tbuckley/cabot-search huggingface dataset:
Time to Study Metastatic-Cancer Survivorship
Authors: Terry Langbaum, Thomas J. Smith
Journal: New England Journal of Medicine (2019)

Interview with Terry Langbaum and Dr. Tom Smith on issues faced by long-term survivors with metastatic cancer. (19:49)Download Long-term survivors with metastatic cancer have not been well studied, but diagnoses of incurable cancer will have substantial effects on patients' families, on workplaces, and on U.S. health care resources in the coming years.
Assessing the Agreement of 5 Ideal Body Weight Calculations for Selecting Medication Dosages for Children With Obesity
Authors: Alexander Moylan, Nicholas Appelbaum, Jonathan Clarke, Calandra Feather, Astrid Flahault Tairraz, Ian Maconochie, Ara Darzi
Journal: JAMA Pediatrics (2019)

This study assesses the agreement of 5 calculations of ideal body weight to determine how well they can determine a dosage necessary to treat a child with obesity.
Abstract 447: Essential Role of Stromal Interaction Molecule 1 in Heart Failure
Authors: Vishal R Mali, Maha Ali, Samuel Haddox, Mohamed Trebak, Khalid Matrougui
Journal: Circulation Research (2016)

Background: Stromal interacting molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum (ER). We previously reported that STIM1 plays opposing roles in vascular smooth muscle cells (SMC) vs. endothelial cell in the regulation of vascular reactivity. However, the role of SMC STIM1 in heart failure is yet to be determined. Methods and Results: We utilize control (C57/Bl6) and mice lacking STIM1 specifically in SMC (Stim1 SMC-/- ). We subjected all mice to left anterior descending coronary artery (LAD) permanent occlusion for 3 weeks. We performed echocardiography before the LAD ligation and 3 week after. In the end, we sacrificed mice and harvested the heart for biochemical and histology studies. The heart weight, collagen, and infarct area were significantly augmented in control mice subjected to LAD occlusion. The diastolic (Ejection fraction) and systolic functions (fractional shortening) were significantly compromised in control mice subjected to LAD occlusion. Interestingly, the cardiac hypertrophy, the collagen content, the infarct area, the ejection fraction, and the fraction shortening were protected in Stim1 SMC-/- mice subjected to LAD occlusion. The protective effect of STIM1 disruption in SMC involved the reduction in ER stress activation, the autophagy, and apoptosis mechanisms. Conclusion: Our results indicate that the disruption of STIM1 in SMC protects the heart against chronic ischemia through the inhibition of ER stress, autophagy, and apoptosis.
Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study
Authors: Ganesh Raghu, Kevin R Flaherty, David J Lederer, David A Lynch, Thomas V Colby, Jeffrey L Myers, Steve D Groshong, Brandon T Larsen, Jonathan H Chung, Mark P Steele, Sadia Benzaquen, Karel Calero, Amy H Case, Gerard J Criner, Steven D Nathan, Navdeep S Rai, Murali Ramaswamy, Lars Hagmeyer, J Russell Davis, Umair A Gauhar, Daniel G Pankratz, Yoonha Choi, Jing Huang, P Sean Walsh, Hannah Neville, Lori R Lofaro, Neil M Barth, Giulia C Kennedy, Kevin K Brown, Fernando J Martinez
Journal: The Lancet Respiratory Medicine (2019)
A Machine Learning Classifier for Assigning Individual Patients With Systemic Sclerosis to Intrinsic Molecular Subsets
Authors: Jennifer M. Franks, Viktor Martyanov, Guoshuai Cai, Yue Wang, Zhenghui Li, Tammara A. Wood, Michael L. Whitfield
Journal: Arthritis & Rheumatology (2019)

