tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes
Authors: Steven P. Marso, Darren K. McGuire, Bernard Zinman, Neil R. Poulter, Scott S. Emerson, Thomas R. Pieber, Richard E. Pratley, Poul-Martin Haahr, Martin Lange, Kirstine Brown-Frandsen, Alan Moses, Simon Skibsted, Kajsa Kvist, John B. Buse
Journal: New England Journal of Medicine (2017)

Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome.Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups.Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).
Phase (Ph) II safety and efficacy results of a single-arm ph ib/II study of capmatinib (INC280) + gefitinib in patients (pts) with EGFR-mutated (mut), cMET-positive (cMET+) non-small cell lung cancer (NSCLC).
Authors: Yi-Long Wu, Dong-Wan Kim, Enriqueta Felip, Li Zhang, Xiaoqing Liu, Cai Cun Zhou, Dae Ho Lee, Ji-Youn Han, Alexander Krohn, Rachel Lebouteiller, Cindy Xu, Matthew Squires, Mikhail Akimov, Daniel Shao-Weng Tan
Journal: Journal of Clinical Oncology (2016)

9020 Background: Most pts withEGFR-mut NSCLC progress on EGFR tyrosine kinase inhibitor (TKI) therapy despite high initial response rates. cMET is dysregulated in 15−25% of NSCLC pts with acquired EGFR TKI resistance. INC280 is a highly selective cMET inhibitor with preclinical and preliminary clinical activity in EGFR-mut, cMET+ NSCLC when combined with EGFR TKIs. This Ph Ib/II study evaluates the safety and efficacy of INC280 + gefitinib in pts with EGFR-mut, cMET+ NSCLC who have progressed on gefitinib, erlotinib, or afatinib (NCT01610336). We report here on the Ph II expansion part. Methods: The Ph II primary objective is to estimate the overall clinical activity of INC280 + gefitinib. Secondary objectives include assessing safety and tolerability, and time-dependent clinical activity. Eligible pts ( ≥ 18 years; ECOG PS ≤ 2) must have documented EGFR-mut (exon19del/L858R; no T790M) NSCLC. Pts must have had RECIST-recorded clinical benefit on prior single-agent EGFR TKI before progression, and centrally assessed cMET+ (IHC 3+, or IHC 2+ and gene copy number [GCN] ≥ 5) post-progression. Pts were treated at the RP2D of INC280 400 mg BID (tablet/capsule) + gefitinib 250 mg QD. Results: As of Sep 28 2015, 83 pts were enrolled in the Ph II expansion part (median age 61 years; 84% Asian; 14% PS 0; 55% had 1 prior line of therapy). 66/83 (80%) pts received EGFR TKI as their last single or combined therapy. 42/83 (51%) pts discontinued treatment, mainly due to disease progression (34%). The most common AEs (regardless of causality) were hypoalbuminemia (29%), peripheral edema (27%), and decreased appetite (23%). The most common Grade 3/4 AE (regardless of causality) was increased amylase (7%). Partial responses (PRs) were seen in 12/65 evaluable pts (ORR 18%) and 40/65 (62%) pts had stable disease (SD); disease control rate [PR + SD] 80%. 10/53 pts with IHC 3+ or IHC 2+ and GCN ≥ 5 had PRs (ORR 19%) and 7/23 pts with GCN ≥ 6 had PRs (ORR 30%). Conclusions: INC280 400 mg BID + gefitinib is well-tolerated and shows encouraging clinical activity in EGFR TKI-resistant NSCLC pts, particularly in pts with high cMET GCN. Clinical trial information: NCT01610336.
Host transcriptomics for diagnosis of infectious diseases: one step closer to clinical application
Authors: Octavio Ramilo, Asuncion Mejias
Journal: European Respiratory Journal (2017)

