tbuckley/cabot-search huggingface dataset:
LBP-12-Phase 1a Study of the Safety, Tolerability and Pharmacokinetics of ABI-H, a Novel Second-Generation HBV Core Inhibitor, in Healthy Volunteers
Authors: Edward Gane, Christian Schwabe, Marc Evanhcik, Eric Ruby, Sandy Liaw, Katia Alves, Richard Colonno, Uri Lopatin
Journal: Journal of Hepatology (2019)
18F-FDG PET/CT for Staging and Evaluation of Therapy in a Patient With Unusual Hairy Cell Leukemia Presentation
Authors: Andrej Doma, Matevž Škerget, Ivana Žagar
Journal: Clinical Nuclear Medicine (2019)

Abstract Hairy cell leukemia is a rare hematologic malignancy characterized by splenomegaly, pancytopenia, and susceptibility to infections. We report a case of a 66-year-old man, diagnosed with hairy cell leukemia, without severe cytopenias and splenomegaly, but with an extensive pathological retroperitoneal mass and infiltration of the spleen and skeletal involvement. All findings were highly avid on pretreatment 18 F-FDG PET/CT scan. Treatment response evaluation 18 F-FDG PET/CT scan showed normalization of FDG uptake on all previously pathological sites.
SAT-325-Implementation of a primary care shear-wave elastography-based pathway to identify non-alcoholic fatty liver disease patients with advanced fibrosis in a large North American urban population
Authors: Abdel-Aziz Shaheen, Kiarash Riazi, Alexandra Medellin, Deepak bhayana, Roy Park, Linda Slocombe, Monica Sargious, Mark G Swain
Journal: Journal of Hepatology (2019)
Abstract 17644: Noninvasive Assessment of Diastolic Myocardial Stiffness by Echocardiography in Patients With Cardiac Amyloidosis
Authors: Mahmoud Alashry, Sushil A Luis, Sorin V Pislaru, Patricia A Pellikka, Martha Grogan, Angela Dispenzieri, Cristina Pislaru
Journal: Circulation (2015)

Background: Cardiac amyloidosis (CA) results from extracellular deposition of insoluble amyloid fibrils in the myocardium, leading to myocardial stiffening, restrictive cardiomyopathy and poor prognosis. Thus, measurements of myocardial stiffness might help with identification of patients with cardiac amyloid deposition. The speed of wave transmission of myocardial stretch (Vm) is a novel measure of myocardial elasticity. Our aim was to investigate the behavior of Vm in the left ventricular (LV) myocardium of patients with CA. We hypothesized this wave speed will be increased in these patients and will partly explain the reduction in systolic myocardial function. Methods: We prospectively studied 23 consecutive patients with systemic amyloidosis, of whom 17 (age 59±13 years) had confirmed cardiac involvement (15 AL, 2 TTR), and compared to 18 control subjects (age 47±13 years) with normal LV function. Comprehensive transthoracic echocardiography was performed. Tissue Doppler cineloops (350-450 frames/s) were acquired from 6 LV walls from 3 standard apical views. Regional and global Vm were measured as the wave speed of the onset of myocardial stretch from LV base to apex (late diastole). Results: Subjects with CA (n=17) had higher Vm compared to normal subjects (2.5±0.8 vs 1.5±0.2 m/s; P&lt;0.001, respectively). They also had lower LV ejection fraction (56±11 vs 65±4%; P=0.02), global longitudinal strain (GLS -14±5 vs -20±2%, P&lt;0.001), and myocardial relaxation (mitral annulus septal e’ velocity 4.7±1.9 vs 9.2±2.4 cm/s; P&lt;0.001) and higher LV mass (150±54 vs 87±18 g/m2; P&lt;0.001), left atrial volume (44±7 vs 27±6 mL/m2; P&lt;0.001), and estimated LV filling pressure (E/e’ 20±9 vs 8±3; P&lt;0.001). There was a strong positive association between Vm and LV wall thickness (R=0.62; P&lt;0.001), GLS (R=0.45; P=0.01) and septal E/e’ (R=0.42; P=0.02) and an inverse correlation between Vm and septal e’ (R=-0.39; P=0.03), but not with ejection fraction (P=0.37). Conclusion: This pilot study indicates that Vm is elevated in patients with CA compared to normal subjects, commensurate with the effects of amyloid deposition on LV structure and function. This novel measurement shows promise for noninvasive assessment of diastolic myocardial stiffness in patients with CA.
