tbuckley/cabot-search huggingface dataset:
A pilot study of pembrolizumab in combination with decitabine and hypofractionated index lesion radiation in pediatric and young adult patients with relapsed and refractory solid tumors or lymphoma.
Authors: Brian Turpin, Ralph Vatner
Journal: Journal of Clinical Oncology (2019)

TPS25 Background: A potential limitation to the use of immune checkpoint inhibitors in younger patients with immune-resistant histologies is related to low tumor associated antigen expression and an immunosuppressive microenvironment. Low dose decitabine, as an inhibitor of DNA methyltransferase, can unrepress immunogenic cancer testes antigen expression, while hypofractionated radiation promotes infiltration of immune effector cells, stimulation of toll-like receptors on dendritic cells, and induction of type I interferons and other cytokines. As induced PD-L1 expression may also result, we hypothesize that decitabine, radiation, and the PD-1 inhibitor, pembrolizumab, will be synergistic. Here, we aim to verify the safety and preliminary activity of the combination. Correlative studies include an investigation of changes in antigen expression, the kinetics of immune effector and regulatory cell phenotype and function, and microbiome. Methods: Treatment program: Every 28 day cycle, patients receive 10 mg/m 2 IV decitabine on days 1-5 and 2 mg/m 2 (max dose 200 mg) IV pembrolizumab on day 8. Hypofractionated radiation (8 Gy x 3) to one or more lesion(s) is given on days 5-7 of the second cycle only. Adult patients may consent to optional biopsy of an irradiated lesion. Beyond cycle 3, patients may undergo elective surgery of one or more lesions. Patients remain on therapy for 27 cycles, absent progression by irRECIST or unacceptable toxicity. Patient eligibility: Patients 12 months to 40 years with available archived tissue may be considered, and must have adequate organ function including an absolute neutrophil count ≥ 750/mm 3 and platelet count ≥ 75,000/mm 3 . Patients may have stable central nervous system metastases. Patients previously treated with radiotherapy may be eligible. Patients previously treated with PD-1 inhibitor therapy may be eligible, unless treated for an immune related adverse event. Current enrollment: This trial has been open to enrollment since February of 2018. No dose limiting toxicities have been observed in 2 patients evaluable for toxicity. Clinical trial information: NCT03445858.
NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology
Authors: Xiaolong He, Weijun Yang, Zhijie Zeng, Yi Wei, Jie Gao, Bao Zhang, Li Li, Liqun Liu, Yu Wan, Qing Zeng, Zelong Gong, Liting Liu, Hanyun Zhang, Yubin Li, Shaojie Yang, Tongtong Hu, Lixian Wu, Eliezer Masliah, Shenghe Huang, Hong Cao
Journal: Cellular and Molecular Immunology (2019)
Association of Work Measures and Specialty With Assigned Work Relative Value Units Among Surgeons
Authors: Christopher P. Childers, Jill Q. Dworsky, Marcia M. Russell, Melinda Maggard-Gibbons
Journal: JAMA Surgery (2019)