High-throughput gene expression profiling of tissue samples from patients with systemic sclerosis (SSc) has identified 4 "intrinsic" gene expression subsets: inflammatory, fibroproliferative, normal-like, and limited. Prior methods required agglomerative clustering of many samples. In order to classify individual patients in clinical trials or for diagnostic purposes, supervised methods that can assign single samples to molecular subsets are required. We undertook this study to introduce a novel machine learning classifier as a robust accurate intrinsic subset predictor.Three independent gene expression cohorts were curated and merged to create a data set covering 297 skin biopsy samples from 102 unique patients and controls, which was used to train a machine learning algorithm. We performed external validation using 3 independent SSc cohorts, including a gene expression data set generated by an independent laboratory on a different microarray platform. In total, 413 skin biopsy samples from 213 individuals were analyzed in the training and testing cohorts.Repeated cross-fold validation identified consistent and discriminative markers using multinomial elastic net, performing with an average classification accuracy of 87.1% with high sensitivity and specificity. In external validation, the classifier achieved an average accuracy of 85.4%. Reanalyzing data from a previous study, we identified subsets of patients that represent the canonical inflammatory, fibroproliferative, and normal-like subsets.We developed a highly accurate classifier for SSc molecular subsets for individual patient samples. The method can be used in SSc clinical trials to identify an intrinsic subset on individual samples. Our method provides a robust data-driven approach to aid clinical decision-making and interpretation of heterogeneous molecular information in SSc patients.
The value of isogenic cell lines in cancer drug discovery: Antitumor activity of WAY-181484, an orally-active, microtubule-binding agent
Authors: Sridhar K. Rabindran, Carl Beyer, Carolyn M. Discafani, John P. McGinnis, Miriam Miranda, Ariamala Gopalsamy, Girija Krishnamurthy, Dennis Powell, Daniel Wang, Nan Zhang
Journal: Cancer Research (2005)

5924  We have used an isogenic pair of human colon carcinoma cell lines (HCT 116 p21+/+ and p21-/-) to screen compounds for antitumor activity [Waldman et al. (1996), Nature 381, 713-716]. This pair of lines was used to select compounds that preferentially induce apoptosis in the p21-deficient cells, relative to the p21-proficient cells. As a downstream effector of the major tumor suppressor p53, p21 arrests cell cycle progression in response to DNA damage and other environmental stresses, by inhibiting the cyclin-dependent kinases (CDKs). Disruption of this cell cycle checkpoint by deletion of the p21 gene, results in the failure of the cell to arrest, leading to endoreduplication, and ultimately, apoptosis. The role of this checkpoint in modulating chemosensitivity of tumor cells is supported by the observation that the p21-deficient cells show increased sensitivity to a variety of clinically used antineoplastic drugs, compared with the isogenic p21-proficient cells. Compounds active in this assay are, therefore, predicted to target tumor cells that lack one or more checkpoints, a hallmark of cancer. WAY-181484 is the lead compound in the pyrazolopyrimidinyl phenyl amide series, a chemical series identified in this screen. WAY-181484 preferentially inhibits p21-/- cells (IC50 =120 nM) compared with p21+/+ cells (IC50 = 5700 nM) producing a selectivity ratio of ∼50. WAY-181484 is microtubule-active agent: it binds tubulin (Kd = 4.3 μM) at the colchicine binding site, and inhibits tubulin polymerization in cell-free systems and in intact cells. It shows potent activity against a panel of colon cell lines (IC50 = 20-60 nM), and inhibits the growth of human tumor xenografts in nude mice when administered orally, once-daily at 20-50 mg/kg. In summary, the identification of WAY-181484, a representative of a novel class of tubulin-binding agents that shows excellent antitumor activity in vitro and in vivo, has validated the use of the p21 isogenic cell-based screen in anticancer drug discovery.
Wake up and smell the coffee: caffeine supplementation and exercise performance—an umbrella review of 21 published meta-analyses
Authors: Jozo Grgic, Ivana Grgic, Craig Pickering, Brad J Schoenfeld, David J Bishop, Zeljko Pedisic
Journal: British Journal of Sports Medicine (2019)

