tbuckley/cabot-search huggingface dataset:
Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity
Authors: Joshua Mayourian, Timothy J. Cashman, Delaine K. Ceholski, Bryce V. Johnson, David Sachs, Deepak A. Kaji, Susmita Sahoo, Joshua M. Hare, Roger J. Hajjar, Eric A. Sobie, Kevin D. Costa
Journal: Circulation Research (2017)

Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved.The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches.Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ≈4-fold compared with non-hMSC-supplemented controls during physiological 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential proarrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium-handling genes (eg, SERCA2a, L-type calcium channel).Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.
A pharmacokinetics (PK) bioequivalence trial of proposed trastuzumab biosimilar, Myl-1401O (A) vs EU-Herceptin (B) and US-Herceptin (C).
Authors: Cornelius F. Waller, Apinya Vutikullird, Tracey E. Lawrence, Andrew Shaw, Mark Shiyao Liu, Mark Baczkowski, Rajiv Sharma, Abhijit Barve, Eduardo J. Pennella
Journal: Journal of Clinical Oncology (2016)

583 Background: Myl-1401O is a proposed trastuzumab biosimilar. The biosimilarity of Myl-1401O to EU-Herceptin has been demonstrated in physicochemical analyses, nonclinical studies, and one previous PK study. Methods: This single-center, randomized, double-blind, three-arm, parallel-group, Phase I study was conducted in healthy adult male volunteers. The primary objective of this study was to establish PK similarity of A to B and C. The subjects were randomized to receive either A, B or C as 8 mg/kg over 90 minutes as an intravenous infusion. For the primary endpoint, the bioequivalence criterion was that the 90% confidence intervals (CI) of the mean ratios of AUC0-∞ , AUC0-last , and Cmax were bounded within 80.00% - 125.00% calculated using natural log-transformed data. As secondary endpoints, λz, tmax and t1/2 along with assessment of safety (including immunogenicity) was performed. Results: A total of 132 subjects (44/treatment) were enrolled and 120 [42 (A), 41(B), 37(C)] subjects were included in analysis. Statistical analyses reveal that the 90% CI fall within 80%-125% for all parameters. Eighty-three [31 (A), 28 (B), 24(C)] subjects experienced a total of 227 [91(A), 80 (B), 56(C)] treatment-emergent adverse events that were mild to moderate in severity. No serious adverse events were reported and there were no instances of treatment related anti-drug antibodies. Conclusions: These results confirm pharmacokinetic bioequivalence for Myl-1401O vs. EU-Herceptin and US-Herceptin. All treatments were well tolerated and no significant safety issues emerged. Clinical trial information: NCT02594761.PK results (dose-normalized) AUC0-last (mcg•hr/mL) AUC0-∞ (mcg•hr/mL) Cmax (mcg/mL) Arithmetic Mean (%CV) A N = 42 48055 (15.92) 48241 (16.19) 200.4 (12.34) B N = 41 49823 (19.61) 50075 (19.81) 192.6 (14.13) C N = 37 49826 (13.98) 50181 (13.86) 197.9 (16.25) LSMEANS Ratio* (90% CI)** A/B 0.97 (91.31% – 103.05%) 0.97 (91.17% – 102.97%) 1.04 (99.00% – 109.82%) A/C 0.96 (90.34% – 102.29%) 0.96 (89.96% – 101.94%) 1.02 (96.42% – 107.26%) * Ratio (A/B) = e [LSMEANS of (LNA – LNB)]; Ratio (A/C) = e [LSMEANS of (LNA – LNC)]; **Used Natural Log Transformed Parameter
Ten year experience of an integrated cancer prevention center screening for multiple cancer types.
Authors: Ido Wolf, Ari Leshno, Eliezer Liberman, Eyal Gur, Hanoch Elran, Miri Sror, Amira Harlap-Gat, Maayan Jean, Moran Steiner, Lior Galazan, Galit Av, Arye Blachar, Ada Kessler, Orit Golan, Shiran Shapira, Ravit Geva, Nadir Arber
Journal: Journal of Clinical Oncology (2017)

