tbuckley/cabot-search huggingface dataset:
Benzopyrene disrupts cell growth dynamics and DNA methylation in breast cancer cells
Authors: Bekim Sadikovic, David I. Rodenhiser
Journal: Cancer Research (2006)

1630  Exposure to environmental carcinogens and unhealthy lifestyle choices can contribute to incidence of breast cancer. Benzo(a)pyrene (BaP) is one such environmental carcinogen present in automobile exhaust, industrial effluent and cigarette smoke. The primary carcinogenic effects of BaP are attributed to covalent DNA modifications and the deregulation of gene expression. Furthermore, disruptions in DNA methylation represent an additional, but poorly-understood mechanism of BaP-induced carcinogenesis. Changes in normal DNA methylation patterns that ensure proper gene expression and chromosomal stability can result in deregulated gene expression and a loss of genomic integrity. However, the specific roles of environmental contaminants as contributors to breast tumourigenesis are poorly understood. We tested the effects of BaP exposure on cellular growth dynamics and DNA methylation in various breast cancer cell lines. Cells were exposed to BaP in a time and concentration dependent manner and we evaluated the effects of BaP-exposure on cell proliferation and cell cycle, as well as gene-specific and global changes in DNA methylation. Our data show drastic differences in BaP-induced proliferative and cell cycle responses across these breast cancer cell lines. Specifically, we observed time and BaP concentration dependent loss of proliferation, S phase and G2M accumulation, and apoptosis in p53 positive MCF-7 and T47-D, (but not p53 negative HCC1806 and MDA MB231 cells). Furthermore, we observed increases in both p53 and p21 protein levels in BaP treated cells, while pretreatment with the p53-specific inhibitor pifithrin led to decreases in p53 and p21 levels and increase in proliferation. We also assessed DNA methylation dynamics using the methylation fingerprinting technique called amplification of intermethylated sites (AIMS), and we performed sequence analysis of differentially methylated DNA. Each cell line showed changes in global DNA methylation levels using the methyl acceptor assay (MAA), as well as gene-specific hypo- and hypermethylation events. Furthermore, we identified specific BaP-induced hypomethylation events in genomic repeats. Our data confirm altered DNA methylation patterns as a consequence of benzopyrene treatment and reinforce the link between environmental exposures, DNA methylation and breast cancer. (Funded by the Canadian Breast Cancer Research Alliance).
Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors
Authors: Mateusz Rytelewski, Karine Haryutyunan, Felix Nwajei, Meenakshi Shanmugasundaram, Patrick Wspanialy, M. Anna Zal, Chao-Hsien Chen, Mirna El Khatib, Shane Plunkett, Sergei A. Vinogradov, Marina Konopleva, Tomasz Zal
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Low availability of oxygen in tumors contributes to the hostility of the tumor microenvironment toward the immune system. However, the dynamic relationship between local oxygen levels and the immune surveillance of tumors by tumor infiltrating T-lymphocytes (TIL) remains unclear. This situation reflects a methodological difficulty in visualizing oxygen gradients in living tissue in a manner that is suitable for spatiotemporal quantification and contextual correlation with individual cell dynamics tracked by typical fluorescence reporter systems. <h3>Methods</h3> Here, we devise a regimen for intravital oxygen and cell dynamics co-imaging, termed 'Fast' Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM). Using FaST-PLIM, we image the cellular motility of T-lymphocytes in relation to the microscopic distribution of oxygen in mouse models of hematological and solid tumors, namely in bone marrow with or without B-cell acute lymphocytic leukemia (ALL), and in lungs with sarcoma tumors. <h3>Results</h3> Both in bone marrow leukemia and solid tumor models, TILs encountered regions of varying oxygen concentrations, including regions of hypoxia (defined as pO<sub>2</sub> below 5 mmHg), especially in advanced-stage ALL and within solid tumor cores. T cell motility was sustained and weakly correlated with local pO<sub>2</sub> above 5 mmHg but it was very slow in pO<sub>2</sub> below this level. In solid tumors, this relationship was reflected in slow migration of TIL in tumor cores compared to that in tumor margins. Remarkably, breathing 100% oxygen alleviated tumor core hypoxia and rapidly invigorated the motility of otherwise stalled tumor core TILs. <h3>Conclusions</h3> This study demonstrates a versatile and highly contextual FaST-PLIM method for phosphorescence lifetime-based oxygen imaging in living animal tumor immunology models. The initial results of this method application to ALL and solid lung tumor models highlight the importance of oxygen supply for the maintenance of intratumoral T cell migration, define a 5 mmHg local oxygen concentration threshold for TIL motility, and demonstrate efficacy of supplementary oxygen breathing in TIL motility enhancement coincident with reduction of tumor hypoxia.
Designing clinical trials in paediatric inflammatory bowel diseases: a PIBDnet commentary
Authors: Dan Turner, Anne M Griffiths, David Wilson, Diane R Mould, Robert N Baldassano, Richard K Russell, Marla Dubinsky, Melvin B Heyman, Lissy de Ridder, Jeffrey Hyams, Javier Martin de Carpi, Laurie Conklin, William A Faubion, Sibylle Koletzko, Athos Bousvaros, Frank M Ruemmele
Journal: Gut (2019)

