tbuckley/cabot-search huggingface dataset:
Abstract 14727: Late Sodium Current Plays a Role in Ventricular Arrhythmias Associated With Increased Intracellular Calcium Concentration
Authors: Xiaohong Wei, Yong Huo, Sihui Huang, Qiaomei Yang, Lu Ren, Lin Wu
Journal: Circulation (2014)

Objective: An increase in intracellular calcium concentration is associated with the prolongation of action potential duration (APD) and polymorphic ventricular tachycardia (PVT). Recent studies indicated that late sodium current inhibitor is effective in preventing ventricular arrhythmias in patients with long QT syndrome 8. The objective of the study was to determine the role of late sodium current in calcium related ventricular arrhythmias. Methods: Hearts from New Zealand female rabbits were perfused in a Langendorff mode. The atrioventricular nodal area was thermally ablated to produce complete atrioventricular block, and then heart was paced at stated frequency. Multiple channel monophasic action potentials (MAP) and pseudo 12-lead electrocardiograms (ECGs) were recorded. Calcium transient and myocyte contraction were determined in rabbit ventricular myocytes. Results: Bay-K 8644 (10-300 nM) increased both epi- and endo- cardial MAPD90 of left ventricle in concentration dependent manners, from (176±6) to (222±13) ms, and (201±6) to (246±10) ms (n=15, p&lt;0.05 vs control), respectively. In the presence of 1 nM ATX-II, Bay-K 8644 caused a greater prolongation of epi-MAPD90 which was increased from (182±6) to (342±21) ms (n=9, p&lt;0.05 vs control). The prolongation of MAPD90 caused by Bay-K 8644 were reversed by 1 μM TTX in both absence and presence of ATX-II. Additionally, the incidence of PVT evoked by Bay-K 8644 was also greater in the presence compared to the absence of ATX-II. 200 nM Bay-K 8644 caused few arrhythmias in absence of ATX-II. In contrast, PVT occurred in 7/9 (77.78%) of hearts treated with 200 nM Bay-K 8644 in the presence of ATX-II. These arrhythmias could be abolished by 1 μM TTX in the continued presence of Bay-K 8644. TTX (1 μM) attenuated the increase by 200 nM Bay-K 8644 of intracellular calcium transient and myocyte contraction amplitude by 10.8% and 14.6%, respectively (n=6, p&lt;0.05). Conclusion: Both endogenous and enhanced late sodium current contributes to the ventricular arrhythmias with increased intracellular calcium concentration. Inhibition of late sodium current may be effective in preventing or treating calcium overload-related ventricular arrhythmias and dysfunction of myocardial contraction.
Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation
Authors: Rosanna Asselta, Stefano Duga, Tatjana Simonic, Massimo Malcovati, Elena Santagostino, Paul L. F. Giangrande, Pier Mannuccio Mannucci, Maria Luisa Tenchini
Journal: Blood (2000)
548. Cyclophilin A as a Cellular Target for Gene Therapy of HIV-1
Authors: Harris S. Soifer, Reena Vishwanath, James Kim, Bret Heale, Lisa J. Scherer, John J. Rossi
Journal: Molecular Therapy (2004)

Cyclophilin A (CYPA), one of several ubiquitously distributed intracellular proteins that possess peptidyl-proloyl cis-trans isomerase activity, is specifically incorporated into newly formed HIV-1 virions through interactions with the Gag polyprotein. When the Gag-CYPA interaction is disrupted, either by pharmacological or genetic manipulation, HIV-1 replication is inhibited. Moreover, virions produced from genetically modified CYPA-/- cells are less infectious, making CYPA a unique cellular target for HIV-1 therapy. We used RNA interference (RNAi) to knockdown expression of endogenous CYPA and determined the effect on HIV-1 infectivity. As a first step towards designing an effective RNAi strategy, we probed the accessibility of the 753-nt CYPA mRNA using an oligonucleotide scanning technique. One of three 21-mer oligonucleotides, predicted to be accessible using free-energy based folding algorithm, promoted endogenous RNase H-mediated cleavage. A short hairpin RNA (shRNA) was derived from this sequence and cloned into a plasmid under a U6+1 promoter. Upon transient transfection of HEK-293 cells, CYPA gene expression was reduced more than 80% (>80%), as measured by quantitative real-time RT-PCR. Depleting HEK-293 cells of endogenous CYPA did not produce observable toxic effects, consistent with previous work that CYPA is not essential for the viability of human cells. We performed cotransfection experiments with the HIV-1 proviral clone pNL4-3, and measured both infectious virion output and infectivity in the presence or absence of CYPA shRNA expression. Virions produced in the presence of CYPA shRNA were equally infectious as virions produced in the absence of CYPA shRNA as determined by the MAGI assay. In contrast, the number of infectious virions produced in the presence of a control shRNA targeting the HIV rev transcript was reduced three orders of magnitude compared to the negative control. The failure of the CYPA shRNA to inhibit HIV replication and infectivity suggests that ample CYPA is already present in the cell to support efficient viral replication. To address this issue we are constructing a lentiviral vector to express the shRNA, allowing depletion of CYPA prior to HIV-1 challenge. The results of these latter experiments will also be presented.
Abstract 11307: Association of Acute Heart Failure Length of Stay With Subsequent Re-Hospitalization and All-Cause Mortality Among Patients With Preserved vs. Reduced Ejection Fraction
Authors: Gregory A Nichols, Kristi Reynolds, Melissa G Butler, Teresa M Kimes, Wing W Chan
Journal: Circulation (2014)

