tbuckley/cabot-search huggingface dataset:
Hepatic β-arrestin 2 is essential for maintaining euglycemia
Authors: Lu Zhu, Mario Rossi, Yinghong Cui, Regina J. Lee, Wataru Sakamoto, Nicole A. Perry, Nikhil M. Urs, Marc G. Caron, Vsevolod V. Gurevich, Grzegorz Godlewski, George Kunos, Minyong Chen, Wei Chen, Jürgen Wess
Journal: Journal of Clinical Investigation (2017)

An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.
Do fears of getting cancer and family history of cancer influence participation in opportunistic screening or organized screening for gastric cancer?
Authors: Myung-Il Hahm, Kui Son Choi, Hoo-Yeon Lee, Mina Suh, Yoon Young Lee, Dong Wook Shin, Bokmi Kim
Journal: Journal of Clinical Oncology (2017)

e13045 Background: Cancer is the leading cause of death in Korea. Individuals with a family history of cancer might overestimate their personal risk for getting cancer and report high cancer-related worry or concern. Those factors could positively or negatively influence on cancer screening behavior. Although Korea has a universal screening program for common cancers, some people still choose opportunistic screening program with out-of-pocket costs. This study was to identify association between fears of getting cancer and participation on opportunistic anc organized screening programs for cancer. Methods: The study population was derived from the Korean National Cancer Screening Survey 2013, which is annual survey conducted by National Cancer Center of Korea in order to investigate trends of participation rates among general population in cancer screening. 3,004 individuals aged over 40 years were finally selected as study subjects. Chi-square tests and multinomial logistic regression model were used to identify factors associated with being screened for gastric cancer. Results: A total of 2,078 of the subjects (69.2%) underwent gastric cancer screening, of which 311 individuals (10.4%) participated in opportunistic and 1,767 individuals (58.8%) participated in organized screening programs. After adjusting socio-demographic factors and health behaviors, worry and concern about cancer were identified as factors positively associated with being screened for gastric cancer. ORs for undergoing gastric cancer screening were elevated for both screening programs according to the level of worry and concern about cancer (p for trend &lt; 0.05). We did not found relationship between family history of gastric cancer and participation. Conclusions: The results of this study suggest that fears of getting cancer such as worry and concerned about cancer had a stronger influence on participation in not only organized screening program but also opportunistic screening program. We could identify that ORs for undergoing the opportunistic screening were slightly higher than those for undergoing the organized screening in terms of cancer worry and cancer concern.
Biopsie-guidée sous échoendoscopie: une technique reproductible au terme d'une année de pratique; à propos d'une série de 93 cas
Authors: L Poincloux, C Darcha, A Achim, C Bonny, F Artigues, M Dapoigny, G Bommelaer
Journal: Endoscopy (2005)

La biopsie-guidée sous échoendoscopie (BGEE) relance la place de l'échoendoscopie notamment en oncologie digestive. La diffusion de cette technique reste corrélée à une bonne reproductibilité. But: Evaluer la faisabilité et la valeur diagnostique de la BGEE au terme d'une année de pratique.
Abstract 17788: Association of Left Atrial Function and Left Atrial Fibrosis in Patients with Atrial Fibrillation: a Cardiac Magnetic Resonance Study
Authors: Mohammadali Habibi, Joao Lima, Irfan Khurram, Stefan L Zimmerman, Vadim Zipunnikov, Kotaro Fukumoto, David Spragg, Hiroshi Ashikaga, John Rickard, Joseph E Marine, Hugh Calkins, Saman Nazarian
Journal: Circulation (2014)

Introduction: Atrial fibrillation (AF) is associated with left atrial (LA) electrical, structural, and contractile remodeling. Cardiac magnetic resonance (CMR), late gadolinium enhancement (LGE) and feature tracking are capable of noninvasive quantification of LA fibrosis and myocardial motion, respectively. Hypothesis: Increased LA fibrosis measured with LGE is associated with worsening of the phasic LA function measured with feature tracking CMR. Methods: The cohort included 90 patients (age 61 ± 10 years, 76% male) with symptomatic drug-resistant AF referred for ablation. Peak global longitudinal LA strain (PLAS), LA systolic strain rate (SR-s), and early (SR-ed) and late diastolic (SR-ld) strain rates were measured using cine-CMR images acquired during sinus rhythm. The degree of LGE was quantified using normalized image intensity. Results: Compared to patients with paroxysmal AF (60% of cohort), those with persistent AF had larger maximum LA volume index (LAVImax, 56 ± 17ml/m2 versus 49 ± 13ml/m2 p=0.036), and increased LGE (27.1± 11.7% versus 36.8 ± 14.8% p&lt;0.001). Aside from LA active emptying fraction, all LA parameters (passive emptying fraction, PLAS, SR-s, SR-ed and SR-ld) were lower in patients with persistent AF (p&lt; 0.05 for all). Increased LA fibrosis was associated with lower LA passive emptying fraction, PLAS, SR-s, SR-ed, and SR-ld after adjusting for age, sex, hypertension, heart failure, left ventricular ejection fraction, type of AF, and LA volume (p&lt;0.05 for all). Conclusions: Increased LA fibrosis is associated with decreased LA reservoir, conduit, and booster pump functions. Phasic measurement of LA function using feature-tracking CMR is feasible and may add important information regarding the physiological importance of LA fibrosis.
Primary care out of hours
Authors: D. Heaney, D. Gorman
Journal: BMJ (1996)