SAT-239-Real life data on elbasvir/grazoprevir efficacy, safety and drug-drug interaction profile in patients with chronic hepatitis C viral infection: A prospective analysis in the PITER cohort
Authors: Maria Giovanna Quaranta, Stefano Rosato, Luigina Ferrigno, Daniela Caterina Amoruso, Monica Monti, Paola Di Stefano, Roberto Filomia, Fiammetta Tamburini, Guglielmo Migliorino, Alberto Zanetto, Elisabetta Degasperi, Luisa Cavalletto, Giuseppina Brancaccio, Pierluigi Blanc, Marco Cannizzaro, Castelli Eleonora, Giulia Morsica, Anna Licata, Loreta Kondili
Journal: Journal of Hepatology (2019)
Sustained reduction of catheter-associated bloodstream infections with enhancement of catheter bundle by chlorhexidine dressings over 11 years
Authors: Philippe Eggimann, Jean-Luc Pagani, Elise Dupuis-Lozeron, Bruce Ekholm MS, Marie-Josèphe Thévenin, Christine Joseph, Jean-Pierre Revelly, Yok-Ai Que
Journal: Intensive Care Medicine (2019)

Prospective randomized controlled studies have demonstrated that addition of chlorhexidine (CHG) dressings reduces the rate of catheter (central venous and arterial)-associated bloodstream infections (CABSIs). However, studies confirming their impact in a real-world setting are lacking.We conducted a real-world data study evaluating the impact of incrementally introducing chlorhexidine dressings (sponge or gel) in addition to an ongoing catheter bundle on the rates of CABSI, expressed as incidence density rates per 1000 catheter-days measured as part of a surveillance program. Poisson regression models were used to compare infection rates over time. Both dressings were used simultaneously during one of the five study periods.From 2006 to 2014, 18,286 patients were admitted (91,292 ICU-days and 155,242 catheter-days). We recorded 111 CABSIs. We observed a progressive but significant decrease of CABSI rates from 1.48 (95% CI 1.09-2.01) without CHG dressings to 0.69 (95% CI 0.43-1.09) and 0.23 (95% CI 0.11-0.48) episodes per 1000 catheter-days when CHG sponge and CHG gel dressings were used (p = 0.0007; p < 0.001). A non-significant lower rate of infections occurred with CHG gel compared with CHG sponge dressings. An identical low rate of allergic skin reactions (0.3/1000 device-days) was observed with both types of CHX dressings. Post-study data until 2018 confirmed a sustained decrease of infection rates over 11 years.The addition of chlorhexidine dressings to all CVC and arterial lines to an ongoing catheter bundle was associated with a sustained 11-year reduction of all catheter-associated bloodstream infections. This large real-world data study further supports the current recommendations for the systematic use of CHG dressings on all catheters of ICU patients.
