tbuckley/cabot-search huggingface dataset:
Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma
Authors: Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D. Wolchok, Anthony M. Joshua, Wen-Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Richard W. Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, Jin Zhang, James Anderson, Scott J. Diede, Scot Ebbinghaus, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2017)

Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
The CARMA3–Bcl10–MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor–Positive Breast Cancer
Authors: Prasanna Ekambaram, Jia-Ying (Lloyd) Lee, Nathaniel E. Hubel, Dong Hu, Saigopalakrishna Yerneni, Phil G. Campbell, Netanya Pollock, Linda R. Klei, Vincent J. Concel, Phillip C. Delekta, Arul M. Chinnaiyan, Scott A. Tomlins, Daniel R. Rhodes, Nolan Priedigkeit, Adrian V. Lee, Steffi Oesterreich, Linda M. McAllister-Lucas, Peter C. Lucas
Journal: Cancer Research (2017)

Abstract The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell–intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell–extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II–dependent NFκB signaling pathways to improve the treatment of this breast cancer subset. Significance: These findings offer a mechanistic rationale to explore the repurposing of drugs that target angiotensin action to improve the treatment of AGTR1-expressing breast cancers. Cancer Res; 78(5); 1225–40. ©2017 AACR.
A standardised method for interpreting the association between mutations and phenotypic drug resistance in<i>Mycobacterium tuberculosis</i>
Authors: Paolo Miotto, Belay Tessema, Elisa Tagliani, Leonid Chindelevitch, Angela M. Starks, Claudia Emerson, Debra Hanna, Peter S. Kim, Richard Liwski, Matteo Zignol, Christopher Gilpin, Stefan Niemann, Claudia M. Denkinger, Joy Fleming, Robin M. Warren, Derrick Crook, James Posey, Sebastien Gagneux, Sven Hoffner, Camilla Rodrigues, Iñaki Comas, David M. Engelthaler, Megan Murray, David Alland, Leen Rigouts, Christoph Lange, Keertan Dheda, Rumina Hasan, Uma Devi K. Ranganathan, Ruth McNerney, Matthew Ezewudo, Daniela M. Cirillo, Marco Schito, Claudio U. Köser, Timothy C. Rodwell
Journal: European Respiratory Journal (2017)

A clear understanding of the genetic basis of antibiotic resistance in Mycobacterium tuberculosis is required to accelerate the development of rapid drug susceptibility testing methods based on genetic sequence. Raw genotype–phenotype correlation data were extracted as part of a comprehensive systematic review to develop a standardised analytical approach for interpreting resistance associated mutations for rifampicin, isoniazid, ofloxacin/levofloxacin, moxifloxacin, amikacin, kanamycin, capreomycin, streptomycin, ethionamide/prothionamide and pyrazinamide. Mutation frequencies in resistant and susceptible isolates were calculated, together with novel statistical measures to classify mutations as high, moderate, minimal or indeterminate confidence for predicting resistance. We identified 286 confidence-graded mutations associated with resistance. Compared to phenotypic methods, sensitivity (95% CI) for rifampicin was 90.3% (89.6–90.9%), while for isoniazid it was 78.2% (77.4–79.0%) and their specificities were 96.3% (95.7–96.8%) and 94.4% (93.1–95.5%), respectively. For second-line drugs, sensitivity varied from 67.4% (64.1–70.6%) for capreomycin to 88.2% (85.1–90.9%) for moxifloxacin, with specificity ranging from 90.0% (87.1–92.5%) for moxifloxacin to 99.5% (99.0–99.8%) for amikacin. This study provides a standardised and comprehensive approach for the interpretation of mutations as predictors of M. tuberculosis drug-resistant phenotypes. These data have implications for the clinical interpretation of molecular diagnostics and next-generation sequencing as well as efficient individualised therapy for patients with drug-resistant tuberculosis.
Abstract 13493: Complete Disruption of All Nitric Oxide Synthase Genes Markedly Reduces Cerebral Infarct Size after Middle Cerebral Artery Occlusion in Mice
Authors: Masato Tsutsui, Haruaki Kubota, Katsuhiko Noguchi, Toshihiro Matsuzaki, Fumiya Hattori, Mayuko Sakanashi, Mika Kina-Tanada, Taro Uchida, Junko Nakasone, Hiroaki Shimokawa, Yusuke Ohya, Kazuhiro Sugahara, Manabu Kakinohana
Journal: Circulation (2014)

