tbuckley/cabot-search huggingface dataset:
N-cadherin overexpression enhances the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes in infarcted mouse hearts
Authors: Xi Lou, Meng Zhao, Chengming Fan, Vladimir G Fast, Mani T Valarmathi, Wuqiang Zhu, Jianyi Zhang
Journal: Cardiovascular Research (2019)

In regenerative medicine, cellular cardiomyoplasty is one of the promising options for treating myocardial infarction (MI); however, the efficacy of such treatment has shown to be limited due to poor survival and/or functional integration of implanted cells. Within the heart, the adhesion between cardiac myocytes (CMs) is mediated by N-cadherin (CDH2) and is critical for the heart to function as an electromechanical syncytium. In this study, we have investigated whether the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) can be enhanced through CDH2 overexpression.CDH2-hiPSC-CMs and control wild-type (WT)-hiPSC-CMs were cultured in myogenic differentiation medium for 28 days. Using a mouse MI model, the cell survival/engraftment rate, infarct size, and cardiac functions were evaluated post-MI, at Day 7 or Day 28. In vitro, conduction velocities were significantly greater in CDH2-hiPSC-CMs than in WT-hiPSC-CMs. While, in vivo, measurements of cardiac functions: left ventricular (LV) ejection fraction, reduction in infarct size, and the cell engraftment rate were significantly higher in CDH2-hiPSC-CMs treated MI group than in WT-hiPSC-CMs treated MI group. Mechanistically, paracrine activation of ERK signal transduction pathway by CDH2-hiPSC-CMs, significantly induced neo-vasculogenesis, resulting in a higher survival of implanted cells.Collectively, these data suggest that CDH2 overexpression enhances not only the survival/engraftment of cultured CDH2-hiPSC-CMs, but also the functional integration of these cells, consequently, the augmentation of the reparative properties of implanted CDH2-hiPSC-CMs in the failing hearts.
Preoperative oxaliplatin (O), docetaxel (D), capecitabine (C), and concurrent radiation therapy (RT) for patients (pts) with localized esophageal cancer: A phase I/II trial of the Minnie Pearl Cancer Research Network
Authors: E. K. Barnes, D. R. Spigel, F. A. Greco, A. A. Meluch, D. A. Yardley, H. A. Burris, D. L. Shipley, J. F. Patton, C. Farley, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2006)

4058 Background: Preoperative chemoradiotherapy improves outcomes for pts with resectable esophageal cancer compared with surgery alone. We previously reported a 41% 3-year progression-free survival (PFS) with preoperative paclitaxel/carboplatin/5FU/RT in a large phase II trial. The present multicenter community trial examined the role of a newer combination regimen. Methods: The primary endpoints were to assess the safety and response rate (RR) of O/D/C/RT in pts with resectable stage I-III cancer of the mid-/distal-esophagus or GE junction. Treatment (tx): O 40 mg/m 2 IV and D 20 mg/m 2 IV weekly x 5; C 1000 mg/m 2 PO BID D1–7, 15–21, 29–35; and RT 45 Gy, 1.8-Gy M-F weekly x 5, starting D1. Pts were resected 4–8 weeks after tx. The phase I portion (n=10) confirmed the safety of O/D/R, and C was added in the phase II portion. Eligibility: measurable disease; ECOG PS 0–1, informed consent. Analysis was by intent to treat. Results: Nineteen pts were enrolled from 9/04 to 10/05 (trial ongoing). Baseline features: median age 60 years (38–77); male/female, 82%/18%; ECOG PS 0/1: 27%/73%; adenocarcinoma/squamous (77%/23%); I (5%), IIA (5%), IIB (33%), III (38%), primary tumor not assessable (19%). All pts completed O/D/C/RT and 14 (74%) were resected. Grade (G) 3/4 non-hematologic toxicity: anorexia (16%), nausea (16%), and fatigue (11%). Other G3/4 non-hematologic toxicities were ≤5%, with no G3/4 esophagitis. No G3/4 hematologic toxicities or tx-related deaths occurred. Complete/partial responses assessed before surgery were seen in 2 pts/11 pts, respectively, for an overall RR of 68% (95% CI 46%-84%). Four pts (21%) had stable disease and 1 pt had progression (1 pt was unevaluable). Pathological complete responses were seen in 8 of 14 evaluable pts (57%). With a median follow-up of 8 months, actuarial 1-year PFS and overall survival (OS) are 66% and 79%, respectively. Median PFS and OS have not been reached. Conclusions: O/D/C/RT is a relatively well-tolerated and active preoperative therapy for pts with resectable esophageal cancer. Additional pts and follow-up are needed to assess this regimen’s benefits. [Table: see text]
Pharmacokinetics and Toxicities after Evomela® (propylene glycol free melphalan) with Autologous Hematopoietic Stem Cell Transplant (AHCT) for Multiple Myeloma and AL Amyloidosis
Authors: Gunjan L. Shah, Heather Landau, Caitlin Sarubbi, Ryan Schofield, Andrew Lin, Valkal Bhatt, Stephen J. Harnicar, Sean M. Devlin, David J. Chung, Parastoo B. Dahi, Guenther Koehne, Roni Tamari, Dean Carlow, Sergio A. Giralt
Journal: Blood (2017)
Detection of <i>DDR2</i> mutations in malignant melanoma: A potentially targetable feature of advanced stage disease.
Authors: Yongbao Wang, Shere S Billouin-Frazier, Justin P Windham, Daniel Jones
Journal: Journal of Clinical Oncology (2013)

