tbuckley/cabot-search huggingface dataset:
Response to letter to the editor by Moayyedi <i>et al</i>
Authors: Ka-Shing Cheung, Wai Keung Leung
Journal: Gut (2018)

We thank Moayyedi et al 1 for their letter on our recent study investigating proton pump inhibitors (PPIs) on gastric cancer (GC) risk after Helicobacter pylori (HP) eradication.2 Although the association detected by an observational study may not mean causation, the possibility of causality can be strengthened by fulfilling the Bradford Hill criteria. In our study, these include strength (HR: 2.43), specificity (stomach is the only organ that PPIs may impose a cancer risk), temporality (all GC cases developed after triple therapy), biological gradient (dose and duration response relationship shown), plausibility (worsening of preneoplastic gastric changes and bacterial overgrowth under profound acid suppression), experiment (as illustrated in animal model studies) and analogy (achlorhydria due to autoimmune gastritis causes GC).

Concerns were raised over inadequate adjustment for socioeconomic status and comorbidities. Hong Kong is a highly urbanised city with excellent sanitation and easily accessible …
A Model of Canine Purkinje Cell Electrophysiology and Ca2+ Cycling
Authors: PanLi, YoramRudy
Journal: Circulation Research (2011)

Purkinje cells (Pcell) are characterized by different electrophysiological properties and Ca2+ cycling processes than ventricular myocytes (Vcell) and are frequently involved in ventricular arrhythmias. Yet, the mechanistic basis for their arrhythmic vulnerability is not completely understood. The objectives were to: (1) characterize Pcell electrophysiology, Ca2+ cycling, and their rate dependence; (2) investigate mechanisms underlying Pcell arrhythmogenicity; and compare Pcell and Vcell electrophysiology, Ca2+ cycling, and arrhythmic properties. We developed a new mathematical model of Pcell. The Ca2+ subsystem includes spatial organization and receptors distribution unique to Pcell. Results were: (1) in Pcell and Vcell, Na+ accumulation via its augmentation of repolarizing INaK dominates action potential duration adaptation and, in Pcell, INaL contributes additional action potential duration shortening at short cycle length; (2) steep Pcell restitution is attributable to slow recovery of INaL; (3) bipha...
Abstract 1295: Single cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes
Authors: Keyue Ma, Alexandra A. Schonnesen, S. Gail Eckhardt, Ning Jiang
Journal: Cancer Research (2018)

Abstract Immunotherapies have been the most promising approaches to treating cancers, while the partial responses in multiple clinical trials suggest the significance of characterizing intertumoral and intratumoral heterogeneity for better prognosis and decision-making in treatment. The lack of intratumoral characterization of immune response-related genes in cancer cells, however, hinders the further development of metrics to select and predict immunotherapies. Therefore, we applied single cell RNA-seq data from lung adenocarcinoma patients to identify intratumoral heterogeneity of immune response-related genes and demonstrated its potential effect on immunotherapy efficacy. We found IFNγ signaling pathway genes are heterogeneously expressed and co-regulated in cancer single cells, including MHC class II molecules (MHCII), a set of favorable prognosis markers. The upregulation of MHCII is also mutually exclusive with upregulation of cell cycle pathways, which are associated with unfavorable prognosis. Moreover, analysis of two candidates of cancer vaccination approaches, neoantigens and cancer testis antigens, revealed their ectopic expression in single cells. These analyses provide the rationale of applying combinatorial therapies to prevent tumor escape and basis for future development of prognosis metrics based on intratumoral heterogeneity. Citation Format: Keyue Ma, Alexandra A. Schonnesen, S. Gail Eckhardt, Ning Jiang. Single cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1295.
Abstract 3841: Biologic evaluation of heterocyclic pyrimidines as novel tubulin inhibitors targeting the colchicine binding site
Authors: Kinsie Arnst
Journal: Cancer Research (2018)

