tbuckley/cabot-search huggingface dataset:
Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling
Authors: Le Tao, Wenting Ma, Liu Wu, Mingyi Xu, Yanqin Yang, Wei Zhang, Wenjun Sha, Hongshan Li, Jianrong Xu, Rilu Feng, Dongying Xue, Jie Zhang, Steven Dooley, Ekihiro Seki, Ping Liu, Cheng Liu
Journal: Gut (2019)

Objective Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. Design GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. Results GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His 39 and Asp 76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. Conclusions GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.
Abstract 847: Overexpression of long noncoding RNA FAM promotes cancer invasion and drug resistance in human liver cancer
Authors: Po-Shuan Huang, Kwang-Huei Lin
Journal: Cancer Research (2019)

Abstract Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Most patients with HCC have an established background of chronic liver disease and cirrhosis, with major etiological and risk factors including chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Long non-coding (lnc)RNAs are a class of non-protein coding transcripts longer than 200 nucleotides that regulate complex cellular functions, such as cell growth, differentiation, metabolism and metastasis. Increasing evidence has shown that lncRNAs regulate gene expression by targeting the production, splicing, decay, or translation of target mRNAs. Although deregulation of lncRNAs expression have been detected in HCC or many tumor types, there are still many novel lncRNAs have not been studied and the mechanisms underlying functional impairment and specific involvement of lncRNAs during hepato-carcinogenesis remain to be established. Here, we aimed to investigate the involvement of specific dys-regulated lncRNA-FAM and its molecular mechanism. FAM is overexpressing in HCC and correlates with tumor size, vascular invasion, and pathology stage. Overexpression FAM accelerates cell proliferation, invasion in HCC cells. Further, FAM is induced in the Doxorubicin (DOX) resistance HCC cells show in the Gene Expression Omnibus (GEO) Datasets analysis. Overexpression FAM did increase DOX-resistant in two HCC cell lines. After overexpression FAM, lysosome-associated membrane protein 2 (LAMP2) expression was enhanced which also correlated with DOX-resistant. From the co-immunoprecipitation analysis, FAM directly interacted with LAMP2 to protect its ubiquitination. Thus, FAM may play an oncogenic role during hepato-carcinogenesis. Citation Format: Po-Shuan Huang, Kwang-Huei Lin. Overexpression of long noncoding RNA FAM promotes cancer invasion and drug resistance in human liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 847.
A carrier-free multiplexed gene editing system applicable for suspension cells
Authors: Anna Ju, Sung Won Lee, Young Eun Lee, Ki-Cheol Han, Jin-Chul Kim, Sang Chul Shin, Hyun Jung Park, Eunice EunKyeong Kim, Seokmann Hong, Mihue Jang
Journal: Biomaterials (2019)

Genetically engineered cells via CRISPR/Cas9 system can serve as powerful sources for cancer immunotherapeutic applications. Furthermore, multiple genetic alterations are necessary to overcome tumor-induced immune-suppressive mechanisms. However, one of the major obstacles is the technical difficulty with efficient multiple gene manipulation of suspension cells due to the low transfection efficacy. Herein, we established a carrier-free multiplexed gene editing platform in a simplified method, which can enhance the function of cytotoxic CD8+ T cells by modulating suspension cancer cells. Our multiple Cas9 ribonucleoproteins (RNPs) enable simultaneous disruption of two programmed cell death 1 (PD-1) ligands, functioning as negative regulators in the immune system, by accessing engineered Cas9 proteins with abilities of complexation and cellular penetration. In addition, combination with electroporation enhanced multiple gene editing efficacy, compared with that by treatment of multiple Cas9 RNPs alone. This procedure resulted in high gene editing at multiple loci of suspension cells. The treatment of multiple Cas9 RNPs targeting both ligands strongly improved Th1-type cytokine production of cytotoxic CD8+ T cells, resulting in synergistic cytotoxic effects against cancer. Simultaneous suppression of PD-L1 and PD-L2 on cancer cells via our developed editing system allows effective anti-tumor immunity. Furthermore, the treatment of multiple Cas9 RNPs targeting PD-L1, PD-L2, and TIM-3 had approximately 70-90% deletion efficacy. Thus, our multiplexed gene editing strategy endows potential clinical utilities in cancer immunotherapy.
Abstract 4097: TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice
Authors: Ramireddy Bommireddy, Luis Munoz, Chrstopher D. Pack, Sampath Ramachandiran, Shaker JC Reddy, Janet Kim, Georgia Chen, Nabil F. Saba, Dong M. Shin, Periasamy Selvaraj
Journal: Cancer Research (2019)

