tbuckley/cabot-search huggingface dataset:
Energy economy of walking with a wheeled ambulatory aid (rollator) in patients with chronic obstructive pulmonary disease (COPD)
Authors: Kylie Hill, Thomas E. Dolmage, Lynda Woon, Dina Brooks, Roger S. Goldstein
Journal: European Respiratory Journal (2011)

Background: Probst et al. (Chest 126: 1102, 2004) reported that, when using a rollator, patients with COPD increased their distance walked in 6 min along with increased oxygen uptake and ventilation. It was difficult to appraise economy (mechanical work to total energy expenditure) because the main determinant of the energy demand, speed, varied between conditions; hence, the authors concluded that rollator use improved distance by increasing ventilatory capacity and/or economy.

Objective: To determine whether walking with a rollator improved the energy economy in patients with COPD. The hypothesis was that oxygen uptake, at the same speed, would be lower (improved economy) when walking with a rollator.

Methods: Subjects completed 2 walks, (with and without a rollator) at individually set and constant speeds. At least 24 h later they repeated the session for a total of 4 walks. Energy expenditure was estimated from measured oxygen uptake using a telemetric system. Since mechanical work was kept constant (speed) during each walk, differences in economy were reflected in differences in energy expenditure in metabolic equivalents (METS).

Results: Ten subjects completed the study. Attainment of a steady state was confirmed during every walk. There was no effect of day (p=0.23) on energy expenditure. There was no significant difference (0.0 [-0.4 to 0.3] METS) in energy expenditure with (3.6 [2.9 to 4.3] METS) or without (3.6 [2.9 to 4.3] METS) the rollator.

Conclusion: Rollator use does not acutely affect walking economy in patients with COPD. A better understanding of how people with COPD benefit from rollator use may facilitate their design and prescription.
Abstract 17830: Are Continuous-Flow Left Ventricular Assist Devices (CF-LVAD) Better Than the Waiting List? A Propensity-score Matched Analysis of CF-LVAD versus Waiting List for Adult Patients in United Network for Organ Sharing Status II (UNOS-II)
Authors: Stefano Mastrobuoni, Alain Poncelet, Angelo Maria Dell’ Aquila, Luc-Marie Jacquet, Jose Garcia
Journal: Circulation (2014)

Introduction:  The improved outcomes of third-generation continuous-flow left ventricular assist devices (CF-LVAD) in bridge-to-transplant and the high attrition rate among patients awaiting an allograft have raised the question whether CF-LVADs are better than the waiting list for transplant eligible patients.   Hypothesis:  we assessed the hypothesis that survival after LVAD is improved compared to waiting list in adult patients listed in UNOS status II.   Methods:  We identified all patients >18 years of age in the Organ Procurement and Transplantation Network (OPTN) database listed for their first heart transplant in the US in UNOS status II with no mechanical circulatory support at time of listing and not candidates to multi-organ transplant between January 2011 and March 2014. Of 2468 patients listed during the study period, 208 patients received a third-generation CF-LVAD. CF-LVAD and NO-LVAD patients were then matched 1:2 by mean of the closest-neighbor Propensity Score and survival of the matched groups was estimated with the Kaplan-Meier method.   Results:  One hundred and ninety CF-LVAD patients were PS-matched with 380 NO-LVAD patients. The matched groups were similar for several baseline characteristics (p=ns). In the CF-LVAD subgroup, 158 patients (83.2%) were transplanted, 21 (11.1%) were still on support and on the list, and 11 patients (5.8%) died or were delisted. In the NO-LVAD group, 314 patients (82.6%) were transplanted, 48 (12.6%) were still on the list and 18 patients (4.7%) died or were delisted. Freedom from death or delisting with CF-LVAD was 80.5% versus 85.5% of NO-LVAD patients at 18 months postoperatively (p=0.4). Cumulative survival considering also the post-transplant period was similar in the two groups at 24 months since listing (80.4% CF-LVAD versus 79.4% NO-LVAD, p=0.3).   Conclusions:  In conclusion, heart transplant candidates listed in status II and supported with CF-LVAD have shown a similar survival on the waiting list compared to candidates without LVAD. Overall survival of patients who received CF-LVAD was similar to survival of patients who did not receive mechanical support. Further studies are needed to clarify whether the allocation advantage given to the LVAD patients on the waiting list is still justified.
Abstract 12811: Two-Dimensional Speckle-Tracking Echocardiographic LV Myocardial Multi-Layer Strain-Determined Compensatory Mechanism in HCM and Severe Aortic Stenosis Patients With Preserved LV Ejection Fraction
Authors: Koya Ozawa, Nobusada Funabashi, Hiroyuki Takaoka, Yoshio Kobayashi
Journal: Circulation (2014)