Abstract Interfering with tubulin dynamics is an attractive strategy for cancer therapy, and tubulin-targeting agents are some of the most widely used chemotherapeutic drugs. Current FDA-approved tubulin inhibitors target either the taxane site (e.g., paclitaxel) or the vinca alkaloid site (e.g., vinblastine). However, their clinical efficacy is often limited by the development of multidrug resistance and a narrow therapeutic index. Tubulin inhibitors interacting with the colchicine site have shown potent anticancer activities, are generally less susceptible to multidrug resistance, and can disrupt tumor vasculature, leading to rapid tumor cell apoptosis. Here, we report on the biologic evaluation of heterocyclic pyrimidines as a new class of tubulin inhibitors targeting the colchicine binding site with a significantly improved therapeutic index. One of the most promising compounds of the series, SB157, was able to strongly inhibit tubulin polymerization and induce cytotoxicity in cancer cells in vitro. We have also obtained the high-resolution X-ray crystal structure for SB157, confirming its direct binding to the colchicine binding site in tubulin, and elucidated the detailed molecular interactions. SB157 significantly inhibited tumor growth in an A375 melanoma xenograft model, and the tumors revealed elevated apoptotic activity and extensive disruption of tumor vasculature. Finally, we demonstrated that SB157 significantly overcame clinically relevant multidrug resistance in a paclitaxel-resistant PC-3/TxR prostate cancer xenograft mouse model. Collectively, these studies provide preclinical proof of concept and structural basis to support the continued development of SB157 and optimization of this scaffold as an improved class of tubulin inhibitors for cancer therapy. Citation Format: Kinsie Arnst. Biologic evaluation of heterocyclic pyrimidines as novel tubulin inhibitors targeting the colchicine binding site [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3841.
Liver Function and Hypertension
Authors: Flemmingraaschou
Journal: Circulation (1954)

The purpose of the present work was to study the incidence of arterial hypertension in a series of autopsied cases of chronic hepatitis. The frequency of patients with hypertension, examined according to three criteria (cerebral hemorrhage, hypertrophy of the heart, and incidence of hypertension as determined by actual measurements of blood pressure during life), is essentially lower in an autopsy series consisting of women who died of or with subchronic hepatitis than in a control series of autopsied female patients with the same age distribution who died of all other diseases.
Abstract 15461: Histone Modification in the Right Ventricle is an Useful Predictor of Right Ventricular Failure Following LVAD Implantation in Non-ischemic Dilated Cardiomyopathy
Authors: NoriyukiKashiyama, ShigeruMiyagawa, KoichiToda, TeruyaNakamura, YasushiYoshikawa, SatsukiFukushima, ShunsukeSaito, DaisukeYoshioka, EmikoIto, AkimaHarada, MakiTakeda, TakayoshiUeno, ToruKuratani, YoshikiSawa
Journal: Circulation (2015)

Introduction: Although right ventricular failure (RVF) is associated with poor outcome following left ventricular assist device (LVAD) implantation, predictive factors of RVF have not been fully established. Epigenetic modification in cardiomyocytes has been recently shown to be related to progression of heart failure (HF). Hypothesis: We herein hypothesized that reduced histone modification including methylation/acethylation of cardiomyocytes in the RV would be associated with RVF after LVAD implantation. Methods: This study enrolled 22 patients who were diagnosed as having non-ischemic dilated cardiomyopathy (NIDCM) and underwent LVAD implantation for bridge-to-transplantation between 2012 and 2015. The RV biopsied prior to LVAD implantation were immunohistologically labeled for histone H3 lysine 9 tri-methylation (H3K9me3) and acethylation (H3K9ac) and scored ranging from 0 to 12 according to intensity and percentage of positively labelled cardiac cell nuclei. Results: Eight patients (40%) presented wi...
Abstract 2667: Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma
Authors: Garrick M. Moll, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2018)

