tbuckley/cabot-search huggingface dataset:
Abstract 1220: Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant
Authors: Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S. Song
Journal: Cancer Research (2018)

Abstract Genome-wide association studies (GWAS) have identified genetic variants that may significantly modulate breast cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; often, it is not even clear whether the GWAS variants are functional themselves or just genetically linked to other functional variants. We here provide an integrated method for identifying functional regulatory variants associated with breast cancer and their target genes by combining the analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) systematically utilizing haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to the breast cancer susceptibility region in 5p12 demonstrates that the GWAS risk allele rs4415084-T is correlated with higher expression levels of the protein-coding gene MRPS30 and lncRNA RP11-53O19.1. We propose that an intergenic SNP, in linkage disequilibrium (LD) with the GWAS SNP rs4415084, is the predicted functional SNP. We provide multiple levels of evidence that the risk allele of the predicted functional SNP, in phase with the GWAS risk allele rs4415084-T, creates a GATA3 binding motif within a regulatory element, resulting in differential GATA3 binding and chromatin accessibility, which thereby promote the transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the risk SNP's role in modulating mitochondrial activities in breast cancer. Our computational framework can be extended to facilitate the rapid functional characterization of other genetic variants modulating cancer susceptibility and provides an effective way of integrating GWAS results with high-throughput genomic and epigenomic data. Citation Format: Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S. Song. Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1220.
Indian doctors raise concerns about oxytocin restrictions
Authors: Dinsa Sachan
Journal: BMJ (2018)

Doctors have warned that moves to restrict the manufacture and sale of oxytocin by the Indian government could leave women at risk of haemorrhage.

The health ministry announced at the end of the April that only one public sector firm—Karnataka Antibiotics and Pharmaceuticals—would be able to make oxytocin from 1 July.1 It also banned the import of the drug and said that chemists would not be allowed to sell it.

The government cited a 2016 judgement by a court in the state of Himachal Pradesh that called for restrictions on the use of oxytocin because of its …
Abstract 18610: High-sensitivity Cardiac Troponin T Level in the Emergency Department and Long-term Mortality in Patients With and Without Myocardial Infarction
Authors: NadiaBandstein, RickardLjung, MagnusJohansson, MartinHolzmann
Journal: Circulation (2014)

Introduction: The level of high-sensitivity cardiac troponin T (hs-cTnT) is related to outcome in patients with myocardial infarction (MI). However, the importance of elevated hs-cTnT levels in patients without MI is unknown. We investigated the association between elevation of hs-cTnT and death in patients with and without MI. Also, we compared the risk of death between patients with and without MI at different levels of hs-cTnT.[[Unable to Display Character:  ]] Methods: We included all patients > 25 years of age who came to the emergency department (ED), at the Karolinska university hospital in Stockholm, Sweden, during 2011 to 2012, with chest pain and at least one hs-cTnT measured. Cox hazard regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI), for all-cause mortality at different levels of first hs-cTnT (5-14, 15-29, 30-49, 50-100, and >100 ng/l), using <5 ng/l as reference category, after adjustment for age, sex, prior MI, stroke, heart failure, renal functi...
Sensitive skin can be small fibre neuropathy: results from a case-control quantitative sensory testing study
Authors: F. Huet, A. Dion, A. Batardière, A.S. Nedelec, F. Le Caër, P. Bourgeois, E. Brenaut, L. Misery
Journal: British Journal of Dermatology (2018)

Sensitive skin syndrome (SSS) is defined as the occurrence of unpleasant sensations (itch, pain, burning, prickling) in response to stimuli that should not normally cause such sensations. Previous studies show that SSS could be a small fibre neuropathy, but quantitative sensory testing (QST) is lacking.Using QST, to determine the presence or absence of tactile sensitivity disorder, mainly heat pain threshold (HPT), in patients with SSS.This monocentric case-control study included 21 patients with SSS and 21 controls. The patients underwent QST. Neuropathic pain was assessed by two questionnaires: the Douleur Neuropathique 4 (DN4) and the Neuropathic Pain Symptom Inventory (NPSI).Forty-two patients were included in the study. The HPT was significantly lower in the cases (14·5 ± 2·8) than in the controls (17·8 ± 2·5) (P < 0·001). Intermediate pain (HPT 5·0) was also significantly decreased in patients with SSS. The DN4 and NPSI scores were significantly higher in the cases than in the controls.The decrease in HPT in patients with SSS compared with controls suggests the presence of hyperalgesia, probably due to the damage of C-fibres. These findings, as well as the increased DN4 and NPSI scores, strengthen the neuronal hypothesis of SSS and are new arguments for consideration of SSS as small fibre neuropathy.
Abstract LB-218: Pathologist reproducibility of combined positive score (CPS) for the evaluation of PD-L1 in gastric or gastroesophageal junction adenocarcinoma tumors
Authors: Lindsay Guerrero, Karina Kulangara, Yen Truong, Sue Schwefel, Debra Hanks
Journal: Cancer Research (2018)