Fluconazole Increases Osmotic Water Transport in Renal Collecting Duct through Effects on Aquaporin-2 Trafficking
Authors: Tanja Vukićević, Christian Hinze, Sandrine Baltzer, Nina Himmerkus, Catarina Quintanova, Kerstin Zühlke, Friederike Compton, Robert Ahlborn, Alessandro Dema, Jenny Eichhorst, Burkhard Wiesner, Markus Bleich, Kai M. Schmidt-Ott, Enno Klussmann
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Dysregulation of vasopressin-induced water reabsorption in the renal collecting duct leads to diabetes insipidus, a congenital or acquired syndrome. Some forms of diabetes insipidus lack effective treatments to prevent the excessive loss of hypotonic urine that characterizes the condition. The authors previously identified the antimycotic drug fluconazole as a potential therapy, acting to modulate the effects of a water channel protein aquaportin-2 (AQP2). In this study, they show in vitro and in vivo that fluconazole induces a vasopressin-independent insertion of AQP2 into the plasma membrane of collecting duct principal cells, thereby lowering urinary output. Hence, fluconazole might have clinical utility in treating certain forms of diabetes insipidus—such as hereditary X-linked nephrogenic diabetes insipidus—in which the kidney responds inappropriately to vasopressin. Background Arginine-vasopressin (AVP) binding to vasopressin V2 receptors promotes redistribution of the water channel aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. This pathway fine-tunes renal water reabsorption and urinary concentration, and its perturbation is associated with diabetes insipidus. Previously, we identified the antimycotic drug fluconazole as a potential modulator of AQP2 localization. Methods We assessed the influence of fluconazole on AQP2 localization in vitro and in vivo as well as the drug's effects on AQP2 phosphorylation and RhoA (a small GTPase, which under resting conditions, maintains F-actin to block AQP2-bearing vesicles from reaching the plasma membrane). We also tested fluconazole's effects on water flow across epithelia of isolated mouse collecting ducts and on urine output in mice treated with tolvaptan, a VR2 blocker that causes a nephrogenic diabetes insipidus–like excessive loss of hypotonic urine. Results Fluconazole increased plasma membrane localization of AQP2 in principal cells independent of AVP. It also led to an increased AQP2 abundance associated with alterations in phosphorylation status and ubiquitination as well as inhibition of RhoA. In isolated mouse collecting ducts, fluconazole increased transepithelial water reabsorption. In mice, fluconazole increased collecting duct AQP2 plasma membrane localization and reduced urinary output. Fluconazole also reduced urinary output in tolvaptan-treated mice. Conclusions Fluconazole promotes collecting duct AQP2 plasma membrane localization in the absence of AVP. Therefore, it might have utility in treating forms of diabetes insipidus ( e.g. , X-linked nephrogenic diabetes insipidus) in which the kidney responds inappropriately to AVP.
Squamous Cell Transformation of Primary Lung Adenocarcinoma in a Patient With EML4-ALK Fusion Variant 5 Refractory to ALK Inhibitors
Authors: Jay Gong, Jeffrey P. Gregg, Weijie Ma, Ken Yoneda, Elizabeth H. Moore, Megan E. Daly, Yanhong Zhang, Melissa J. Williams, Tianhong Li
Journal: Journal of the National Comprehensive Cancer Network (2019)

Histologic transformation from adenocarcinoma to squamous cell carcinoma in lung cancer has not been reported as a mechanism of resistance to ALK inhibition. This report describes the clinical course of a female former light smoker with metastatic lung adenocarcinoma whose tumor underwent histologic transformation from a well-differentiated lung adenocarcinoma to a well-differentiated lung squamous cell carcinoma in the same location at the left mainstem bronchus while maintaining the ALK fusion oncogene without any resistance mutations. After experiencing disease progression while on crizotinib, the patient participated in clinical trials that provided early access to the novel ALK inhibitors ceritinib and alectinib before they were commercially available. Tumor recurrence occurred at the primary and metastatic central nervous system sites (ie, brain and spine). At tumor progression, liquid biopsy and tumor genomic profiling of plasma cell-free DNA next-generation sequencing (NGS) provided an accurate diagnosis with a short turnaround time compared with the tissue-based targeted capture NGS. The patient received several courses of radiation primarily to the brain and spine during her disease course. Her disease did not respond to the immune checkpoint inhibitor nivolumab, and she died on home hospice approximately 4 years after diagnosis. This case supports the importance of both histopathologic assessment and comprehensive genomic profiling in selecting appropriate treatment for patients with refractory, metastatic, ALK oncogene–driven non–small cell lung cancer. Use of symptom-directed radiation in tandem with ALK inhibitors contributed to the disease and symptomatic control and prolonged survival in this patient.