Introduction:  Length of stay (LOS) during acute heart failure (AHF) hospitalizations is associated with the risk of re-hospitalization and mortality.   Hypothesis:  We explored whether the association of LOS, re-hospitalizations, and all-cause mortality (ACM) differed between patients with preserved (HF p EF) vs. reduced ejection fraction (HF r EF).   Methods:  We identified members of Kaiser Permanente in the Northwest and Southern California regions who had an ejection fraction (EF) measured during an index AHF hospitalization and were discharged alive in 2008-2011 (n=6,524). After excluding 677 patients with borderline EF values (41-49%), we assessed the risk of re-hospitalization and mortality within 30 days and 1 year comparing patients with HF p EF (EF ≤50%) vs. HF r EF (EF    Results:  Patients were 53% male with mean age 74±13 years; 16% were African-American, 20% Hispanic and 57% White. Mean LOS of the index hospitalization was 3.9±3.7 days among HF p EF patients (62% of the sample) and 4.0±3.5 among HF r EF patients (38%). Re-hospitalization and ACM rates within 30 days and 1 year were similar between the two groups. Among both groups, each day of the index hospitalization was associated with an adjusted 3-4% risk of re-hospitalization within 30 days and a 2-3% risk within 1 year. Among HF p EF patients, each day of the index hospitalization was associated with a 7% risk of mortality within 30 days (1.07, 95% CI 1.04-1.09) and a 4% risk within 1 year (1.04, 1.03-1.05). In contrast, each day of the index hospitalization was associated with a 12% risk of mortality within 30 days (1.12, 95% CI 1.08-1.15) and an 8% risk within 1 year (1.08, 1.06-1.10) among HF r EF patients.   Conclusions:  In this large diverse sample of patients hospitalized for AHF, longer LOS during the index hospitalization was significantly and similarly associated with an increased risk of re-hospitalization within 30 days and 1 year among HF p EF and HF r EF patients. However, each day of the index hospitalization conferred nearly twice the risk of mortality within 30 days and 1 year among HF r EF vs. HF p EF patients.
The effectiveness of child and adolescent psychiatric treatments in a naturalistic outpatient setting
Authors: MAREILE BACHMANN, CHRISTIAN J. BACHMANN, KATJA JOHN, MONIKA HEINZEL-GUTENBRUNNER, HELMUT REMSCHMIDT, FRITZ MATTEJAT
Journal: World Psychiatry (2010)

Data concerning the effectiveness of naturalistic treatments (treatment-as-usual) in child and adolescent psychiatric (CAP) services are scarce. The purpose of this prospective observational study was to examine the effectiveness of CAP treatments in a naturalistic outpatient setting. Three hundred six patients (attention-deficit/hyperactivity disorder, ADHD, n=94; conduct disorder, CD, n=57; anxiety disorder, AD, n=53; depressive disorder, DD, n=38; other diagnostic categories, n=64), from nine child and adolescent psychiatric practices in Germany, were evaluated. Treatment effects were compared between patients who received frequent treatment and patients who only participated in diagnostics and short interventions. Since randomization was not feasible, propensity score analysis methods were used. Regarding the total sample, no significant treatment effects were found. However, a subgroup analysis of the four most frequent disorders (ADHD, CD, AD, DD) showed small to moderate treatment effects in patients with ADHD and AD. In CD and DD subgroups, no significant treatment effects could be found. "Real-world" CAP outpatient treatment seems to produce significant effects for ADHD and AD, but not for CD and DD. Compared to efficacy studies, our results show that naturalistic treatment might be better than expected.
Prognostic Value of Midregional Pro-Adrenomedullin in Patients With Acute Myocardial Infarction
Authors: Sohail Q. Khan, Russell J. O’Brien, Joachim Struck, Paulene Quinn, Nils Morgenthaler, Iain Squire, Joan Davies, Andreas Bergmann, Leong L. Ng
Journal: Journal of the American College of Cardiology (2007)
Identification of the testis-specific protein 10 (TSGA10) as serologically defined tumour-associated antigen in primary cutaneous T-cell lymphoma
Authors: S.M. Theinert, M.M. Pronest, K. Peris, W. Sterry, P. Walden
Journal: British Journal of Dermatology (2005)