Background: The clinically relevant and highly reproducible combined positive score (CPS) algorithm is used in conjunction with PD-L1 IHC 22C3 pharmDx for evaluation of programmed death ligand 1 (PD-L1) expression in gastric or gastroesophageal junction (GEJ) adenocarcinoma specimens. PD-L1 IHC 22C3 pharmDx and the CPS algorithm were approved by the United States Food and Drug Administration (FDA) on September 22, 2017 to aid in identifying patients likely to respond to pembrolizumab.Objective: Assessment of pathologist reproducibility in the gastric and GEJ adenocarcinoma Early Validation Program (EVP).Methods: Immunohistochemical (IHC) staining for PD-L1 was performed on thirty gastric or GEJ adenocarcinoma surgical resection specimens with PD-L1 IHC 22C3 pharmDx. All specimens were evaluated by in-house pathologists and assigned a reference CPS. Inter-pathologist and intra-pathologist reproducibility was assessed in ten pathologists from five clinical labs. Acceptance criteria was based on a minimum of 85% agreement with the reference CPS.Results: Nine pathologists met acceptance criteria for inter-observer reproducibility (87-100% agreement) and intra-observer reproducibility (87-100% agreement). One pathologist had 90% inter-pathologist agreement and 80% intra-pathologist agreement. This pathologist received additional training and achieved 87% intra-pathologist agreement upon re-testing. Upon completion of EVP, all ten participating pathologists were certified to score gastric or GEJ adenocarcinoma specimens stained with PD-L1 IHC 22C3 pharmDx. Inter-pathologist (87.6% overall agreement) and intra-pathologist (93% overall agreement) studies performed in analytical validation demonstrate similar reproducibility.Conclusion:The CPS algorithm is highly reproducible within and among pathologists for gastric or GEJ adenocarcinoma specimens stained with PD-L1 IHC 22C3 pharmDx, as demonstrated in analytical validation.Citation Format: Lindsay Guerrero, Karina Kulangara, Yen Truong, Sue Schwefel, Debra Hanks. Pathologist reproducibility of combined positive score (CPS) for the evaluation of PD-L1 in gastric or gastroesophageal junction adenocarcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-218.
Abstract 911: Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer
Authors: Rentian Wu, Qian Nie, Phillip A. Kubica, Zhiquan Wang, Shikshya Shrestha, Colbren S. Trogstad-Isaacson, Calvin R. Jerde, Erin E. Tapper, Kelly J. Bouchonville, Steven M. Offer, Robert B. Diasio
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is the third most common cancer and is expected to cause approximately 50,000 deaths in the US in 2017. The antimetabolite 5-fluorouracil (5-FU) is the cornerstone of first-line adjuvant chemotherapy regimens for CRC. Resistance to 5-FU-based chemotherapies develops over time and is the greatest obstacle to effective management in this disease. However, the resistance mechanisms of 5-FU are largely unknown. Approximately 50% of the CRC cases have activating mutations in KRAS or BRAF. Based on recent clinical data, it is now appreciated that KRAS/BRAF mutations are associated with worse survival in 5-FU-based chemotherapies for CRC. Therefore, there is an urgent unmet need for improved therapeutic options to treat mutant KRAS/BRAF tumors. We analyzed the differential activation status of enhancers in KRAS/BRAF mutant and wildtype CRC cell lines. Enhancers that associated with genes regulating pyrimidine metabolism were significantly enriched in KRAS/BRAF mutant CRC cells. Among them, the differential activation of an enhancer located ~400kb upstream of the DPYD promoter was most significant. By using CRISPR-dCas9 system, specifically targeting of p300 to the enhancer significantly increased DPYD expression, and Ezh2 significantly decreased expression. Knockout (KO) of this enhancer resulted in reductions in DPD expression and increased resistance to 5-FU. In mouse xenograft studies, enhancer-KO cells responded to doses of 5-FU that were otherwise ineffective against control cells. Treating KRAS mutant CRC cells with CBP30, H3K27 acetyl-transferase inhibitor, significantly reduced DPYD expression. Synergistic interactions was identified between CBP30 and 5-FU. Finally, mouse xenograft studies strongly suggest that inhibition of H3K27ac may significantly improve 5-FU effectiveness against KRAS mutant tumors. In summary, the present studies advance our understanding of how mutant KRAS/BRAF epigenetically regulates DPYD expression and results in 5-FU resistance in CRC. We showed that clinical treatment of CRC might be significantly improved by the development of future pharmacologic approaches targeting enhancers that are activated by mutant KRAS/BRAF. Citation Format: Rentian Wu, Qian Nie, Phillip A. Kubica, Zhiquan Wang, Shikshya Shrestha, Colbren S. Trogstad-Isaacson, Calvin R. Jerde, Erin E. Tapper, Kelly J. Bouchonville, Steven M. Offer, Robert B. Diasio. Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 911.
Abstract 12593: Comparison Between Appropriateness of Exercise EKG and Stress Myocardial Perfusion Imaging Based on 2013 Multimodality Appropriate Use Criteria
Authors: AshishMahajan, SusanBal, HarveyHahn
Journal: Circulation (2014)