Health related quality of life (HRQOL) in older adults with cancer: The potential of a single-item screen.
Authors: Mackenzi Pergolotti, Allison Mary Deal, Grant Richard Williams, Jeannette T Bensen, Ashley Leak Bryant, Bryce B. Reeve, Hyman B. Muss
Journal: Journal of Clinical Oncology (2015)

9533 Background: Older adults with cancer often value maintaining or recovering their HRQOL over overall survival. This study aims to (1) describe patient reported global measures of physical and mental HRQOL in a large sample of older adults with cancer and (2) to evaluate associations with demographics and other measures of health status to better screen and identify populations at-risk of poor HRQOL. Methods: The Health Registry/Cancer Survivorship Cohort is an institutional database at University of North Carolina designed to aid in cancer survivorship research (http://unchealthregistry.org). Outcome measures of patient-reported HRQOL included FACT-G (range 0-108), PROMIS global Physical and Mental health (mean = 50, SD = 10 in general US population). Higher scores indicate better HRQOL. Other measures of health status: the single item Patient-Generated Subjective Global Assessment Performance Assessment (PG-SGA-PA), number of co-morbidities, FACT Cognitive Function, PROMIS Sexual Function, and global physical activity. Results: Of the 807 older adults (65y+) with cancer, mean age was 72y, 60% female, and 88% Caucasian. The cohort was comprised of 25% genitourinary, 24% breast, 22% gastrointestinal, and 15% gynecologic malignancies. Only 37% reported a high level of physical activity, 24% had ≥ 4 co-morbid conditions, and 25% reported that they lived alone. Mean scores for HRQOL were: FACT-G (85, range: 25-108); PROMIS-Physical (48, range: 16-67) and PROMIS-Mental (51, range: 21-67). In the multivariable models including demographics and health status measures, ≥ 4 comorbidities, poor PG-SGA-PA and lower levels of cognition were associated with poor HRQOL for each outcome measure (all p < .0001). Conclusions: Older adults with cancer with a high comorbidity burden, reduced cognition, and poorer scores on the PG-SGA-PA have poorer HRQOL. This study found that the single item PG-SGA-PA was independently associated with complex measures of global physical and mental health and with further validation could be a useful tool for oncologists to quickly identify older adults with poor HRQOL.
Genome-wide RNAi Screening Identifies RFC4 as a Factor That Mediates Radioresistance in Colorectal Cancer by Facilitating Nonhomologous End Joining Repair
Authors: Xue-Cen Wang, Xin Yue, Rong-Xin Zhang, Ting-Yu Liu, Zhi-Zhong Pan, Meng-Jie Yang, Zhen-Hai Lu, Zi-Yang Wang, Jian-Hong Peng, Li-Yuan Le, Gao-Yuan Wang, Qi-Hua Peng, Yuan Meng, Wenlin Huang, Ran-Yi Liu
Journal: Clinical Cancer Research (2019)

Neoadjuvant chemoradiotherapy (neoCRT) is a standard treatment for locally advanced rectal cancer (LARC); however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to identify factors involved in the radioresistance of colorectal cancer and to clarify the underlying mechanisms.A genome-wide RNAi screen was used to search for candidate radioresistance genes. After RFC4 knockdown or overexpression, colorectal cancer cells exposed to X-rays both in vitro and in a mouse model were assayed for DNA damage, cytotoxicity, and apoptosis. Moreover, the regulatory effects and mechanisms of RFC4 in DNA repair were investigated in vitro. Finally, the relationships between RFC4 expression and clinical parameters and outcomes were investigated in 145 patients with LARC receiving neoCRT.RFC4, NCAPH, SYNE3, LDLRAD2, NHP2, and FICD were identified as potential candidate radioresistance genes. RFC4 protected colorectal cancer cells from X-ray-induced DNA damage and apoptosis in vitro and in vivo. Mechanistically, RFC4 promoted nonhomologous end joining (NHEJ)-mediated DNA repair by interacting with Ku70/Ku80 but did not affect homologous recombination-mediated repair. Higher RFC4 expression in cancer tissue was associated with weaker tumor regression and poorer prognosis in patients with LARC treated with neoCRT, which likely resulted from the effect of RFC4 on radioresistance, not chemoresistance.RFC4 was identified as a radioresistance factor that promotes NHEJ-mediated DNA repair in colorectal cancer cells. In addition, the expression level of RFC4 predicted radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in patients with LARC.
