tbuckley/cabot-search huggingface dataset:
Benchmarking life expectancy and cancer mortality: global comparison with cardiovascular disease 1981-2010
Authors: Bochen Cao, Freddie Bray, Hiram Beltrán-Sánchez, Ophira Ginsburg, Samir Soneji, Isabelle Soerjomataram
Journal: BMJ (2017)

<b>Objective</b> To quantify the impact of cancer (all cancers combined and major sites) compared with cardiovascular disease (CVD) on longevity worldwide during 1981-2010. <b>Design</b> Retrospective demographic analysis using aggregated data. <b>Setting</b> National civil registration systems in member states of the World Health Organization. <b>Participants</b> 52 populations with moderate to high quality data on cause specific mortality. <b>Main outcome measures</b> Disease specific contributions to changes in life expectancy in ages 40-84 (LE<sub>40-84</sub>) over time in populations grouped by two levels of Human Development Index (HDI) values. <b>Results</b> Declining CVD mortality rates during 1981-2010 contributed to, on average, over half of the gains in LE<sub>40-84</sub>; the corresponding gains were 2.3 (men) and 1.7 (women) years, and 0.5 (men) and 0.8 (women) years in very high and medium and high HDI populations, respectively. Declines in cancer mortality rates contributed to, on average, 20% of the gains in LE<sub>40-84,</sub> or 0.8 (men) and 0.5 (women) years in very high HDI populations, and to over 10% or 0.2 years (both sexes) in medium and high HDI populations. Declining lung cancer mortality rates brought about the largest LE<sub>40-84</sub> gain in men in very high HDI populations (up to 0.7 years in the Netherlands), whereas in medium and high HDI populations its contribution was smaller yet still positive. Among women, declines in breast cancer mortality rates were largely responsible for the improvement in longevity, particularly among very high HDI populations (up to 0.3 years in the United Kingdom). In contrast, losses in LE<sub>40-84</sub> were observed in many medium and high HDI populations as a result of increasing breast cancer mortality rates. <b>Conclusions</b> The control of CVD has led to substantial gains in LE<sub>40-84</sub> worldwide. The inequality in improvement in longevity attributed to declining cancer mortality rates reflects inequities in implementation of cancer control, particularly in less resourced populations and in women. Global actions are needed to revitalize efforts for cancer control, with a specific focus on less resourced countries.
Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates
Authors: Mary Jane Masson Hinrichs, Pauline M. Ryan, Bo Zheng, Shameen Afif-Rider, Xiang Qing Yu, Michele Gunsior, Haihong Zhong, Jay Harper, Binyam Bezabeh, Kapil Vashisht, Marlon Rebelatto, Molly Reed, Patricia C. Ryan, Shannon Breen, Neki Patel, Cui Chen, Luke Masterson, Arnaud Tiberghien, Phillip W. Howard, Nazzareno Dimasi, Rakesh Dixit
Journal: Clinical Cancer Research (2017)

Purpose: To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity.Experimental Design: A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).Results: Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (Cmax). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with Cmax than AUC.Conclusions: We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. Clin Cancer Res; 23(19); 5858-68. ©2017 AACR.
Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness
Authors: Pei-Chi Hou, Yo-Hua Li, Shih-Chieh Lin, Shau-Chieh Lin, Jenq-Chang Lee, Bo-Wen Lin, Jing-Ping Liou, Jang-Yang Chang, Ching-Chuan Kuo, Yi-Min Liu, H. Sunny Sun, Shaw-Jenq Tsai
Journal: Cancer Research (2017)

Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens. Cancer Res; 77(16); 4305-16. ©2017 AACR.
Abstract 17286: P2y12 Reaction Unit (PRU), Baseline Value, and % Inhibition From VerifyNow System Are Influenced by Hemoglobin Level
Authors: Young Jin Youn, Kyung-Min Kim, Ji Hyun Lee, Jun-Won Lee, Sung Gyun Ahn, Min-Soo Ahn, Jang-Young Kim, Byung-Su Yoo, Seung-Hwan Lee, Junghan Yoon, Kyung-Hoon Choe
Journal: Circulation (2013)