Objective To systematically review, summarise and appraise findings of published meta-analyses that examined the effects of caffeine on exercise performance. Design Umbrella review. Data sources Twelve databases. Eligibility criteria for selecting studies Meta-analyses that examined the effects of caffeine ingestion on exercise performance. Results Eleven reviews (with a total of 21 meta-analyses) were included, all being of moderate or high methodological quality (assessed using the Assessing the Methodological Quality of Systematic Reviews 2 checklist). In the meta-analyses, caffeine was ergogenic for aerobic endurance, muscle strength, muscle endurance, power, jumping performance and exercise speed. However, not all analyses provided a definite direction for the effect of caffeine when considering the 95% prediction interval. Using the Grading of Recommendations Assessment, Development and Evaluation criteria the quality of evidence was generally categorised as moderate (with some low to very low quality of evidence). Most individual studies included in the published meta-analyses were conducted among young men. Summary/conclusion Synthesis of the currently available meta-analyses suggest that caffeine ingestion improves exercise performance in a broad range of exercise tasks. Ergogenic effects of caffeine on muscle endurance, muscle strength, anaerobic power and aerobic endurance were substantiated by moderate quality of evidence coming from moderate-to-high quality systematic reviews. For other outcomes, we found moderate quality reviews that presented evidence of very low or low quality. It seems that the magnitude of the effect of caffeine is generally greater for aerobic as compared with anaerobic exercise. More primary studies should be conducted among women, middle-aged and older adults to improve the generalisability of these findings.
Abstract 13887: Lower Extremity Artery Calcification Predicts Amputation and Mortality in Advanced Peripheral Arterial Disease Patients
Authors: Chi-Lun Huang, I-Hul Wu, Wen-Jeng Lee, Wei-Shiung Yang
Journal: Circulation (2013)

Objective: The clinical application of coronary artery calcium score has been well-demonstrated. However, little is known about the association of lower extremity artery calcium score with clinical...
Molecular Imaging of Deoxycytidine Kinase Activity Using Deoxycytidine-Enhanced CEST MRI
Authors: Zheng Han, Yuguo Li, Jia Zhang, Jing Liu, Chuheng Chen, Peter C. van Zijl, Guanshu Liu
Journal: Cancer Research (2019)

Deoxycytidine kinase (DCK) is a key enzyme for the activation of a broad spectrum of nucleoside-based chemotherapy drugs (e.g., gemcitabine); low DCK activity is one of the most important causes of cancer drug-resistance. Noninvasive imaging methods that can quantify DCK activity are invaluable for assessing tumor resistance and predicting treatment efficacy. Here we developed a "natural" MRI approach to detect DCK activity using its natural substrate deoxycytidine (dC) as the imaging probe, which can be detected directly by chemical exchange saturation transfer (CEST) MRI without any synthetic labeling. CEST MRI contrast of dC and its phosphorylated form, dCTP, successfully discriminated DCK activity in two mouse leukemia cell lines with different DCK expression. This dC-enhanced CEST MRI in xenograft leukemic cancer mouse models demonstrated that DCK(+) tumors have a distinctive dynamic CEST contrast enhancement and a significantly higher CEST contrast than DCK(-) tumors (AUC0-60 min = 0.47 ± 0.25 and 0.20 ± 0.13, respectively; P = 0.026, paired Student t test, n = 4) at 1 hour after the injection of dC. dC-enhanced CEST contrast also correlated well with tumor responses to gemcitabine treatment. This study demonstrates a novel MR molecular imaging approach for predicting cancer resistance using natural, nonradioactive, nonmetallic, and clinically available agents. This method has great potential for pursuing personalized chemotherapy by stratifying patients with different DCK activity. SIGNIFICANCE: A new molecular MRI method that detects deoxycytidine kinase activity using its natural substrate deoxycytidine has great translational potential for clinical assessment of tumor resistance and prediction of treatment efficacy.
About Face: Molecular Aberrations in Head and Neck Mucosal Melanomas
Authors: Alexander N. Shoushtari
Journal: Clinical Cancer Research (2019)

