tbuckley/cabot-search huggingface dataset:
OC-016 Regional variations in faecal occult blood testing screening for colorectal cancer in the united kingdom – results from a multicentre study
Authors: AT George, S Aggarwal, S Dharmavaram, A Menon, M Dube, M Vogler, A Field
Journal: Gut (2017)

Introduction  To compare regional outcomes of Faecal Occult Blood testing(FOBT)screening  Method  National Bowel Cancer Audit Programme data from three NHS Hospitals,for colorectal cancers(CRC)in the screening age group(60–74 years)over a 2 year period(August 2011–2013)were linked for their FOBT screening status( BCSP database/Eastern Hub ).Patient locations were divided into 4 regions(based on home postcodes):Mansfield(Mfd)postcodes(NG17-21);Newark(Nw)postcodes(NG22-25);Nottingham(Ngh)postcodes(NG1-NG16);Derby(Drby)postcodes(DE1-DE75).Patient/tumour demographics and survival for Interval cancers(IC-screening patients developing cancers within 2 years of a negative FOB test),screen-detected cancers(SDC)and cancers in those who declined the screening programme(DSP)were analysed.All regions and centres involved were in incident rounds of screening.Tumours at and beyond splenic flexure were considered left-sided.1-year mortality was looked at as all patients had a minimum of 1 year follow-up.  Results  Of the 496 cancers detected,123 (25%)were IC,219 (44%)were DSP and 154 (31%)were SDC. Demographic parameters were comparable between regions including male: female ratio (Mfd (51:27); Nw (20:18); Ngh (134:88); Drby (102:58):p=0.52, X2=2.22); age (mean) at cancer diagnosis (years) (Mfd(65.9); Nw (65.9); Ngh (66.2); Drby (67.9): p=0.46, X2=4.67). Tumour characteristics including left:right-sided (Mfd(59:19); Nw(27:11); Ngh (168:54); Drby (104:54): p=0.17,X2=5.02) and Duke’s staging Low(A/B): High (C/D) (Mfd(39:39); Nw (24:14); Ngh (109:113); Drby (67:91): p=0.126,X2=5.70) were comparable.Ethnic demographics,deprivation index,d patient follow-up were comparable between the four regions.Mfd region had a higher proportion of IC compared to other regions (Mfd(n=78); IC-25 (32%), DSP-25 (32%), SDC-28 (36%); Nw (n=38); IC-7 (18%), DSP-22 (58%), SDC-9(24%); Ngh (n=222); IC-44 (20%), DSP-111 (50%), SDC-67(30%); Drby (n=158); IC-47(30%), DSP-61 (38%), SDC-50(32%):  p =  0.025,X2=14.41  ). Mfd had a significantly higher 1 year mortality compared to other regions (Mfd 13:IC-5.DSP-3.SDC-5; Nw 2: IC-1. DSP-1.SDC-0; Ngh 22: IC-6, DSP-16,SDC-0; Drby 12:IC-7, DSP-5, SDC-0:  p=   0.002, X2 = 20.07).   The median time (months) between cancer diagnosis and death was shortest for the Mfd region (Mfd-7; Nw-13.5; Ngh-15; Drby-15.5)  Conclusion  Our findings for the first time highlight regional variations in CRC mortality. We cannot explain our findings based on existing literature or on the known behaviour of colorectal cancer. Though there remains the possibility that our findings may be incidental, this also raises the possibility of the existence of hitherto undetected regional variations in colorectal cancer phenotypes.  Disclosure of Interest  None Declared
Future directions for studying the evolution of general intelligence
Authors: Judith M. Burkart, Michèle N. Schubiger, Carel P. van Schaik
Journal: Behavioral and Brain Sciences (2017)

