tbuckley/cabot-search huggingface dataset:
P3.CR-09 MET-UBE2H fusion as a novel mechanism of acquired EGFR resistance in lung adenocarcinoma" with "MET fusion as a novel mechanism of acquired EGFR resistance in lung adenocarcinoma
Authors: W. Wang, C. Xu, Q. Zhang, W. Zhuang, Y. Zhu, Z. Song, Y. Chen, G. Chen, M. Fang, T. Lv, Y. Song
Journal: Journal of Thoracic Oncology (2018)
Abstract 16598: The Role of Paraoxonase 2 in Myocardial Ischemia/Reperfusion Injury
Authors: Jingyuan Li, Victor R Grijalva, Srinivasa T Reddy, Mansoureh Eghbali
Journal: Circulation (2015)

Objectives: Paraoxonases (PON) gene family consists of three proteins PON1, PON2, and PON3. PON2 is an intracellular membrane-associated protein that is widely expressed in vascular cells and many tissues. At the subcellular level, PON2 is localized to both the ER and mitochondria, and protects against oxidative stress. Hypothesis: The aim of this study was to investigate the role of PON2 in myocardial ischemia reperfusion injury. Methods: PON2 deficient (PON2-/-) and WT male mice were subjected to in-vivo ischemia/reperfusion injury. The left anterior descending coronary artery was occluded for 30 min followed by 24 hr of reperfusion. The infarct size, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) generation were measured. The expression of C/EBP homologous protein (CHOP), GSK3b and phosphate GSK3b protein were examined by Western Blot. The number of animals was 5-7/group and data were expressed as mean±SEM. T test were used for statistical analysis. Probability values &lt;0.05 were considered statistically significant. Results: The infarct size was ~2 fold larger in PON2 deficient mice compared to WT mice (p&lt;0.05). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to calcium overload was much lower in PON2-/- mice compared with WT mice (173±19 in PON2-/-, 250±41 in WT, nmol/mg-mitochondrial protein, p&lt;0.05). The ROS production was ~2 fold higher in isolated cardiac mitochondria from PON2-/- mice compared with WT mice (p&lt;0.05). ER stress protein CHOP increased significantly in PON2-/- mice compared to WT mice (normalized to WT: 1±0.05 in WT, 1.66±0.08 in PON2-/-, p&lt;0.001). Phospho-GSK3b level was significantly downregulated in in PON2-/- mice compared to WT mice (pGSK3b/GSK3b normalized to WT: 1±0.06 in WT 0.67±0.08 in PON2-/-, p&lt;0.05). Conclusions: PON2 regulates myocardial ischemia/reperfusion injury via inhibiting the opening of mPTP, which is associated with reduced mitochondria ROS production, deactivation of ER stress signaling CHOP and GSK3b.
Response to: ‘Clinical evidence guidelines in systemic lupus erythematosus: revaluation’ by Scheinberg
Authors: Bernardo A Pons-Estel, Eloisa Bonfa, Enrique R Soriano, Mario Humberto Cardiel, Ariel Izcovich, Gloria Vázquez, Graciela S Alarcón
Journal: Annals of the Rheumatic Diseases (2018)

We want to thank Dr Morton Scheinberg for his interest1 in our recent lupus guidelines communication.2 In his letter, he points out several concerns regarding belimumab which we had recommended at the same therapeutic level as other immunosuppressants for joint and skin manifestations. Few clarifications are needed.