Abstract Detailed molecular characterization of a large cohort of mucosal melanomas, most arising from head and neck primaries, suggests that chromosomal translocations and other complex rearrangements have prognostic importance. CDK4 amplification is a frequent event in these rare tumors, and CDK4/6 inhibition may represent a rational clinical trial strategy. See related article by Zhou et al., p. 3548
Early Modeled Longitudinal CA-125 Kinetics and Survival of Ovarian Cancer Patients: A GINECO AGO MRC CTU Study
Authors: Olivier Colomban, Michel Tod, Alexandra Leary, Isabelle Ray-Coquard, Alain Lortholary, Anne Claire Hardy-Bessard, Jacobus Pfisterer, Andreas Du Bois, Christian Kurzeder, Alexander Burges, Julien Péron, Gilles Freyer, Benoit You
Journal: Clinical Cancer Research (2019)

Regarding cancer antigen 125 (CA-125) longitudinal kinetics during chemotherapy, the actual predictive value of the Gynecologic Cancer Intergroup (GCIG) CA-125 response criterion is questioned. The modeled CA-125 elimination rate constant KELIM exhibited higher prognostic value in patients with recurrent ovarian cancer enrolled in the CALYPSO trial. The objective was to validate the higher predictive and prognostic values of KELIM during first-line treatments.Data from three large phase III trials were analyzed: AGO OVAR 9 [learning set: carboplatin-paclitaxel (CP) ± gemcitabine; n = 1,288]; AGO OVAR 7 (validation set: CP ± topotecan; n = 192); and ICON7 (validation set: CP ± bevacizumab; n = 1,388). The CA-125 profiles were fit with a nonlinear mixed-effect model during the first 100 days, and the individual KELIM were calculated. KELIM prognostic and predictive values for survival were assessed against GCIG criterion and other prognostic factors in univariate/multivariate analyses.The GCIG CA-125 endpoint provided no meaningful predictive/prognostic information. C-index analyses confirmed the higher predictive value of KELIM compared with GCIG criterion for progression-free survival and overall survival (OS). KELIM provided reproducible prognostic information. Patients with favorable KELIM ≥ upper tercile (0.0711 per days) consistently experienced better OS, with HRs between 0.44 and 0.58 (e.g., median OS >65 months vs. <35 months).Modeled KELIM provides higher predictive and prognostic information based on CA-125 longitudinal kinetics compared with GCIG response criteria during first-line chemotherapy. Integration of this endpoint in guidelines may be considered. Individual KELIM and survival simulations can be calculated at http://www.biomarker-kinetics.org/. Further assessment of the surrogate value of KELIM treatment-related variations in a GCIG meta-analysis is warranted.See related commentary by Maitland et al., p. 5182.
RETRACTED: Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Breast Cancer
Authors: Cheng-Cao Sun, Shu-Jun Li, Wei Hu, Jian Zhang, Qun Zhou, Cong Liu, Lin-Lin Li, Yi-Yan Songyang, Feng Zhang, Zhen-Long Chen, Guang Li, Zhuo-Yue Bi, Yong-Yi Bi, Feng-Yun Gong, Tao Bo, Zhan-Peng Yuan, Wei-Dong Hu, Bo-Tao Zhan, Qian Zhang, Qi-Qiang He, De-Jia Li
Journal: Molecular Therapy (2019)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Molecular Therapy is retracting this article. After a reader raised concerns about the article, the Editor-in-Chief found that Figure 1 was reused without attribution to the authors' previous work (Sun et al., 2018, Aging (Albany NY) 10, 973-987, https://dx.doi.org/10.18632/aging.101441) (although the pan-cancer analysis of E2F family using Oncomine database shared the same image to summarize the transcriptional levels of E2F family in different cancer types), and images were also duplicated in Figure 4. The author maintains that Figure 1 was not reused because it was generated using Oncomine.org, and the image duplications in Figure 4 were the result of unintentional errors that do not affect the interpretation of the results. The editors maintain that these issues have raised serious concerns about the validity of the results. This reuse (and in part, misrepresentation) of data without appropriate attribution represents a severe abuse of the scientific publishing system. Retraction Notice to: Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Breast CancerSun et al.Molecular TherapyMay 23, 2022In Brief(Molecular Therapy 27, 1153–1165, June 2019) Full-Text PDF
Trust admits that patients should not have had pelvic floor mesh surgery
Authors: Clare Dyer
Journal: BMJ (2019)