Combination treatment with hypofractionated radiotherapy plus IL-2/anti-IL-2 complexes and its theranostic evaluation
Authors: Hua Jing, Michael Hettich, Simone Gaedicke, Elke Firat, Mark Bartholomä, Gabriele Niedermann
Journal: Journal for ImmunoTherapy of Cancer (2019)

Immunogenic radiotherapy (RT) can act synergistically with immune checkpoint blockers (ICBs). However, alternatives are needed for non-responding patients and those with pre-existing or ICB-induced autoimmune symptoms. Combination of RT with IL-2 could be an alternative. But IL-2 has a short half-life, and, by binding to its high-affinity receptor, it strongly stimulates immunosuppressive CD4+ Tregs and seems to promote potentially life-threatening vascular leakage. IL-2/anti-IL-2 complexes (IL-2c), which bind to the low-affinity receptor, have been reported to circumvent these disadvantages but they have not yet been thoroughly tested in conjunction with radiotherapy.We evaluated, in three mouse models, the antitumoral effects induced by hypofractionated RT (hRT) plus IL-2c. We also used non-invasive imaging with a newly developed PET tracer based on therapeutically active IL-2c and a PD-L1 PET tracer for the theranostic evaluation of the treatment and its side effects.Treatment of mice bearing established B16 melanomas with hRT + IL-2c was superior to hRT + uncomplexed IL-2 or hRT alone; IL-2c alone was not effective. hRT + IL-2c was also synergistic in mice bearing C51 colon carcinomas or 4T1 mammary carcinomas. The better antitumor response correlated with increased tumor-specific CD8+ T cells and NK cells, but not CD4+ Tregs, in the irradiated tumor and in lymphoid organs. With the new PET tracer, we visualized the whole-body distribution of IL-2c and the bound receptors in naïve mice and tumor-bearing mice. Surprisingly, the tumor uptake was non-specific and only moderate. This prompted experiments demonstrating that specific IL-2c binding in the tumor is limited by IL-2 secreted by tumor-resident effector cells and that extratumorally expanded T and NK cells can infiltrate the irradiated tumor, which suggests that systemic immune activation considerably contributed to the reduction of tumor growth. Lastly, we show that a side effect of IL-2c treatment - a quite dramatic non-specific expansion of CD8+ T and NK cells - is only transient, and we visualized the associated splenomegaly as well as side effects on liver and lung by contrast-enhanced CT and PD-L1 PET.Our results show that the combination of immunogenic RT with IL-2c that are directed towards the low-affinity IL-2 receptor can be synergistic and more effective than the combination with uncomplexed IL-2. In addition, our theranostic evaluation provided insights into the mechanism of action and the side effects of IL-2c treatment.