9100 Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a subset of non-small cell carcinoma of the lung. In lung cancer, targeting of DDR2 with the inhibitor dasatinib has been shown to inhibit DDR2-mutated cell line growth. Responses to dasatinib in DDR2-mutated lung tumors are currently being investigated in clinical trials. We investigated whether somatic DDR2 mutations also occur in melanomas using a set of different clinical subtypes bearing a variety of melanoma-associated molecular alterations. Methods: DNA was extracted from macrodissected FFPE sections of 168 melanomas and subjected to next-generation sequencing using a custom-designed 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. PCR products were prepared by Access Array, sequenced on the Ion Torrent PGM, and analyzed using Sequence Pilot software. All DDR2 mutations were confirmed by bidirectional Sanger sequencing. Relative expression analysis of the DDR2 gene was performed using RT-PCR on RNA extracted from FFPE sections, with levels normalized to ABL1 and GAPDH. Results: Heterozygous DDR2 point mutations were identified in 3.4% of BRAF-mutated melanoma (n=117) but not in any cases that lacked BRAF mutations (n = 51). All DDR2-mutated melanomas were advanced stage with lymph node and/or extensive soft tissue involvement and included both BRAF V600K and V600E cases. In contrast to the range of mutation sites reported in lung cancers, DDR2 mutations in melanoma (I488S, F574C, S667F and L701F) were at highly evolutionarily conserved positions in the kinase domain. The mutations are expected to be disruptive and may therefore modulate kinase activity. DDR2 transcripts were expressed in tumor cells in all mutated cases. Conclusions: DDR2 mutations in advanced stage melanoma may provide a targetable genetic feature for tyrosine kinase inhibitors such as dasatinib. The invariant association of DDR2 mutation with activating BRAF mutations suggests synergy in transformation between these distinct signaling pathways.
Prevalence of Hepatitis B Virus Exposure in the Veterans Health Administration and Association With Military-Related Risk Factors
Authors: Lauren A. Beste, George N. Ioannou, Michael F. Chang, Christopher W. Forsberg, Anna M. Korpak, Edward J. Boyko, Jennifer L. Sporleder, Nicholas L. Smith, Charles Maynard, Maggie Chartier, Jason A. Dominitz
Journal: Clinical Gastroenterology and Hepatology (2019)

Military veterans have been reported to have higher odds of hepatitis B virus (HBV) exposure after adjustment for demographic factors, family income, and birthplace. It is not clear whether military-related exposures are associated with risk of HBV exposure in veterans.A random sample of veterans receiving care from 1998 through 2000 in the national Veterans' Health Administration system completed a risk factor survey and underwent phlebotomy analysis (N = 1146). Stored serum samples were reanalyzed to determine prevalence of HBV exposure (core antibody positive), infection (surface antigen or DNA positive), and immunity (surface antibody positive, surface antigen negative, and core antibody negative). Associations between military-related risk factors and HBV exposure were assessed using logistic regression.The prevalence values for infection, exposure, and immunity were 0.7% (95% CI, 0.3-1.5), 13.6% (95% CI, 11.5-16.1), and 6.2% (95% CI, 4.7-8.2), respectively. Evidence of HBV exposure was highest among respondents with traditional risk factors (such as drug use or high-risk sexual practices). More than half the individuals with HBV exposure (53%) reported no history of traditional risk factors; of these, 59.5% reported a history of combat exposure. After adjustment for demographic and traditional risk factors, service in a combat zone (adjusted odds ratio, 1.56; 95% CI, 1.01-2.41) and being wounded in combat (adjusted odds ratio, 1.79; 95% CI, 1.04-3.08) were associated independently with exposure to HBV.In an analysis of US military veterans, we found the prevalence of exposure to HBV to be highest among veterans with traditional risk factors but also independently related to military combat or being wounded in combat. Studies are needed to determine whether veterans with combat exposure before the era of universal vaccination should be screened for HBV exposure.
Evaluation of algorithms for Multi-Modality Whole Heart Segmentation: An open-access grand challenge
Authors: Xiahai Zhuang, Lei Li, Christian Payer, Darko Štern, Martin Urschler, Mattias P. Heinrich, Julien Oster, Chunliang Wang, Örjan Smedby, Cheng Bian, Xin Yang, Pheng-Ann Heng, Aliasghar Mortazi, Ulas Bagci, Guanyu Yang, Chenchen Sun, Gaetan Galisot, Jean-Yves Ramel, Thierry Brouard, Qianqian Tong, Weixin Si, Xiangyun Liao, Guodong Zeng, Zenglin Shi, Guoyan Zheng, Chengjia Wang, Tom MacGillivray, David Newby, Kawal Rhode, Sebastien Ourselin, Raad Mohiaddin, Jennifer Keegan, David Firmin, Guang Yang
Journal: Medical Image Analysis (2019)