Introduction: A multi-layer technique of speckle-tracking transthoracic echocardiography (TTE) can produce quantitative strain measurements of endocardial and epicardial layers of the left ventricle (LV) to evaluate myocardial function and characteristics.

Aim: To evaluate compensatory mechanisms in hypertrophic cardiomyopathy (HCM) and severe aortic stenosis (AS) subjects, both with hypertrophied LV myocardium and preserved ejection fraction (EF), we measured 2D LV global longitudinal (GLS) and circumferential strain (GCS) using speckle TTE, and compared the findings to controls.

Methods: Eighty subjects, 40 with HCM (30 male, 62±15 yrs, 5 Maron type 2, 16 Maron type 3, 14 Maron type 5, and 5 Maron type 2 or 3+5), 20 with severe AS (12 male, 74±5 yrs, transaortic maximum velocity 4.9±0.6 m/s, aortic valve area index 0.45±0.13 cm2/m2), and 20 controls (10 male, 59±10 yrs) underwent TTE (Vivid E9, GE Healthcare). Apical 4-, 2-, and 3-chamber views for GLS and parasternal short-axis views at the level of mitral valve, papillary muscle, and apex for GCS were acquired. Quantitative strain measurements of endocardial and epicardial layer were performed.

Results: GLS values were significantly smaller in the HCM subjects than severe AS subjects and controls (all P<0.001), and GLS values were significantly smaller in severe AS subjects than controls in the endocardial and epicardial layers (all P<0.01). There were no significant differences in endocardial GCS at the level of mitral valve and papillary muscle between the groups. Endocardial GCS at the mitral valve and papillary muscle level was significantly positively correlated with LV EF (R=0.446 and 0.34, respectively) in the HCM subjects. Similarly, in severe AS subjects, endocardial GCS at the mitral valve and papillary muscle levels was significantly positively correlated with LV EF (R=0.59 and 0.609, respectively).

Conclusions: In HCM and severe AS patients with preserved LV EF, GLS from each was significantly smaller than controls. We speculate that in such subjects, endocardial GCS at the mitral valve and papillary muscle levels is maintained in compensation for GLS decrement, and possible may contribute to maintaining LVEF.
Clinical Signs and Symptoms In Non-Transfused Patients With Paroxysmal Nocturnal Hemoglobinuria From a Korean Prospective PNH Registry
Authors: Jong Wook Lee, Jun Ho Jang, Jin Seok Kim, Je-Hwan Lee, Deog-Yeon Jo, Yeo-Kyeoung Kim, Jooseop Chung, Jeong-A Kim, Jae Hoon Lee, Chul-Won Choi, Yong Park, Jun Sung Park
Journal: Blood (2013)
Abnormal splice variants of SIVA in Waldenstrom’s macroglobulinemia (WM).
Authors: Sophia Adamia, Evdoxia Hatjiharissi, Yang Cao, Leukothea Ioakimidis, Zachary Hunter, Robert Manning, Bryan Ciccarelli, Chris Patterson, Steven Treon
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2695 