1549 Background: Cancer is the leading cause of mortality worldwide. Prevention and early detection are pivotal tools for reducing cancer burden. Methods: We describe the 10 year experience (2006-2016) of an integrated cancer prevention center that provides screening for prevention and early detection of 11 most common cancer types. Healthy individuals (20-80 yr) were included. Extensive clinical and epidemiological data was obtained. DNA was extracted from all participants and genotyped for APC I1307K and E1317Q. Patients were examined by specialists in internal medicine, surgery, plastic surgery, OBGYN, urology, oncology, oral surgery, gastroenterology, and others. Women underwent vaginal US and pap smear and (40yr) mammography and US/MRI with a clinical indication. PSA and free PSA for Men ( &gt; 40yr). LDCT for heavy smokers. Colonoscopy was recommended to all subjects ( &gt; 40yr). Results: A total of 6258 (49%) men and 6461 (51%) women mean age 47.0±11.5 year were screened. New malignant lesions were detected in 389 (1.75%) of screeners. The most common cancers were of skin (74, 0.6%), prostate (62, 0.5%), thyroid (51, 0.4%), breast (36, 0.3%), colorectal (22, 0.2%), ovarian (19, 0.1%), uterus (14, 0.1%), testis (12, 0.09%) urinary (9, 0.07%) and lung (10, 0.08%). In 28 patients (0.22%) more than one cancer was detected. Twenty eight of the cancer patients (7.2%) died after 32.4±28.1 months at a mean age of 69.4±14.2 years. Significantly, better than the expected cancer mortality. The APC I1307K and E1317Q variants were detected in 572 (4.8%) and 182 (1.5%) subjects respectively. First degree family member with cancer (OR = 2.02), I1307K carrier ship (OR = 1.53), female gender (OR = 1.23) and advanced age (OR = 1.06) were all associated with statistically significant (P &lt; 0.05) increased cancer risk. Advanced age and first degree family history were also associated with detection of more than one cancer types. Conclusions: One stop shop screening, in the setting of a multidisciplinary outpatient clinic, is feasible and can prevent and detect cancer at an early stage. It significantly improve morbidity and mortality. Impressively the APC I1307K carries an overall increase cancer risk.
Sédation par propofol sous la responsabilité du gastro-entérologue pendant la coloscopie: résultats d'une étude prospective, randomisée et contrôlée
Authors: A Laquière, L Poincloux, F Monzy, F Artigues, C Bonny, JE Bazin, M Dapoigny, G Bommelaer
Journal: Endoscopy (2006)

L'utilisation du propofol par le gastro-entérologue dans la sédation pour la coloscopie, a fait l'objet ces dernières années de nombreuses études montrant l'efficacité et la sûreté de cette technique. Cependant cette sédation n'a jamais été comparée à l'anesthésie générale réalisée par les anesthésistes. L'objectif de cette étude était de comparer la satisfaction et la sécurité des patients durant la sédation contrôlée par les endoscopistes à celles d'une anesthésie conduites par les anesthésistes.
Patient Reported Outcomes to Assess Quality of Hemophilia Care in North India - Results of a Global Partnership
Authors: Akshat Jain, Sudhir Mehta, Mrinal Joshi, Kapil Garg, Laxmi Kant Goyal, Aric Parnes, Hasan Al-Sayegh, Clement Ma, Ellis J. Neufeld
Journal: Blood (2016)
Breast cancer in Morocco: Results from the first prospective database.
Authors: Hassan Errihani, Fouzia Mamouch, Amine Souadka, Hind Mrabti, Othman Akkar, Hamza Ettahri, Saber Boutayeb, Brahim el Ghissassi, Narjiss Berrada
Journal: Journal of Clinical Oncology (2016)

e13097 Background: Breast cancer is the most common female cancer in Midlle east and north africa. Approximatly 5000 new patients are diagnosed per years in Morocco. No prospective database are availible. The aim of our study is to determine the demographic, clinicopathological and therapeutic features of breast cancer in Morocco. Methods: This is the first prospective database of breast cancer in collected at the National institute of oncology of Rabat in Morocco, between January 2014 and December 2014. Epidemiological, clinical, histological and therapeutic data were analyzed Results: A total of 1183 patients had suspected breast malignancy, 1129 signed consent the consent. The median age was 58 years. 53.6 % were analphabets, 67.8 % had no profession. 54.86% were married. 67.5% urban. 53% are premenopausal. 52 % take contraceptifs. 3.2 % of postmenopausal patients take substitif hormonal. 20.3 % had familal history of cancer. 74.3% of the suspected mass were discovered by self examination. 21.3% had ACR IV lesion, 30% ACR V. breast cancer charcteristics (subgroups, stages and treatment) are being updated for the meeting Conclusions: Our final results will reflet the chacateristics of breast cancer in Morocco and north africa
Regulation of brain insulin signaling: A new function for tau
Authors: Maud Gratuze, Emmanuel Planel
Journal: The Journal of Experimental Medicine (2017)