Abstract Introduction: Head and neck cancer is a leading cause of cancer related deaths accounting for approximately 3% of all cancer related mortalities in the US. Currently, there is no cure for the advanced squamous cell carcinoma of the head and neck (SCCHN) thus development of efficacious therapies is urgently needed. To test whether vaccine-induced immunity inhibits tumor growth, we investigated efficacy of a tumor membrane-based vaccine immunotherapy in a murine SCCHN (SCC VII) model. Materials and Methods: The SCC VII tumors grown subcutaneously in C3H/HeJ mice were harvested to generate tumor membrane vesicles (TMVs). TMVs were then protein transferred with glycolipid-anchored immunostimulatory molecules mouse GPI-B7.1 and mouse GPI-IL-12 to generate the TMV vaccine. Mice were vaccinated with TMV vaccine either before (prophylactic) or after SCC VII tumor cell challenge (therapeutic) and tumor growth was monitored every 3 days. Survival was then assessed using a Kaplan-Meier survival curve and significance determined using a Log-rank test for comparison analysis. Results: SCCVII cells express MHC I, CD44, CD47 and respond to IFN-γ in vitro. The therapeutic TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. Tumor-free mice remained protective from rechallenge with SCCVII cells. Conclusions: These observations suggest that tumor tissue-based vaccines can be harnessed to develop an effective immunotherapy for SCCHN. Funding: Supported by Head and Neck SPORE pilot funding from Emory Winship Cancer Institute. Citation Format: Ramireddy Bommireddy, Luis Munoz, Chrstopher D. Pack, Sampath Ramachandiran, Shaker JC Reddy, Janet Kim, Georgia Chen, Nabil F. Saba, Dong M. Shin, Periasamy Selvaraj. TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4097.
Abstract 9293: 320 Slice Computed Tomography Imaging-Based Semiquantitative Assessment of Left Ventricular Wall Motion: Comparison with Transthoracic Echocardiography
Authors: Akihisa Kataoka, Nobusada Funabashi, Hiroyuki Takaoka, Masae Uehara, Akiyo Takahashi, Yoshio Kobayashi
Journal: Circulation (2011)

Methods: Retrospective review of ECG-gated 320 slice CT (Aquilion one, Toshiba Medical) of 22 subjects with asynergy of LV wall motion TTE (13 men, 9 female, mean age 68.5±10.5 years, 5 old myocardial infarction, 5 hypertrophic cardiomyopathy, 4 cardiac sarcoidosis, 2 takotsubo cardiomyopathy, 2 idiopathic arrhythmia, 1 dilated cardiomyopathy, 1 left ventricular non compaction, and 1 drug-induced cardiomyopathy). Retrospective, ECG-gated, conventional enhanced 320-slice CT with tube current dose modulation was performed with a slice thickness of 0.5mm and a tube voltage of 120 kilovolts. CT images were reconstructed every 5% from 0-95% of the R-R interval of the ECG and 4D CT images were generated (Virtual Place, Aze) and LV wall motion was evaluated at 17 segments by American Society of Echocardiography criteria, by two experienced cardiologists, as was TTE. They analyzed TTE (IE-33, Philips) retrospectively, blinded to the CT results. Results: For 374 segments, kappa coefficients for the 5 classifications (aneurysmal, dyskinesis, akinesis, hypokinesis, normal kinesis) by the two assessors were 0.458 and 0.606 for CT and TTE data, respectively. Agreement between CT and TTE was 0.255 and 0.555 for the two observers. Kappa coefficients of the 7 classifications (aneurysmal, dyskinesis, akinesis, severe, moderate and mild hypokinesis, normal kinesis) by the two assessors were 0.367 and 0.439 for CT and TTE data, respectively. Agreement between CT and TTE was 0.158 and 0.423 for the two. Conclusions: Semiquantitative LV wall motion assessment by 320 slice CT and TTE showed good inter-observer agreement but there were some discrepancies between 320 slice CT and TTE by the two assessors.
Effect of Stroke Education Pamphlets vs a 12-Minute Culturally Tailored Stroke Film on Stroke Preparedness Among Black and Hispanic Churchgoers
Authors: Olajide Williams, Jeanne Teresi, Joseph P. Eimicke, Amparo Abel-Bey, Madeleine Hassankhani, Lenfis Valdez, Luisa Gomez Chan, Jian Kong, Mildred Ramirez, Joseph Ravenell, Gbenga Ogedegbe, James M. Noble
Journal: JAMA Neurology (2019)