used internationally for comparative purposes and, with full histopathological examination (as in our paediatric and adult studies), provide information significantly superior to clinical data alone.3We acknowledge that necropsies underestimate bacteraemia and enteritis.24Pyogenic pneumonia (diagnosed on the basis of large zones of lungs with polymorphs in alveoli) was the prime cause of death in 32% (49/155) of the children and was found in 37% (57/155); the corresponding proportions in the adults infected with HIV were 8% and 30%, respectively.2With regard to differences between adults and children, the common diseases in childhood in Africa (acute respiratory infection, malnutrition, meningitis, etc) were found frequently in both HIV positive and HIV negative children.Clinical syndromes are similar in the two groups, and symptoms and signs are poorly predictive of HIV status.'With the exception of Pneumocystis carinji infection, individual AIDS defining infections were uncommon in HIV positive children.In contrast, the range of disease in HIV positive adults in Abidjan is quite different from that in HIV negative adults,2 as is the case in Nairobi.The, rarity of tuberculosis in the young children in whom necropsy was carried out is consistent with the annual risk of infection with Mycobacterium tuberculosis in sub-Saharan Africa-about 2%.We predict that, with a median age at death of <2 years, most African children with HIV infection die without having encountered this mycobacterium.We were not reluctant to emphasise this but believed that the implications were evident.Finally, the 1991 article by Chin that we referenced emphasises the prevalence of HIV infection in Africa.
Effects of county-level attributes on geographic variation in female breast cancer mortality rates across counties in United States.
Authors: Hari Krishna Raju Sagiraju, Ismail Jatoi, Melissa Valerio, Lung-Chang Chien, David Gimeno
Journal: Journal of Clinical Oncology (2017)

e13093 Background: Though studies have examined geographic disparities in breast cancer mortality among United States (U.S.) counties, county-level risk factors were not accounted for. The aim of this study is to efficiently map the spatial association between female breast cancer mortality rates &amp; socioeconomic attributes across U.S. counties for identifying high risk geographical clusters in terms of socioeconomic attributes. Methods: County-specific age standardized breast cancer mortality rates for women ≥20 years in the U.S. were obtained for 3,109 counties in 48 contiguous states from Surveillance Epidemiology and End Results program from 1990-2012. County-level attributes such as percentages of Hispanic white, Non-Hispanic white, Non-Hispanic black, &lt; high school education, below 200% poverty, urban, foreign born, language isolation, women aged ≥ 40 years with mammography within last 2 years, and median household income were gathered from U.S. decennial census. Factor analysis condensed county attributes into three factor covariates namely Hispanic immigrants, health care access among urban high socioeconomic population, and non-Hispanic black unemployment. Spatiotemporal analysis was carried out by structured additive regression model to incorporate spatial functions &amp; Markov chain Monte Carlo simulation techniques. Results: Moran’s index suggested existence of spatial dependence for breast cancer mortality among U.S. counties. As mammography screening, %urban population, % with high socioeconomic status and non-Hispanic black unemployment increased in counties of the Southwest region, Rocky mountain region and those in the western border of Midwest region of U.S, risk of breast cancer mortality increased significantly above the national average. As the Hispanic immigrant culture increased, counties of Midwest region of U.S had significantly higher mortality rates compared to national average. Conclusions: These initial results describe socio-economic, cultural, and healthcare access factors for observed geographic variations in female breast cancer mortality, and in turn, could support a stronger theoretical basis for public health policy.
BONADIUV trial: A single blind, randomized placebo controlled phase II study using oral ibandronate for osteopenic women receiving adjuvant aromatase inhibitors: Final safety analysis.
Authors: Lorenzo Livi, Icro Meattini, Vieri Scotti, Calogero Saieva, Isacco Desideri, Giulio Alberto Carta, Monica Lo Russo, Carla De Luca Cardillo, Daniela Greto, Jacopo Nori, Marco Bernini, Donato Casella, Lorenzo Orzalesi, Luis Jose Sanchez, Stefano M. Magrini, SImonetta Bianchi
Journal: Journal of Clinical Oncology (2016)