<h3>Importance</h3> The primary data sources used to generate and update work relative value units (RVUs) are surveys of small groups of specialists who are asked to estimate the time and intensity needed to perform surgical procedures. Because these surveys are conducted by specialty societies and rely on subjective data, these sources have been challenged as potentially biased. <h3>Objective</h3> To assess whether objective work measures are associated with a surgical procedure's assigned work RVUs and whether differences exist by surgical specialty. <h3>Design, Setting, and Participants</h3> This cross-sectional study obtained data from the 2016 and 2017 participant use files of the American College of Surgeons National Surgical Quality Improvement Program. The 2017 physician fee schedule of the Centers for Medicare &amp; Medicaid Services was a secondary data source. Procedures were included if they had at least 100 patient-level observations over the 2-year period. Data were analyzed from August 29, 2018, to April 2, 2019. <h3>Main Outcomes and Measures</h3> The dependent variable was a procedure's assigned work RVU. Independent variables of work RVUs were 4 procedure-level work measures (median operative time, median postoperative length of stay, all-cause 30-day readmission rate, and all-cause 30-day reoperation rate) and surgeon specialty (10-level category using general surgery as the reference). <h3>Results</h3> The data set included 628 unique<i>Current Procedural Terminology</i>(<i>CPT</i>) codes and 726<i>CPT</i>-specialty combinations from 1 239 991 patient observations. Statistically significant associations were found between each work measure and assigned work RVU, as follows: median operative time (<i>R2</i> = 0.74; 95% CI, 0.71-0.78), postoperative length of stay (<i>R2</i> = 0.42; 95% CI, 0.36-0.48), rate of readmission (<i>R2</i> = 0.18; 95% CI, 0.13-0.23), and rate of reoperation (<i>R2</i> = 0.15; 95% CI, 0.10-0.20). Including all 4 measures explained 80.2% (95% CI, 77.3%-83.1%) of the variation. Adding the surgical specialty improved the overall fit of the model (likelihood ratio test χ<sup>2</sup> = 231.27;<i>P</i> &lt; .001). Cardiac (7.78; 95% CI, 4.25-11.31;<i>P</i> &lt; .001) and neurosurgery (2.46; 95% CI, 1.08-3.83;<i>P</i> &lt; .001) had higher work RVUs compared with general surgery, whereas orthopedics (–1.53; 95% CI, –2.48 to –0.59;<i>P</i> = .002), urology (–1.58; 95% CI, –2.88 to –0.29;<i>P</i> = .02), plastics (–2.70; 95% CI, –4.39 to –1.01;<i>P</i> = .002), and otolaryngology (–3.05; 95% CI, –4.69 to –1.42;<i>P</i> &lt; .001) had lower work RVUs compared with general surgery. <h3>Conclusions and Relevance</h3> Objective work measures appeared to be associated with assigned work RVUs, predominantly with operative time; registry data can be used to augment and inform the generation and updating processes of the work RVUs.
Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma
Authors: Mario Castro, Adalberto S. Rubin, Michel Laviolette, Jussara Fiterman, Marina De Andrade Lima, Pallav L. Shah, Elie Fiss, Ronald Olivenstein, Neil C. Thomson, Robert M. Niven, Ian D. Pavord, Michael Simoff, David R. Duhamel, Charlene McEvoy, Richard Barbers, Nicolaas H.T. ten Hacken, Michael E. Wechsler, Mark Holmes, Martin J. Phillips, Serpil Erzurum, William Lunn, Elliot Israel, Nizar Jarjour, Monica Kraft, Narinder S. Shargill, John Quiring, Scott M. Berry, Gerard Cox
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists.A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%).The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively).BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).
Messenger RNA vaccination and B-cell responses in NSCLC patients.
Authors: Martin Sebastian, Lotta von Boehmer, Alfred Zippelius, Frank Mayer, Martin Reck, Djordje Atanackovic, Michael Thomas, Folker Schneller, Jan Stoehlmacher-Williams, Eray Goekkurt, Helga Bernhard, Andreas Groeschel, Birgit Scheel, Sven D. Koch, Thomas Lander, Gerd Rippin, Volker Wiegand, Ulrike Senta Gnad-Vogt, Karl-Josef Kallen, Alexander Knuth
Journal: Journal of Clinical Oncology (2012)

2573^ Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive ) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400µg, 800µg and 1600µg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3 rd and 5 th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 µg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.
Metabolomic discrimination of intestinal- and diffuse-type gastric cancer tissues using capillary electrophoresis time-of-flight mass spectrometry.
Authors: Masanori Terashima, Masatoshi Kusuhara, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Tamaki Fujimori, Hiroyuki Yamamoto, Kenjiro Kami, Yoshiaki Ohashi
Journal: Journal of Clinical Oncology (2012)