Abstract The goal of our target article was to lay out current evidence relevant to the question of whether general intelligence can be found in nonhuman animals in order to better understand its evolution in humans. The topic is a controversial one, as evident from the broad range of partly incompatible comments it has elicited. The main goal of our response is to translate these issues into testable empirical predictions, which together can provide the basis for a broad research agenda.
mGlu <sub>7</sub> potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome
Authors: Rocco G. Gogliotti, Rebecca K. Senter, Nicole M. Fisher, Jeffrey Adams, Rocio Zamorano, Adam G. Walker, Anna L. Blobaum, Darren W. Engers, Corey R. Hopkins, J. Scott Daniels, Carrie K. Jones, Craig W. Lindsley, Zixiu Xiang, P. Jeffrey Conn, Colleen M. Niswender
Journal: Science Translational Medicine (2017)

mGlu 7 positive allosteric modulation rescues long-term potentiation, learning, and memory phenotypes and prevents apneas in a mouse model of Rett syndrome.
Comment on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126–2140
Authors: Sanjay Kalra, Yatan Pal Singh Balhara
Journal: Diabetes Care (2017)

We welcome the timely publication of the American Diabetes Association (ADA) Position Statement “Psychosocial Care for People With Diabetes” by Young-Hyman et al. (1). This document seeks to provide diabetes care providers with evidence-based guidelines for psychosocial assessment and care of persons with diabetes as well as their family members. We highlight a few comparisons between this statement (1) and India’s national recommendations on the psychosocial management of diabetes (2).

ADA supports the integration of psychosocial care in medical care and its universal provision …
パクリタキセルの高容量高分子ミセル:安全性とin vivoでの抗癌活性に対する高用量薬物療法の意義【Powered by NICT】
Authors: He Zhijian, Wan Xiaomeng, Schulz Anita, Bludau Herdis, A Dobrovolskaia Marina, T Stern Stephan, A Montgomery Stephanie, Yuan Hong, Li Zibo, Alakhova Daria, Sokolsky Marina, B Darr David, M Perou Charles, Jordan Rainer, Luxenhofer Robert, V Kabanov Alexander
Journal: Biomaterials (2016)
Three gene molecular signature for prostate cancer recurrence
Authors: Ubaradka Sathyanarayana, Janice Riley, Jackie Neri, John Hurley, Bruce Dalkin, Phillip Miller, Raymond Nagle, Gary Pestano
Journal: Cancer Research (2008)

4429   Tumorigenesis is caused by the inactivation of multiple tumor suppressor genes and/or activation of proto-oncogenes. It has become critically important to develop assays that simultaneously detect multiple genetic abnormalities that may lead to the modulation of genes involved in the development of malignancy. Early detection of these genetic changes may help to prevent cancer, or aid in prognosis and therapy. The goal of this study was to utilize widely available formalin-fixed paraffin embedded (FFPE) samples to identify signatures of genetic abnormalities in prostate cancer. A subset of patient cases, n = 28, was selected from the University of Arizona Prostate Cancer Bank as the test population. Primary biopsies from individual cases with or without prostate cancer recurrence at least five years post-surgery, were selected for multiplexed mRNA analysis. Cancer recurrence was determined by rising PSA levels. Total RNA was isolated from the test FFPE cores and subjected to expression analysis. Control samples were freshly isolated RNA samples from cell lines and tissues. Of the 502 genes analyzed, message was detectable for 367. No clear molecular signature for prostate cancer recurrence was determined with unsupervised clustering analyses on all samples for all genes. Instead, the determination of signatures was dependent on the stringency of detection obtained for specific samples. Samples (n = 9) with low background signals, defined as weak binding to irrelevant probes, were easily sorted into recurrent or non-recurrent groups for prostate cancer. Marked over-expression of the proto-oncogene, WNT5a, and the thymidine kinase, TK1, was noted in samples in which prostate cancer later recurred. The expression of the growth-arrest specific gene, GAS1, was most associated with non-recurrence of prostate cancer. Significantly, this pattern of expression was consistently observed for the three genes when the larger sample set was re-analyzed. This study highlights the feasibility of conducting highly multiplexed biomarker discovery assays utilizing mRNA recovered from FFPE tissues. We have identified a small gene signature, characterized by over-expression of WNT5a and TK1, and down-regulation of GAS1, that may predict the likelihood of prostate cancer recurrence.
Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease
Authors: Vladimir Tesar, Kazimierz Ciechanowski, York Pei, Irina Barash, Megan Shannon, Ray Li, Jason H. Williams, Matteo Levisetti, Steven Arkin, Andreas Serra
Journal: Journal of the American Society of Nephrology (2017)