Introduction The optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children. Methods A writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of &gt;80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of &gt;80% on all statements. Comments from the members were incorporated in the text. Results The commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text. Conclusion The viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.
Abstract 12515: Enhanced Transforming Growth Factor β Signaling Rescues Defective Differentiation of Smooth Muscle Cell in Bicuspid Aortic Valve With Thoracic Aortic Aneurysm
Authors: Bo Yang, Jiao Jiao, Wei Xiong, Lunchang Wang, Eugene Chen
Journal: Circulation (2015)

Individuals with bicuspid aortic valves (BAV) are at a high risk to develop a thoracic aortic aneurysms (TAA) than patients with trileaflet aortic valves (TAV), most commonly involving ascending aorta and sparing the descending aorta. Smooth muscle cells (SMCs) in the ascending and descending aorta arise from neural crest and paraxial mesoderm, respectively. We hypothesize the aortopathy associated with BAVs is due to aberrant differentiation of neural crest stem cells (NCSCs) to SMCs. Induced pluripotent stem cell (iPSC) lines were established from a patient with BAV/TAA, and control patients with TAV and a normal aorta. The iPSCs pluripotency was verified by standard stem cell markers and teratoma formation in SCID mice. iPSCs were differentiated into NCSCs and paraxial mesoderm cells (PMCs) separately, and verified by specific neural crest markers and paraxial mesoderm markers. Both NCSCs and PMCs were differentiated into SMCs, NCSC-SMCs and PMC-SMCs, by treating with TGFβ1 and PDGF-bb. With differentiation, both SMCs lines expressed SMC specific markers including MYH11, CNN1, ACTA2, and TAGLN by quantitative RT-PCR and immunohistochemical staining. However, NCSC-derived SMCs from BAV/TAA patient demonstrated significantly decreased expression and protein levels of MYH11 and ACTA2 and impaired contraction by gel contraction assay compared to NCSC-SMCs derived from control. In contrast, the PMC-derived SMCs from BAV/TAAD patient had similar or higher expression and levels of contractile proteins, including MYH11, CNN1, ACTA2, and TAGLN, and contractile response to carbacol treatment when compared with control PMC-SMCs. The defective differentiation of NCSC-SMC from the BAV/TAA patient was coupled with the decreased TGFβ signaling as assessed by decreased gene expression of TGFβ1 and connective tissue growth factor (CTGF) when compared to control cells. Increasing the concentration of TGFβ1, rescued the gene expressions of TGFβ1, CTGF, MYH11 and ACTA2 in the NCSC-SMCs from the BAV/TAA. Taken together, our data demonstrate that defective TGFβ signaling and differentiation of specifically NCSC-derived SMCs contributes to aortopathy in BAV with ascending aortic aneurysm.
PS-205-Longitudinal prognostic value of the most common algorithms for fibrosis in non-alcoholic fatty liver disease: An international study in non-cirrhotic, biopsy-proven patients
Authors: Ramy Younes, Chiara Rosso, Maria Jose Garcia Blanco, Salvatore Petta, Luca Miele, Antonio Liguori, Paolo Francione, Anna Ludovica Fracanzani, Luca Valenti, Quentin Anstee, Elisabetta Bugianesi
Journal: Journal of Hepatology (2019)
Drug Delivery Strategies for the Treatment of Metabolic Diseases
Authors: Sanjun Shi, Na Kong, Chan Feng, Aram Shajii, Claire Bejgrowicz, Wei Tao, Omid C. Farokhzad
Journal: Advanced Healthcare Materials (2019)

