tbuckley/cabot-search huggingface dataset:
Abstract 3255: The roles of ALDH2, ADH1B and ADH1C gene polymorphism in predicting upper digestive tract multiple primary malignancies in head and neck cancer patients
Authors: Shiang-Fu Huang, Huei-Tzu Chien, Sou-De Cheng, Chun-Ta Liao, Hung-Ming Wang
Journal: Cancer Research (2018)

Abstract Head and neck cancer was closely related with habitual use of cigarette and alcohol. The genes involving in the metabolism of alcohol are reported to play roles in increasing risks of head and neck cancer. In this study, we investigated the single nucleotide polymorphisms (SNPs) of alcohol metabolizing enzymes (ALDH2, ADH1B and ADH1C) in their distributions among different tumor subsites and their risks of developing multiple primary cancers. We recruited 659 male head and neck cancer patients between Mar 1996 and Feb 2017. Four hundred and twenty-seven normal controls were also recruited. The SNPs in ALDH2 (rs671), ADH1B (rs1229984) and ADH1C (rs698) were analyzed by Taqman PCR primers and TaqMan probes synthesized by Applied Biosystems (Foster City, CA). Genotyping was performed using the Taqman-based allelic discrimination method on an Applied Biosystems 7500 Real-Time Polymerase Chain Reaction System (Applied Biosystems, Foster City, CA). The A allele carriers than G/G homozygotes in ALDH2 is significantly higher in oral cavity cancer (p = 0.016), oropharynx (p = 0.018) and hypopharynx cancer (p = 0.051) than normal population but not in tonsillar cancer (p = 0.099). In ADH1B, the G allele carriers is significantly higher than A/A homozygotes in oropharynx (p = 0.012), tonsillar cancer (p = 0.050) and hypopharynx cancer (p &amp;lt; 0.001) than normal population but not in oral cavity cancer (p = 0.406). We did not observe ADH1C (rs698) SNP significantly related with HNSCC tumor subsites (p &amp;gt; 0.05). For ALDH2 (A allele carriers vs G/G homozygotes) and ADH1B (G allele carriers vs A/A homozygotes), they significantly increased risks to develop multiple primary cancers in upper digestive tract (p &amp;lt; 0.001, OR [95% confidence interval, C.I.]: 5.358 [2.565-11.195]. and p &amp;lt; 0.001, OR [95% C.I.]: 2.907 [1.598 - 5.290]). Conclusion:ALDH2 (rs671) A allele carriers and ADH1B (rs1229984) G allele carriers had higher risks of developing multiple primary cancers in upper digestive tract. For those with high risk allele carriers, routine screening of upper digestive tract including laryngoscope and esophagoscope is suggested to detect new primaries early. Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Sou-De Cheng, Chun-Ta Liao, Hung-Ming Wang. The roles of ALDH2, ADH1B and ADH1C gene polymorphism in predicting upper digestive tract multiple primary malignancies in head and neck cancer patients [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 3255.
Assessment of Resistance Mechanisms and Clinical Implications in Patients With<i>EGFR</i>T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib
Authors: Geoffrey R. Oxnard, Yuebi Hu, Kathryn F. Mileham, Hatim Husain, Daniel B. Costa, Philip Tracy, Nora Feeney, Lynette M. Sholl, Suzanne E. Dahlberg, Amanda J. Redig, David J. Kwiatkowski, Michael S. Rabin, Cloud P. Paweletz, Kenneth S. Thress, Pasi A. Jänne
Journal: JAMA Oncology (2018)

Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to osimertinib is a growing clinical challenge that is poorly understood.To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.Of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
Abstract 4712: AT1965, a novel B cell-activating immunotherapy, exerts potent anticancer activity
Authors: Monideepa Roy, Vineeth Krishna, Aniruddha Sengupta, Sudip Roy, Ashish Kulkarni, Shiladitya Sengupta
Journal: Cancer Research (2018)