Overactivation of Src has been linked to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). This phase 2, multisite study assessed the efficacy and safety of bosutinib, an oral dual Src/Bcr-Abl tyrosine kinase inhibitor, in patients with ADPKD. Patients with ADPKD, eGFR≥60 ml/min per 1.73 m 2 , and total kidney volume ≥750 ml were randomized 1:1:1 to bosutinib 200 mg/d, bosutinib 400 mg/d, or placebo for ≤24 months. The primary endpoint was annualized rate of kidney enlargement in patients treated for ≥2 weeks who had at least one postbaseline magnetic resonance imaging scan that was preceded by a 30-day washout (modified intent-to-treat population). Of 172 enrolled patients, 169 received at least one study dose. Per protocol amendment, doses for 24 patients who initially received bosutinib at 400 mg/d were later reduced to 200 mg/d. The annual rate of kidney enlargement was reduced by 66% for bosutinib 200 mg/d versus placebo (1.63% versus 4.74%, respectively; P =0.01) and by 82% for pooled bosutinib versus placebo (0.84% versus 4.74%, respectively; P &lt;0.001). Over the treatment period, patients receiving placebo or bosutinib had similar annualized eGFR decline. Gastrointestinal and liver-related adverse events were the most frequent toxicities. In conclusion, compared with placebo, bosutinib at 200 mg/d reduced kidney growth in patients with ADPKD. The overall gastrointestinal and liver toxicity profile was consistent with the profile in prior studies of bosutinib; no new toxicities were identified. (ClinicalTrials.gov: NCT01233869).
Abstract 357: Manganese Superoxide Dismutase: a Novel Mediator of Heart Failure Development and Progression
Authors: Sumitra Miriyala, Mini Chandra, Benjamin Maxey, Daret K St. Clair, Manikandan Panchatcharam
Journal: Circulation Research (2015)

Manganese Superoxide Dismutase (MnSOD), an antioxidant enzyme that catalyzes the conversion of superoxide radicals (O 2 •-) in mitochondria. Constitutive activation mitochondrial reactive oxygen species (ROS) has been implicated in both the pathogenesis and the progression of cardiovascular disease. Absence of SOD2 (gene that encodes MnSOD) is found to be embryonic lethal in animal models due to impairment of mitochondrial function, most noticeably in the heart. In our earlier investigation, we have shown that the MnSOD mimetic, MnTnBuOE-2-PyP 5+ distributes 3-fold more in mitochondria than in cytosol. The exceptional ability of MnTnBuOE-2-PyP 5+ to dismute O 2 •- parallels its ability to reduce ONOO– and CO3–. Based on our earlier reports, we have generated mice that specifically lack MnSOD in cardiomyocytes (Mhy6-SOD2 Δ ). These mice showed early mortality ~4 months due to cardiac mitochondrial dysfunction. Oxidative phosphorylation (OXPHOS) in mitochondria is the predominant mode for O 2 consumption in cells, and the mitochondria are the primary source of ROS in cells due to leaked electrons. FACS analyses using Mito-Tracker Green indicated that the mass of mitochondria per cell was slightly decreased in the Mhy6-SOD2 Δ to the wild type. We then examined OXPHOS levels in Mhy6-SOD2 Δ v.s. wild type using a Seahorse XF analyzer. The rate of oxygen consumption per cells was signi[[Unable to Display Character: &amp;#64257;]]cantly lower in Mhy6-SOD2 Δ cardiomyocytes than that in wild type. The most noticeable difference in the O 2 consumption was found in the presence of FCCP (H+ ionophore / uncoupler). FCCP is an inner membrane pore opener which resets the proton gradient between the mitochondrial matrix and the interspace, resulting in continuous transport of protons and consuming O 2 at the maximum potential. Remarkably, while the FCCP treatment increased O 2 consumption in wild type, the treatment showed no effect on the O 2 consumption in the Mhy6-SOD2 Δ cardiomyocytes. The result indicated that the low basal OXPHOS activity in Mhy6-SOD2 Δ was due to unusually low OXPHOS potential. We examined glycolysis in these cells by measuring extracellular acidi[[Unable to Display Character: &amp;#64257;]]cation (ECAR) and the pattern exactly opposite to that of oxygen consumption rate (OCR) was observed for glycolysis rates between Mhy6-SOD2 Δ and wild type.
ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model
Authors: Ernest Moles, Silvia Galiano, Ana Gomes, Miguel Quiliano, Cátia Teixeira, Ignacio Aldana, Paula Gomes, Xavier Fernàndez-Busquets
Journal: Biomaterials (2017)
Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration
Authors: Huseyin Naci, Katelyn R. Smalley, Aaron S. Kesselheim
Journal: JAMA (2017)

Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements.To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval.Publicly available FDA documents were reviewed to identify the preapproval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA's database of postmarketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017.Granting of accelerated approval.Characteristics of preapproval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized.The FDA granted accelerated approval to 22 drugs for 24 indications (19 for indications involving cancer treatment) between 2009 and 2013. A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, -15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements, including reliance on surrogate measures as outcomes.
RNF43変異型膵腫瘍のWnt‐FZD5シグナル伝達回路がドラッガブルな脆弱性であることが,ゲノム全体にわたるCRISPRスクリーニングによって示された
Authors: Steinhart Zachary, Robitaille Melanie, Angers Stephane, Pavlovic Zvezdan, Chandrashekhar Megha, Hart Traver, Wang Xiaowei, Zhang Xiaoyu, Brown Kevin R, Adams Jarrett, Pan James, Sidhu Sachdev, Moffat Jason, Jaksani Sridevi, Overmeer Rene, Boj Sylvia F, Clevers Hans
Journal: Nature Medicine (2017)
Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer
Authors: Nicholas A. Taylor, Sarah C. Vick, Michael D. Iglesia, W. June Brickey, Bentley R. Midkiff, Karen P. McKinnon, Shannon Reisdorf, Carey K. Anders, Lisa A. Carey, Joel S. Parker, Charles M. Perou, Benjamin G. Vincent, Jonathan S. Serody
Journal: Journal of Clinical Investigation (2017)

Claudin-low breast cancer is an aggressive subtype that confers poor prognosis and is found largely within the clinical triple-negative group of breast cancer patients. Here, we have shown that intrinsic and immune cell gene signatures distinguish the claudin-low subtype clinically as well as in mouse models of other breast cancer subtypes. Despite adaptive immune cell infiltration in claudin-low tumors, treatment with immune checkpoint inhibitory antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were ineffective in controlling tumor growth. CD4+FoxP3+ Tregs represented a large proportion of the tumor-infiltrating lymphocytes (TILs) in claudin-low tumors, and Tregs isolated from tumor-bearing mice were able to suppress effector T cell responses. Tregs in the tumor microenvironment highly expressed PD-1 and were recruited partly through tumor generation of the chemokine CXCL12. Antitumor efficacy required stringent Treg depletion combined with checkpoint inhibition; delays in tumor growth were not observed using therapies that modestly diminished the number of Tregs in the tumor microenvironment. This study provides evidence that the recruitment of Tregs to the tumor microenvironment inhibits an effective antitumor immune response and highlights early Treg recruitment as a possible mechanism for the lack of response to immune checkpoint blockade antibodies in specific subtypes of cancer that are heavily infiltrated with adaptive immune cells.
Letter by El-Battrawy et al Regarding Article, “The Brugada Syndrome Susceptibility Gene <i>HEY2</i> Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity”
Authors: Ibrahim El-Battrawy, Siegfried Lang, Martin Borggrefe, Xia-Bo Zhou, Ibrahim Akin
Journal: Circulation Research (2017)
Outcomes of Cardiac Resynchronization Therapy With or Without Defibrillation in Patients With Nonischemic Cardiomyopathy
Authors: Francisco Leyva, Abbasin Zegard, Edmund Acquaye, Christopher Gubran, Robin Taylor, Paul W.X. Foley, Fraz Umar, Kiran Patel, Jonathan Panting, Howard Marshall, Tian Qiu
Journal: Journal of the American College of Cardiology (2017)