Knowledge of whole heart anatomy is a prerequisite for many clinical applications. Whole heart segmentation (WHS), which delineates substructures of the heart, can be very valuable for modeling and analysis of the anatomy and functions of the heart. However, automating this segmentation can be challenging due to the large variation of the heart shape, and different image qualities of the clinical data. To achieve this goal, an initial set of training data is generally needed for constructing priors or for training. Furthermore, it is difficult to perform comparisons between different methods, largely due to differences in the datasets and evaluation metrics used. This manuscript presents the methodologies and evaluation results for the WHS algorithms selected from the submissions to the Multi-Modality Whole Heart Segmentation (MM-WHS) challenge, in conjunction with MICCAI 2017. The challenge provided 120 three-dimensional cardiac images covering the whole heart, including 60 CT and 60 MRI volumes, all acquired in clinical environments with manual delineation. Ten algorithms for CT data and eleven algorithms for MRI data, submitted from twelve groups, have been evaluated. The results showed that the performance of CT WHS was generally better than that of MRI WHS. The segmentation of the substructures for different categories of patients could present different levels of challenge due to the difference in imaging and variations of heart shapes. The deep learning (DL)-based methods demonstrated great potential, though several of them reported poor results in the blinded evaluation. Their performance could vary greatly across different network structures and training strategies. The conventional algorithms, mainly based on multi-atlas segmentation, demonstrated good performance, though the accuracy and computational efficiency could be limited. The challenge, including provision of the annotated training data and the blinded evaluation for submitted algorithms on the test data, continues as an ongoing benchmarking resource via its homepage (www.sdspeople.fudan.edu.cn/zhuangxiahai/0/mmwhs/).
Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905)
Authors: Anne S. Tsao, Jieling Miao, Ignacio I. Wistuba, Nicholas J. Vogelzang, John V. Heymach, Frank V. Fossella, Charles Lu, Mario R. Velasco, Brandy Box-Noriega, James G. Hueftle, Shirish Gadgeel, Mary W. Redman, David R. Gandara, Karen Kelly
Journal: Journal of Clinical Oncology (2019)

PURPOSE Antiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy. PATIENTS AND METHODS SWOG S0905 (ClinicalTrials.gov identifier: NCT01064648 ) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test. RESULTS Ninety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed. CONCLUSION The addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM.
<i>TP53</i> status is an important prognostic marker for patients with hepatic metastases from colorectal carcinoma
Authors: D. G. Mollevi, T. Serrano, M. M. Ginesta, J. Valls, J. Torras, E. Ramos, J. Germà, V. Moreno, G. Capella, J. Figueras, A. Villanueva
Journal: Journal of Clinical Oncology (2006)

10092 Background: The aim of this study was to analyze the value of TP53 gene mutations as a prognostic marker to improve the selection of patients candidates to surgery in a consecutive series of liver metastases from colorectal cancer patients. Methods: 91 patients with liver metastases from colorectal carcinoma (CRC) were included. Mutational study of TP53 gene, exons 4 to 10, was assessed both in paraffin-embedded hepatic metastasis and normal liver parenchyma by SSCP (Single Strand Chain Polymorphism) followed by sequencing of abnormal electrophoretic mobility patterns. Immunostaining of P53 and P21 proteins were assessed in the same group of patients. Results: Forty-eight out 91 (50.05%) metastases showed mutation in TP53. Higher incidence of mutations was detected in exons 5–8, although exons 9 and 10 were mutated in 28.26% of metastases. Protein-truncating mutations (nonsense and frameshift) occur in 47.8% of metastasis harboring TP53 mutations. TP53 mutation was associated with poor prognosis in univariate (P=0.0062) and multivariate Cox proportional hazard model (P=0.012) analysis. Prognosis association was maintained in the group of patients undergoing radical resection, named R0 series (n=79; P=0.008). High prevalence of TP53 mutations happen in patients with &gt;3 metastases (65.6%; P=0.034), primary tumors Duke’s C-D stages (57.4%; 63.0%; respectively; p=0.026) and patients with age &lt;57 years at resection. Interestingly, patients with TP53 mutations in their metastases relapsed earlier after the resection of the primary tumor (P=0.026). Postoperative 5-FU-based chemotherapy showed a better survival outcome in patients with wild-type TP53 hepatic metastases (HR: 2.92; 95% CI: 1.32–6.46; P=0.006). Conclusions: TP53 mutational status seems to be an important prognostic factor in patients with hepatic metastases from CRC. No significant financial relationships to disclose.
Physical activity and COPD development. Time to advocate
Authors: Judith Garcia Aymerich
Journal: Thorax (2019)