Background: The role of each nitric oxide synthase (NOS) isoform in the pathogenesis of cerebral infarction has been studied in individual NOS isoform-deficient mice. It has been reported that, in a model of middle cerebral artery occlusion (MCAO), neuronal and inducible NOSs exacerbate cerebral infarction, whereas endothelial NOS conversely alleviates cerebral infarction. Although the role of the whole NOSs system in cerebral infarction has been examined in pharmacological studies with non-selective NOS inhibitors, the results are quit inconsistent, possibly because of non-specificity of the agents. In this study, we addressed this point in mice in which all three NOS genes are completely disrupted. Method and Results: We newly generated triple NOSs-deficient mice and wild-type littermates by crossbreeding single NOS -/- mice. Transient (1 hour) and permanent MCAO was performed in male triple NOSs -/- and wild-type mice at 8-12 weeks of age (n=9-11). Cerebral infarct size was evaluated by triphenyltetrazolium chloride (TTC) staining. There was no anatomical difference in the structure of cerebral arteries between the triple NOSs -/- and wild-type mice (n=3 each). Reductions in cerebral blood flow during MCAO were identical between the two mice. However, cerebral infarct size at 24 hours after transient MCAO was markedly smaller in the triple NOSs -/- than in the wild-type mice ( P &lt;0.05, n=8-12). Cerebral infarct size at 24 hours after permanent MCAO was also markedly decreased in the triple NOSs -/- mice as compared with the wild-type mice ( P &lt;0.05, n=8-10). In addition, neurological deficit was significantly less and the survival rate was significantly better in the triple NOSs -/- mice compared with the wild-type mice (both P &lt;0.05, n=8-12). Conclusions: These results provide the first evidence that complete disruption of all NOS genes markedly reduces cerebral infarct size after MCAO in mice, demonstrating a novel injurious role of the entire NOSs system in cerebral infarction. Inhibition of the NOSs system may be a novel therapeutic option in the treatment of cerebral infarction.
Leukotriene B4-Mediated Neutrophil Recruitment Causes Pulmonary Capillaritis during Lethal Fungal Sepsis
Authors: Esther K.S. Lee, Mark R. Gillrie, Lu Li, Jason W. Arnason, Jung Hwan Kim, Liane Babes, Yuefei Lou, Amir Sanati-Nezhad, Stephen K. Kyei, Margaret M. Kelly, Christopher H. Mody, May Ho, Bryan G. Yipp
Journal: Cell Host & Microbe (2017)
Reported Incidence and Survival of Fallopian Tube Carcinomas: A Population-Based Analysis From the North American Association of Central Cancer Registries
Authors: Britton Trabert, Sally B Coburn, Andrea Mariani, Hannah P Yang, Philip S Rosenberg, Gretchen L Gierach, Nicolas Wentzensen, Kathy A Cronin, Mark E Sherman
Journal: JNCI Journal of the National Cancer Institute (2017)

Recognition that serous tubal intraepithelial carcinoma (STIC) may represent the first manifestation of many high-grade cancers that were once considered ovarian primary tumors has led to changes in diagnostic practices that could dramatically increase the reporting of tubal carcinomas in US population-based cancer registries. Further, increased detection of early-stage tubal carcinomas through increased recognition coupled with meticulous pathology processing protocols raises important unanswered questions about the clinical behavior of such lesions, which can only be answered using large data sets. However, rates of tubal carcinomas have not been recently analyzed. Accordingly, we analyzed population-based incidence and survival data for fallopian tube carcinoma in situ (CIS; an imperfect surrogate of STIC), tubal carcinomas, and for comparison, ovarian carcinomas, in the North American Association of Central Cancer Registries (NAACCR) registries.Total counts, standardized incidence rates, and stage-specific survival were computed using 30 NAACCR registries (1999-2012). Temporal incidence rate patterns were analyzed by joinpoint regression with estimates of annual percentage change (APC). All statistical tests were two-sided.Fallopian tube CIS incidence rates were stable from 1999 to 2002, then increased from 2002 to 2012 (APC = 16.2%, 95% confidence interval [CI] = 10.9% to 21.7%, P < .001). Rates of early- and late-stage tubal carcinomas showed similar patterns, whereas high-grade serous ovarian carcinoma rates were relatively stable. Five-year cause-specific survival was 97.9% (95% CI = 93.7% to 99.3%) for tubal CIS and 83.2% (95% CI = 77.3% to 87.7%) for early-stage high-grade serous tubal carcinoma.Reporting of tubal CIS and tubal carcinoma have increased in recent years, likely reflecting changes in pathology processing of specimens and diagnosis. Developing standardized reporting for tubal neoplasms is needed to enable analysis of outcomes for these comparatively uncommon but increasingly recognized tumors.
Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer
Authors: Douglass W. Tucker, Christopher R. Getchell, Eric T. McCarthy, Anders W. Ohman, Naoko Sasamoto, Shuyun Xu, Joo Yeon Ko, Mamta Gupta, Amy Shafrir, Jamie E. Medina, Jonathan J. Lee, Lauren A. MacDonald, Ammara Malik, Kathleen T Hasselblatt, Wenjing Li, Hong Zhang, Samuel J. Kaplan, George F. Murphy, Michelle S. Hirsch, Joyce F. Liu, Ursula A. Matulonis, Kathryn L. Terry, Christine G. Lian, Daniela M. Dinulescu
Journal: Clinical Cancer Research (2017)