More than 50 patients who had controversial pelvic floor surgery involving artificial mesh should not have been operated on, an NHS trust has admitted.

North Bristol NHS Trust has told 57 women and men who had the procedure at Southmead Hospital in Bristol that they should have been offered alternative treatment first. The review follows an independent investigation into laparoscopic ventral mesh rectopexy (LVMR) cases between 2007 and 2017.

Surgeon Tony Dixon, a pioneer in the use of the technique, was suspended in 2017 after concerns were raised. He has also had his practising privileges withdrawn by the private …
Abstract 11250: Long-term Outcomes for Patients With Atrial fibrillation and a Rapid Ventricular Response: A Comparison of Those With Reduced Versus Preserved Ejection Fraction at Initial Hospitalization
Authors: Mina M Benjamin, Ashish Chaddha, Emmanuel Sampene, Michael E Field, Peter Rahko
Journal: Circulation (2016)

Background: Patients presenting with new onset atrial fibrillation with rapid ventricular response (AFRVR) may present with a reduced left ventricular ejection fraction (LVEF). We hypothesized that these patients have worse outcomes than patients presenting with preserved LVEF. Methods: Retrospective cohort study of 385 consecutive patients with new onset AFRVR, presenting between 01/2006 and 08/2014. Patients with a history of coronary artery disease or known cardiomyopathy were excluded. Patients were divided into those with reduced EF (REF) (LVEF ≤ 55%, n=147), and those with a preserved EF (PEF) (LVEF&gt; 55%, n=238). Echocardiographic parameters, stroke rates, all-cause, and cardiovascular mortality were compared at baseline and a minimum of 1 year follow-up. Results: Mean age was 68 +/- 1.1 in REF versus 60 +/- 7.4 in PEF (p=0.39). There were no significant differences in baseline comorbidities. Mean LVEF was 47.7+/- 0.8% in REF vs 65.5 +/- 0.3% in PEF. The average duration of follow-up was 2.8 years. REF patients had higher all-cause mortality (32.7% REF vs 20.6% PEF, OR 2.17, p= 0.008) but similar cardiovascular mortality (15% REF vs 15.1% PEF, p=0.97). REF patients had higher rates of subsequent clinic or ER visits for AFRVR (32% REF vs 22.7% PEF, p=0.044). The incidence of stroke was similar between both groups (17% REF vs 18.9% PEF, p=0.639). Of REF patients, 29.7% had subsequent EF recovery; this subset had similar outcomes compared to PEF patients. Baseline left ventricular end diastolic diameter (LVEDD) predicted all-cause mortality (OR 1.14, p=0.003) in REF group. None of the echocardiographic parameters predicted EF recovery. Conclusion: In this cohort of patients with new AFRVR, REF was associated with higher long-term all-cause mortality and AFRVR recurrence. Those with subsequent LVEF recovery after medical therapy appear to have outcomes similar to those with PEF.
A Positive Feedback Loop Between Cancer Stem‐Like Cells and Tumor‐Associated Neutrophils Controls Hepatocellular Carcinoma Progression
Authors: Shao‐Lai Zhou, Dan Yin, Zhi‐Qiang Hu, Chu‐Bin Luo, Zheng‐Jun Zhou, Hao‐Yang Xin, Xin‐Rong Yang, Ying‐Hong Shi, Zheng Wang, Xiao‐Wu Huang, Ya Cao, Jia Fan, Jian Zhou
Journal: Hepatology (2019)