Recent studies have cast doubt on the benefit of cardiac resynchronization therapy (CRT) with defibrillation (CRT-D) versus pacing (CRT-P) for patients with nonischemic cardiomyopathy (NICM). Left ventricular myocardial scar portends poor clinical outcomes. The aim of this study was to determine whether CRT-D is superior to CRT-P in patients with NICM either with (+) or without (−) left ventricular midwall fibrosis (MWF), detected by cardiac magnetic resonance. Clinical events were quantified in patients with NICM who were +MWF (n = 68) or −MWF (n = 184) who underwent cardiac magnetic resonance prior to CRT device implantation. In the total study population, +MWF emerged as an independent predictor of total mortality (adjusted hazard ratio [aHR]: 2.31; 95% confidence interval [CI]: 1.45 to 3.68), total mortality or heart failure hospitalization (aHR: 2.02; 95% CI: 1.32 to 3.09), total mortality or hospitalization for major adverse cardiac events (aHR: 2.02; 95% CI: 1.32 to 3.07), death from pump failure (aHR: 1.95; 95% CI: 1.11 to 3.41), and sudden cardiac death (aHR: 3.75; 95% CI: 1.26 to 11.2) over a maximum follow-up period of 14 years (median 3.8 years [interquartile range: 2.0 to 6.1 years] for +MWF and 4.6 years [interquartile range: 2.4 to 8.3 years] for −MWF). In separate analyses of +MWF and −MWF, total mortality (aHR: 0.23; 95% CI: 0.07 to 0.75), total mortality or heart failure hospitalization (aHR: 0.32; 95% CI: 0.12 to 0.82), and total mortality or hospitalization for major adverse cardiac events (aHR: 0.30; 95% CI: 0.12 to 0.78) were lower after CRT-D than after CRT-P in +MWF but not in −MWF. In patients with NICM, CRT-D was superior to CRT-P in +MWF but not −MWF. These findings have implications for the choice of device therapy in patients with NICM.
An Important Step for Thrombocardiology
Authors: Eugene Braunwald
Journal: New England Journal of Medicine (2017)

It has been known for more than a century that coronary-artery thrombosis is the most common precipitant of acute myocardial infarction and that atherosclerotic plaques in the coronary arteries are often responsible for angina pectoris. When anticoagulants and antiplatelet agents became available, clinical investigators rushed to study their efficacy and safety in patients with coronary artery disease. Attention was focused on two large populations — patients with acute coronary syndromes and those with stable ischemic disease, many of whom had previously had an acute event. Hundreds of trials, registries, and systematic analyses on the benefits and risks of individual and . . .
Abstract 13264: Varying Ventilation Strategies During Cardiac Arrest Has Minimal Impact on Hemodynamics
Authors: Norman Paradis, Karen Moodie, Christopher L Kaufman, Joshua W Lampe
Journal: Circulation (2016)

Introduction: Prolonged duty cycle ventilation and hyperventilation are associated with reduced venous return during CPR. Meanwhile, the 30:2 compressions-ventilation method requires pauses in compressions, which could also negatively affect hemodynamics. We investigated the effect of varying ventilation strategies on hemodynamics in a swine model of cardiac arrest. Hypothesis: Continuous ventilations with a short duty cycle, as compared to longer duty cycles and standard 30:2 ventilation, would be associated with improvements in hemodynamics. Methods: CPR was performed on eight domestic swine (~30 kg) using standard physiological monitoring. Blood flow was measured in the inferior vena cava (IVC). Ventricular fibrillation (VF) was electrically induced. Mechanical chest compressions (CC) were started after four minutes of VF. CC were delivered at a rate of 100 compressions per minute and a depth of 2” for a total of 12 min. Animals were intubated and mechanically ventilated throughout the experiment. Three ventilation strategies were tested: 1) continuous ventilator-driven ventilation (CV-DV) at a rate of 6 breaths per minute and a 0.20 duty cycle, 2) CV-DV at a rate of 6 breaths per minute and a 0.50 duty cycle, and 3) standard 30:2 at a 0.20 duty cycle. All tidal volumes were calculated as 7 ml/kg. PEEP was set to zero for all ventilations. Results: Across 12 minutes of CPR, aortic pressure and coronary perfusion pressure was greater with CV-DVs of 0.20 and 0.50 duty cycle as compared to 30:2 (Table). Overall net flow in the IVC was not different among ventilation strategies. Conclusions: As compared to the 30:2 method, CV-DVs at 0.20 and 0.50 duty cycles produced small increases in blood pressures but no changes in venous return. Further research is needed to determine if hemodynamics can be improved by synchronizing continuous ventilations to CC and if this association reflects elimination of the interruptions in chest compressions.