Physical activity is nowadays a widely accepted determinant of the progression of COPD.1 However, its role in preventing COPD development remains unclear. Several epidemiological analyses using population-based adult cohorts have reported longitudinal associations between higher physical activity levels and higher lung function levels, attenuated lung function decline and/or lower COPD incidence.2–7 In cohorts of patients with asthma8 9 or COPD,10 higher physical activity levels appear to attenuate lung function decline. In childhood, higher physical activity levels (assessed by accelerometer) relate to higher lung function at adolescence,11 which will likely impact on adult COPD risk.12 

In the current issue of Thorax , Hansen et al 13 provide additional evidence supporting a role for physical activity on COPD risk, although they used physical fitness as a marker of physical activity . The authors report a longitudinal association between cardiorespiratory fitness (determined as maximal oxygen uptake (VO2max) by ergometer test) and both COPD incidence and mortality in 4730 Danish adult men (mostly active smokers at baseline) followed for 46 years, after adjustment for age, socioeconomic status, smoking intensity, alcohol consumption, self-reported physical activity, body mass index, arterial hypertension and diabetes mellitus. In order to remove reverse causation (ie, COPD affects physical fitness via reduced physical activity), Hansen and colleagues restricted the analysis to events that happened 10 years or more after baseline. This approach is of special relevance because reverse …
Lessons Learned From the Opioid Epidemic
Authors: Joshua M. Sharfstein, Yngvild Olsen
Journal: JAMA (2019)

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Hodgkin lymphoma in United Arab Emirates UAE, epidemeology, histological types and treatments outcome: Case series of 47 cases from Mafraq Hospital, Abu Dhabi, UAE.
Authors: Aladdin Maarraoui, Ahmed AlMessabi, Omar Al Teneji, Yasmeen Maarraoui
Journal: Journal of Clinical Oncology (2019)

e19016 Background: Approximately 9,050 Americans gets diagnosed annually with Hodgkin's Lymphoma HL and approximately 1,150 dies each year from HL(1).Nodular Lymphocyte-predominant LP (NLPHL) represents 5% of HL (2). Mafraq Hospital is a tertiary hospital in Abu Dhabi, UAE, We suspected that we are seeing more than expected cases of NLPHL.Therefore, we carried a retrospective study to review all cases of HL seen at our oncology unit for the period from 01/01/2016 till 30/06/ 2018. Methods: We developed Excel data collection tool. After Ethics approval, Electronic Medical Records of all cases seen with the diagnosis of HL between 01/2016 and 06/2018 at Mafraq Hospital were reviewed. Results: Total of 47 case were collected. 8 cases (17%) were found to have NLPHL, The rest of cohort were 39 cases, 22 (57%) of them had nodular sclerosis HL, 4 cases (10%) mixed cellularity HL, 2 (5%) lymphocyte rich HL, no cases of lymphocyte depleted HL. 9 (23%) of cases were classical HL with no type as diagnosis was made from core biopsies. 2 cases (5%) unlisted type.The stage for the 42 case were as follows Stage I: 1 case = 2.3%, Stage II: 24 case = 57.1%Stage III: 11 case = 26.1%Stage IV: 6 cases = 14.2%. Conclusions: We saw 23 (49%) females and 24 (51%) males. Our hypothesis that NLPHL is more frequently seen in UAE seems to be correct as 17% of all HL cases seen were from this subtype. Mean age at diagnosis of all HL cases is 33 years. In the NLPHL there were 2 (25%) females and 6 (75%) males. Mean age at diagnosis for NLPHL is 31.8 years. Most HL patients received ABVD as first line regimen. This is documented in 38 out of 47 case. Mean overall survival registered at the closure of the study is 45 months. It is important that this overall survival is premature as no patient has relapsed or died.