Waldenstrom’s macroglobulinemia (WM) is an incurable B cell malignancy characterized by the accumulation of IgM secreting lymphoplasmacytic cells (LPC). Despite intense research efforts, the mechanism(s) by which WM LPC fail to undergo apoptosis remain to be defined. One potential mechanism for B-cell homeostasis is signaling of CD70 through CD27, which induces apoptosis in normal B-cells including CD27+ memory B-cells from which WM LPC are thought to derive. WM cells often show no or diminished expression of CD27, or secrete high levels of soluble CD27 which may lead to CD70 signaling blockade (Ho et al, Blood 2008). As part of these effort we sought to elaborate on intracellular mechanisms for CD70-CD27 signaling, by focusing on SIVA, a pro -apoptotic proteincontaining a death domain which interacts with the cytoplasmic tail of CD27. Two splice variants of SIVA ( SIVA1 and SIVA2) have so far been identified in humans . We therefore evaluated the expression patterns of SIVA in 25 WM patients and 6 healthy donors (HD). Through gene profiling, we detected the constitutive expression of SIVA 1 and its variant SIVA2 , which results from deletion of exon 2. However, in contrast to previous findings, we detected three novel aberrant splice variants of SIVA , which we have designated as SIVA-Va, -Vb, and -Vc, at least one of which alone or combination with each other were present in 25/25 patients with WM versus 1/6 HD (p=0.00004). The breakdown for the frequency of expression for these variants in WM patients was as follows: SIVA -Va (10/25); -Vb (6/25); -Vc (13/25), whereas in HD only SIVA-Vc was present in one individual. Cloning, sequencing and alignment analysis of SIVA variants from 4 WM patients revealed that SIVA-Va and SIVA-Vb resulted from partial intron retention, while SIVA-Vc was derived from the deletion of two exons. DNA alignment and bioinformatics analysis demonstrated that all splice variants of SIVA encoded for novel proteins. This prediction was verified by transient tranfection of GFP-SIVA-FL and DsRed-SIVA variant constructs into HeLa cells. As expected, SIVA-FL protein was expressed in the nucleus and transported to the membrane, while splice variants were localized on the membrane. Co-transfection analysis of SIVA-FL and splice variants verified their co-localization at the membrane 6 hours after proteins production. The results of these studies suggest that SIVA variants compete for CD27 binding and may therefore interfere with B-cell homeostasis regulated by CD70-CD27 interactions.
Influenza A(H1N1)pdm09 vaccination policies and coverage in Europe
Authors: J Mereckiene, S Cotter, J T Weber, A Nicoll, F D'Ancona, P L Lopalco, K Johansen, A M Wasley, P Jorgensen, D Lévy-Bruhl, C Giambi, P Stefanoff, L Dematte, D O’Flanagan, Collective the VENICE project gatekeepers group
Journal: Eurosurveillance (2012)

In August 2010 the Vaccine European New Integrated Collaboration Effort (VENICE) project conducted a survey to collect information on influenza A(H1N1)pdm09 vaccination policies and vaccination coverage in the European Union (EU), Norway and Iceland. Of 29 responding countries, 26 organised national pandemic influenza vaccination and one country had recommendations for vaccination but did not have a specific programme. Of the 27 countries with vaccine recommendations, all recommended it for healthcare workers and pregnant women. Twelve countries recommended vaccine for all ages. Six and three countries had recommendations for specific age groups in children and in adults, countries for specific adult age groups. Most countries recommended vaccine for those in new risk groups identified early in the pandemic such as morbid obese and people with neurologic diseases. Two thirds of countries started their vaccination campaigns within a four week period after week 40/2009. The reported vaccination coverage varied between countries from 0.4% to 59% for the entire population (22 countries); 3% to 68% for healthcare workers (13 countries); 0% to 58% for pregnant women (12 countries); 0.2% to 74% for children (12 countries). Most countries identified similar target groups for pandemic vaccine, but substantial variability in vaccination coverage was seen. The recommendations were in accordance with policy advice from the EU Health Security Committee and the World Health Organization.
Abstract 156: The Efficacy of Real-Time Regional Cerebral Oxygen Saturation (rSO2) Monitoring as an Indicator of Quality of Chest Compression Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest Patients
Authors: Tomohiko Orita, Yukitoshi Toyoda, Motoyasu Yamazaki, Tomohiro Funabiki, Masayuki Shimizu, Shokei Matsumoto, Tomohiro Sato, Motojiro Takebe, Nao Hiroe, Taku Kazamaki, Yoshimi Nakamichi, Mitsuhide Kitano
Journal: Circulation (2013)