Later sibling recurrence of ASD and ADHD: clinical and mechanistic insights
Authors: Tony Charman, Emily J H Jones
Journal: JAMA Pediatrics (2018)

In this issue of JAMA Pediatrics, Miller and colleagues1 report on the within- and cross-condition recurrence of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) in later-born siblings of children (probands) with those conditions. The relatively high heritability of both conditions is well established from twin studies assessing both trait variance2 and diagnostic recurrence.3 Two recent large-scale Scandinavian studies extended this work to show that the 2 conditions also occur together in families.4,5 One population-based study of children with ASD (N = 3578) estimated the combined (older and younger) sibling recurrence of ASD in siblings to be 10.5%, but also reported that 5.3% had siblings with a diagnosis of ADHD, giving relative risks of 11.8 and 3.7 compared with matched controls without ASD.4
SAT-356-Anti-metabolic, anti-inflammatory and anti-fibrotic properties of ART-, a novel phosphodiesterase 4 inhibitor as a potential clinical candidate for non-alcoholic steatohepatitis
Authors: Yuichiro Amano, Shuntarou Tsuchiya, Mitsuharu Matsumoto, Hikaru Ueno, Nobuhiro Nishigaki, Osamu Isono, Guido Hanauer, Kazumasa Miyawaki, Kimio Tohyama, Hirohisa Miyashita, Mayumi Imai, Fumi Shimizu, Akira Tanaka, Hiroshi Nagabukuro
Journal: Journal of Hepatology (2019)
FRI-401-Direct-acting antiviral agents are not associated with an increased risk of hepatocellular carcinoma recurrence in liver transplant recipients with hepatitis C
Authors: Chung Sang Tse, Judong Yang, Omar Mousa, Surakit Pungpapong, Andrew Keaveny, Kevin Nelson, Aqel Bashar, Rolland Dickson, Hugo E. Vargas, Gregory Gores, Lewis Roberts, Michael Leise
Journal: Journal of Hepatology (2019)
Long noncoding RNA TUG1 inhibits osteogenesis of bone marrow mesenchymal stem cells via Smad5 after irradiation
Authors: Weiwei Zhang, Li Chen, Jiang Wu, Jiuxuan Li, Xiaomei Zhang, Yang Xiang, Fengjie Li, Chun Wu, Lixin Xiang, Qian Ran, Zhongjun Li
Journal: Theranostics (2019)

Irradiation can greatly inhibit osteogenesis of bone marrow mesenchymal stem cells (BM-MSCs).However, the mechanism remains unclear.Methods: We analyzed the expression profile of long noncoding RNAs (lncRNAs) in BM-MSCs using microarray data.LncRNA TUG1 (Taurine Upregulated Gene 1) was selected and tested in radiated BM-MSCs and non-radiated BM-MSCs.Functional analyses (in vitro) were performed to confirm the role of TUG1 in the osteogenic inhibition induced by irradiation.A RIP (RNA immunoprecipitation) assay was performed to detect the interaction of TUG1 and Smad5.Smad5 and the phosphorylated Smad5 (p-Smad5) were tested by western blot.The nuclear translocation of p-Smad5 were tested by immunofluorescence analysis.Furthermore, a series of Smad5 deletions was constructed to identify the TUG1 binding site of Smad5.Results: We found that numerous lncRNAs, including TUG1, exhibit significant expression differences after irradiation.After irradiation TUG1 was significantly increased in BM-MSCs and inhibited osteogenesis.Furthermore, TUG1 directly bound to Smad5, an osteogenic enhancer.Although the phosphorylation level of Smad5 was increased following irradiation, osteogenesis of BM-MSCs was decreased.Mechanistically, TUG1 interacting with the 50-90 aa region of Smad5 and blocks the nuclear translocation of p-Smad5, abolishing osteogenic signalling after irradiation. Conclusion:These results indicate that TUG1 is a negative regulator of Smad5 signalling and suppresses osteogenesis of BM-MSCs after irradiation.
PS-128-Risk of gall bladder cancer in patients with primary sclerosing cholangitis and gall bladder polyps: an opportunity to revisit the guidelines
Authors: Liselot van Erp, Morven Cunningham, Manasa Narasimman, Hamideh Aleali, Kartik Jhaveri, J.P.H. Drenth, Harry Janssen, Cynthia Levy, Gideon Hirschfield, Bettina Hansen, Aliya Gulamhusein
Journal: Journal of Hepatology (2019)