Introduction: The American College of Cardiology recently published 2013 multimodality Appropriate Use Criteria (AUC) for the detection and risk assessment of stable Ischemic Heart Disease. The criteria present potential diagnostic tests for common indications using a side-by-side rating system. Exercise EKG is a commonly used non-invasive test with excellent negative predictive value for coronary artery disease. The 2013 multimodality AUC are the first to define appropriate use of exercise EKG. The objective of our study was to evaluate appropriateness of exercise EKG in patients who underwent Stress Myocardial Perfusion Imaging (MPI). Methods: A total of 403 patients who underwent stress MPI at our institute were included in the study. Each stress MPI was classified into Appropriate, May be Appropriate or Rarely Appropriate based on 2013 multimodality AUC. The exercise EKG AUC was then applied to the same cohort of patients. For patients who underwent Stress MPI for Rarely Appropriate indications, appro...
Abstract 5705: The key role of kynurenine in anti-PD-1 failure
Authors: Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Annalina Pisano, Michela Roberto, Elisa Onesti, Francesca Romana DI Pietro, Chiara Napoletano, Laura Pizzuti, Patrizia Vici, Giulia D'Amati, Federica Mazzuca, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti
Journal: Cancer Research (2018)

Abstract Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of severe and often fatal disease, as metastatic lung cancer, demonstrating long-term tumor control and extended patient survival. Unfortunately, only 25-30% of patients have a long-term benefit from immunotherapy, while the remaining 70-75% demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) has been proposed as a possible mechanism of resistance to anti-PD1 treatment. Indeed, IDO catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn), which seems to enhance the activity of Treg, leading to an immunosuppressive microenvironment. Methods: The serum concentrations of Trp and Kyn were measured by high-performance liquid chromatography tandem mass spectrometry in 26 patients affected by non-small cell lung cancer (NCLSC) before the start of the second-line therapy with nivolumab. The IDO activity was expressed with Kyn/Trp ratio. The associations between Kyn/Trip ratio and early progression, PS, age, sex, brain metastases and pleural effusion were analyzed using Spearman test and Mann Whitney test. Results: 14 out of 26 patients (54%) presented early progression (defined as progression of the disease within 6 months from the beginning of nivolumab treatment). The median value of Kyn/Trp ratio was 0.073 (0.024-0.18). We found a significant association between Kyn/Trp ratio and early progression (p= 0.009), while no statistical associations were found between Kyn/Trp ratio and PS, age, sex, brain metastases and pleural effusion. Indeed, patients with early progressive disease presented a median value of Kyn/Trp ratio significantly higher than other patients (0.094 vs 0.052; p= 0.01). Conclusion: The pretreatment evaluation of IDO activity, expressed as Kyn/Trp ratio, seems to be associated with response to immunotherapy. In particular, higher Kyn/Trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in patients with high level of Kyn/Trp ratio. Citation Format: Andrea Botticelli, Bruna Cerbelli, Luana Lionetto, Ilaria Zizzari, Annalina Pisano, Michela Roberto, Elisa Onesti, Francesca Romana DI Pietro, Chiara Napoletano, Laura Pizzuti, Patrizia Vici, Giulia D'Amati, Federica Mazzuca, Maurizio Simmaco, Marianna Nuti, Paolo Marchetti. The key role of kynurenine in anti-PD-1 failure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5705.
Synergistic Opportunities in the Interplay Between Cancer Screening and Cardiovascular Disease Risk Assessment
Authors: Catherine E. Handy, Renato Quispe, Xavier Pinto, Michael J. Blaha, Roger S. Blumenthal, Erin D. Michos, Joao A.C. Lima, Eliseo Guallar, Seungho Ryu, Juhee Cho, James A. Kaye, Josep Comin-Colet, Xavier Corbella, Miguel Cainzos-Achirica
Journal: Circulation (2018)