Metabolic diseases occur when normal metabolic processes are disrupted in the human body, which can be congenital or acquired. The incidence of metabolic diseases worldwide has reached epidemic proportions. So far, various methods including systemic drug therapy and surgery are exploited to prevent and treat metabolic diseases. However, current pharmacotherapeutic options for treatment of these metabolic disorders remain limited and ineffective, especially reducing patient compliance to treatment. Therefore, it is desirable to exploit effective drug delivery approaches to effectively treat metabolic diseases and reduce side effects. This brief review summarizes novel delivery strategies including local, targeted, and oral drug delivery strategies, as well as intelligent stimulus-responsive drug delivery strategy, for the treatment of metabolic disorders including diabetes, obesity, and atherosclerosis.
Pivotal role of sphingomyelin synthase (SGMS) expression and activity in glioma patient survival presents a potential therapeutic target.
Authors: Pablo V. Escriba, Xavier Busquets, Victoria LLado, Desamparados Roda, Begona Jimenez, Rhoda Molife, Ruth Plummer, Jordi Rodon, Analia Azaro, Elisabet Sicart, Edwin Klumper
Journal: Journal of Clinical Oncology (2015)

e22214 Background: In human glioma (U118, SF767) cell membranes,sphingomyelin (SM) levels are lower and phosphatidylethanolamine (PE) levels are higher compared to non-tumor (MRC5) cells. This membrane lipid composition acts as a proliferation signal switch regulating cell membrane microdomain dynamics and type of membrane-bound signaling. SM synthase (SGMS, which converts PE into SM) and other lipid metabolism enzymes are key regulators of the membrane lipid composition, tumorigenesis, and median survival in glioma patients. Methods: Membrane lipids were determined in human cancer cells using HP-TLC, and GC. Protein expression was determined, in glioma cells using immunoblotting and RT-PCR and, in human samples, DNA microarray analysis (Affymetrix). Analysis of the REMBRANDT database for glioma patients was carried out with the tools provided on the website (https://caintegrator.nci.nih.gov/rembrandt/home.do). Results: In human glioblastoma (GBM; U118) cells, the PE:SM ratio was 2.52 compared to 0.89 in MRC5 fibroblasts. After treatment with the SGMS activator, 2-hydroxyoleic acid (2-OHOA) the PE:SM ratio reduced to 0.24 (P < 0.001) in U118 cells. No significant changes were observed in MRC5 fibroblasts. Moreover, 2-OHOA induced glioma cell death with IC50 values in the range of 100-250 mM, whilst inhibiting MRC-5 cell growth with IC50> 5,000 mM. In animal models of human glioma it has shown improved efficacy with respect to temozolomide. Additionally, glioma patients showing low SGMS1 expression (84/343) had a median survival of 12.8 months (m). Glioma patients with intermediate SGMS1 expression (258/343) had significantly (P < 0.001) higher median survival (ca. 24 m). Similarly, GBM patients with lower SGMS1 expression (64/180) showed lower median survival (8.3 m) with respect to patients with intermediate expression (116/180; 14 m; P < 0.001). Conclusions: The anticancer agent 2-OHOA is a SGMS activator that normalizes the membrane levels of PE and SM. 2-OHOA induces tumor regression in animal models of human glioma and an ongoing first-in-man trial has demonstrated early evidence of activity in GBM (PI/IIa MIN-001-1203 study: Roda et al.).
Dermatologist wins £6000 and injunction to remove defamatory blog
Authors: Clare Dyer
Journal: BMJ (2019)

A consultant dermatologist has won £6000 (€7000; $7900) damages and a High Court injunction over a blog entitled “Worst liposuction ever” posted by a former patient.1

Aikaterini Charakida sued Hollie Jackson over the blog about the Vaser liposuction procedure, carried out at a private clinic in London. Charakida also works as an NHS consultant.