e12043 Background: Aromatase inhibitors (AI) are a highly effective treatment for postmenopausal hormonal positive status breast cancer (BC). However its use is associated with accelerated bone loss and potential increase in treatment related adverse events. We present the final analysis concerning trial safety results. Methods: We enrolled between 2011 and 2014 osteopenic early BC patients candidate to 3-5 years of adjuvant AI. All patients were treated with vitamin D supplementation, for an overall treatment of 24 months. Patients were also stratified by menopausal age, body mass index and age. Adverse events monitoring was a secondary endpoint of trial. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 were utilized to record toxicity events. We performed different stratified analysis for bisphosphonate-related, AI-related, and overall symptoms incidence rates. The primary endpoint of the trial was the change in BMD at lumbar spine or hip after 12 and 24 months of follow up. Recruiting is complete (final safety analyses: January 2016). Local ethics committee and institutional review board approved this clinical research; informed consent was obtained for all subjects. This trial is registered with ClinicalTrials.gov as NCT02616744. Results: A total of 202 patients have been randomized. We recorded a quite high drop out rate (25%), but well balanced among arms. Only four patients enrolled in ibandronate arm withdrew the study due to treatment toxicity (3.8%). Bisphosphonate-related (all grades, 38.7% versus 34.4% placebo; p = 0.56), AI-related (all grades, 30.2% versus 34.4% placebo; p = 0.55), and overall symptoms (p = 1.0) did not significantly differ among arms. In details, absolute rates of dyspepsia (12.3% versus 7.3%; p = 0.35), and flu-like symptoms (8.5% versus 3.1%; p = 0.14), were higher in ibandronate arm, but these differences did not reached statistical significance. Conclusions: Adjuvant bisphosphonates treatment with monthly oral ibandronate is overall safe in patients treated with adjuvant AI for early BC. Clinical trial information: NCT02616744.
DECURION: A new model for predicting breast and ovarian cancer risks based on family history using French population incidences and Institut Curie’s database.
Authors: Gregory Nuel, Tinhinan Belaribi, Dorothee Le Gal, Olivier Bouaziz, Flora Alarcon, Severine Eon-Marchais, Nadine Andrieu, Marie-Gabrielle Dondon, Antoine de Pauw, Dominique Stoppa-Lyonnet
Journal: Journal of Clinical Oncology (2016)

1534 Background: Nowadays, assessing the cancer risk of patients with severe history of cancer is a routine task for the clinical genetic centers. Due to the complex genetic and environmental factors involved in cancers, risk assessment requires sophisticated probabilistic/statistical models whose parameters (incidence, relative hazards, allele frequencies, etc.) are both population-dependent and delicate to calibrate. Methods: We introduce a new model similar to BOADICEA [1] where cancer hazards depend both on individual genetic factors X (e.g. BRCA1, BRCA2) and on a familial frailty Z (e.g. unmeasured polygenic factors or shared environmental exposures). Model computations are performed combining survival analysis with state-of-art belief propagation methods [2] (i.e. generalization of Elston-Stewart algorithm to arbitrary pedigrees). Calibration of model parameters are done combining French population incidences with Institut Curie’s database (a total of 6,262 families, 22% of the tested families being BRCA carriers). Results: The new model has several advantages: 1) it fully exploits the extensive Institute Curie’s database and hence provides better risk assessment for the French patients; 2) it takes into account rigorously and efficiently any consanguinity or mating loops; 3) it provides the full posterior distribution of any individual in the pedigree and provides an individual exact posterior incidence adjusted on age; 4) it allows to consider jointly groups of individuals (ex: siblings) and to compute collective risks (ex: at least one sibling is a carrier, competitive cancer incidence in the group, etc.); 5) it benefits from a user-friendly graphical interface which considerably reduces the input burden for the clinicians. Conclusions: Taking advantage of both a solid mathematical background and of the extensive databases of Institut Curie, the new DECURION model seems to provide better risk estimates that its direct competitors and could be a promising tool for any clinician interested in cancer genetics. [1] Antoniou, Pharoah, Smith, and Easton (2004). British journal of cancer. [2] Koller and Friedman (2009). MIT Press.
Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary
Authors: Jonathan Finder, Oscar Henry Mayer, Daniel Sheehan, Hemant Sawnani, R. Ted Abresch, Joshua Benditt, David J. Birnkrant, Tina Duong, Erik Henricson, Kathi Kinnett, Craig M. McDonald, Anne M. Connolly
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.
IRTKS is correlated with progression and survival time of patients with gastric cancer
Authors: Li-Yu Huang, Xuefei Wang, Xiao-Fang Cui, He Li, Junjie Zhao, Chong-Chao Wu, Lingqiang Min, Zhicheng Zhou, Lixin Wan, Yu-Ping Wang, Chao Zhang, Wei-Qiang Gao, Yihong Sun, Ze-Guang Han
Journal: Gut (2017)

IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear.We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53.IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53+/- mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/- MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation.IRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.
A Phase II study of weekly nab-paclitaxel in combination with gemcitabine in patients with metastatic breast cancer.
Authors: Yannan Zhao, Fangfang Lv, Shen Chen, Yunhua Lu, Enying Cao, Zhonghua Wang, Jian Zhang, Sheng Zhang, Jun Cao, Chunlei Zheng, Leiping Wang, Biyun Wang, Xichun Hu
Journal: Journal of Clinical Oncology (2016)

e12514 Background: Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy and safety profiles especially no hypersensitivity risk compared with solvent-based paclitaxel. We performed a single arm, phase II study to evaluate the efficacy and safety of weekly nab-paclitaxel and gemcitabine combination in patients with metastatic breast cancer. Methods: Nab-paclitaxel (125mg/m2) and gemcitabine (800mg/m2) were administered on day 1, 8, and 15 in a 4-week cycle. Patients with HER2 positive disease could receive trastuzumab at the same time. Results: Eighty-five patients were enrolled in the study. Sixty-nine (82.1%) had visceral metastases and forty-seven (56.0%) had three or more metastatic sites. Two (2.4%) patients had complete response and 42 (50.00%) had partial response according to RECIST 1.1 criteria. Median progression free survival was 7.9 months (95%CI, 6.6-9.2) and median OS was 25.8 months (95 % CI, 20.4-31.1). The most common toxicities were neutropenia (75.0% for all events,45.2% for grade 3 and greater),but only two patients (2.4%) developed febrile neutropenia. Peripheral neuropathy was the most common non-hematologic toxicity (50.0% for all the events and 7.14% for grade 3 and greater). Conclusions: The regimen had a favorable efficacy and safety profile in metastatic breast cancer patients. Clinical trial information: NCT01550848.
Association between distinct intratumoral and stromal tumor infiltrating immune cells and pathologic complete response (pCR) in different breast cancer subtypes after neoadjuvant chemotherapy (NAC).
Authors: Lucia Gonzalez-Cortijo, Raquel Murillo, Agustin Acevedo, Ricardo Sainz de la Cuesta, Gines Hernandez-Cortes, Vicente Martinez de Vega, Susana Linares, Ramon Perez-Carrion, Federico Gonzalez, Cristina Rodriguez-Marquez, Alexandra Henriquez, Elia del Cerro, Ana Diaz-Gavela, Antonio Maldonado, Silvia Fuertes, Jose Luis Martin del Yerro, Ignacio Sanz, Javier Hornedo
Journal: Journal of Clinical Oncology (2016)

1033 Background: Tumor-infiltrating lymphocytes (TILs) are emerging as prognostic factors in early breast cancer and have shown to predict response to NAC, especially in triple-negative breast cancer (TNBC). However, it is not clear whether all intratumoral and stromal immune cells show the same predictive value or if there is a specific cell subtype involved in response and prognosis Methods: We retrospectively analyzed the diagnostic biopsies of breast cancer patients treated with NAC in our institution in the last 4 years. 3-4µm thick sections were subjected to immunohistochemistry using antibodies against CD3, CD4, CD8 and CD20. Intratumoral and stromal lymphocytes were measured and expressed in positive cells per mm². Every patient received chemotherapy with weekly paclitaxel and doxorubicin-cyclophosphamide and HER2 positive tumors were treated with trastuzumab. All patients received surgery. pCR was defined as no residual invasive tumor in the breast and the axilla. Descriptive statistics are reported as median (IQR, interquartile range) or mean (SD, standard deviation) for continuous variables, and as absolute or relative frequencies for categorical variables Results: From 144 evaluable specimens, 72 were estrogen-receptor and/or progesterone-receptor positive, 27 were TNBC and 45 were HER2 positive tumors. 70 pCR were documented. The expression of stromal CD3, CD4 and CD20 lymphocytes was significantly associated with pCR in all breast cancer subtypes: CD3 (28,00 [27,25], p < 0.001); CD4 (16,00 [23,75], p = 0.007); CD20 (2,50 [7,25], p = 0.046). In the subgroup analysis, both stromal CD3 (34,00 [24,00], p = 0.004), intratumoral CD3 (7,50 [19,50], p = 0.013), and intratumoral CD8 (3,00 [17,50], p = 0.041) lymphocytes were significantly associated with pCR in TNBC. In HER2 positive tumors stromal CD3 and CD4 were predictive of pCR ((26,00 [26,00], p < 0.001) and (16,00 [24,00], p = 0.042) respectively) Conclusions: Stromal CD3 lymphocytes are the most significant predictive factor of pCR in all breast cancer subtypes after NAC. In TNBC both intratumoral and stromal CD3 expression was associated with pCR.