One of the most common and challenging situations that physicians face in their daily clinical practice is the diagnosis and management of patients with acute respiratory infections. Until recently, the most common and "practical" approach followed by clinicians was to treat the majority of these patients empirically with antibiotics. The pragmatic argument has been that antibiotics are prescribed to treat the bacteria causing the respiratory infection, even if symptoms suggest a viral infection because of the risk of a concomitant or potential superimposed bacterial infection. Arguments against this practical approach have become more evident in recent years as new studies have shed light on the true impact of this strategy. Traditionally, most concerns regarding the use of unnecessary antimicrobial agents have been related to the development of resistant bacteria [1]. This concern was mostly perceived as an epidemiological, global issue, not affecting the individual patient whose symptoms need to be addressed at that precise moment. Studies in the last decade, however, have revealed the negative effects of antimicrobial therapy on the composition of the microbiome of the individual patient and its potential consequences [2, 3]. We learned the importance of the microbiome in directing the normal physiological maturation of the immune system and how changes on its composition can increase the risk of a number of immune-mediated and infectious conditions affecting the gastrointestinal and respiratory tracts. Furthermore, studies have shown that excessive antibiotic use can be associated with poor outcomes in critically ill children [4, 5]. This evidence has dramatically shifted the perception of the impact of inappropriate antibiotic use, from a vague global concern to the individual patients we treat every day in our clinical practice. This new awareness has encouraged the establishment of new antimicrobial stewardship programmes aimed at educating clinicians about the appropriate use of antimicrobial agents [6, 7]. Advancing host transcriptomics for diagnosis of infectious diseases <http://ow.ly/4CQq30c24SM>
Anti-Myeloma Activity of a Syringolin Analog: A Dual 20S Proteasome Inhibitor of Beta 2 and 5 Subunits
Authors: Takashi Yoshida, Masaki Ri, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Reham Ashour, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Satoshi Ichikawa, Shinsuke Iida
Journal: Blood (2016)
INJURY PATTERNS IN GERMAN MEN'S PROFESSIONAL BASKETBALL AND HANDBALL – A COMPARISON
Authors: Patrick Luig, Hendrik Bloch, Christian Klein
Journal: British Journal of Sports Medicine (2017)

Background Basketball (BB) and handball (HB) are both dynamic and physical indoor transition team sports. However, performance profiles, specifically with regard to allowed legal physical contact, differ widely. Knowledge of injury risk and injury patterns, particularly in regular league play, is limited. Objective Comparative analysis of injury risk and injury patterns in German men's professional BB and HB. Design Prospective observational cohort study. Setting Two highest German professional leagues in men's BB and HB. Participants All first and second league BB (n=514) and HB (n=804) players who played in at least one competitive club match during the 2014–2015 season. Interventions (or Assessment of Risk Factors) Analysis of all injuries that were registered by clubs or physicians with the VBG as part of the occupational accident reporting and that either led to player's short-term disability (time-loss) and/or to medical treatment costs (medical-attention). Main Outcome Measurements Injury prevalence, injury incidence, injured body parts, type of injury, medical costs, short-term disability. Results 992 of the 1.318 observed players were injured. A total of 3,071 injuries were recorded. Prevalence rate (BB: 70.0%; HB: 78.6%) and cumulative incidence rate (BB: 2.0 injuries/season; HB: 2.5 injuries/season) were significantly higher in HB. By contrast, BB (95.4 injuries/1,000 h) showed higher match incidences than HB (74.7 injuries/1,000 h). The ankle (19.6%) in BB and the knee (15.2%) in HB were the body parts most commonly affected. Moreover, in both sports injury risk and patterns varied considerably according to level of play (league) and playing position. Conclusions Both, German men's professional BB and HB are associated with a high risk of injury in regular league play. However, injury patterns in professional men's BB and HB differ extensively reflecting varying performance profiles. Preventive strategies and measures should therefore be tailored towards sport-specific and, moreover, position-specific risks and patterns.
Lysosomal Disruption Augments Obinutuzumab-Induced Direct Cell Death
Authors: Antoni Domagala, Malgorzata Bobrowicz, Joanna Stachura, Marta Siernicka, Piotr Mrowka, Michal Dwojak, Beata Pyrzynska, Malgorzata Firczuk, Magdalena Winiarska
Journal: Blood (2016)
The oral commensal Streptococcus mitis activates the aryl hydrocarbon receptor in human oral epithelial cells
Authors: Stian A Engen, Gro H Rørvik, Olav Schreurs, Inger JS Blix, Karl Schenck
Journal: International Journal of Oral Science (2017)