The development of our guidelines followed a rigorous methodology in which the evidence on effect estimates should come, when available, from randomised controlled trials (RCTs). We did not identify any clinical trial comparing belimumab against other immunosuppressants. Therefore, in considering this comparison, the development group had to rely on indirect evidence (the difference in belimumab effect against placebo and other immunosuppressants against …
Effectiveness of the Stand More AT (SMArT) Work intervention: cluster randomised controlled trial
Authors: Charlotte L Edwardson, Tom Yates, Stuart J H Biddle, Melanie J Davies, David W Dunstan, Dale W Esliger, Laura J Gray, Benjamin Jackson, Sophie E O’Connell, Ghazala Waheed, Fehmidah Munir
Journal: BMJ (2018)

Abstract Objectives To evaluate the impact of a multicomponent intervention (Stand More AT (SMArT) Work) designed to reduce sitting time on short (three months), medium (six months), and longer term (12 months) changes in occupational, daily, and prolonged sitting, standing, and physical activity, and physical, psychological, and work related health. Design Cluster two arm randomised controlled trial. Setting National Health Service trust, England. Participants 37 office clusters (146 participants) of desk based workers: 19 clusters (77 participants) were randomised to the intervention and 18 (69 participants) to control. Interventions The intervention group received a height adjustable workstation, a brief seminar with supporting leaflet, workstation instructions with sitting and standing targets, feedback on sitting and physical activity at three time points, posters, action planning and goal setting booklet, self monitoring and prompt tool, and coaching sessions (month 1 and every three months thereafter). The control group continued with usual practice. Main outcome measures The primary outcome was occupational sitting time (thigh worn accelerometer). Secondary outcomes were objectively measured daily sitting, prolonged sitting (≥30 minutes), and standing time, physical activity, musculoskeletal problems, self reported work related health (job performance, job satisfaction, work engagement, occupational fatigue, sickness presenteeism, and sickness absenteeism), cognitive function, and self reported psychological measures (mood and affective states, quality of life) assessed at 3, 6, and 12 months. Data were analysed using generalised estimating equation models, accounting for clustering. Results A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (−83.28 min/workday, 95% confidence interval −116.57 to −49.98, P=0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (−50.62 min/workday, −78.71 to −22.54, P&lt;0.001) and six months (−64.40 min/workday, −97.31 to −31.50, P&lt;0.001) and daily sitting time at six months (−59.32 min/day, −88.40 to −30.25, P&lt;0.001) and 12 months (−82.39 min/day, −114.54 to −50.26, P=0.001). Group differences (in favour of the intervention group compared with control) were found for prolonged sitting time, standing time, job performance, work engagement, occupational fatigue, sickness presenteeism, daily anxiety, and quality of life. No differences were seen for sickness absenteeism. Conclusions SMArT Work successfully reduced sitting time over the short, medium, and longer term, and positive changes were observed in work related and psychological health. Trial registration Current Controlled Trials ISRCTN10967042 .
Climate change and African trypanosomiasis vector populations in Zimbabwe's Zambezi Valley: A mathematical modelling study
Authors: Jennifer S. Lord, John W. Hargrove, Stephen J. Torr, Glyn A. Vale
Journal: PLoS Medicine (2018)

Background Quantifying the effects of climate change on the entomological and epidemiological components of vector-borne diseases is an essential part of climate change research, but evidence for such effects remains scant, and predictions rely largely on extrapolation of statistical correlations. We aimed to develop a mechanistic model to test whether recent increases in temperature in the Mana Pools National Park of the Zambezi Valley of Zimbabwe could account for the simultaneous decline of tsetse flies, the vectors of human and animal trypanosomiasis. Methods and findings The model we developed incorporates the effects of temperature on mortality, larviposition, and emergence rates and is fitted to a 27-year time series of tsetse caught from cattle. These catches declined from an average of c. 50 flies per animal per afternoon in 1990 to c. 0.1 in 2017. Since 1975, mean daily temperatures have risen by c. 0.9°C and temperatures in the hottest month of November by c. 2°C. Although our model provided a good fit to the data, it cannot predict whether or when extinction will occur. Conclusions The model suggests that the increase in temperature may explain the observed collapse in tsetse abundance and provides a first step in linking temperature to trypanosomiasis risk. If the effect at Mana Pools extends across the whole of the Zambezi Valley, then transmission of trypanosomes is likely to have been greatly reduced in this warm low-lying region. Conversely, rising temperatures may have made some higher, cooler, parts of Zimbabwe more suitable for tsetse and led to the emergence of new disease foci.
The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target
Authors: Shuang G Zhao, Jonathan Lehrer, S Laura Chang, Rajdeep Das, Nicholas Erho, Yang Liu, Martin Sjöström, Robert B Den, Stephen J Freedland, Eric A Klein, R Jeffrey Karnes, Edward M Schaeffer, Melody Xu, Corey Speers, Paul L Nguyen, Ashley E Ross, June M Chan, Matthew R Cooperberg, Peter R Carroll, Elai Davicioni, Lawrence Fong, Daniel E Spratt, Felix Y Feng
Journal: JNCI Journal of the National Cancer Institute (2018)

Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets.We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided.Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03).In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer
Authors: Nicholas C. Turner, Dennis J. Slamon, Jungsil Ro, Igor Bondarenko, Seock-Ah Im, Norikazu Masuda, Marco Colleoni, Angela DeMichele, Sherene Loi, Sunil Verma, Hiroji Iwata, Nadia Harbeck, Sibylle Loibl, Fabrice André, Kathy Puyana Theall, Xin Huang, Carla Giorgetti, Cynthia Huang Bartlett, Massimo Cristofanilli
Journal: New England Journal of Medicine (2018)

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We report the results of a prespecified analysis of overall survival. We randomly assigned patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety. Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib-fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo-fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo-fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib-fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo-fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib-fulvestrant group, as compared with 8.8 months in the placebo-fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up. Among patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib-fulvestrant resulted in longer overall survival than treatment with placebo-fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135 .).
Association of autoimmunity and long‐term complete remission in patients with Sézary syndrome treated with mogamulizumab
Authors: P. Bonnet, M. Battistella, M. Roelens, C. Ram‐Wolff, F. Herms, L. Frumholtz, J.‐D. Bouaziz, P. Brice, H. Moins‐Teisserenc, M. Bagot, A. Masson
Journal: British Journal of Dermatology (2018)
Might Brushed Nasal Cells Be a Surrogate for CFTR Modulator Clinical Response?
Authors: Iwona Pranke, Aurelie Hatton, Alexandra Masson, Thomas Flament, Muriel Le Bourgeois, Frederique Chedevergne, Celine Bailly, Valerie Urbach, Alexandre Hinzpeter, Aleksander Edelman, Isabelle Sermet-Gaudelus
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Intermittent or continuous panitumumab (PAN) plus FOLFIRI for first-line treatment of patients (pts) with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC): A randomized phase II trial (IMPROVE)
Authors: A. De Stefano, G. Nasti, A. Febbraro, G. Rosati, F. Giuliani, D. Santini, G. Aprile, M. Scartozzi, F. Silvestris, G. Luppi, I. Lolli, C. Mastroianni, S. Leo, V. Montesarchio, C. Gridelli, C. Pozzo, E. Sperti, D. Giannarelli, A. Budillon, A. Avallone
Journal: Annals of Oncology (2018)
Trends in Emergency Department Visits and Admission Rates Among US Acute Care Hospitals
Authors: Michelle P. Lin, Olesya Baker, Lynne D. Richardson, Jeremiah D. Schuur
Journal: JAMA Internal Medicine (2018)