Black individuals and Hispanic individuals are less likely to recognize stroke and call 911 (stroke preparedness), contributing to racial/ethnic disparities in intravenous tissue plasminogen activator use.To evaluate the effect of culturally tailored 12-minute stroke films on stroke preparedness vs the usual care practice of distributing stroke education pamphlets.Cluster randomized clinical trial between July 26, 2013, and August 16, 2018, with randomization of 13 black and Hispanic churches located in urban neighborhoods to intervention or usual care. In total, 883 congregants were approached, 503 expressed interest, 375 completed eligibility screening, and 312 were randomized. Sixty-three individuals were ineligible (younger than 34 years and/or did not have at least 1 traditional stroke risk factor).Two 12-minute stroke films on stroke preparedness for black and Hispanic audiences.The primary outcome was the Stroke Action Test (STAT), assessed at baseline, 6 months, and 12 months.In total, 261 of 312 individuals completed the study (83.7% retention rate). Most participants were female (79.1%). The mean (SD) age of participants was 58.57 (11.66) years; 51.1% (n = 159) were non-Hispanic black, 48.9% (n = 152) were Hispanic, and 31.7% (n = 99) had low levels of education. There were no significant end-point differences for the STAT at follow-up periods. The mean (SD) baseline STAT scores were 59.05% (29.12%) correct for intervention and 58.35% (28.83%) correct for usual care. At 12 months, the mean (SD) STAT scores were 64.38% (26.39%) correct for intervention and 61.58% (28.01%) correct for usual care. Adjusted by education, a post hoc subgroup analysis revealed a mean (SE) intervention effect of 1.03% (0.44%) (P = .02) increase per month in the low-education subgroup (about a 10% increase in 12 months). In the high-education subgroup, the mean (SE) intervention effect was -0.05% (0.30%) (P = .86). Regarding percentage correct, the low-education intervention subgroup improved from 52.4% (7 of 21) to 66.7% (14 of 21) compared with the other subgroups.No difference was observed in stroke preparedness at 12 months in response to culturally tailored 12-minute stroke films or conventional stroke education pamphlets. Additional studies are required to confirm findings from a post hoc subgroup analysis that suggested a significant education effect.ClinicalTrials.gov identifier: NCT01909271.
Is the endoscopic Dor fundoplication definitely effective?
Authors: Wen-Ping Wang, Han-Lu Zhang, Long-Qi Chen
Journal: Endoscopy (2019)

See also: Peroral endoscopic myotomy and fundoplication: a novel NOTES procedureEndoscopy eFirstDOI: 10.1055/a-0820-2731 See also: Reply to Wang et al.Endoscopy 2019; 51(07): 698-698DOI: 10.1055/a-0877-6922
The Potential of Exosomes Derived from Chronic Myelogenous Leukemia Cells As Biomarker Based on the BCR-ABL mRNA Transcript
Authors: Ka-Won Kang, Jik-han Jung, Woojune Hur, Jaena Park, Hyunku Shin, ByeongHyeon Choi, Hyesun Jeong, Dae Sik Kim, Eun Sang Yu, Se Ryeon Lee, Hwa Jung Sung, Seok Jin Kim, Chul Won Choi, Byung Soo Kim, Hyun Koo Kim, Sunghoi Hong, Ji-ho Park, Yeonho Choi, Yong Park
Journal: Blood (2017)
Gvhd after PBSC-Haploidentical Stem Cell Transplantation (Haplo-SCT) with Post Transplantation-Cyclophosphamide (PT-Cy)
Authors: Angela Granata, Raynier Devillier, Stefania Bramanti, Sabine Furst, Faezeh Legrand, Samia Harbi, Catherine Faucher, Christian Chabannon, Claude Lemarie, Boris Calmels, Jacopo Mariotti, Valerio Maisano, Pierre Jean Weiller, Luca Castagna, Didier Blaise
Journal: Blood (2017)
Polyunsaturated fatty acids in cod evoke chemotaxis and mobilize intracellular calcium in human eosinophils in part <i>via</i> FFAR4
Authors: Christine Lingblom, Elin Redvall, Kerstin Andersson, Christine Wennerås
Journal: Allergy (2019)

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Abstract 3559: A crowd-control approach for castration-resistant prostate cancer therapeutics
Authors: Girish C. Shukla
Journal: Cancer Research (2019)