In this issue of JEM, Marciniak et al. (https://doi.org/10.1084/jem.20161731) identify a putative novel function of tau protein as a regulator of insulin signaling in the brain. They find that tau deletion impairs hippocampal response to insulin through IRS-1 and PTEN dysregulation and suggest that, in Alzheimer’s disease, impairment of brain insulin signaling might occur via tau loss of function.
Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma
Authors: Hiromichi Mitsuyasu, Kenji Izuhara, Xiao-Quan Mao, Pei-Song Gao, Yojiro Arinobu, Tadao Enomoto, Mitsuru Kawai, Sei Sasaki, Yasuhiro Dake, Naotaka Hamasaki, Taro Shirakawa, Julian M. Hopkin
Journal: Nature Genetics (1998)
L'échoendoscopie (EE) est elle suffisante pour éliminer les tumeurs kystiques du pancréas à potentiel malin? Suivi de 163 patients asymptomatiques
Authors: B Napoléon, R Gincoul, I Modolell, B Pujol, C Lefort, JY Scoazec, JC Souquet, JA Chayvialle
Journal: Endoscopy (2005)

Si la chirurgie reste le traitement de référence des tumeurs kystiques à potentiel malin (TKM), une surveillance peut être proposée pour les tumeurs kystiques à potentiel bénin (TKB) comme les cystadénomes séreux (CS) ou les kystes congénitaux (CC). Cependant, le diagnostic de TKB reste difficile à affirmer. En 1991, nous avions défini les critères en EE permettant de conclure à une TKB. Nous présentons maintenant la plus grande série de surveillance de patients sélectionnés selon ces critères afin de confirmer leur efficacité pour le diagnostic des TKB.
Endoscopic gastroplication for proton pump inhibitor-refractory gastro-oesophageal reflux disease
Authors: PM Lynch, T Tham
Journal: Endoscopy (2005)

Background: Endoscopic gastroplication (EG) offers a new treatment option to patients with gastro-oesophageal reflux disease (GORD). The benefit of EG in those with symptomatic GORD despite proton pump inhibitor (PPI) therapy is unknown and so our study aim was to evaluate the effectiveness of EG in such patients.
Identification of genetic test results with conflicting interpretations in prospective registry of multiplex testing (PROMPT).
Authors: Judith Balmaña, Laura Digiovanni, Pragna Gaddam, Michael Francis Walsh, Judy Ellen Garber, Fergus J. Couch, Kenneth Offit, Mark E. Robson, Susan M. Domchek
Journal: Journal of Clinical Oncology (2016)