Backgrounds and Objective: It has been suggested that brain tissue oxygenation is crucial for a prognosis in post cardiac arrest syndrome (PCAS). Recently several studies have suggested that region...
Expression of survivin and p53 protein in pulmonary tumours
Authors: Erika Halasova, Marian Adamkov, Tatiana Matakova, Elena Kavcova, Eva Rozborilova, Dusan Dobrota
Journal: European Respiratory Journal (2011)

Survivin is a member of the inhibitor of apoptotic gene family, which has been implicated in both the inhibition of apoptosis and mitosis regulation. p53 is one of the tumour suppressor genes; prevents tumour formation through cell cycle blocking and eliminates damaged cells via activation of apoptosis. To investigate the possible regulation of survivin by p 53 we examined the expression of both proteins in 67 patients with diagnosed lung cancer using immohistochemical visualisation. Survivin was predominantly expressed in both nucleus and cytoplasm, whereas p53 was expressed in nucleus. There was negative correlation between survivin and p53 expression. Decreased intensity of expression and less number of positive cells for survivin in small cell lung cancer in comparison to other lung cancer types was detected. There was no significant difference in intensity of expression and in number of positive cells for p53 between small cell and non-small cell lung cancer types.  This work was supported by project “Center of excellency for research in personalized therapy (CEVYPET) co-financed from EC sources and European Regional Development Fund.
Aberrant and function of protease activated receptor 4 (PAR4) in human colon cancer cells
Authors: Valerie Gratio, Therese Lehy, Francine Walker, Marc Laburthe, Dalila Darmoul
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4379 

The thrombin receptor, Proteinase-activated receptor-4 (PAR4, belongs to a new G protein-coupled receptor subfamily activated by serine proteinases. The presence and role of PAR4 in human gastrointestinal system functions have not been fully investigated. The aim of this study is to investigate the expression and the potential role of the thrombin receptor PAR4 in human colon cancer. The presence of PAR4 in colon cancer cell lines was assessed by immunofluorescence detection and RT-PCR, and its presence in resected human colonic tumors and normal colon was assessed by immunohistochemistry. By using the serine protease thrombin and the specific receptor-activating peptide (AYPGKF-NH) AP4, we tested the functionality of PAR-4 on calcium mobilization and cell proliferation in human colon cancer cells HT29. The following results were obtained: 1) immunofluorescence studies using polyclonal anti-PAR4 antibodies revealed expression of PAR-4 in HT29 cells . Immunohistochemical studies on paraffin embedded section of human colonic cancer showed a strong staining with the PAR4 antibody in some dysplastic areas and cancers. In contrast no staining was observed in normal human colonic epithelium; 2) RT-PCR analysis showed expression of PAR-4 mRNA in most human colon cancer cell lines (10 out of 14). In contrast, no mRNA was detected in normal epithelial cells from human colon; 3) microspectrofluorimetry using Fura 2-loaded cells demonstrated a prompt increase in intracellular calcium ([Ca2+]i) transients in HT29 in response to thrombin (10 nM) or AP4 (10-200 µM) challenges; 4) HT-29 cells exhibited dramatic mitogenic responses when grown in serum-deprived media supplemented with thrombin or AP4. This stimulatory effect on cell proliferation was observed also in several other human colon cancer cell lines; 5) we also show here that the PAR4-dependent increase in HT29 cell proliferation isdependent on src activity and transactivation of epidermal growth factorreceptor (EGFR). Indeed, PAR4-mediated cell proliferation wasblocked by the src inhibitor PP2, the metalloproteinase inhibitor batimastat and the specificEGFR tyrosine kinase inhibitors AG1478 and PD 168393.