Background The number of identified tumour‐associated antigens for cutaneous lymphoma is still very restricted, which limits the elucidation of the tumour immunology of these malignancies and the development of specific immunotherapies and immunodiagnostics. Objectives To identify new serologically defined antigens associated with cutaneous lymphoma. Methods A phage expression library of the human testis transcriptom was established and immunoscreened with sera from 100 patients with cutaneous lymphoma and nine with parapsoriasis, and 81 age‐matched control donors. Positive expression clones were sequenced to identify the respective antigen. Results The testis‐specific protein 10 (TSGA10) was identified as an antigen recognized by sera of two patients with Mycosis fungoides but not by sera from healthy donors. By reverse transcription–polymerase chain reaction analysis, TSGA10 was found expressed in all cutaneous lymphoma samples tested, various tumour cell lines, testis, peripheral blood mononuclear cells, skin, isolated lymphocytes, keratinocytes and fibroblasts. TSGA10 overexpression had previously been reported for other cancers. Conclusions TSGA10 is a new tumour‐associated antigen of cutaneous lymphoma.
Principles of Forensic Medicine
Authors: Stephen P Robinson
Journal: BMJ (1843)

Introduction 1. Clinical records 2. Consent 3. Disclosure and confidentiality 4. Statement, report writing and witness statements 5. Fitness to be detained 6. Fitness to be interviewed 7. Examination in cases of assault 8. Examination of victim of alleged sexual assault 9. Examination of suspect in sexual assault 10. The scene of death 11. Mental health 12. Road traffic offences 13. Appendices.
Abstract IA13: Acinar cell transdifferentiation sets the stage for early tumor heterogeneity
Authors: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford
Journal: Cancer Research (2015)

Abstract Prior to PanIN formation, acinar cells harboring oncogenic Kras gradually lose their acinar character and take on a ductal phenotype in a process known as acinar-to-ductal metaplasia. Rather than mimicking a normal pancreatic duct, metaplastic ducts take on a proliferative biliary progenitor phenotype, marked by the expression of SOX17 and PDX1 and the presence of numerous tuft cells, recently identified as a PanIN initiating cells. Manipulation of SOX17 and PDX1 in vivo reveal them to be a transdifferentiation promoter and suppressor, respectively, both greatly affecting tuft cell genesis and tumor formation. These opposing roles of developmental transcription factors during tumorigenesis implicate the usurpation of a differentiation program that significantly contributes to cellular heterogeneity within early pre-cancerous lesions of the pancreas. Citation Format: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford. Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA13.
Abstract 3280: Differential Effects of Cholesterol Absorption Inhibition by Plant Sterol and Plant Stanol Esters on Expression of Monocytes, Lymphocytes, Endothelial Function, Atherogenesis and CNS Sterol Concentrations
Authors: Oliver Weingartner, Christof Ulrich, Kenan Ismail, Dieter Lutjohann, Michael Bohm, Ulrich Laufs
Journal: Circulation (2008)

Plant sterol (PSE) and plant stanol esters (PSA) are used as food supplements to reduce serum cholesterol levels. We assessed the hypothesis that PSE and PSA differentially affect blood monocytes, lymphocytes, endothelial function, atherogenesis and central nervous system (CNS) sterol concentrations. Male apoE −/− mice (n=30) were randomized to 3 different diets for 6 weeks (n=10 per group): high cholesterol (1.25%) western-type diet (WTD), WTD+2% PSE, WTD+2% PSA. Both dietary supplements reduced serum cholesterol significantly. WTD+PSE resulted in increased plant sterol serum concentrations and increased expression of pro-atherogenic monocytes (CD11b+Ly-6C), WTD+PSA increased plant stanol serum concentrations and expression of CD11b+Ly-6C lymphocytes. Despite of a significant reduction of serum cholesterol concentrations both dietary interventions resulted in endothelial dysfunction compared to WTD alone (p<0.05). Animals on WTD exhibited most pronounced atherosclerotic lesion development. WTD+PSA result...
Abstract 2562: Evaluate in vivo efficacy of anti-tumor immuno-therapeutics using MixenoTM mouse models
Authors: Juan Zhang, Junzhuan Qiu, Ziyong Sun, Xin Dong, Zha Jiping, Qian Shi
Journal: Cancer Research (2014)