Cardiovascular disease (CVD) and cancer continue to be the 2 leading causes of death in developed countries despite significant improvements in the prevention, screening, and treatment of both diseases. They remain significant public health problems, growing in importance globally. Despite this threat, the fields of cardiology and oncology have been relatively disconnected. With many shared modifiable risk factors, cancer and CVD often coexist in the same individuals; those diagnosed with lung cancer, breast cancer, and colon cancer are at higher risk of CVD, and those with CVD are at higher risk of developing many types of common cancers. Screening paradigms have been established in parallel, but there are opportunities for combined risk assessments for cancer and CVD risk. Joining forces for combined cardiovascular and hemato-oncological preventive and research efforts will likely have synergistic, worldwide public health benefits.
Abstract 2375: Concurrent HER or PI3K inhibition potentiates the anti-tumor effect of ERK inhibitor BVD-523 (ulixertinib) in preclinical pancreatic cancer models
Authors: Hongmei Jiang, Mai Xu, Lin Li, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian-Huat Lim
Journal: Cancer Research (2018)

Abstract To date, effective treatments for inoperable pancreatic ductal adenocarcinoma (PDAC) remain elusive. Targeting KRAS, the gene that is mutated in &amp;gt;95% of PDAC, is a heavily pursued strategy, but unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK represents the next best strategy. However, RAF or MEK inhibitors have not shown promising clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to re-activate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. BVD-523 (ulixertinib) is a first-in-class ERK-specific inhibitor that has demonstrated anti-tumor activity in clinical trials. In this study, we showed that BVD-523 effectively inhibits transformed growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, using reverse-phase protein array analysis, we identified potential mechanisms by which PDAC cells may adopt to tolerate ERK inhibition. On this basis, we proposed and tested two rational combinatorial approaches with BVD-523 that showed promising preclinical efficacy in vitro and in mouse xenografts. Overall, we provide the first evidence that PDAC cells may readily adapt to pharmacologic ERK inhibition, and provide combinatorial therapeutic strategies that could benefit patients. Citation Format: Hongmei Jiang, Mai Xu, Lin Li, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian-Huat Lim. Concurrent HER or PI3K inhibition potentiates the anti-tumor effect of ERK inhibitor BVD-523 (ulixertinib) in preclinical pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2375.
Determination of Fraction of Left Ventricular Volume Ejected per Beat and of Ventricular End-Diastolic and Residual Volumes
Authors: Rolandfolse, Eugenebraunwald
Journal: Circulation (1962)

A technic has been developed for determining the fraction of left ventricular end-diastolic volume that is ejected during each cardiac cycle. Radioiodinated Diodrast was rapidly injected into the left ventricle at the time of transseptal left heart catheterization and the fraction of isotope discharged from this chamber per beat was determined with a well-shielded scintillation probe placed on the chest wall over the left ventricle. Left ventricular end-diastolic volume was estimated from the stroke volume, determined by the dye-dilution method, and the fraction of isotope discharged per beat. Difficulties resulting from inadequate mixing of isotope in the left ventricle were minimized by this technic, since the probe detected indicator in the entire left ventricular cavity. The accuracy of this technic was first demonstrated in a circulatory model and then in open-chest dogs in which ventricular dimensions were continuously monitored by means of mercury-in-rubber gages. In 21 patients without detectable ...
Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes
Authors: Hsien-Yen Chang, Sonal Singh, Omar Mansour, Sheriza Baksh, G. Caleb Alexander
Journal: JAMA Internal Medicine (2018)

Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation.To quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer).A retrospective cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation.New use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones).Foot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes.Among 2.0 million potentially eligible individuals, a total of 953 906 (516 046 women and 437 860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39 869 new users of SGLT-2 inhibitors (4.2%), 105 023 new users of DPP-4 inhibitors (11.0%), and 39 120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10 000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10 000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses.Use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.