were enrolled in high-deductible health plans, almost half (46.9%) had a family out-of-pocket health care burden exceeding 20% of family disposable income.Although only 22% of the overall low-income population had full-year employersponsored insurance, their financial burden is of concern because, owing to the fact that they have offers of employersponsored insurance, they are likely not eligible for the premium and cost-sharing subsidies in the health care Marketplace that other adults in this income group can access.Moreover, they may not be eligible for Medicaid depending on their income and whether their state expanded Medicaid.For clinicians and patients, high out-of-pocket costs for lowincome adults with employer-sponsored insurance may create a barrier to achieving effective treatment to manage multiple chronic conditions.
HMOX1 and acute kidney injury in sickle cell anemia
Authors: Santosh L. Saraf, Maya Viner, Ariel Rischall, Rasha Raslan, Binal N. Shah, Xu Zhang, Jin Han, Michel Gowhari, Shivi Jain, Robert E. Molokie, Roberto F. Machado, James P. Lash, Victor R. Gordeuk
Journal: Blood (2018)
Spatiotemporal Loss of <i>NF1</i> in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway
Authors: Zhiguo Chen, Juan Mo, Jean-Philippe Brosseau, Tracey Shipman, Yong Wang, Chung-Ping Liao, Jonathan M. Cooper, Robert J. Allaway, Sara J.C. Gosline, Justin Guinney, Thomas J. Carroll, Lu Q. Le
Journal: Cancer Discovery (2018)

Abstract Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a “modifier” for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. Significance: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target. This article is highlighted in the In This Issue feature, p. 1
A dysbiotic microbiome triggers T <sub>H</sub> 17 cells to mediate oral mucosal immunopathology in mice and humans
Authors: Nicolas Dutzan, Tetsuhiro Kajikawa, Loreto Abusleme, Teresa Greenwell-Wild, Carlos E. Zuazo, Tomoko Ikeuchi, Laurie Brenchley, Toshiharu Abe, Charlotte Hurabielle, Daniel Martin, Robert J. Morell, Alexandra F. Freeman, Vanja Lazarevic, Giorgio Trinchieri, Patricia I. Diaz, Steven M. Holland, Yasmine Belkaid, George Hajishengallis, Niki M. Moutsopoulos
Journal: Science Translational Medicine (2018)

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.
Abstract 19544: The Familial Hypercholesterolemia Phenotype in the United States is Associated With an Age-dependent Increase in Long-term Coronary Heart Disease Risk
Authors: Amanda K Marma, Sarah D de Ferranti, Holly C Gooding, Hongyan Ning, John T Wilkins, Donald M Lloyd-Jones
Journal: Circulation (2015)

Introduction: Heterozygous familial hypercholesterolemia (FH) has an estimated prevalence of 1:200-500, affecting up to 1,500,000 individuals in the US. Available CHD risk prediction equations do not account for lifetime exposure to elevated LDL-C in FH patients, and while relative risks of 7-100 have been reported for CHD in FH, US outcomes of FH are unknown. We aimed to evaluate long-term CHD risk in US adults with an FH phenotype. Methods: Using pooled data from 6 US epidemiologic cohorts, participants were stratified by LDL-C level at index ages 25, 35, 45, 55, 65 and 75 years. LDL-C≥190 and &lt;130 mg/dL defined the FH phenotype and referent groups, respectively. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with the hazard for fatal/nonfatal MI and CHD death and to generate 30-year event-free survival curves. Results: A total of 42,390 baseline person-exams were available across the index ages. The table shows the 30-year event rates for patients with the FH phenotype (LDL-C≥190 mg/dL) compared with the referent from each index age, as well as covariate-adjusted HRs for CHD death or fatal/nonfatal MI. As expected, the relative increase in 30-year events is highest for the youngest individuals, with rates up to 12 times higher for CHD death, and attenuates at older index ages. After adjustment, HRs for both CHD death and fatal/nonfatal MI are more modest but show a similar age-dependent pattern. The figure shows the adjusted 30-year survival free of fatal/nonfatal MI for the youngest two index ages, by LDL-C stratum. Conclusions: In the US, the FH phenotype is associated with substantial long-term CHD risk in younger adults, with more modest elevations in risk at older ages. The absolute HRs are lower than previously described, possibly due to unique features in the US population, improved management compared to other historical cohorts, or misclassification of some participants who did not have longstanding high LDL-C.