tbuckley/cabot-search huggingface dataset:
Abstract B27: Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib
Authors: Bengt Hallberg, Ganseh Umapathy, Jikui Guan, Dan Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djoos, Tommy Martinsson, Ruth Palmer
Journal: Cancer Research (2018)

Abstract The RAS-RAF-MEK-ERK pathway is a major player in initiation and progression of multiple cancers where it can be hyperactivated by upstream regulatory proteins, such as tyrosine kinases, phosphatases, and GTPases. Several inhibitors targeting the RAS-MAPK pathway exhibit anticancer activity and are approved as single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK, EGFR, and K-RAS mutant lung cancer and neuroblastoma containing hyperactivating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, and NF1 genes, leading to hyperactivation of RAS-MAPK signaling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors, since monotreatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacologic inhibition of the MEK-ERK pathway in ALK-positive neuroblastoma cells results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by the mTORC2 complex protein SIN1. Taken together, our results indicate that blocking MEK-ERK leads to increased activation of AKT signaling core in ALK-positive neuroblastoma, intensifying survival signals in these cells. Our results contraindicate use of MEK inhibitors as an effective single- and polytherapeutic strategy in ALK-positive neuroblastoma. Citation Format: Bengt Hallberg, Ganseh Umapathy, Jikui Guan, Dan Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djoos, Tommy Martinsson, Ruth Palmer. Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B27.
Case 31-2018: A 37-Year-Old Man with a Self-Inflicted Gunshot Wound
Authors: Chana A. Sacks, Shahmir Kamalian, Peter T. Masiakos, George A. Alba, Eva D. Patalas
Journal: New England Journal of Medicine (2018)

A 37-year-old man was admitted to the surgical intensive care unit because of a self-inflicted gunshot wound to the face. Management decisions were made.
GW29-e0845 Differences in Physical Examination of Patients with Symptomatic and Asymptomatic Fluid Overload and Low Ejection fraction
Authors: Thach Nguyen, Tran Ngoc Minh Chau, Nguyen Tri Si, Thao Dang, Tu NT. Nguyen, Tarneem Darwish, Gianluca Rigatelli, Ernest Talarico
Journal: Journal of the American College of Cardiology (2018)
Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial
Authors: Désirée van der Heijde, Xenofon Baraliakos, Lianne S Gensler, Walter P Maksymowych, Vira Tseluyko, Oleg Nadashkevich, Walid Abi-Saab, Chantal Tasset, Luc Meuleners, Robin Besuyen, Thijs Hendrikx, Neelufar Mozaffarian, Ke Liu, Joy M Greer, Atul Deodhar, Robert Landewé
Journal: The Lancet (2018)
Serum Nardilysin, a Surrogate Marker for Epithelial–Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection
Authors: Tomoaki Yoh, Etsuro Hatano, Yosuke Kasai, Hiroaki Fuji, Kiyoto Nishi, Kan Toriguchi, Hideaki Sueoka, Mikiko Ohno, Satoru Seo, Keiko Iwaisako, Kojiro Taura, Rina Yamaguchi, Masato Kurokawa, Jiro Fujimoto, Takeshi Kimura, Shinji Uemoto, Eiichiro Nishi
Journal: Clinical Cancer Research (2018)

Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC.Experimental Design: We measured serum NRDC levels in 98 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzed NRDC mRNA levels in cancerous tissue specimens from 43 patients with ICC. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing.High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n = 79) and validation (n = 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman ρ = 0.413; P = 0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown of NRDC was also accompanied by significant changes in the expression of several epithelial-mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1, in surgical specimens from patients with ICC.Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.
Effect of Community Health Worker Support on Clinical Outcomes of Low-Income Patients Across Primary Care Facilities
Authors: Shreya Kangovi, Nandita Mitra, Lindsey Norton, Rory Harte, Xinyi Zhao, Tamala Carter, David Grande, Judith A. Long
Journal: JAMA Internal Medicine (2018)