Abstract Emerging clinical evidence implicate B cells in long term survival in cancer. However, a therapeutic activation of a B cell response against cancer has not been explored. Here we describe the results with AT1965, which exerts a potent anticancer effect via the activation of B cells. AT1965 completely regressed aggressive 4T1 breast tumors established in balb/c mice. Immunophenotyping revealed that IGKC, a B cell marker, was the dominant immune biomarker that is over-expressed following AT1965 treatment. The lack of functional B cells in vivo, via the deletion of the JH gene results in the loss of heavy chain production, blocked this anti-cancer activity of AT1965. Activation of a B cell response is associated with long term memory, which should prevent relapse. To test this, tumor-bearing animals were treated with AT1965 to induce regression; Not a single animal relapsed, i.e. developed the tumor when re-challenged with the tumor thirty days after the primary tumors had regressed. T and B cells are natural partners in an immune response. We therefore tested the combination of a PD1 immune checkpoint inhibitor and AT1965 in an immunocompetent lung cancer model. Only 12.5% of the animals treated with AT1965 or the PD1-inhibitor exhibited a complete regression of lung cancer, while 37.5% exhibited delayed tumor progression. In contrast, 50% of the animals underwent complete tumor regression and 25% exhibited tumor growth inhibition when the two drugs were combined, consistent with the basic immunology premise that both B and T cells work together to mount a complete immune response. Our results indicate that B cell activation could emerge as the next paradigm in cancer immunotherapy. Citation Format: Monideepa Roy, Vineeth Krishna, Aniruddha Sengupta, Sudip Roy, Ashish Kulkarni, Shiladitya Sengupta. AT1965, a novel B cell-activating immunotherapy, exerts potent anticancer activity [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 4712.
Lipoprotein(a) Enhances the Expression of Intercellular Adhesion Molecule-1 in Cultured Human Umbilical Vein Endothelial Cells
Authors: ShigekiTakami, ShizuyaYamashita, ShinjiKihara, MasatoIshigami, KaoruTakemura, NoriakiKume, ToruKita, YujiMatsuzawa
Journal: Circulation (1998)

Background—We reported an increase in serum lipoprotein(a) [Lp(a)] levels in patients with thromboangiitis obliterans, suggesting that Lp(a) could also contribute to the pathogenesis of cardiovascular diseases by a mechanism different from atherosclerosis. Adhesion molecules were shown to contribute to the development of not only atherosclerotic but also inflammatory vascular diseases. Methods and Results—We evaluated the effect of Lp(a) on the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in human umbilical vein endothelial cells by a cell ELISA. Lp(a) dramatically enhanced the levels of ICAM-1 in a dose-dependent manner. A discernible increase in ICAM-1 expression was observed at a physiological concentration of 0.26 mmol cholesterol/L Lp(a) after 48-hour incubation. A 1.8-fold increase in ICAM-1 expression was observed 48 hours after the addition of Lp(a) (1.04 mmol cholesterol/L). Northern blot analysis demonstrated that the amount of ...
Treatment of low grade dysplasia in Barrett’s esophagus with a new-generation cryoballoon device
Authors: Joana Castela, Ingrid Demedts, Raf Bisschops
Journal: Endoscopy (2018)

A 53-year-old man with Barrett's esophagus (BE; C1M4), who was under regular surveillance, developed multifocal low grade dysplasia (LGD) without visible lesions ([Fig. 1 a]). The diagnosis of LGD was confirmed by a second expert pathologist.
Abstract 14845: Masquerading Bundle Branch Block: An Electrocardiographic Marker of Poor Prognosis
Authors: Thiago G Schroder e Souza, Rômulo L Almeida, Gabriel P Targueta, Sandro P Felicioni, Virginia B Cerutti Pinto, Marcelo P Moretti, Mariana F de Marchi, Francisco Faustino A França
Journal: Circulation (2015)