In conclusion thrombin exerts proliferative responses in colon cancer cells through aberrant expression of PAR4.
Updated results of a phase Ib/II study of carfilzomib (CFZ) in patients (pts) with relapsed malignancies.
Authors: P. Lee, A. F. Wong, H. A. Burris, K. Papadopoulos, E. A. Sausville, P. J. Rosen, D. S. Mendelson, J. R. Infante, A. Patnaik, M. S. Gordon
Journal: Journal of Clinical Oncology (2010)

8147 Background: CFZ is a novel, highly selective peptide epoxyketone proteasome inhibitor. This Ph Ib/II study assesses the maximum recommended dose, safety, efficacy, pharmacokinetics, and pharmacodynamics of IV bolus and infusion CFZ in pts with relapsed malignancies. Methods: The Ph I bolus trial enrolled pts with solid tumors failing ≥2 prior treatments. CFZ was given on days (d) 1, 2, 8, 9, 15, and 16 every 28d for ≤12 cycles (C). C1 d1, d2 dosing in all cohorts was 20 mg/m2 with subsequent escalation to 20, 27, or 36 mg/m2 on d8. At 20/36 mg/m2, 1 pt had dose-limiting toxicity of grade (G) 3 fatigue. This was selected as the Ph II dose. Using a Simon 2-stage design, Ph II enrolled 14 pts into each of 5 cohorts (NSCLC, SCLC, RCC, ovarian, and other). Responses were measured every 2 C. The Ph I infusion trial delivered CFZ over a 30-min period. A separate treatment arm was added for multiple myeloma (MM). Planned doses range from 36–88 mg/m2. Ph II will be repeated once the MTD is established. Results: To date 79 pts (12 SCLC, 17 NSCLC, 16 ovarian, 10 renal, and 24 other) have been enrolled (14 in Ph I, 65 in Ph II). Pts received a median of 1.5 C of bolus CFZ (range 1-12). 20 pts have been enrolled to the Ph I infusion study (14 solid tumor, 6 MM). Efficacy data are detailed below (Table). Common adverse events (AEs) with bolus CFZ included fatigue, headache, diarrhea, nausea, and constipation. Peripheral neuropathy >G1, severe hematologic toxicities, and hepatotoxicity were not observed. Early data show that CFZ is also well-tolerated and efficacious when administered as a 30-min infusion. Updated data for the Ph II bolus and Ph I infusion studies will be presented. Conclusions: Single-agent IV CFZ is active and well-tolerated as a bolus or an infusion with a manageable side effect profile in relapsed malignancies. PRs have been achieved in renal, SCLC, and MM as well as SD >16 wks in a variety of other tumor types. Trial Best response Tumor type Prior regimens Time on study (months) Bolus (Ph I) PR Renal 3 11a SCLC 6 12b SD Mesothelioma 4 5.1a Bolus (Ph II) SD NSCLC 3 11b 2 4.1a Ovarian 4 12b Renal 3 8.5a 3 5.2c 3 5.2a 6 5.2a Cervical 4 5.2a Endometrial 4 5.1a SCLC 2 4.5a Infusion (Ph I) VGPR MM 4 3.2 PR MM 1 5.9 6 5.4 1 5.3 a Discontinued, progression. b Completed study. c Withdrew consent. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Onyx Onyx Onyx Onyx, Premiere Oncology
Brief Report: Identification of a Pathogenic Variant in TREX1 in Early‐Onset Cerebral Systemic Lupus Erythematosus by Whole‐Exome Sequencing
Authors: Julia I. Ellyard, Rebekka Jerjen, Jaime L. Martin, Adrian Y. S. Lee, Matthew A. Field, Simon H. Jiang, Jean Cappello, Svenja K. Naumann, T. Daniel Andrews, Hamish S. Scott, Marco G. Casarotto, Christopher C. Goodnow, Jeffrey Chaitow, Virginia Pascual, Paul Hertzog, Stephen I. Alexander, Matthew C. Cook, Carola G. Vinuesa
Journal: Arthritis & Rheumatology (2014)

