent resistance. To view this SnapShot, open or download the PDF...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28536307/gene-expression-profiling-in-braf-mutated-melanoma-reveals-patient-subgroups-with-poor-outcomes-to-vemurafenib-that-may-be-overcome-by-cobimetinib-plus-vemurafenib
#11
Matthew J Wongchenko, Grant A McArthur, Brigitte Dréno, James Larkin, Paolo A Ascierto, Jeffrey Sosman, Luc Andries, Mark Kockx, Stephen D Hurst, Ivor Caro, Isabelle Rooney, Priti S Hegde, Luciana Molinero, Huibin Yue, Ilsung Chang, Lukas Amler, Yibing Yan, Antoni Ribas
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF(V600)-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures...
May 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28494868/interferon-receptor-signaling-pathways-regulating-pd-l1-and-pd-l2-expression
#12
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
#13
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...
August 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28298179/preparation-of-peptide-mhc-and-t-cell-receptor-dextramers-by-biotinylated-dextran-doping
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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