Abstract Treatment success in lymphoma, the most common hematopoietic cancer seen in dogs and cats, continues to be elusive. The clinical arsenal is limited to a few conventional chemotherapeutic drug protocols that result in short-term responses. In this study, dog and cat patient-derived tumor cells were tested via high-throughput screening (HTS) against a pool of over 100 FDA-approved compounds for human cancer treatment as a means to identify potential treatment strategies that can be relatively easily adapted to the dog and cat, as well as over 500 protein kinase inhibitors as a means to identify potential oncogenic driver pathways. Cells from lymph node fine needle aspirates, pleural effusions, or peripheral blood mononuclear cells from over 20 lymphoma patients were placed in cell culture media with and without growth factors. Cells from two cases, ZS15 from a Boxer dog and MT16 from a domestic shorthair cat, have continued to expand for over 12 and 6 months, respectively. Characterization by flow cytometry for detection of CD3 and CD21 identified these patient-derived cells to be T-cell lymphocytes. HTS and follow-up dose response curve (DRC) assays were performed, identifying multiple drugs effective in inhibiting growth of MT16 and ZS15 cells at nanomolar concentrations in vitro; these included anthracenedione/anthracycline-class and actinomycin-class drugs, as well as mRNA synthesis, microtubule/spindle formation, proteasome, histone deacetylase, or insulin growth factor-1 receptor inhibitors, many of which are currently not used in veterinary species. Notably, ZS15 cell growth was inhibited by mammalian target of rapamycin (mTOR) inhibitors, corroborating previous exome sequencing data of Boxer T-cell lymphomas that identified recurrent driver mutations in the PTEN-mTOR pathway. In addition, many of these drugs showed much higher IC50s in HTS and DRC assays on primary canine and feline fibroblasts, used as surrogates for normal tissue, revealing the specificity of their action on the cancer cells. These results advocate use of HTS and DRC assays as a means for identification of oncogenic driving mechanisms and for identification of drugs novel to veterinary medicine that warrant further investigation as alternative treatments for lymphoma in companion animals, which in turn can serve as valuable and accessible models for human lymphomas. Citation Format: Garrick M. Moll, Vilma Yuzbasiyan-Gurkan. Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2667.
Sixty seconds on . . . tongue splitting
Authors: Abi Rimmer
Journal: BMJ (2018)

It’s a procedure where the tongue is cut in half to create a snake-like, forked effect.

Nope. It usually starts with a tongue piercing, after which different methods can be used to split the tongue. Practitioners often use a scalpel to simply cut the tongue from the point of the piercing to the tip. They may also use a cauterisation tool to burn the tongue in half or may …
Abstract 3128: Immune microenvironment of colorectal tumors and matched liver metastases
Authors: Vegar J. Dagenborg, Serena Elizabeth Marshall, Krzysztof Grzyb, Åsmund A. Fretland, Marius Lund-Iversen, Gunhild M. Mælandsmo, Anne-Lise Børresen-Dale, Anne H. Ree, Bjørn Edwin, Sheraz Yaqub, Kjersti Flatmark
Journal: Cancer Research (2018)

Abstract Introduction: The presence of tumor-infiltrating lymphocytes, in particular T-cells in the tumor and its microenvironment, has been shown to be associated with prognosis in primary colorectal cancer (CRC) and CRC liver metastases (CLM). In this study we examined T-cell composition in the immune microenvironment in surgical specimens from 64 cases with CRC and resectable CLM. Methods: Patients were enrolled in the Oslo-CoMet randomized trial (NCT 01516710). CRC and corresponding CLM were examined by immunohistochemistry to quantify all T-cells (Ttot) and subpopulations of cytotoxic (CTL), helper (TH), and regulatory T-cells (Treg). Densities of T-cells and subtypes (cells/mm2) were calculated at T-cell hotspots in the invasive margin (IM) and intra-tumoral (IT) locations. Median densities with interquartile ranges were calculated and compared for each region in CRC and CLM. Results (Table 1): The highest density of Ttot was observed in the IM for both primary CRC and CLM, with the density in CLM being two-fold higher than CRC (CLMIM median 2853 cells/mm2 vs CRCIM 1257 cells/mm2; p&amp;lt;0.001). For IT regions, the density of Ttot was much lower than in IM, and slightly higher in CRC compared to CLM (CRCIT median 486 vs CLMIT 332; p=0.02). Examining T-cell subtypes, the differences in CTL and TH mirrored Ttot, with the highest densities in the IM (CLMIM&amp;gt;CRCIM) and lower densities in IT regions (CLMIT&amp;lt;CRCIT). For the Treg, the IM densities were similar, while for IT, again, the density was lower in CLM than CRC. Conclusion: In this study, we analyzed the immune microenvironment in matched CRC and CLM surgical specimens. We are currently analyzing associations with long-term outcome and results will be presented at the conference. Table 1: Median T-cell density (interquartile range).CRCIMCLMIMCRCITCLMITTtot1257 (931 - 1735)2853 (2305 - 3813)486 (285 - 704)332 (189 - 564)CTL497 (315 - 722)1083 (762 - 1426)106 (51 - 209)99 (49 - 219)nsTH759 (584 - 983)1888 (1449 - 2745)348 (192 - 480)198 (118 - 383)Treg222 (155 - 375)233 (126 - 375)ns144 (75 - 225)43 (22 - 82)CRC and CLM densities at each location (IM and IT) were compared using the Mann-Whitney U test. P-values were &amp;lt;0.05 for all comparisons unless indicated by ns. Citation Format: Vegar J. Dagenborg, Serena Elizabeth Marshall, Krzysztof Grzyb, Åsmund A. Fretland, Marius Lund-Iversen, Gunhild M. Mælandsmo, Anne-Lise Børresen-Dale, Anne H. Ree, Bjørn Edwin, Sheraz Yaqub, Kjersti Flatmark. Immune microenvironment of colorectal tumors and matched liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3128.
Paediatric, adolescent, wild type, syndromic gastrointestinal stromal tumours (PAWS-GIST): Report from United Kingdom PAWS-GIST clinic.
Authors: Venkata Ramesh Bulusu, Ruth Casey, Olivier Giger, Eamonn Maher, Richard Hardwick, Nicholas Carroll, Michael Gordon Leahy, Robin Lewis Jones, Charlotte Benson, Palma Dileo, Ian Robert Judson
Journal: Journal of Clinical Oncology (2018)