1510 Background: Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. The ACMG and AMP outlined guidelines for variant classification; however, the weight laboratories and providers attribute significance to the variables may differ and lead to conflicting interpretations and reporting, and lately to inappropriate medical management. We describe conflicting interpretations between commercial laboratories for variants reported to PROMPT, an online genetics registry for patients who completed multiplex panel testing for cancer susceptibility. Methods: 1196 individuals tested clinically for mutations in cancer susceptibility genes self-enrolled in PROMPT 9/2014-9/2015 and submitted clinical data and genetic results. We report on 518 participants with a result (603 genetic findings) interpreted by more than one laboratory and submitted in ClinVar Results: Of the 603 variants, 221 (37%) were classified as VUS, 191 (32%) as pathogenic, 34 (5%) as benign, and 157 (26%) as conflicting interpretation. The genes with more frequent discordant interpretation findings were CHEK2 (N = 41, 10 variants) and ATM (N = 32, 12 variants), followed by RAD51C, PALB2, BARD1, NBN, BRIP1, among others. The variants p.Ile157Thr (n = 18) and p.Ser428Phe (n = 12) in CHEK2 were in this category, as well as p.Gln60Argfs and p.Trp1038Ter in PALB2, and the p.Pro47Ala in BRIP1. Among all participants, 58 of 518 (11%) had variants with conflicting interpretations that might alter medical management as the interpretations ranged from pathogenic/likely pathogenic to VUS. Conclusions: A quarter of the findings reported in the PROMPT registry and identified by multiplex panel testing have a conflicting interpretation of clinical pathogenicity. Collaborative efforts are needed to identify the reasons for discrepancies in variant classification and for homogenization of their interpretation. Conflicting classification type (N = 157) N (%) Pathogenic/likely pathogenic vs. VUS 52 (33%) Pathogenic/likely pathogenic vs. VUS vs. benign/likely benign 6 (4%) VUS vs. benign/likely benign 99 (63%)
Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors
Authors: Anthony W. Tolcher, Mario Sznol, Siwen Hu-Lieskovan, Kyriakos P. Papadopoulos, Amita Patnaik, Drew W. Rasco, Donna Di Gravio, Bo Huang, Dhiraj Gambhire, Ying Chen, Aron D. Thall, Nuzhat Pathan, Emmett V. Schmidt, Laura Q.M. Chow
Journal: Clinical Cancer Research (2017)

Abstract Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors. Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method. Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders. Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR. See related commentary by Pérez-Ruiz et al., p. 5326
High prevalence of toxin a-negative, toxin b-positive clostridium difficile in Dublin, Ireland
Authors: D Drudy, N Harnedy, S Fanning, R O'Mahony, A Baird, L Kyne
Journal: Endoscopy (2006)

Clostridium difficile is a major cause of infectious diarrhoea in hospitalised patients. Most pathogenic C. difficile strains produce two toxins A and B, however clinically relevant toxin-A-negative-toxin-B-positive (A-B+) strains of C. difficile that cause diarrhoea and colitis have been isolated worldwide. The geographical distribution and significance of these strains in Irish hospitals is unknown. The aim of this study was to determine the prevalence of A-B+ strains in 12 health-care facilities in Dublin, Ireland. Following culture, 123 C. difficile isolates were examined using toxin immunoassays, cytotoxicity assays and PCR. 52 isolates were not detected with the toxin-A ELISA and demonstrated variant cytopathic effects with the cytotoxicty assay. PCR-RFLP revealed that these 52 strains had a 1.8-kb deletion in the tcdA gene and restriction enzyme analysis revealed the loss of polymorphic restriction sites. These 52 A-B+ isolates were designated toxinotype VIII (C. difficile strain-1470). The overall prevalence of A-B+ isolates was 42%, with institutional prevalence rates varying from 0–61%. The prevalence of A-B+ C. difficile in Dublin, Ireland is higher compared with reported prevalence in other countries. This report expands our understanding of this pathogen, identifying a geographical cluster of toxin-variant C. difficile strains in a major Irish population centre.
Effect of silencing thymosin beta 4 gene expression on stemness and invasiveness in glioblastoma.
Authors: Ghazaleh Tabatabai, Shanmugarajan Krishnan, Ana-Maria Florea, Karl Frei, Kathy Hasenbach, Guido Reifenberger, Niklaus Krayenbuehl, Michael Weller, Hans-Georg Wirsching
Journal: Journal of Clinical Oncology (2013)