Addressing the social determinants of health has been difficult for health systems to operationalize.To assess a standardized intervention, Individualized Management for Patient-Centered Targets (IMPaCT), delivered by community health workers (CHWs) across 3 health systems.This 2-armed, single-blind, multicenter randomized clinical trial recruited patients from 3 primary care facilities in Philadelphia, Pennsylvania, between January 28, 2015, and March 28, 2016. Patients who resided in a high-poverty zip code, were uninsured or publicly insured, and who had a diagnosis for 2 or more chronic diseases were recruited, and patients were randomized to either the CHW intervention or the control arm (goal setting only). Follow-up assessments were conducted at 6 and 9 months after enrollment. Data were analyzed using an intention-to-treat approach from June 2017 to March 2018.Participants set a chronic disease management goal with their primary care physician; those randomized to the CHW intervention received 6 months of tailored support.The primary outcome was change in self-rated physical health. The secondary outcomes were self-rated mental health, chronic disease control, patient activation, patient-reported quality of primary care, and all-cause hospitalization.Of the 592 participants, 370 (62.5%) were female, with a mean (SD) age of 52.6 (11.1) years. Participants in both arms had similar improvements in self-rated physical health (mean [SD], 1.8 [11.2] vs 1.6 [9.9]; P = .89). Patients in the intervention group were more likely to report the highest quality of care (odds ratio [OR], 1.8; 95% CI, 1.4-2.4; risk difference [RD], 0.12; P < .001) and spent fewer total days in the hospital at 6 months (155 days vs 345 days; absolute event rate reduction, 69%) and 9 months (300 days vs 471 days; absolute event rate reduction, 65%). This reduction was driven by a shorter average length of stay (difference, -3.1 days; 95% CI, -6.33 to 0.22; P = .06) and a lower mean number of hospitalizations (difference, -0.3; 95% CI, -0.6 to 0.0; P = .07) among patients who were hospitalized. Patients in the intervention group had a lower odds of repeat hospitalizations (OR, 0.4; 95% CI, 0.2-0.9; RD, -0.24; P = .02), including 30-day readmissions (OR, 0.3; 95% CI, 0.1-0.9; RD, -0.17; P = .04).A standardized intervention did not improve self-rated health but did improve the patient-perceived quality of care while reducing hospitalizations, suggesting that health systems may use a standardized intervention to address the social determinants of health.ClinicalTrials.gov identifier: NCT02347787.
Association of Antenatal Steroid Exposure With Survival Among Infants Receiving Postnatal Life Support at 22 to 25 Weeks’ Gestation
Authors: Danielle E. Y. Ehret, Erika M. Edwards, Lucy T. Greenberg, Ira M. Bernstein, Jeffrey S. Buzas, Roger F. Soll, Jeffrey D. Horbar
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Although evidence of antenatal steroids (ANS) efficacy at 22 to 25 weeks’ gestation is limited, increasingly these infants are treated with postnatal life support. <h3>Objectives</h3> To estimate the proportion of infants receiving postnatal life support at 22 to 25 weeks’ gestation who had exposure to ANS, and to examine if the provision of ANS was associated with a higher rate of survival to hospital discharge and survival without major morbidities. <h3>Design, Setting, and Participants</h3> This multicenter observational cohort study consisted of 33 472 eligible infants liveborn at 431 US Vermont Oxford Network member hospitals between January 1, 2012, and December 31, 2016. We excluded infants with recognized syndromes or major congenital anomalies. Of the eligible infants, 29 932 received postnatal life support and were included in the analyses. Data analysis was conducted from July 2017 to July 2018. <h3>Exposure</h3> Antenatal steroids administered to the mother at any time prior to delivery. <h3>Main Outcomes and Measures</h3> Survival to hospital discharge, major morbidities among survivors, and the composite of survival to discharge without major morbidities. <h3>Results</h3> Among 29 932 infants who received postnatal life support, 51.9% were male, with a mean (SD) gestational age of 24.12 (0.86) weeks and mean (SD) birth weight of 668 (140) g; 26 090 (87.2%) had ANS exposure and 3842 (12.8%) had no ANS exposure. Survival to hospital discharge was higher for infants with ANS exposure (18 717 of 25 892 [72.3%]) compared with infants without ANS exposure (1981 of 3820 [51.9%]); the adjusted risk ratio for 22 weeks was 2.11 (95% CI, 1.68-2.65), for 23 weeks was 1.54 (95% CI, 1.40-1.70), for 24 weeks was 1.18 (95% CI, 1.12-1.25), and for 25 weeks was 1.11 (95% CI, 1.07-1.14). Survival to hospital discharge without major morbidities was higher for infants with ANS exposure (3777 of 25 833 [14.6%]) compared with infants without ANS exposure (347 of 3806 [9.1%]); the adjusted risk ratio for 22 through 25 weeks was 1.67 (95% CI, 1.49-1.87). <h3>Conclusions and Relevance</h3> Concordant receipt of ANS and postnatal life support was associated with significantly higher survival and survival without major morbidities at 22 through 25 weeks’ gestation compared with life support alone. Although statistically higher with ANS, survival without major morbidities remains low at 22 and 23 weeks. There is an opportunity to reevaluate national obstetric guidelines, allowing for shared decision making at the edge of viability with concordant obstetrical and neonatal treatment plans.
Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer
Authors: Ulka N. Vaishampayan, Izabela Podgorski, Lance K. Heilbrun, Jawana M. Lawhorn-Crews, Kimberlee C. Dobson, Julie Boerner, Karri Stark, Daryn W. Smith, Elisabeth I. Heath, Joseph A. Fontana, Anthony F. Shields
Journal: Clinical Cancer Research (2018)

Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured.Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range, -85 to -5%, n = 11) and -41% (range, -60 to -25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit.Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.
The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol
Authors: Gordan M. Vujanić, Manfred Gessler, Ariadne H. A. G. Ooms, Paola Collini, Aurore Coulomb-l’Hermine, Ellen D’Hooghe, Ronald R. de Krijger, Daniela Perotti, Kathy Pritchard-Jones, Christian Vokuhl, Marry M. van den Heuvel-Eibrink, Norbert Graf
Journal: Nature Reviews Urology (2018)

On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel. In this Consensus Statement, the pathology panel of the International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RSTG) present the pathology and molecular biology protocol for Wilms tumours in the UMBRELLA SIOP-RTSG 2016 protocol.
Abstract 12176: Outcomes and Genetic Characteristics of Hypertrophic Cardiomyopathy With Severe Right Ventricular Hypertrophy
Authors: Xiying Guo, Lei Tian, Yanling Liu, Shihua Zhao, Fujian Duan, Yishi Li, Chaomei Fan
Journal: Circulation (2015)

Introduction: Severe right ventricular hypertrophy (SRVH) is extremely rare in hypertrophic cardiomyopathy (HCM). Hypothesis: We assessed the hypothesis that patients with HCM with SRVH may have multiple mutations and poor prognosis. Methods: We performed a retrospective cohort study involving 2415 HCM patients. Patients with HCM with a maximum right ventricular wall thickness ≥10 mm, either with or without a pressure gradient at the RV outflow tract (RVOT) exceeding 25 mmHg, were enrolled. Deep (30X) whole-genome sequencing was performed in 11 patients using the Illumina HiSeq X platform. The patients'clinical features, cardiovascular mortality and morbidity were analyzed. The survival estimates were calculated using the Kaplan-Meier method, and risk of either cardiovascular death or event was determined using a multivariate Cox hazards regression model. Results: Of the 2415 HCM patients, 43 patients (1.6%) with SRVH were identified and 12 of them demonstrated isolated RVOT obstruction. The mean age at diagnosis was 31.1 ± 16.3 years, and 24 (55.8%) of them were women. The maximum average RV wall thickness was 13.3 ± 2.4 mm. The multivariate Cox regression analysis identified 2 independent predictors of cardiovascular death, including NYHA class ≥III, with a hazard ratio of 8.6 (95% CI: 1.70-43.38, p = 0.009), and a left ventricular end-diastolic diameter ≥50 mm, with a hazard ratio of 6.0 (95% CI: 1.67-21.92, p = 0.006). Age ≤18 years was with a 3-fold increased risk cardiovascular events (95% CI: 1.14-7.16, p = 0.002). At least one variant in a specific sarcomere gene was identified in 10 patients (90.9%), of which the MYH7 mutation was the most common (n = 6, 54.5%), and 10 novel locations were detected. Double mutations involving HCM-related genes were observed in 8 (73%) patients. All patients exhibited either double or multiple mutations, either in arrhythmogenic right ventricular, dilated cardiomyopathy or ion-channel disease genes. Conclusions: HCM with SRVH was characterized by an early onset of disease and increased cardiovascular mortality and morbidity. Double or multiple sarcomere gene mutations might be responsible for this phenotype with multiple mutations in other forms of cardiomyopathy and ion-channel disease associated genes.
Model-based assessment of benefit-risk profile of nivolumab (NIVO) flat dosing schedules (Q2W and Q4W) across multiple tumor types
Authors: X. Zhao, J. Shen, M. Gopalakrishnan, Y. Feng, B.J. Schmidt, P. Statkevich, T. Kelleher, M. Rashford, V. Ivaturi, J.V.S. Gobburu, S. Agrawal, A. Bello, A. Roy
Journal: Annals of Oncology (2018)
Abstract 14981: Incidence and Outcomes of Myocardial Infarction in Patients Admitted With Acute Ischemic Stroke
Authors: Fahad Alqahtani, Sami Aljohani, Tatiana Busu, Abdulrahman Tarabishy, Amelia Adcock, Almoutassim Trabulsi, Ahmad Almustafa, Ali Hama Amin, Mohamad Adnan Alkhouli
Journal: Circulation (2017)