Background: The VerifyNow system (Accumetrics, San Diego, California) is widely used to assess the platelet hyperreactivity predictive of clinical events. As a whole blood assay, results of VerifyN...
Feasibility of monitoring of body temperature for patients undergoing stem cell transplant or intensive chemotherapy.
Authors: Nina Dambrosio, John Gannon, Jon Eager, David Sylvan, Marcos J.G. De Lima, Nathan Levitan, Ehsan Malek
Journal: Journal of Clinical Oncology (2017)

e21630 Background: Early detection of fever and prompt use of broad-spectrum antibiotics is crucial in neutropenic patients (pts). Episodic monitoring of temperature serves as standard-of-care (SOC) method in inpatient settings may suffer from delay in fever detection, whereas self-reported fever can be less reliable in the outpatient setting. Therefore, a continuous real time method of body temperature measurement may serve as a clinical decision support tool to improve outcomes. In this study, we proposed to test a device that continuously monitors body temperature. Methods: Pts admitted for stem cell transplant or high dose chemotherapy for leukemia were included. Body temperature was measured every 4 hours as SOC throughout hospital stay. Temperature Rise (TR) was defined as spikes above 100.4 °F. We used TempTraq patch (Blue Spark, Ohio), a FDA class II device, to monitor body temperature in real time. It transmits the data to a receiver (iPad or Smartphone) via Bluetooth to display body temperature data with the ability to set alerts. A questionnaire was designed to capture patient’s adherence, compliance and satisfaction. Results: The patches were applied every 24 hours on 10 pts throughout hospital stay. Body temperature was recorded remotely with 10 minutes intervals (14, 342 temperature measurements). There were 23 episodes of TR among all pts by SOC method, 21 of them were detected by the patch with a median of 140.1 minutes (range: 30-180 minutes) sooner than SOC. The patch data was successfully transmitted and displayed on the study iPad invariably. Ten out of 10 pts were able to wear the patch daily through hospital admission and felt the patch was easy to apply. Nine out of 10 pts felt the patch was comfortable and did not irritate their skin. Eight out of 10 pts were interested in wearing the patch for temperature monitoring in future. Eight out of 10 pts were completely satisfied with the patch. Conclusions: Our data suggest that real time body temperature measurement by the patch sensor used in this study is feasible and convenient. Also, it is able to detect the rise in temperature earlier in majority of cases. Further studies to assess reliability of this device in outpatient setting are warranted.
The TORC that Gets the GC Cycling
Authors: Elissa K. Deenick, Stuart G. Tangye
Journal: Immunity (2017)

The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation.
Biliopancreatic diversion with duodenal switch leads to better postprandial glucose level and beta cell function than sleeve gastrectomy in individuals with type 2 diabetes very early after surgery
Authors: Andréanne Michaud, Thomas Grenier-Larouche, Dominique Caron-Dorval, Simon Marceau, Laurent Biertho, Serge Simard, Denis Richard, André Tchernof, André C. Carpentier
Journal: Metabolism (2017)
Can we use frozen section analysis of sentinel lymph nodes mapped with methylene blue dye for decision making upon one-time axillary dissection in breast carcinoma surgery in developing countries?
Authors: Igor Djurisic, Nada Santrac, Marko Buta, Merima Goran, Ivan Markovic, Srdjan Nikolic, Milan Zegarac, Radan Dzodic
Journal: Journal of Clinical Oncology (2016)

e12037 Background: The aim was to evaluate accuracy of intraoperative frozen section analysis (FSA) of sentinel lymph nodes (SLN) mapped using methylene blue dye (MBD) and its usefulness for selecting patients with breast carcinomas and positive axillary lymph nodes (ALN) for one-time axillary dissection. Methods: Following 2005 ASCO guidelines, 152 female patients with T1/T2 breast carcinomas and clinically negative ALNs were selected for mapping using MBD (1%) from October 2010 to December 2011. Patients underwent FSA of mapped SLNs and ALN dissection. The accuracy of SLN-FSA was tested by comparison of these findings with definite pathohistology on SLNs, as well as on other ALNs. Sensitivity, specificity, positive and negative predictive values were calculated. Results: There was a 98%-match between FSA and definite pathohistology findings on SLNs, which suggests the high accuracy of FSA in this series. None of 3 patients with false-negative SLNs on FSA had additional axillary metastases. One out of 20 (5%) patients with metastases in other ALNs had “clear” SLNs, both on FSA and definite pathohistology (false negative). Method’s accuracy is 94.1%. Conclusions: SLN-FSA enables adequate selection of patients for one-time axillary dissection. MBD mapping technique is cheap, feasible and enables easy and precise detection of first draining ALNs. Using FSA of SLNs mapped with MBD, patients with breast carcinoma benefit from complete surgical treatment during one hospitalization, the risk of undergoing anaesthesia twice is reduced, as well as the treatment cost, which is important for developing countries.
Comparative study of receptor expression diversity between primary and recurrent lesions in patients with metastatic breast cancer.
Authors: Gokmen Umut Erdem, Nuriye Özdemir, Suleyman Sahin, Nebi Serkan Demirci, Fatih Karatas, Yakup Bozkaya, Aydin Aytekin, Ali Riza Sever, Nurullah Zengin, Mustafa Kadri Altundag
Journal: Journal of Clinical Oncology (2016)