e14635 Background: Clinicopathological characteristics of gastric cancer patients strongly depend on histological type. In contrast with gene and protein expressions, metabolic properties of intestinal- and diffuse-type gastric cancer have been largely unknown. Here, we conducted metabolome analysis of paired non-tumor and tumor gastric tissues by using capillary electrophoresis and liquid chromatography combined with time-of-flight mass spectrometry (CE- and LC-TOFMS, respectively) in order to metabolomically characterize non-tumors (NTs), intestinal-type tumors (ITs), and diffuse-type tumors (DTs). Methods: Tumor and surrounding non-tumor tissues were surgically excised pair-wise from 27 gastric cancer patients (18 ITs and 9 DTs) who underwent gastrectomy at our institution between February and May 2011. Following tissue homogenization and metabolite extraction, we measured 254 and 138 metabolites, respectively, by CE-TOFMS and LC-TOFMS. Results: Metabolomic profiles of tumor tissues, especially ITs, were well-distinguished from those of NTs: Lactate and most glycolytic intermediate levels in ITs were significantly higher than those in NTs, which reaffirms the Warburg effect of cancer, but the significance was lesser in DTs. Levels of all the measured amino acids were significantly higher in ITs and relatively higher in DTs than in NTs, showing high capacities of cancer cells for protein synthesis. Although levels of ATP, GTP, and energy charge in ITs and DTs were lower than those in NTs, purine contents were rather higher in the tumors than in NTs, which may support their high demand for DNA replication. Moreover, reduced glutathione in DTs were the lowest among others, implying their potential vulnerability against oxidative stress. Conclusions: Metabolomic profiles of NTs, ITs, and DTs were discriminated by CE- and LC-TOFMS analyses: Considerably high lactate, amino acid, and purine levels highlighted the metabolome of tumors, especially of ITs. Relatively low energy and redox statuses of DTs, however, could be targeted for developing more effective cancer therapeutics.
Improving preparedness to respond to cross-border hepatitis A outbreaks in the European Union/European Economic Area: towards comparable sequencing of hepatitis A virus
Authors: Theresa Enkirch, Ettore Severi, Harry Vennema, Lelia Thornton, Jonathan Dean, Maria-Louise Borg, Anna Rita Ciccaglione, Roberto Bruni, Iva Christova, Siew Lin Ngui, Koye Balogun, Vratislav Němeček, Mia Kontio, Mária Takács, Andrea Hettmann, Rita Korotinska, Arthur Löve, Ana Avellón, Milagros Muñoz-Chimeno, Rita de Sousa, Denisa Janta, Jevgenia Epštein, Sofieke Klamer, Vanessa Suin, Stephan W Aberle, Heidemarie Holzmann, Kassiani Mellou, Josefine Lundberg Ederth, Lena Sundqvist, Anne-Marie Roque-Afonso, Sanja Kurečić Filipović, Mario Poljak, Line Vold, Kathrine Stene-Johansen, Sofie Midgley, Thea Kølsen Fischer, Mirko Faber, Jürgen J Wenzel, Johanna Takkinen, Katrin Leitmeyer
Journal: Eurosurveillance (2019)

Introduction Sequence-based typing of hepatitis A virus (HAV) is important for outbreak detection, investigation and surveillance. In 2013, sequencing was central to resolving a large European Union (EU)-wide outbreak related to frozen berries. However, as the sequenced HAV genome regions were only partly comparable between countries, results were not always conclusive. Aim The objective was to gather information on HAV surveillance and sequencing in EU/European Economic Area (EEA) countries to find ways to harmonise their procedures, for improvement of cross-border outbreak responses. Methods In 2014, the European Centre for Disease Prevention and Control (ECDC) conducted a survey on HAV surveillance practices in EU/EEA countries. The survey enquired whether a referral system for confirming primary diagnostics of hepatitis A existed as well as a central collection/storage of hepatitis A cases’ samples for typing. Questions on HAV sequencing procedures were also asked. Based on the results, an expert consultation proposed harmonised procedures for cross-border outbreak response, in particular regarding sequencing. In 2016, a follow-up survey assessed uptake of suggested methods. Results Of 31 EU/EEA countries, 23 (2014) and 27 (2016) participated. Numbers of countries with central collection and storage of HAV positive samples and of those performing sequencing increased from 12 to 15 and 12 to 14 respectively in 2016, with all countries typing an overlapping fragment of 218 nt. However, variation existed in the sequenced genomic regions and their lengths. Conclusions While HAV sequences in EU/EEA countries are comparable for surveillance, collaboration in sharing and comparing these can be further strengthened.
No association between NQO1 polymorphism and breast cancer risk in Siberian population
Authors: M. L. Filipenko, E. V. Pechkovsky, O. V. Mishukova, A. F. Lazarev, V. D. Petrova, I. A. Selezneva, T. V. Sinkina, J. N. Dimitriadi, N. A. Zarubina, S. A. Terekhova
Journal: Journal of Clinical Oncology (2007)

21185 Background: NQO1 is a two-electron reductase, which metabolizes a variety of xenobiotics. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. This protein's enzymatic activity prevents the one electron reduction of quinones that results in the production of radical species. Mutations in this gene have been associated with tardive dyskinesia (TD), an increased risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer. Genetic polymorphism of NQO1 is a C to T point mutation at base pair 609 of exon 6, which codes for a proline to serine substitution in NQO1 protein. This mutation results in a loss of NQO1 activity. Previously it was reported that wild-type NQO1 increased lung adenocarcinoma risk among male smokers in Taiwan. The association of the P187S polymorphism with breast cancer found in study of two independent populations (one from Tyrol, Austria, and the other from Prague, Czech Republic) (Menzel et al., 2004). Methods: The purpose of this study was to determine whether polymorphism in the NQO1 gene may influence breast cancer risk in Siberian population. The prevalent case-control design was used. The cases were 203 patients with breast cancer. Controls consisted of 182 noncancer outpatients. Genotyping for detecting of NQO1 gene polymorphism was performed using PCR amplification with the primer set of 5'- ACGCTAGCTCTGAACTGATTCTCT -3' and 5'- TTTTCTCCTCATCCTGTACCTCT –3’. The amplified PCR products were digested with HinfI and analyzed using electrophoresis on a 2.5% agarose gel. Results: Compared to subjects having C alleles (genotype CC), odds ratio (chi2=0.04, p=0.84309) were 1.116 (0.376–3.311) for subjects having genotype TT. Conclusions: These results suggest that polymorphic variation P187S of the NQO1 gene has no influence on breast cancer risk in Siberian women. No significant financial relationships to disclose.
Circular RNAs: A Novel Class of Functional RNA Molecules with a Therapeutic Perspective
Authors: Laura Santer, Christian Bär, Thomas Thum
Journal: Molecular Therapy (2019)