Abstract Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389–401. ©2017 AACR.
SCH 727965, a novel cyclin-dependent kinase inhibitor, has potent anti-tumor acitivity in a wide-spectrum of human tumor xenograft models
Authors: Yaolin Wang, Xiaoying Wang, Lipari Philip, Bo Yaremko, Ming Liu, Lingling Wu, Martin Oft, Satya Medicherla, David Parry, Emma Lees, Dan Hicklin, Paul Kirschmeier
Journal: Cancer Research (2008)

1594  The cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that play a critical role in regulation of the eukaryotic cell cycle. A hallmark of human tumors is their rapid progression through the cell cycle comparing to normal tissues. Inhibition of CDK1/CDK2 in tumors is predicted to provoke cell cycle arrest and apoptosis. Hence, inhibition CDK2 and CDK1 represents an attractive therapeutic strategy for human cancers. SCH 727965 is a potent inhibitor of CDK1, CDK2 and CDK9 activities in vitro with IC50 of 1-4 nM with cell-based IC50 at 10-20 nM. SCH 727965 has been shown to be effective as a single agent against a wide-spectrum of human tumor xenograft models including lung, prostate, breast, ovarian and multiple myeloma, with tumor growth inhibition from 12% to 150% (regression) at 5 mpk and 20 mpk once a dose schedule. Treatment with SCH 727965 in vivo results in decreased Rb phosphorylation accompanied by reduction of proliferation marker Ki-67. In addition, we have demonstrated that combination of SCH 727965 with various cytotoxics and targeted anti-cancer agent results in significantly enhanced anti-tumor efficacy in vivo. SCH 727965 is a potent anti-tumor agent in preclinical models and is currently undergoing evaluation in clinical trials.
CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1–Mediated ERK and BCL2/Cyclin D1 Pathways
Authors: Shiri Klein, Michal Abraham, Baruch Bulvik, Elia Dery, Ido D. Weiss, Neta Barashi, Rinat Abramovitch, Hanna Wald, Yaniv Harel, Devorah Olam, Lola Weiss, Katia Beider, Orly Eizenberg, Ori Wald, Eithan Galun, Yaron Pereg, Amnon Peled
Journal: Cancer Research (2017)

CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471-83. ©2017 AACR.
Prevention and management of gastroesophageal varices
Authors: Yeon Seok Seo
Journal: Clinical and Molecular Hepatology (2017)

Bleeding from gastroesophageal varices is a serious complication in patients with liver cirrhosis and portal hypertension. Although there has been significance improvement in the prognosis of variceal bleeding with advancement in diagnostic and therapeutic modalities for its management, mortality rate still remains high. Therefore, appropriate prevention and rapid, effective management of bleeding from gastroesophageal varices is very important. Recently, various studies about management of gastoesophageal varices, including prevention of development and aggravation of varices, prevention of first variceal bleeding, management of acute variceal bleeding, and prevention of variceal rebleeding, have been published. The present article reviews published articles and practice guidelines to present the most optimal management of patients with gastroesophageal varices.
Association of Immunotherapy With Durable Survival as Defined by Value Frameworks for Cancer Care
Authors: Omer Ben-Aharon, Racheli Magnezi, Moshe Leshno, Daniel A. Goldstein
Journal: JAMA Oncology (2017)