e12062 Background: Tumor phenotype may alter during the progression of breast cancer (BC). Our aim in this study is to compare the discordance in estrogen receptor (ER) / progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between primary and recurrent / metastatic lesions (RML) and also to evaluate the prognostic significance of change in tumor phenotype on survival of patients with metastatic BC. Methods: Medical records of 6638 patients with BC from two large center followed between January 1992 and August 2015 were retrospectively analyzed. Of these population, 393 patients whose recurrence or progression were histologically proven by biopsy or surgical resection were enrolled into this study. Results: Fifty-three of patients (13.5%) had metastatic disease at presentation. Recurrent biopsy was performed from distant metastasis sites in 252 (64.1%) patients or from locoregional soft tissues / lymph-nodes in 141 (35.9%) patients. At a median follow up time of 74.8 months (range 3.8-358.4), about 54.2 % of patients (n = 213) expired. Receptor discordance in ER, PR and HER2 expressions between primary and RML were 27.2% (McNemar's test P=0.32), and 38.6% (McNemar's test P<0.001) and 14.4% (McNemar's test P=0.007), respectively. While patients with a gain in ER and PR expressions showed significantly higher OS and PRS (post recurrence survival) durations compared with the corresponding concordant-negative patients (ER: 119 vs. 57 months, P=0.001 and 56 & 31 months, P=0.03, PR: 148 & 58 months, P=0.003 and 64 & 31 months, P=0.01), loss of hormone expressions were found to be associated with worse survival. Likewise, patients showing loss of HER2 expression had poorer PFS and OS durations compared to those having stable HER2 expression (median 21 vs 60 months, P =0.009 for RFS and median 60 vs 111 months, P = 0.06 for OS, respectively). Conclusions: This study confirms the discordance in ER / PR and HER2 receptor expressions between primary lesions and RML in patients with metastatic BC. As the loss of receptor expression is the most responsible factor for the discordance, treatments of metastatic / recurrent tumors should be privatized on the basis of molecular and genomic properties.
The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability
Authors: Giulia Campostrini, Mattia Bonzanni, Alessio Lissoni, Claudia Bazzini, Raffaella Milanesi, Elena Vezzoli, Maura Francolini, Mirko Baruscotti, Annalisa Bucchi, Ilaria Rivolta, Matteo Fantini, Stefano Severi, Riccardo Cappato, Lia Crotti, Peter J. Schwartz, Dario DiFrancesco, Andrea Barbuti
Journal: Cardiovascular Research (2017)

Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability.We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae. Two ion channels known to interact and co-immunoprecipitate with the cav-3, hKv1.5 and hHCN4, interact also with T78M cav-3 and reside in lipid rafts. Electrophysiological analysis showed that the T78M cav-3 causes hKv1.5 channels to activate and inactivate at more hyperpolarized potentials and the hHCN4 channels to activate at more depolarized potentials, in a dominant way. In spontaneously beating neonatal cardiomyocytes, the expression of the T78M cav-3 significantly increased action potential peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential. We also found that in a small cohort of patients with supraventricular arrhythmias, the T78M cav-3 variant is more frequent than in the general population. Finally, in silico analysis of both sinoatrial and atrial cell models confirmed that the T78M-dependent changes are compatible with a pro-arrhythmic effect.This study demonstrates that the T78M cav-3 induces complex modifications in ion channel function that ultimately alter membrane excitability. The presence of the T78M cav-3 can thus generate a susceptible substrate that, in concert with other structural alterations and/or genetic mutations, may become arrhythmogenic.
Effects of cranial irradiation on dendritic spine complexity in the rat hippocampus and to induce memory decline.
Authors: Shengjun Ji
Journal: Journal of Clinical Oncology (2017)