Streptococcus mitis (S. mitis) is a pioneer commensal bacterial species colonizing many of the surfaces of the oral cavity in healthy individuals. Yet, not much information is available regarding its interaction with the host. We used examination of its transcriptional regulation in oral keratinocytes to elucidate some of its potential roles in the oral cavity. Transcription factor analysis of oral keratinocytes predicted S. mitis-mediated activation of aryl hydrocarbon receptor (AhR). Activation and functionality of AhR was confirmed through nuclear translocation determined by immunofluorescence microscopy and real-time polymerase chain reaction with reverse transcription analysis of CYP1A1, the hallmark gene for AhR activation. Addition of Streptococcus mutans or Streptococcus gordonii did not induce CYP1A1 transcription in the keratinocyte cultures. Introduction of an AhR-specific inhibitor revealed that S. mitis-mediated transcription of CXCL2 and CXCL8 was regulated by AhR. Elevated levels of prostaglandin E2 (enzyme-linked immunosorbent assay) in supernatants from S. mitis-treated oral epithelial cells were also attenuated by inhibition of AhR activity. The observed AhR-regulated activities point to a contribution of S. mitis in the regulation of inflammatory responses and thereby to wound healing in the oral cavity. The concept that the oral commensal microbiota can induce AhR activation is important, also in view of the role that AhR has in modulation of T-cell differentiation and as an anti-inflammatory factor in macrophages. A bacterium living in the mouth facilitates oral wound healing by activating a protein involved in immune and inflammatory responses. Stian Engen and colleagues from the University of Oslo in Norway cultured human oral epithelial cells with Streptococcus mitis, a bacterium that colonizes surfaces in healthy peoples' mouths. Its presence altered the activity of 29 proteins involved in transcribing RNA from DNA. Further analyses were conducted on one of these "transcription factors", the aryl hydrocarbon receptor, which is known to have a role in immune and inflammatory responses. The researchers found that its activation by S. mitis helps heal oral wounds by stimulating the generation of molecules that attract white blood cells to the area to regulate inflammation. This is followed by the release of a lipid that helps in wound repair.
Effect of Obesity and Underweight Status on Perioperative Outcomes of Congenital Heart Operations in Children, Adolescents, and Young Adults
Authors: Michael L. O’Byrne, Sunghee Kim, Christoph P. Hornik, Babatunde A. Yerokun, Roland A. Matsouaka, Jeffrey P. Jacobs, Marshall L. Jacobs, Richard A. Jonas
Journal: Circulation (2017)

Background: Extreme body mass index (BMI; either very high or very low) has been associated with increased risk of adverse perioperative outcome in adults undergoing cardiac surgery. The effect of BMI on perioperative outcomes in congenital heart disease patients has not been evaluated. Methods: A multicenter retrospective cohort study was performed studying patients 10 to 35 years of age undergoing a congenital heart disease operation in the Society of Thoracic Surgeons Congenital Heart Surgery Database between January 1, 2010, and December 31, 2015. The primary outcomes were operative mortality and a composite outcome (1 or more of operative mortality, major adverse event, prolonged hospital length of stay, and wound infection/dehiscence). The associations between age- and sex-adjusted BMI percentiles and these outcomes were assessed, with adjustment for patient-level risk factors, with multivariate logistic regression. Results: Of 18 337 patients (118 centers), 16% were obese, 15% were overweight, 53% were normal weight, 7% were underweight, and 9% were severely underweight. Observed risks of operative mortality ( P =0.04) and composite outcome ( P &lt;0.0001) were higher in severely underweight and obese subjects. Severely underweight BMI was associated with increased unplanned cardiac operation and reoperation for bleeding. Obesity was associated with increased risk of wound infection. In multivariable analysis, the association between BMI and operative mortality was no longer significant. Obese (odds ratio, 1.28; P =0.008), severely underweight (odds ratio, 1.29; P &lt;0.0001), and underweight (odds ratio, 1.39; P =0.002) subjects were associated with increased risk of composite outcome. Conclusions: Obesity and underweight BMI were associated with increased risk of composite adverse outcome independently of other risk factors. Further research is necessary to determine whether BMI represents a modifiable risk factor for perioperative outcome.
Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression
Authors: Jayu Jen, Yen-An Tang, Ying-Hung Lu, Che-Chung Lin, Wu-Wei Lai, Yi-Ching Wang
Journal: Molecular Cancer (2017)

Oct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression. Oct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses. We confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients. Our study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis.
Association of TNF Alpha -308 GG Genotype with Post Operative Infections in Oesophageal Cancer Patients
Authors: K Azim, J Reynolds, D Kelleher, R McManus
Journal: Endoscopy (2004)

Aim: To find the effect of TNF alpha gene biallelic single nucleotide polymorphism (snp) at -308 position on the outcome of Surgery in Oesophageal Cancer patients.
Genomic Profiling of Small-Bowel Adenocarcinoma
Authors: Alexa B. Schrock, Craig E. Devoe, Robert McWilliams, James Sun, Thomas Aparicio, Philip J. Stephens, Jeffrey S. Ross, Richard Wilson, Vincent A. Miller, Siraj M. Ali, Michael J. Overman
Journal: JAMA Oncology (2017)

Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking.
Feasibility Trial for Primary Stroke Prevention in Children with Sickle Cell Anemia in Nigeria (SPIN Trial)
Authors: Najibah Aliyu Galadanci, Shehu Umar Abdullahi, Leah Danielle Vance, Musa Tabari, Shehi Abubakar, Belonwu Raymond, Salihu Auwal, Aisha Amal Galadanci, Binta WUDIL Jibir, Halima Bello-Manga, Kathleen A Neville, Fenella Kirkham, Yu Shyr, Sharon E. Phillips, Brittany Covert, Adetola A. Kassim, Lori Jordan, Muktar Aliyu, Michael DeBaun
Journal: Blood (2016)
Oncostatin M induces detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells
Authors: Cheryl L. Jorcyk, Ryan G. Holzer, Randall E. Ryan
Journal: Cancer Research (2004)