Abstract The past few years have witnessed a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances associated with the development of immunomodulatory agents, e.g. monoclonal antibodies targeting the immune inhibitory pathways (CTLA-4 and PD-1/PD-L1). Often, the preclinical efficacy assessments are based on the evaluation of surrogate anti-mouse target antibodies using mouse syngenic tumor models, because of the need for T cell activation in an immune competent system. However, this strategy is limited due to the fact that the immune systems in human and mouse are different, and a surrogate molecule needs to be tested in those syngenic models. Here we set out to validate mouse models that harbor human immune cells by pre-engrafting the immuno-deficient mice with human PBMC (the MixenoTM model), and use them for efficacy evaluation of the humanized anti-PD-1 antibody. PD-L1 high-expression human tumor cell lines are selected for these in vivo models. T cell activation, infiltration and the cytokine production were analyzed to illustrate the immune cell involvement. In conclusion, the MixenoTM models are useful tools in immunotherapeutic antibody development, and may greatly increase the clinical translatability of animal studies. Citation Format: Juan Zhang, Junzhuan Qiu, Ziyong Sun, Xin Dong, Zha Jiping, Qian Shi. Evaluate in vivo efficacy of anti-tumor immuno-therapeutics using MixenoTM mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2562. doi:10.1158/1538-7445.AM2014-2562
PEPCOL: A randomized noncomparative phase II study of PEP02 (MM-398) or irinotecan in combination with leucovorin and 5-fluorouracil as second-line therapy in patients with unresectable metastatic colorectal cancer—A GERCOR Study.
Authors: Benoist Chibaudel, Frederique Maindrault-Goebel, Thierry André, Jean Baptiste Bachet, Christophe Louvet, Ahmed Khalil, Olivier Jean Marie Dupuis, Pascal Hammel, Marie Line Garcia, Mostefa Bennamoun, David Brusquant, Claire Arbaud, Yi-Wen Wang, Grace Yeh, Franck Bonnetain, Aimery De Gramont
Journal: Journal of Clinical Oncology (2015)

751 Background: PEP02 is a highly stable nanoliposomal irinotecan. This randomized non-comparative phase II (PEPCOL) study evaluated the efficacy and safety of PEP02 (MM-398) or irinotecan in combination with LV/5-FU in the second-line treatment of metastatic colorectal cancer (mCRC). (EudraCT 2010-020468-39A, NCT01375816). Methods: Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomly assigned to FUPEP (PEP02 80 mg/m² d1, folinic acid (FA) 400 mg/m² d1, 5-FU 2,400 mg/m² d1-2) or FOLFIRI (FOLFIRI1: irinotecan 180 mg/m² d1, FA 400 mg/m² d1, 5-FU bolus 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2; or modified FOLFIRI3: irinotecan 90 mg/m² d1 and 3, FA 400 mg/m² d1, 5-FU infusion 2,400 mg/m² d1-2). Bevacizumab q2w (5 mg/kg) was allowed in both arms as of June 2012 (TML study report). The primary endpoint was the objective tumor response (OR). Results: Fifty-five patients were randomized (FUPEP, n=28; FOLFIRI, n=27). In the evaluable population (n=50), OR rate were 16.7% (n=4/24) and 11.5% (n=3/26) in the FUPEP and the FOLFIRI arms, respectively. Most common grade 3-4 adverse events reported in the respective FUPEP and the FOLFIRI arms were diarrhea (21% vs 33%), neutropenia (11% vs 30%), mucositis (11% vs 11%), and alopecia (G2: 25% vs 26%). Conclusions: FUPEP regimen exhibits promising tumor response and safety profile, and can be combined with bevacizumab, for oxaliplatin-pretreated patients. Hence PEP02 (MM-398) may provide a new second-line treatment option for mCRC. Based on the safety profile of the FUPEP regimen in this PEPCOL study, it was added as the third arm to the positive phase III metastatic pancreatic cancer (NAPOLI-1) study. Clinical trial information: NCT01375816.
A novel IL36RN/IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis
Authors: K. Sugiura, T. Takeichi, M. Kono, Y. Ogawa, Y. Shimoyama, Y. Muro, M. Akiyama
Journal: British Journal of Dermatology (2012)
Prostate-Specific Membrane Antigen (PSMA) targeted prodrug “smartbombs” as therapy for prostate cancer
Authors: Annastasiah Mhaka, Pratap Singh, Marc Rosen, Craig A. Dionne, Soeren B. Christensen, John T. Isaacs, Samuel R. Denmeade
Journal: Cancer Research (2006)