e13545 Background: Cognitive deficit was the most serious complication of cranial irradiation in brain metastatic carcinoma. However, the underlying mechanisms remain obscure. Dendrites are the anatomic bases of synaptic contact and action potential propagation. Alterations of dendritic architecture may contribute to radiation-induced memory dysfunction. Methods: 21-day-old Sprague-Dawley rats received 10Gy cranial irradiation. 1 and 3 months later, Morris Water Maze, Fear Conditioning test and novel object recognition were used to test the memory function. Golgi staining was used to assess changes in dendritic spine density and morphology. Moreover, cytoskeletal proteins PSD-95 were analyzed with Western blot. Results: Our data showed that 10Gy cranial irradiation induced significant decline in the spatial memory and memory retention of rats and accompanied the morphological changes in dendritic spines. The result revealed significant reductions in spine density at 1 month (40.58%) and 3 months (28.92%) in the DG. In CA1 basal dendrites, irradiation resulted in a significant reduction (33.29%) in spine density only at 1month postirradiation. Compared to control, mushroom spines reduced at 1 month (7.17%, 10.01%) and 3 months (9.29%, 11.94%) post irradiation in DG and CA1 basal dendrites, respectively. Also, we found PSD-95 depletion coincided in time with alteration in dendritic spines. Conclusions: These data suggest that cranial irradiation decreased the dendritic spine density and mushroom spines, which may be associated with radiation-induced memory dysfunction. Acknowledgment: This study was supported by the National Natural Science Foundation of China 81402517 and the Suzhou Science and Technology Project SYS201651.
59 The association between physical activity and oesophago-gastric cancer: a prospective cohort study within the uk biobank
Authors: KP Mallon, AT Kunzmann, RF Hunter, CR Cardwell, UC McMenamin, AD Spence, HG Coleman
Journal: Gut (2017)

Background  Physical activity has been proposed as a modifiable risk factor for a number of cancers but few observational studies have investigated its effect on oesophageal and gastric carcinoma according to anatomical and histological subsite.  Aim  This prospective cohort study aims to analyse the association between physical activity and risk of oesophageal or gastric adenocarcinoma.  Method  A cohort of 3 59 425 adults aged 40-69 years (2006-2010) were identified from the UK biobank who completed a self-report International Physical Activity Questionnaire (IPAQ). Of this cohort, 295 incident oesophageal and 218 gastric cancer cases were identified. Adjusted HRs and 95% CIs for the associations between hours per week from physical activity and categories of physical activity based on IPAQ guidelines (Low, medium and high) and risk of oesophageal cancer and gastric cancer were calculated.  Results  When compared with low physical activity, high activity was not associated with oesophago-gastric cancer risk. However moderate level physical activity was associated with a reduction in risk of oesophageal adenocarcinoma by 35% after adjustment for confounders (adjusted HR=0.65, 95% CI 0.45 to 0.95). This held for moderate vs low physical activity and any oesophago-gatric adenocarcinoma (adjusted HR=0.70, 95% CI 0.53 to 0.92). This protective effect was not observed for oesophageal squamous cell carcinoma or total gastric cancer risk across physical activity categories.  Conclusions  In this large prospective cohort, high physical activity levels were not associated with overall risk of oesophago-gastric cancer. However, moderate physical activity was associated with a reduced risk of oesophageal adenocarcinoma tumours.
Phase I/II study of neoadjuvant carboplatin, eribulin mesylate, and trastuzumab (ECH) for operable HER2 positive (HER2+) breast cancer.
Authors: Lee Steven Schwartzberg, Kurt W. Tauer, Robert C. Hermann, Petros G. Nikolinakos, Arthur C. Houts
Journal: Journal of Clinical Oncology (2013)

TPS659 Background: Carboplatin, docetaxel and trastuzumab (TCH) regimen yields substantial pathologic complete response (pCR) in operable HER2+ breast cancer. Eribulin mesylate (E) is a tubulin inhibitor recently shown to improve overall survival compared to taxanes and other agents in heavily pretreated metastatic breast cancer patients. This trial was designed to determine the maximum tolerated dose (MTD) of E in combination with CH (Phase I) and to determine efficacy and safety of the ECH regimen (Phase II) given as neoadjuvant therapy to early stage HER2+ breast cancer with pathologic complete response the primary endpoint. Methods: This is a multicenter prospective open label single arm trial. Eligible patients were operable stage IIA – IIIB HER2+ breast cancer, ECOG 0-1, normal LVEF, QTc &lt; 480 msec, &lt; grade 1 neuropathy and no history of invasive cancer within the past 3 years. Phase I planned up to 12 patients from 4 centers to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for Phase II. Starting dose level 0 was 1.1 mg/m 2 with escalation to dose level +1 at 1.4 mg/m 2 and de-escalation to dose level -1 at 0.9 mg/m 2 if necessary. ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8 mg/kg loading dose d1C1 and 6 mg/kg d1C2-C6. H is scheduled to continue after surgery to complete 1 year of treatment. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia, anemia, or neutropenia lasting &gt; 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; inability to deliver all three agents at assigned dose and schedule. Standard 3+3 dose escalation design was used. At present, 6 patients have been enrolled at dose 0 and 6 have been enrolled at dose +1. The MTD for E has not yet been determined. Phase II has planned enrollment of 44 additional patients from 8 centers with primary endpoint rate of pCR at surgery to be performed 4-8 weeks after completion of ECH and secondary endpoints of safety to include peripheral neuropathy and cardiac toxicity at treatment completion and 1 year follow up. Clinical trial information: NCT101388647.