Modern immuno-oncology agents have generated great excitement because of their potential to provide durable survival for some patients. However, there is concern regarding the cost of cancer care, and multiple frameworks have been developed to assess value. The American Society of Clinical Oncology (ASCO) framework awards bonus points if substantial durable survival is demonstrated.To assess whether modern immuno-oncology agents reach defined efficacy thresholds in value frameworks.In this analysis, all US Food and Drug Administration (FDA) approvals for immuno-oncology agents between March 2011 and August 2017 were reviewed. Data required for the ASCO framework were collected, specifically improvement in proportion of patients alive with the test regimen and survival rate with standard treatment.Awarding of bonus points for durable survival based on the ASCO criteria.Twenty-three metastatic indications for 6 immuno-oncology agents (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab) were approved by the FDA from March 2011 to August 2017. Ten (43%) of the approvals were based on survival end points, while 13 (57%) were based on response rates. Only 3 drug indications fulfilled the threshold defined for the survival rate of patients receiving standard care (minimum 20%). Nine indications achieved the required level of improvement in proportion to patients alive in the test regimen compared with the standard (above 50%). There was overlap between these 2 criteria for 3 drug indications, allowing them to gain the durable survival bonus points awarded by the ASCO framework.Durable survival and response rates of modern immuno-oncology agents are rarely recognized as significant by current oncology value frameworks. This may be due to insufficient demonstration of efficacy of such agents or inappropriately calibrated value frameworks.
Nitrite/Nitrate and Estrogen Receptor-alpha Activation
Authors: David J. Veselik, Jasmine Turner, Kelly Graham, Katie Olesnanik, Mary Beth Martin
Journal: Cancer Research (2006)

3658  The incidence of breast cancer is 1 out of 7 women in the United States. Although the exact cause of breast cancer is not known, studies suggest that environmental and dietary exposures to chemicals that mimic estrogens may be risk factors for the disease. Nitrite and nitrate are anions that we are exposed to through the environment as well as the diet. To determine whether nitrite and/or nitrate have estrogen-like activity, the effects of these anions on estrogen receptor-alpha (ERα), estrogen-regulated genes and protein were measured in MCF-7 human breast cancer cells. Treatment of cells with 1uM nitrite or 1uM nitrate resulted in a 2.5-fold increase in progesterone receptor (PgR) mRNA and a 2.9-fold increase in PgR protein that were blocked by the antiestrogen ICI-182,780 suggesting that the effects of nitrite and nitrate are mediated by ERα. Treatment of cells with 1uM nitrite or 1uM nitrate also induced a 2.5-fold increase in pS2 mRNA and a 2-fold increase in cathepsin D mRNA that were blocked by the antiestrogen ICI-182,780 further suppporting a role of ERα. In transient cotransfection assays of wild type ERα and an estrogen response element-reporter construct, nitrite and nitrate stimulated chloramphenicol acetyltransferase (CAT) activity 2.5-3 fold. In growth assays, both anions significantly stimulated the proliferation of MCF-7 cells compared with cells grown in estrogen-depleted medium. By day four, there was a 4-fold increase in cell number. The addition of an antiestrogen blocked growth. In binding assays, nitrite blocked the binding of estradiol to ERα with an approximate Ki = 10-10 M, suggesting that the compound has a high affinity interaction with the ligand binding domain of the receptor. Cos-1 cells transfected with the chimeric receptor GAL-ER, containing the ligand binding domain of ERα, showed that the effects of nitrite and nitrate are mediated through the hormone binding domain of the receptor. Mutational analysis demonstrated that the amino acids C381, C417, C447, H516, K520, K529 and N532 in the ligand binding domain may be involved in interactions with nitrite and nitrate. In summary, this data show that nitrite and nitrate may be potential risk factors for breast cancer.
Perception of ABC (asymmetry, borders, and color) parameters in the screening for melanoma: Model exercise with experienced dermatologists
Authors: Luigi Naldi, Giuseppe Falgheri, Antonello De Bitonto, Anna Di Landro, Luigi Foiadelli, Gianlorenzo Imberti, Francesco Riva, Simone Cazzaniga
Journal: Journal of the American Academy of Dermatology (2017)