Objective Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole‐exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole‐exome sequencing. Methods We performed whole‐exome sequencing in a 4‐year‐old girl with early‐onset SLE and conducted biochemical analysis of the putative defect. Results Whole‐exome sequencing in a 4‐year‐old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene ( TREX1 ) that was predicted to be highly deleterious. The TREX1 R97H mutant protein had a 20‐fold reduction in exonuclease activity and was associated with an elevated interferon‐α (IFNα) signature in the patient. The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications. The patient is now a candidate for neutralizing anti‐IFNα therapy. Conclusion Our study is the first to demonstrate that whole‐exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.
Expression of β-catenin, CDX1 and CDX2 in esophageal adenocarcinoma: association with survival after esophageal resection
Authors: Lara J. Williams, Laurette Geldenhuys, Nadine M. Vaninetti, Duane L. Guernsey, Alan G. Casson
Journal: Clinical Cancer Research (2006)

A25   Background: The Wnt/β-catenin signaling pathway is a key regulator of cellular growth and differentiation, and its dysregulation has recently been implicated in the molecular pathogenesis of human esophageal adenocarcinoma (EADC). Similarly, the caudal-related homologues (CDX1 and CDX2) are integral to gastrointestinal proliferation and differentiation, and are transcriptional targets of the Wnt/ β-catenin pathway. The aim of this study was to characterize β-catenin,  CDX  1 , and  CDX  2  mRNA and protein expression in human EADC and to correlate expression profiles with histo-pathologic and clinical parameters including patient survival.Methods: Total RNA was extracted from human esophageal tissues (tumor and matched normal) obtained with informed consent from 28 patients who underwent esophageal resection for primary EADC between 2002 and 2003. Semi-quantitative RT-PCR using primers to amplify target sequences of β-catenin,  CDX  1  and  CDX  2  was performed and normalized to β-actin as an internal control. Levels of mRNA expression in EADC were determined relative to histologically normal esophageal squamous epithelia from the same patient. Immunohistochemistry (IHC) was used to study protein distribution in corresponding formalin-fixed, paraffin-embedded tissue sections. Statistical analyses were performed to determine associations between expression levels of β-catenin,  CDX  1 ,  CDX  2 , and selected clinico-pathologic parameters (including tumor grade and stage) and postoperative survival (median survival below or greater than 14 months).Results: Overexpression of β-catenin mRNA was found in 10/28 EADCs, and was associated with survival over 14 months (9/10 vs. 9/18, p=0.034). Overexpression of  CDX  1  and  CDX  2  mRNA was seen in 13/28 and 15/28 EADCs, respectively, but no association with clinico-pathologic parameters or outcome was seen. Although not statistically significant,  CDX  1  mRNA overexpression was associated with increased β-catenin mRNA expression (7/10 vs. 6/18, p=0.062). IHC revealed heterogenous patterns of immunoreactivity, with cell nuclear positivity for β-catenin in 12 tumors, and cytoplasmic staining for CDX2 in 21 EADCs.Conclusions: The significant association between β-catenin mRNA expression and survival after esophagectomy suggests that β-catenin may be a useful molecular prognostic marker in patients with EADC. Furthermore, these exploratory studies implicate CDX1 in the molecular pathogenesis of EADC, perhaps through modulation of the Wnt/ β-catenin pathway.