Introduction: Masquerading bundle branch block (MBBB) is a rare cardiac conduction anomaly characterized in the Electrocardiogram (EKG) by Right Bundle Branch Block in the precordial leads and Left Bundle Branch Block in frontal leads. The available evidence indicates that it carries poor prognosis and that it is often underdiagnosed. We studied epidemiological peculiarities, electrocardiographic features and prognosis of this rare kind of ventricular conduction delay. Methods: In a review of over 600,000 EKGs from the database of Tele-Electrocardiography department of Dante Pazzanese Institute of Cardiology during the last seven years, we found twenty-five cases of MBBB. Diagnostic criteria were presence of QRS ≥ 0.12 s, dominant positive waves in V1, left axis deviation and absent or minimal S wave in DI and aVL. Epidemiological data was collected for each EKG and the follow-up of patient′s health status was assessed by telephone contact. Kaplan-Meier survival curves were based on the following endpoints: mortality, pacemaker implantation and the composite of both. Results: We identified twenty-five cases (21 males and 4 females) of MBBB. The average age was 69 (±14) years. Sinus rhythm was present in 17 patients (68%), atrial fibrillation in 7 (28%) and atrial flutter in one (4%). Average heart rate, PR interval, QRS length, QTc and QRS axis were, respectively: 70 (±17) bpm, 205 (±50) ms, 159 (±24) ms, 463 (±37) ms and -76° (±6) degrees. Follow-up data was successfully obtained from 15 patients: 4 (26.6%) had a pacemaker implanted, 7 (46.6%) died and 9 had combined endpoints (60%). According to the Kaplan-Meier survival curve, at 48 months, the estimated ratios of death, pacemaker implantation or combined endpoints were 41.4%, 38.9% and 80.2%, respectively. Conclusions: MBBB represents a high-risk condition and, although rare, this EKG pattern should be taken into consideration due to the poor prognosis associated with its presence.
AMPK: Potential Therapeutic Target for Ischemic Stroke
Authors: Shuai Jiang, Tian Li, Ting Ji, Wei Yi, Zhi Yang, Simeng Wang, Yang Yang, Chunhu Gu
Journal: Theranostics (2018)

5'-AMP-activated protein kinase (AMPK), a member of the serine/threonine (Ser/Thr) kinase group, is universally distributed in various cells and organs.It is a significant endogenous defensive molecule that responds to harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, neurodegenerative diseases (NDD).Cerebral ischemia, which results from insufficient blood flow or the blockage of blood vessels, is a major cause of ischemic stroke.Ischemic stroke has received increased attention due to its '3H' effects, namely high mortality, high morbidity, and high disability.Numerous studies have revealed that activation of AMPK plays a protective role in the brain, whereas its action in ischemic stroke remains elusive and poorly understood.Based on existing evidence, we introduce the basic structure, upstream regulators, and biological roles of AMPK.Second, we analyze the relationship between AMPK and the neurovascular unit (NVU).Third, the actions of AMPK in different phases of ischemia and current therapeutic methods are discussed.Finally, we evaluate existing controversy and provide a detailed analysis, followed by ethical issues, potential directions, and further prospects of AMPK.The information complied here may aid in clinical and basic research of AMPK, which may be a potent drug candidate for ischemic stroke treatment in the future.
Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium
Authors: KazufumiNakamura, KengoKusano, YoichiNakamura, MikioKakishita, KeikoOhta, SatoshiNagase, MikaYamamoto, KatsumasaMiyaji, HironoriSaito, HiroshiMorita, TetsuroEmori, HiromiMatsubara, ShinyaToyokuni, TohruOhe
Journal: Circulation (2002)

Background— Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating β-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results— Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myo...
Functional Inhibition of Ras by S-trans,trans-Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice
Authors: JacobGeorge, ArnonAfek, PninaKeren, ItzhakHerz, IrisGoldberg, RoniHaklai, YoelKloog, GadKeren
Journal: Circulation (2002)

Background— Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. Methods and Results— We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E–deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes fro...
Abstract 13989: Duration of Interventricular Septal Shift Predicts Clinical Outcome in Patients With Precapillary Pulmonary Hypertension: A CMR Study
Authors: GeorgeGiannakoulas, Sophia-AnastasiaMouratoglou, AlexandrosKallifatidis, StavrosHadjimiltiades, GeorgiaPitsiou, IoannisStanopoulos, HaralambosKarvounis
Journal: Circulation (2015)