Jackson did not acknowledge service of the claim form and took no part in the litigation. The judge, Mr Justice Warby, dealt with the case as a …
Burden of inpatient care and treatments in terminally-ill cancer patients: results from a population-based, retrospective study from administrative data in France.
Authors: Lucas Morin, Regis Aubry, Yvan Beaussant, Philippe Rochigneux, Francois Goldwasser, Christophe Tournigand
Journal: Journal of Clinical Oncology (2015)

9527 Background: Over the past decades, dramatic changes in the treatment of advanced cancer have raised concerns regarding the quality of end-of-life care in terminally-ill patients. However, Earle et al.’s indicators of aggressive care near the end of life have never been used in population-based studies in Europe. We aimed to examine the use of inpatient care and treatments in the last months of life of cancer patients who died in hospitals in France. Methods: A nationwide, retrospective cohort study was conducted using administrative data. We included all cancer patients (irrespective of the tumour type) aged 20 years or older, who died in acute and rehabilitation hospital facilities between January 2010 and December 2013 in France. Results: Among 516,244 cancer decedents, 39% were female and 48% were 75 years or older. Main primary malignancies were gastrointestinal (30%), respiratory (20%) and haematological (10%). 17% of the patients spent their last 30 days of life in a hospital facility, 10% died in ICU, 10% in a palliative care unit, 2% within the emergency department and 64% in acute care wards. 33.8% received chemotherapy during their last 3 months of life, 28.0% over the last 2 months, 17.9% over the last month and 10.9% over the last 2 weeks before death. Between 2010 and 2013, while adjusting for sex, age and cancer type, we measured a significant increase in the likelihood of receiving chemotherapy over the last month of life (OR = 1.05, 95%CI = 1.03-1.07). Younger decedent, patients with hematological malignancies and patients with metastatic cancer were the most likely to be prescribed such treatments over the last 90 and 30 days before death (p < 0.001). Over the course of the last month before death, 3.3% of the decedents had more than one emergency department visit, 22.4% were admitted to an Intensive Care Unit and 21% received blood transfusion. Conclusions: This population-based study provides unprecedented insight into the burden of care and treatment in the last months of life of cancer patients in France. We believe these results can provide useful support for discussions regarding cancer care management near the end of life.
SAT-380-Liver-resident memory CD8 T cells do not egress into hepatic venous blood
Authors: Sergio Rodríguez-Tajes, Laura J Pallett, Mireia Garcia-López, Anna Baiges, Elena Perpiñán, Sabela Lens, Nekisa Zakeri, David Patch, Dominic Yu, Juan Carlos García-Pagán, George Koutsoudakis, Sofía Pérez-del-Pulgar, Mala K. Maini, Xavier Forns
Journal: Journal of Hepatology (2019)
Nurse Practitioner and Physician Assistant Waivers to Prescribe Buprenorphine and State Scope of Practice Restrictions
Authors: Joanne Spetz, Christopher Toretsky, Susan Chapman, Bethany Phoenix, Matthew Tierney
Journal: JAMA (2019)

This study uses SAMHSA data to describe the proportions of nurse practitioners and physician assistants with waivers to prescribe buprenorphine for treating opioid use disorder and associations with state regulations restricting their scope of practice.
SAT-022-Transjugular intrahepatic portosystemic shunts is still an effective treatment for refractory variceal haemorrhage in patients with high MELD/Child Pugh scores
Authors: Rigers Cama, Vedat Barut, David Fidler, Amine Benmassaoud, Hannah Fenn, Mukur Ghosh, Raj Mookerjee, Dominic Yu, Jennifer Ryan, Neil Davies, David Patch, Rachel Westbrook
Journal: Journal of Hepatology (2019)
PS-104-Prognosis assessment of acute-on-chronic liver failure in patients with hepatitis B virus-related cirrhosis requires specific criteria
Authors: Gu Wenyi, Guohong Deng, Xin Zheng, Jinjun Chen, Xian-bo Wang, Yan Huang, Yanhang Gao, Zhong-ji Meng, Zhiping Qian, Feng Liu, Xiao-bo Lu, Jia Shang, Hai Li, Shaoyang Wang, Shan Yin, Shuning Sun, yan xiong, beiling li, Yixin Hou, Jun Chen, Na Gao, Qing Lei, Liujuan Ji, Jing Li, Fangrong Jie, Jun Ping Liu, Taofa Lin, Amoros Alex, Liuying Chen, Wenting Tan, Congcong Zou, Xiuhua Jiang, Qun Zhang, Zebing Huang, Chunyan Liu, Sen Luo, Yuyi Zhang, Tao Li, Shijin Wang, Bao-yan Xu, Shue Xiong, Xiaoxiao Liu, Chen Wang, Wei Yuan, Yan Zhang, Liang Qiao, Jonel Trebicka, Richard Moreau, Rajiv Jalan, Vicente Arroyo, Hai Li
Journal: Journal of Hepatology (2019)
GS-09-Ramucirumab for patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein following sorafenib: Outcomes by liver disease aetiology from two randomised, placebo-controlled phase 3 studies (REACH-2 and REACH)
Authors: Peter Galle, Masatoshi Kudo, Josep M. Llovet, Richard Finn, Mark Karwal, Pezet Denis, Tae-You Kim, Tsai-Sheng Yang, Vittorina Zagonel, Jiri Tomasek, Jean-Marc Phelip, Yann Touchefeu, Su-Jin Koh, Guido Stirnimann, Chunxiao Wang, Ryan Widau, Yanzhi Hsu, Paolo B. Abada, Andrew Zhu
Journal: Journal of Hepatology (2019)
Abstract 15863: Delivery of Hepatocyte Growth Factor mRNA From Nanofibrillar Scaffolds for Treatment of Peripheral Arterial Disease
Authors: Ngan F Huang, Luqia Hou, Cynthia A Alcazar, Zachary Strassberg, Eduard Yakubov, Tatiana Zaitseva, Michael Paukshto
Journal: Circulation (2017)