Circular RNAs (circRNAs) are a subclass of non-coding RNAs that lack free 3' and 5' ends and, thus, exist as continuous loop RNAs. Such circular transcripts have been identified for thousands of genes, are regulated in developmental stages and pathophysiological conditions, and are often expressed in a tissue- or cell-type-specific manner. For a long time, circular transcripts were considered as aberrant splicing by-products. However, high-throughput transcriptome sequencing and focused molecular characterization of individual circRNAs uncovered their ubiquity. Evidence emerges suggesting circRNAs are functional molecules. In this review, we illustrate the current knowledge of circRNA formation and circRNA detection methods. We summarize different molecular mechanisms of action and highlight circRNAs with specific roles in cardiovascular disease. Finally, we describe a number of tools for circRNA manipulation, which may be exploited for circRNA-based therapeutic interventions in the future.
Abstract 11885: Prognostic Value at 6 Months of Discharge RPVO in Intermediate- to High-Risk Pulmonary Embolism
Authors: Nicolas F Meneveau, Omar Ider, Vincent Descotes-Genon, Marie-France Seronde, Romain Chopard, Francois Schiele
Journal: Circulation (2011)

Aim: We aimed to evaluate the prognostic value at 6 months of residual pulmonary vascular obstruction (RPVO) measured before hospital discharge in pts with intermediate- or high-risk PE. Methods: 4...
Abstract 17841: Elevation of N-Terminal Pro-B-Type Natriuretic Peptide at Discharge is Associated With 2-Year Composite Endpoint of All-Cause Mortality and Heart Failure Hospitalization After Transcatheter Aortic Valve Replacement: Insights From a Multicenter Prospective OCEAN-TAVI Registry
Authors: Kazuki Mizutani, Masahiko Hara, Tsukasa Okai, Keiko Kajio, Takashi Murakami, Toshihiko Shibata, Minoru Yoshiyama, Toru Naganuma, Futoshi Yamanaka, Akihiro Higashimori, Norio Tada, Kensuke Takagi, Motoharu Araki, Hiroshi Ueno, Minoru Tabata, Shinichi Shirai, Yusuke Watanabe, Masanori Yamamoto, Kentaro Hayashida
Journal: Circulation (2017)

Background: We sought to investigate the 2-year prognostic impact of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at discharge, following transcatheter aortic valve replacement (TAV...
Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups
Authors: Kenneth W. Mahaffey, Meg J. Jardine, Severine Bompoint, Christopher P. Cannon, Bruce Neal, Hiddo J.L. Heerspink, David M. Charytan, Robert Edwards, Rajiv Agarwal, George Bakris, Scott Bull, George Capuano, Dick de Zeeuw, Tom Greene, Adeera Levin, Carol Pollock, Tao Sun, David C. Wheeler, Yshai Yavin, Hong Zhang, Bernard Zinman, Norman Rosenthal, Barry M. Brenner, Vlado Perkovic
Journal: Circulation (2019)

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67–0.95]; P =0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49–0.94]) and secondary (HR, 0.85 [95% CI, 0.69–1.06]) prevention groups ( P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61–1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59–1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56–1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups ( P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02065791.
Association between the cervicovaginal microbiome, BRCA1 mutation status, and risk of ovarian cancer: a case-control study
Authors: Nuno R Nené, Daniel Reisel, Andreas Leimbach, Dorella Franchi, Allison Jones, Iona Evans, Susanne Knapp, Andy Ryan, Shohreh Ghazali, John F Timms, Tobias Paprotka, Line Bjørge, Michal Zikan, David Cibula, Nicoletta Colombo, Martin Widschwendter
Journal: The Lancet Oncology (2019)