Introduction: Data on the incidence and outcomes of acute Myocardial Infarction (AMI) complicating acute ischemic stroke (AIS are limited. We aim to evaluate the incidence, treatment patterns and o...
Abstract 21182: Single-Cell Sequencing Analysis Reveals Impaired Adipose Tissue Stem Cell Program in Obesity
Authors: Chuan Li, Alexander M Tseng, Zheping Huang, Willie Dong, Anthony Vella, Beiyan Zhou
Journal: Circulation (2017)

The properly programmed “stemness” of tissue specific stem cells, including adipose tissue stem cells (ASCs), is the core feature for their function of tissue regeneration. Although ASCs harbor great potential for clinical application, it is poorly understood how ASCs respond to obesity, an affliction now affect over one third of the national population and health risks of cardiovascular diseases. We recently identified a set of cell surface markers to enrich ASCs from murine visceral adipose tissue. We observed that adipose tissue stromal cells bearing CD45 - CD31 - Sca-1 + CD49f - CD34 + were highly enriched for cells with sphere-initiation and multilineage differentiation capacity. Interestingly, the frequency of ASCs was markedly reduced in obese visceral stroma and their capability to derive multilineage progeny were severely impaired, compared to those in lean mice. Given the heterogeneity of isolated ASCs, we performed single cell sequencing analysis to understand mechanisms underlying the impaired “stemness” of obese ASCs. Freshly isolated ASCs from obese or age matched lean mice were subjected to single cell library generation (10X Genomics), followed by high-throughput sequencing. An average of 5500 UMI (unique molecular index) were detected in each cell and a total of 18,835 genes were detected in each sample (mapped to mm10). Interestingly, ASCs isolated from lean or obese adipose tissue displayed distinct pattern after K-mean clustering. Further, functional analysis revealed that critical networks in ASCs are significantly altered under obese conditions, including suppressed adipogenic program initiation and impaired impaired antioxidative defense. Further, multiple signaling networks triggered by both innate and adaptive immune responses displayed high activation Z-score in obese ASCs than that in lean ASCs. Overall, our results suggested that obesity severely impaired ASCs “stemness”, which may be attributed to multiple factors in obese adipose tissue, including the proinflammatory microenvironment. Further analyses of these profiles will provide critical information on how obesity alters the “stemness” program in ASCs and how to “revive” obese ASCs tissue regenerative ability.
Folate-targeted nanostructured chitosan/chondroitin sulfate complex carriers for enhanced delivery of bortezomib to colorectal cancer cells
Authors: Zar Chi Soe, Bijay Kumar Poudel, Hanh Thuy Nguyen, Raj Kumar Thapa, Wenquan Ou, Milan Gautam, Kishwor Poudel, Sung Giu Jin, Jee-Heon Jeong, Sae Kwang Ku, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Folate-targeting self-assembled nanoparticles (NPs) using biocompatible and biodegradable natural polymers chitosan (Cs) and chondroitin sulfate (Chs) were developed to address the major challenge in cancer treatment, the selective delivery of nanoparticles to the target site. In this study, we successfully incorporated a hydrophobic drug, bortezomib (Bor), into folic acid (FA)-conjugated Cs/Chs self-assembled NPs (Bor/Cs/Chs-FA) for colorectal cancer therapy. The particle size and polydispersity index of Bor/Cs/Chs-FA were ∼196.5 ± 1.2 nm and ∼0.21 ± 0.5, respectively. A pH-dependent release profile was observed, facilitating cancer cell-targeted drug release under an acidic tumor microenvironment. Moreover, in vitro data revealed enhanced cellular uptake and apoptosis in folate receptor-expressing colorectal cancer cells (HCT-116 and HT-29) as compared to that in lung cancer cells (A549), which do not express folate receptors. Furthermore, intravenous administration of Bor/Cs/Chs-FA in a HCT-116 bearing xenograft mouse model showed that the NPs were a safe and effective drug delivery system. The results suggest that folate-targeted nanoparticle can be effectively applied for efficient chemotherapy of colorectal cancer.