3081  PSMA is a type II membrane carboxypeptidase that possesses a number of characteristics that make it a suitable candidate for targeted cancer therapy. PSMA expression is highly restricted to prostate tissue with strongest expression in both primary and metastatic prostate cancers and is upregulated upon androgen withdrawal. PSMA, however, is also expressed by the neovasculature within most solid tumors, but not by normal tissue vasculature. Functionally, PSMA is both an N-acetylated α-linked acidic dipeptidase (NAALADase) and a pteroyl poly-γ-glutamyl carboxypeptidase (folate hydrolase) whose extracellular domain is accessible to agents in the extracellular peri-tumoral fluid. To develop a prodrug that can be activated selectively within prostate cancer cells or tumor vasculature by PSMA’s enzymatic activity, PSMA selective peptide carriers were identified consisting primarily of α- or γ-carboxyl linked glutamic and or aspartic acids. These peptides were coupled to the amino terminus of 8-O-(12Aminododecanoyl)-8-O debutanoylthapsigargin (12ADT), a potent cytotoxic analog of the natural plant product thapsigargin (TG) that inhibits the ER Ca2+ ATPase pump and induces proliferation independent apoptosis in all cell types. PSMA hydrolysis of the peptide-12ADT prodrug yields Asp- or Glu-12ADT as the final product. Computer modeling demonstrated that these amino acid containing analogs should potently inhibit the Ca2+ pump and these findings were confirmed in vitro with observed IC50 values for Asp- and Glu-12ADT of ∼ 50 nM against prostate cancer cell lines. A series of peptide-12ADT prodrugs were then synthesized and several were identified that were efficiently hydrolyzed by PSMA and stable to hydrolysis in plasma. Dipeptide and pentapeptide prodrugs were identified that were selectively toxic to PSMA expressing prostate cancer cells in vitro but were 10-60 fold less toxic to non-PSMA expressing cells. A lead prodrug (i.e. G202) was identified from these in vitro studies. After identifying a clinically acceptable formulation vehicle (i.e. PEG/Solutol) pharmacokinetic studies were performed. A single dose of 60 mg/kg of G202 produced a Cmax of ∼ 800 μM and a plasma half-life of ∼5hr. Efficacy studies against PSMA-producing CWR22RH xenografts in castrated mice demonstrated tumor regression and significant growth delay following a single 3-day (60 mg/kg/day) or 10-day (18 mg/kg/day) course of G202. On the basis of these results, further preclinical development of G202 is warranted and large scale synthesis and toxicologic studies are in process.
Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell apoptosis by epigenetic silencing of KLF2
Authors: Ming-de Huang, Wen-ming Chen, Fu-zhen Qi, Rui Xia, Ming Sun, Tong-peng Xu, Li Yin, Er-bao Zhang, Wei De, Yong-qian Shu
Journal: Journal of Hematology & Oncology (2015)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in China. And the mechanism of its progression remains poorly understood. Growing evidence indicates that long non-coding RNAs (lncRNAs) are found to be dysregulated in many cancers, including HCC. ANRIL, a lncRNA co-clustered mainly with p14/ARF has been reported to be dysregulated in gastric cancer, esophageal squamous cell carcinoma, and lung cancer. However, its clinical significance and potential role in HCC are still not documented.In this study, expression of ANRIL was analyzed in 77 HCC tissues and matched normal tissues by using quantitative polymerase chain reaction (qRT-PCR). ANRIL expression was upregulated in HCC tissues, and the higher expression of ANRIL was significantly correlated with tumor size and Barcelona Clinic Liver Cancer (BCLC) stage. Moreover, taking advantage of loss-of-function experiments in HCC cells, we found that knockdown of ANRIL expression could impair cell proliferation and invasion and induce cell apoptosis both in vitro and in vivo. We also found that ANRIL could epigenetically repress Kruppel-like factor 2 (KLF2) transcription in HCC cells by binding with PRC2 and recruiting it to the KLF2 promoter region. We also found that SP1 could regulate the expression of ANRIL.Our results suggest that lncRNA ANRIL, as a growth regulator, may serve as a new biomarker and target for therapy in HCC.