2081 Background: Thymosin β4 (TB4) is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. TB4 gene silencing promotes differentiation of neural progenitor cells whereas TB4 overexpression initiates cortical folding of developing brain hemispheres. However, a role of TB4 in malignant gliomas has not yet been investigated. Methods: We first analyzed TB4 expression on tissue microarrays and performed REMBRANDT and TCGA database interrogations. We analyzed TB4 expression in a panel of 8 long-term glioma cell lines and 7 glioma-initiating cell lines. Using lentiviral transduction, we modulated TB4 expression in LNT-229, U87MG and the glioma-initiating cell line GS-2. We studied clonogenic survival, migration, invasion, self-renewal, differentiation capacity of TB4-depleted or TB4-overexpressing glioma cells in vitro and tumorigenicity upon orthotopic implantation in vivo. Finally, we performed an Affymetrix gene chip analysis to unravel the molecular network of TB4 signaling effects. Results: TB4 expression increased with the grade of malignancy in gliomas and correlated with patient survival. In vitro, TB4 gene silencing by lentiviral transduction decreased migration, invasion, growth and self-renewal, and promoted differentiation and the susceptibility to undergo apoptotic cell death upon nutrient depletion in LNT-229, U87MG and the glioma stem-cell line GS2, respectively. In vivo, survival of nude mice bearing tumors derived from TB4-depleted glioma cells was improved and the tumorigenicity of the GS2 glioma stem-cell line was decreased. The gene expression pattern was shifted from the mesenchymal towards the pro-neural gene signature upon TB4 gene silencing. The clustering of differentially regulated genes involved TGF-β and p53 signaling networks. Conclusions: TB4 may be a key regulator of malignancy in glioblastoma and therefore a novel candidate molecular target for anti-glioma therapies.
Efficacy and safety of the combination of pertuzumab (P) plus trastuzumab (T) plus docetaxel (D) for HER-2 positive metastatic breast cancer (MBC) in pretreated patients (pts) with trastuzumab in the neo/adjuvant setting: A real-life study.
Authors: Giuseppina Ricciardi, Corrado Ficorella, Laura Iezzi, Paolo Marchetti, Laura Pizzuti, Angela Prestifilippo, Silvia Schifano, Sergio Maimone, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2017)

e12516 Background: The discovery of new anti-HER2 targeted therapies has significantly improved the outcomes in the metastatic setting. However, the population enrolled in clinical trials is not always representative of the clinical practice. Moreover, only 7% of breast cancers (BCs) present as metastatic disease at the first clinical observation. In most cases, metastatic disease is diagnosed in pts with a history of BC already treated in the neo/adjuvant setting. This latter subgroup is largely under-represented in clinical trials. The aim of this study was to assess in real-life the efficacy and safety of dual HER2 blockade as 1 st line in Trastuzumab-pretreated pts in the neo/adjuvant setting. Methods: This is a multicenter, observational, retrospective study conducted in 6 Oncology Italian Centers. Primary end-points: progression free survival (PFS) and overall survival (OS). Secondary end-points: response rate and cardiac safety. PFS and OS curves were estimated using the Kaplan-Meier method. Tumor response was assessed according to RECIST 1.1 and safety with CTCAE v4.0. Results: We evaluated 35 HER2-positive MBC from November 2013 to December 2016, 60% with tumors Luminal B, 40% HER2-enriched. The most common metastatic sites were: lung (20%), lymph nodes (14.3%) and liver (11.4%). Median (m) age: 50 (range 20-71), mECOG PS 0 (range 0-1). At a m follow-up of 55.6 months (mos) (range 6-170), all pts were evaluable for efficacy and safety. The m number of cycles administrated was 6 (range 2-10). The mPFS was 12 mos (95% CI 2-38). The mOS was 15.2 mos (95% CI 2-36). 14.3% of pts had a complete response, 60% a partial response and 25.7% a stable disease. m baseline LVEF was 65%, final LVEF 61%. Conclusions: Our preliminary data confirmed the efficacy and no increase in cardiac toxicity of the combination Pertuzumab, Trastuzumab and Docetaxel in Trastuzumab-pretreated pts, mirroring the PFS data but not the OS reported in the Cleopatra study. A longer follow-up for OS is needed for a comprehensive evaluation of the antitumor activity of dual-HER2 blockade in Trastuzumab-pretreated pts.
Finances, targets, and workforce are on NHS agenda for next parliament, hears meeting
Authors: Z. Kmietowicz
Journal: BMJ (2015)

Tackling the black hole in the NHS’s finances, relaxing targets, and building an NHS workforce to meet the needs of the population are likely to feature strongly in discussions concerning the NHS in the next few years, participants at a debate on the priorities in the coming parliament have heard.

However, a major NHS reorganisation is unlikely, and competition in the NHS seems to be taking a backseat, heard doctors, commissioners, policy makers, and managers at the debate organised by the health think tank the King’s Fund on Thursday 21 May.

That Jeremy Hunt has been reappointed as health secretary for England will provide continuity for the NHS, said Saffron Cordery, director of policy and strategy at NHS Providers, the membership organisation for public providers of NHS services. And with the prospect of no major legislative changes for the NHS in the Queen’s speech …