5042   Oncostatin M (OSM), an IL-6 family cytokine, has previously been shown to inhibit the proliferation of several breast cancer cell lines in vitro. Our studies report additional effects of OSM treatment on the human breast carcinoma cell line T-47D. OSM treatment of T-47D cells for 1 to 3 days alters cell morphology from a normal epithelial phenotype to more mesenchymal phenotype. These changes are followed by a 250% increase in cell detachment after 5 to 8 days of OSM treatment. Detached aggregates of cells are viable and easily readhere to several extracellular matrix components. In addition, immunoblots of concentrated conditioned media collected from OSM-treated T-47D cells showed an increase in the expression of the proteases cathepsin D and cathepsin L, which have been implicated in metastasis. Importantly, OSM treated T-47D cells show an almost 300% increase in invasive capacity as measured by the Matrigel invasion chamber assay. Collectively, these data demonstrate that OSM induces a metastatic phenotype in T-47D cells in vitro, and suggest that OSM could enhance metastasis in vivo. Our results suggest that experimental therapeutic approaches utilizing OSM as a treatment for human breast cancer should proceed with caution, and that OSM itself may be a valid therapeutic target.
Addition of carboplatin to standard chemotherapy in the adjuvant treatment of unselected triple negative breast cancers (TNBC).
Authors: Marcus Vetter, Spyridon Fokas, Ewelina Biskup, Thomas Schmid, Fabienne Schwab, Andreas Schoetzau, Uwe Gueth, Christoph Rochlitz, Rosanna Zanetti-Daellenbach
Journal: Journal of Clinical Oncology (2016)

1034 Background: Anthracycline- and taxane-based adjuvant chemotherapy is the common systemic treatment in TNBC to date. Addition of platinum derivatives in the neo-adjuvant setting showed improved pathological complete response. In the advanced/metastatic setting, complete and partial responses were improved in patients with BRCA1/2 mutations but not in an unselected population. Data on platinum-derivatives in the adjuvant setting are limited. Our study evaluated the role of carboplatinum in addition to standard adjuvant therapy in early TNBC patients after primary surgery. Methods: We conducted a retrospective, single-center study in a Swiss cohort. All patients with stage I – III TNBC who underwent primary breast surgery and axillary staging between 2003 and 2014 were included. Patients with neoadjuvant or palliative treatment were excluded. Two cohorts were identified: Cohort A with standard chemotherapy (anthracyclines and taxanes), cohort B with additional carboplatinum-treatment. Results: Eighty-three patients with TNBC post breast surgery and axillary staging with subsequent adjuvant chemotherapy were identified. Stage and grade were well balanced between cohorts. Patients in cohort A (N = 54) were treated with anthracycline- and taxane-based regimes while patients in cohort B (N = 29) additionally received carboplatin. Most commonly, patients received 4 cycles of epirubicin/cyclophosphamide, followed by 4 cycles of docetaxel/carboplatin. There was no significant difference in relapse free (distant or local) survival (p = 0.755). Mean relapse free survival was 100 vs. 98 months. There was also no difference in overall survival between the two cohorts (p = 0.208). Mean survival was 98 vs. 91 months. In cohort A, 43.47% had 6 or more cycles of treatment vs. 89.7% in cohort B (p < 0.001). Conclusions: In an unselected cohort of early TNBC, addition of carboplatin in an adjuvant setting was not beneficial. The sample is too small to define subgroups of patient, which might benefit from carboplatin therapy. Further prospective trials to evaluate the addition of platinum in the adjuvant setting are warranted.
Successful closure of anastomotic dehiscence after colon–rectal cancer resection using the Apollo overstitch suturing system
Authors: Valerio Belfiori, Fillipo Antonini, Samuele Deminicis, Barbara Marraccini, Simona Piergallini, Walter Siquini, Giampiero Macarri
Journal: Endoscopy (2017)

Anastomotic dehiscence is the most common cause of postoperative morbidity and mortality. The Overstitch endoscopic suturing system (Apollo Endosurgery, Austin, Texas, USA) is a disposable, single-use suturing device that is mounted onto a double-channel therapeutic endoscope and allows placement of either running or interrupted full-thickness sutures. Several reports have described endoscopic suturing as a treatment option for management of gastrointestinal defects and for stent anchorage [1] [2] [3] [4] [5]. To our knowledge, there is no report on the closure of colonic anastomotic dehiscence with this device.