Abstract Castration-resistant prostate cancer (CRPC) is defined by affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), epithelial-mesenchymal transition (EMT) and dysregulation of transcription factors including androgen receptor (AR) and c-Myc. Development of CRPC post Androgen-deprivation therapy is indicated by tumor microenvironment heterogeneity, compensating cellular pathways and recurrence of AR expression leading to the failure of androgen-signaling inhibitors including Enzalutamide and Abiraterone Acetate. We have discovered that miR-644a potentiates Enzalutamide efficacy both, in vitro and in vivo prostate cancer models. In depth analyses revealed that miR-644a downregulated expression of diverse tumor microenvironment regulators including c-Myc, AR, AR co-regulators and the anti-apoptosis factors Bcl-xl and Bcl-2, EMT factors ZEB1, cdk6, and Snail. Enhanced miR-644a expression also suppressed the Warburg effect by direct down-regulating c-Myc, Akt, IGF-1R and GAPDH expression. Taken together, our data demonstrate that the adjunctive miRNA expression down-regulated several oncogenesis promoting cellular pathways and functions cooperatively with Enzalutamide. We propose that a “crowd-control” approach to pacifying aggressive tumorigenesis and metastasis supporting cellular pathways by a miRNA with a wide range of gene targets is likely to potentiate the efficacy of cancer treating drugs and potentially preventing the drug-resistance. Note: This abstract was not presented at the meeting. Citation Format: Girish C. Shukla. A crowd-control approach for castration-resistant prostate cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3559.
Concomitant chemoradiotherapy in women with stage II-III breast cancer.
Authors: Eduardo arnoldo Richardet, Perelli Laura, Martin Eduardo Richardet, Nicolas Castagneris, Matias Nicolas Cortes, Matias Molina
Journal: Journal of Clinical Oncology (2012)

e11501 Background: To demonstrate the compliance of radiotherapy and chemotherapy with concomitant taxanes by avoiding delays initiation of that treatment Methods: Retrospective, observational, and descriptive. We analyzed the medical records of 50 patients from June 2006 to December 2010 with an average follow up of 27.26 months (9 months to 56 months), in which all completed conservative surgery. The chemotherapy used was AC x 4 cycles (doxorubicin 60 mg/m2, Cyclophosphamide 600 mg/m2 on day 1 every 21 days) followed by weekly paclitaxel 80 mg/m2 for twelve weeks, concomitant with radiation in the affected breast. Standardized treatment was indicated to patients with positive hormone receptors. Results: Patients`s age averaged 53.58 years (33 years and 74 years) All patients received the planned chemotherapy, with a delay of 63.24 days, from the surgery to the first cycle of chemotherapy (20 days to 110 days. The radiation treatment was initiated in 143.4 days (90 to 205 days) on average after the surgical treatment.It was reported that 8% (n = 4) discontinued the treatment due to the toxicity of the radiation therapy: actinic dermatitis grade 3 and 4. The average number of days without radiation therapy due to toxicity was 6 days (3 to 9 days).With respect to chemotherapy, 22% (11) interrupted it because of hematologic toxicities (neutropenia, thrombocytopenia), constitutional toxicities (fatigue) and arthralgias. Regarding chemotherapy, the average time without treatment was 18 days (1 to 4 cycles).There were no cardiac or lung related adverse events. All other toxicities were well tolerated with concomitant medication. Conclusions: In our population, it is possible to carry out concomitant chemo-radiotherapy with acceptable early toxicities and compliance in patients with breast cancer.
Impaired Right Ventricular Performance Is Associated with Adverse Outcome after Hypoxic Ischemic Encephalopathy
Authors: Regan E. Giesinger, Amr I. El Shahed, Michael P. Castaldo, Colm R. Breatnach, Vann Chau, Hilary E. Whyte, Afif F. El-Khuffash, Luc Mertens, Patrick J. McNamara
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Asphyxiated neonates with hypoxic ischemic encephalopathy (HIE) are at risk of myocardial dysfunction; however, echocardiography studies are limited and little is known about the relationship between hemodynamics and brain injury.Objectives: To analyze the association between severity of myocardial dysfunction and adverse outcome as defined by the composite of death and/or abnormal magnetic resonance imaging.Methods: Neonates with HIE undergoing therapeutic hypothermia were enrolled. Participants underwent echocardiography at 24 hours, 72 hours (before rewarming), and 96 hours (after rewarming). Cerebral hemodynamics were monitored by near-infrared spectroscopy and middle cerebral artery Doppler.Measurements and Main Results: Fifty-three patients with a mean gestation and birthweight of 38.8 ± 2.0 weeks and 3.33 ± 0.6 kg, respectively, were recruited. Thirteen patients (25%) had mild encephalopathy, 27 (50%) had moderate encephalopathy, and 13 (25%) had severe encephalopathy. Eighteen patients (34%) had an adverse outcome. Severity of cardiovascular illness (P < 0.001) and severity of neurologic insult (P = 0.02) were higher in neonates with adverse outcome. Right ventricle (RV) systolic performance at 24 hours was substantially lower than published normative data in all groups. At 24 hours, lower tricuspid annular plane systolic excursion (P = 0.004) and RV fractional area change (P < 0.001), but not pulmonary hypertension, were independently associated with adverse outcome on logistic regression. High brain regional oxygen saturation (P = 0.007) and low middle cerebral artery resistive index (P = 0.04) were associated with RV dysfunction on post hoc analysis.Conclusions: RV dysfunction is associated with the risk of adverse outcome in asphyxiated patients with HIE undergoing hypothermia. Echocardiography may be a valuable diagnostic and prognostic tool in this vulnerable population.