Tumor-associated neutrophils (TANs) play a crucial role in tumor development and progression in the cancer microenvironment. Despite increased understanding of TAN contributions to hepatocellular carcinoma (HCC) progression and prognosis, the direct interaction between TANs and HCC cells is not fully understood. In this study, we tested the effect of TANs on HCC cells in vitro and in vivo and investigated the mechanism of interaction between them. Our results showed that TANs secreted bone morphogenetic protein 2 and transforming growth factor beta 2 and triggered microRNA 301b-3p (miR-301-3p) expression in HCC cells, subsequently suppressed gene expression of limbic system-associated membrane protein (LSAMP) and CYLD lysine 63 deubiquitinase (CYLD), and increased stem cell characteristics in HCC cells. These TAN-induced HCC stem-like cells were hyperactive in nuclear factor kappa B signaling, secreted higher levels of chemokine (C-X-C motif) ligand 5 (CXCL5), and recruited more TAN infiltration, suggesting a positive feedback loop. In clinical HCC samples, increased TANs correlated with elevated miR-301b-3p, decreased LSAMP and CYLD expression, and increased nuclear p65 accumulation and CXCL5 expression, all of which predicted patient outcome. Conclusion: Our work identified a positive feedback loop governing cancer stem-like cells and TANs in HCC that controls tumor progression and patient outcome.
Abstract 19538: KChIP2 Regulates the Cardiac Ca2+ Transient by Targeting Ryanodine Receptor Activity
Authors: Drew Nassal, Xiaoping Wan, Haiyan Liu, Kenneth R Laurita, Isabelle Deschenes
Journal: Circulation (2016)

Introduction: Cardiac ion channels and their respective interacting accessory subunits are critical in maintaining proper cardiac electrical activity. K+ channel interacting protein (KChIP2) was or...
Giant atypical hyperplastic lesions on Barrett’s esophagus and at the esophagogastric junction resected by endoscopic submucosal dissection
Authors: Thomas Couronne, Pierre-Marie Lavrut, Jérôme Rivory, François Bouculat, Valérie Hervieu, Charles Ber, Mathieu Pioche
Journal: Endoscopy (2019)

Barrett’s esophagus (BE) neoplasms are usually flat or slightly depressed and should be treated by endoscopic resection when lesions are visible, according to European Society of Gastrointestinal Endoscopy (ESGE) guidelines [1].
Abstract 16903: Circulating Growth Differentiation Factor 15 (GDF-15) in Patients With Heart Failure With Reduced Ejection Fraction: Insights From PARADIGM-HF
Authors: Nadia Bouabdallaoui, Brian L Claggett, Michael R Zile, John J McMurray, Eileen O'Meara, Milton Packer, Margaret Prescott, Jean L Rouleau, Karl Swedberg, Scott D Solomon
Journal: Circulation (2017)

Background: Growth Differentiation Factor 15 (GDF-15) is an emerging biomarker involved in the inflammatory response, tissue remodelling and apoptosis that is associated with prognosis in cardiovas...
State GP indemnity scheme launches but questions remain over historical claims
Authors: Abi Rimmer
Journal: BMJ (2019)

The government funded clinical negligence scheme for general practice has come into effect, but there are few details existing liabilities coverage.

The scheme aims to provide more affordable indemnity cover for GPs in England. It will provide automatic, comprehensive cover for all GPs (including partners, salaried GPs, and locums, and those working out of hours) and practice staff (including nurses and allied health professionals) for clinical negligence claims relating to NHS work from 1 April 2019.

The BMA has advised, however, that GPs will still need medical defence organisation cover for non-NHS activities, such as GMC or coroner’s court representation and private work.1

Simon Kayll, chief executive of the Medical Protection Society (MPS) said that GPs would also continue to need cover for regulatory matters and complaints …