Introduction: Biological approaches to augment angiogenesis are promising for treatment of peripheral arterial disease (PAD). We propose the use of scaffold-based modified mRNA (mmRNA) delivery as a favorable approach for transient, localized gene delivery. Hypothesis: We hypothesized that hepatocyte growth factor (HGF) mmRNA-seeded nanofibrillar scaffolds will enable localized and temporally controlled delivery of mmRNA, leading to augmentation of angiogenesis in a murine model of PAD. Methods: To establish the efficacy of mmRNA therapy, mmRNA encoding green fluorescence protein (GFP) was used as a fluorescent reporter for quantification of transfection efficiency. Aligned nanofibrillar collagen scaffolds were loaded with mmRNA and lipofectamine transfection agent. The temporal kinetics of mmRNA release into media was measured by ribogreen assay. To determine the transfection efficiency, human fibroblasts were cultured on the aligned nanofibrillar scaffolds, or on tissue culture plastic, and the efficien...
Proton versus conventional radiotherapy for pediatric salivary gland tumors: Acute toxicity and dosimetric characteristics.
Authors: Stephen Richard Grant, David Grosshans, Anita Mahajan
Journal: Journal of Clinical Oncology (2015)

10040 Background: Adjuvant radiotherapy (RT) is often a component of treatment for high-risk salivary gland tumors. Minimizing irradiation of surrounding normal tissues is particularly important for pediatric patients. We compared acute toxicity profiles, clinical outcomes, and dosimetric data for children with parotid or submandibular tumors treated with adjuvant photon/electron-based RT (X/E RT) or proton RT (PRT). Methods: We retrospectively identified 24 pediatric patients who had received adjuvant RT at a single institution for salivary gland tumors (20 parotid, 4 submandibular). Demographic, disease control and survival data were extracted from the medical records and dosimetric data from the treatment planning systems. Toxicity was scored according to the Common Terminology Criteria for Adverse Effects 4.0. Results: Eleven patients received X/E RT and 13 PRT. The median prescribed dose was 60 Gy for each group. PRT was associated with significantly lower mean doses to the thyroid (1.5 vs. 22.5 Gy, P< 0.05), oral cavity (4.6 vs. 20.7 Gy, P< 0.05), and larynx (11.3 vs. 44.3 Gy, P< 0.05); and the contralateral parotid (0.0 vs. 4.6, P< 0.05), hemi-mandible (0.0 vs. 11.9 Gy, P< 0.05), and submandibular gland (0.0 vs. 13.5 Gy, P< 0.05). In the X/E RT group, 27% had acute grade 3 dermatitis, 18% grade 3 mucositis, and 9% grade 3 dysphagia, and the median weight loss was 5.3%. No patient in the PRT group experienced acute grade 3 toxicity, and a median weight gain of 1.2% was noted. At a median follow-up time of 35 months, no disease recurrence or deaths were observed in either group. Conclusions: Compared with X/E RT, PRT significantly reduced the radiation dose to many surrounding normal tissues, which translated to reductions in clinical acute toxicity. Continued follow-up is needed to identify any differences in long-term toxicity and disease control.