Introduction: Right ventricular pressure overload results in interventricular septal (IVS) shift towards the left ventricle in patients with precapillary pulmonary hypertension (pPH). Hypothesis: The duration of IVS shift towards left ventricle during the cardiac cycle, as expressed by a novel marker called curvature duration index (CDi), predicts clinical outcome in pPH patients. Methods: This was a prospective study. All patients underwent cardiac magnetic resonance (CMR, Avanto Siemens 1,5T). CMR parameters of right ventricular function and dimensions were assessed. CDi (duration of IVS shift towards left ventricle x 100/cardiac cycle duration) was defined in the short-axis view at the level of papillary muscles (Figure 1). Time from enrollment to clinical failure (hospitalization due to pPH, initiation of parenteral prostanoid therapy, atrial septostomy or death) was recorded. Results: Our study included 36 consecutive patients (28 women, mean age 50.6±13.8 years) with pPH. Over a median follow-up per...
Transgenic Remodeling of the Contractile Apparatus in the Mammalian Heart
Authors: JosephPalermo, JamesGulick, MelissaColbert, JasonFewell, JeffreyRobbins
Journal: Circulation Research (1996)

Abstract The structure-function relationships of the sarcomeric proteins in the mammalian cardiac compartment remain ill-defined because of the lack of a suitable model in which they can be readily manipulated or exchanged in vivo. To establish the validity of the transgenic paradigm for remodeling the mammalian heart, the murine α-cardiac myosin heavy chain gene promoter was used to express a ventricular myosin light chain-2 transgene (MLC2v) in both the atria and ventricles of the adult animal. Expression resulted in high levels of the transgene’s transcript in both compartments. In the ventricle, the transgene was expressed against the background expression of the normal isoform. In the atrium, the transgene’s expression would be ectopic, in that normally, MLC2v expression is restricted to the ventricle. Ectopic expression of the transgene in the atria resulted in a complete replacement of the atrial myosin light chain-2 protein isoform, although the endogenous isoform’s steady state transcript levels ...
Perceptions of Factors Associated With Inclusive Work and Learning Environments in Health Care Organizations
Authors: Jaya Aysola, Frances K. Barg, Ana Bonilla Martinez, Matthew Kearney, Kareha Agesa, Carlos Carmona, Eve Higginbotham
Journal: JAMA Network Open (2018)

Diversifying the health care workforce remains a critical goal for health care organizations focused on reducing disparities in care. However, it remains unknown what factors create inclusive health system environments and help organizations retain a diverse workforce.To understand from members of the health care workforce what factors contribute to inclusive work and learning environments and what can be done to improve inclusion within health care organizations.A qualitative narrative analysis of responses to a weekly email call for narratives within health care organizations sent June 1, 8, 15, and 22, 2016. The email contained an anonymous link to 2 open-ended stimulus questions asking for stories reflecting inclusion or lack thereof within participants' work environments as well as demographic questions. The study took place at 6 hospitals, including a free-standing children's hospital and a Veterans Affairs medical center, 4 health sciences schools (Medicine, Nursing, Dental, and Social Policy and Practice), and outpatient facilities within a university-based health care system in Pennsylvania. There were 315 completed narratives submitted from health care system executives (n = 3), staff (n = 113), academic faculty (n = 97), trainees or students (n = 99), and 3 who declined to specify their positions.Workplace experiences with inclusivity, implications of these experiences, and recommendations to improve inclusion within environments.Of 315 narratives submitted from members of the health care system, in 188 (59.7%) the writer self-identified as female; in 10 (3.2%), as transgender/queer; in 38 (12.1%), as non-Hispanic black; in 152 (48.3%), as non-Christian; in 31 (9.8%), as having a language other than English as their primary language; and in 14 (4.4%), as having a disability. Analysis of the narratives revealed 6 broad factors that affected inclusion within health care organizations: (1) the presence of discrimination; (2) the silent witness; (3) the interplay of hierarchy, recognition, and civility; (4) the effectiveness of organizational leadership and mentors; (5) support for work-life balance; and (6) perceptions of exclusion from inclusion efforts. Challenges with inclusion had negative effects on job performance and well-being, with reports of stress, anxiety, and feelings of hopelessness. Most respondents referenced a systemic culture that influenced their interpersonal dynamics and provided specific strategies to improve organizational culture that focused on leadership training and expanding collegial networks.This narrative analysis provides a taxonomy of factors that health care organizations can use to assess inclusion within their learning and work environments as well as strategies to improve inclusion and retain a diverse health care workforce.