e23519 Background: Paediatric, adolescent, wild type and syndromic Gastro Intestinal Stromal Tumours (PAWS-GIST) consortium was formed in UK as a joint effort between GIST specialists, patients and carers. The aim was to raise awareness,undertake research, understand the biology and develop new treatments. The clinic was established in Cambridge, UK in 2014 and is held 3 times a year. We present our 3 years experience. Methods: Patients with wild type GISTS were invited to register for the clinic on website (www.pawsgistclinic.org.uk). Patients were reviewed by a panel of experts- oncologists, surgeon, pathologist, endocrinologist and cancer geneticist. 8 patients were seen in each clinic. Molecular testing including succinate dehydrogenase (SDH)B immunohistochemistry, sequencing of SDH genes, SDHC promoter hypermethylation were performed. Patients and families were offered germline testing of the SDH genes after counseling. All patients and carers were actively encouraged to provide feedback on their experience. Results: N = 60. Male:female 20:40. Median age 38 years (range 14-76 years). Primary tumour location-67% were gastric and 33% small bowel. SDHB deficient GISTs (n-23) were gastric, with male:female ratio of 9:14. Germline testing preliminary results show SDHA subunit mutations being the most common followed by mutations in SDHB, C and D subunits and epimutations in SDHC. 10 GISTs were observed in patients with neurofibromatosis-1 (NF-1), mostly located in small bowel and often multifocal. 20 patients have been treated with tyrosine kinase inhibitors. No objective responses were seen with imatinib. Stabilization of disease was most commonly seen with regorafenib. Conclusions: PAWS-GIST clinic is the second clinic of its kind in the world after the National Institute of Health USA clinic in Bethesda. The emphasis during first three years was raising the awareness, data collection,gaining experience and developing a research platform. UK national GIST tumour bank has been established. The clinic has helped us to focus on the needs of the patients and carers and to collaborate with other teams for developing new therapies for this rare subgroup of GIST patients.
Use of 18F-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography and Sonication for Detection of Infection After Peripheral Stent Fracture
Authors: XavierBerard, Jean-BaptistePinaquy, LaurentStecken, HeidiWille, SebastienDeglise, EricDucasse, DominiqueMidy, LaurenceBordenave
Journal: Circulation (2014)
Remodeling of Cell-Cell and Cell–Extracellular Matrix Interactions at the Border Zone of Rat Myocardial Infarcts
Authors: TsutomuMatsushita, MasahitoOyamada, KazushiFujimoto, YukoYasuda, ShinsukeMasuda, YukioWada, TakahiroOka, TetsuroTakamatsu
Journal: Circulation Research (1999)

Abstract—At the border zone of myocardial infarcts, surviving cardiomyocytes achieve drastic remodeling of cell-cell and cell–extracellular matrix interactions. Spatiotemporal changes in these interactions are likely related to each other and possibly have significant impact on cardiac function. To elucidate the changes, we conducted experimental infarction in rats and performed 3-dimensional analysis of the localization of gap junctions (connexin43), desmosomes (desmoplakin), adherens junctions (cadherin), and integrins (β1-integrin) by immunoconfocal microscopy. After myocardial infarction, changes in the distribution of gap junctions, desmosomes, and adherens junctions showed a similar but nonidentical tendency. In the early phase, gap junctions almost disappeared at stumps (longitudinal edges of cardiomyocytes facing the infarct), and, although desmosomes and adherens junctions decreased, they still remained. In the healing phase, at stumps, connexin43, desmoplakin, and cadherin were closely associate...
Int6/eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances Wound Healing by Upregulating Hypoxia-Induced Factor 2α Expression
Authors: AlexanderEndler, KazuyoUchida, Shin-ichiroHoriguchi, YoshihitoMorizane, OsamuIijima, MasakazuToi, FutoshiShibasaki
Journal: Circulation (2010)

Background— We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2α (HIF2α) activity. Small interfering RNA (siRNA)–Int6 adequately stabilized HIF2α, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. Methods and Results— We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure ...
Abstract 17687: Comparison of Two-dimensional Echocardiography and Cardiac Magnetic Resonance for the Assessment of Left Ventricular Volume and Systolic Functions in Patients With Non-ischemic Cardiomyopathy: Impact of Myocardial Fibrosis
Authors: Teerapat Yingchoncharoen, Tomoko Negishi, Zoran B Popovic, Scott D Flamm, Deborah H Kwon
Journal: Circulation (2013)

Background: The accuracy of echocardiographic assessment of LV size and function is limited due to underlying geometric assumptions of LV shape. In patients with non-ischemic cardiomyopathy (NICM) ...
Abstract 17309: Selective Deletion of Brain-specific Renin Isoform Causes Hypertension and Elevated Sympathetic Nerve Activity
Authors: Keisuke Shinohara, Xuebo Liu, Donald A Morgan, Justin L Grobe, Kamal Rahmouni, Curt D Sigmund
Journal: Circulation (2016)

Introduction: The renin-angiotensin system (RAS) in the brain plays a critical role in regulating blood pressure and metabolism via sympathetic nerve activity. A dominant renin isoform in the brain...
Temporal variation of <i>Staphylococcus aureus</i> clonal complexes in atopic dermatitis: a follow‐up study
Authors: M.‐L. Clausen, S.M. Edslev, L.B. Nørreslet, J.A. Sørensen, P.S. Andersen, T. Agner
Journal: British Journal of Dermatology (2018)

A strong link between disease severity and Staphylococcus aureus colonization of the skin has been reported in patients with atopic dermatitis (AD).To examine temporal variations in S. aureus colonization and S. aureus CC type in patients with AD, and to investigate links to disease severity, skin barrier properties and filaggrin gene (FLG) mutations.This was a follow-up study of a cohort of 101 adult patients with AD recruited from an outpatient clinic. Bacterial swabs were taken at baseline and follow-up from lesional skin, nonlesional skin and the nose. Swabs positive for S. aureus were characterized by spa and the respective clonal complex (CC) type was assigned. Patients were characterized with respect to disease severity [Scoring Atopic Dermatitis (SCORAD)], skin barrier properties [transepidermal water loss (TEWL), pH] and FLG mutations.In total, 63 patients participated in a follow-up visit. Twenty-seven patients (43%) were colonized at both visits, 27 were colonized at only one visit and nine (14%) were not colonized at either visit. Of patients colonized at both visits, 52% remained colonized with the same CC type at follow-up. Change in CC type was related to an increase in SCORAD of 10·7 points; patients who carried the same CC type had a reduction in SCORAD of 4·4 points. Significantly higher skin pH was found in patients colonized at both visits, while change in CC type was not related to TEWL, pH or FLG mutations.The data indicate that temporal variation in S. aureus CC type is linked to flares of the disease.