tbuckley/cabot-search huggingface dataset:
Tachycardia-Induced Changes in Na <sup>+</sup> Current in a Chronic Dog Model of Atrial Fibrillation
Authors: Rania Gaspo, Ralph F. Bosch, Elias Bou-Abboud, Stanley Nattel
Journal: Circulation Research (1997)

Abstract We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n=6) and 42 days (P42, n=5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n=6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na + current ( I Na ) density was reduced by 28% at −40 mV ( P &lt;.0001, n=59 cells). I Na changes were even more decreased under P42 conditions, by ≈52% at −40 mV ( P &lt;.0001): from −78.7±4.6 pA/pF (P0, n=28 cells) to −37.7±3.0 pA/pF (P42, n=43 cells). I Na was significantly reduced at all voltages ranging from −65 to −10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean I Na in each dog ( r 2 =.573, P &lt;.001). We conclude that rapid atrial activation significantly reduces both conduction velocity and I Na density. Since I Na is a major determinant of conduction velocity, our data point to I Na reduction as a potentially important mechanism contributing to the substrate for AF in this model.
Generation of Functional Culture–Derived Platelets From CD34 <sup>+</sup> Progenitor Cells to Study Transgenes in the Platelet Environment
Authors: Martin Ungerer, Mario Peluso, Angelika Gillitzer, Steffen Massberg, Ulrich Heinzmann, Christian Schulz, Götz Münch, Meinrad Gawaz
Journal: Circulation Research (2004)

Abstract:— The possibility of evaluating the function of transgenes in platelets requires the generation of platelets from nucleated progenitor cells in vitro. In this article, we provide effective culture conditions for generating functional culture-derived (CD) human and mouse platelets from CD34 + progenitor cells that allow expression of any foreign protein of interest. We have evolved an effective cytokine cocktail (thrombopoietin, stem cell factor, interleukin [IL]-1β, IL-6) that induces a high yield of CD platelets and optimal shedding from cultivated megakaryocytes generated from CD34 + progenitor cells. CD platelets showed similar functional and morphological characteristics compared with isolated blood platelets, including surface expression of platelet antigens (CD41, CD42, CD62P), aggregation, release of granule constituents (P-selectin, platelet factor 4, serotonin). Moreover, transmission electron microscopy revealed the presence of typical α- and dense granules and dense tubular system in CD platelets. Additionally, we showed that stable transgene expression in CD platelets can be performed through infection of CD34 + progenitor cells using adenoviral vectors. Thus, we describe a methodology that enables studying functional consequences of transgenes of interest in the natural environment of platelets that may impose substantial impact on potential future platelet research and therapeutic target evaluation. The full text of this article is available online at http://circres.ahajournals.org.
Insulin Pump Therapy
Authors: Jill Weissberg-Benchell, Jeanne Antisdel-Lomaglio, Roopa Seshadri
Journal: Diabetes Care (2003)

OBJECTIVE—To conduct a meta-analysis of the metabolic and psychosocial impact of continuous subcutaneous insulin infusion (CSII) therapy on adults, adolescents, and children. RESEARCH DESIGN AND METHODS—Studies were identified and data regarding study design, year of publication, sample size, patient’s age, diabetes duration, and duration of CSII therapy were collected. Means and SDs for glycohemoglobin, blood glucose, insulin dosages, and body weight for CSII and comparison conditions were subjected to meta-analytic procedures. Data regarding pump complications and psychosocial functioning were reviewed descriptively. RESULTS—A total of 52 studies, consisting of 1,547 patients, were included in the meta-analysis. Results indicate that CSII therapy is associated with significant improvements in glycemic control (decreased glycohemoglobin and mean blood glucose). A descriptive review of potential complications of CSII use (e.g., hypoglycemia, diabetic ketoacidosis [DKA], pump malfunction, and site infections) suggests a decreased frequency of hypoglycemic episodes but an increased frequency of DKA in studies published before 1993. CONCLUSIONS—CSII therapy is associated with improved glycemic control compared with traditional insulin therapies (conventional therapy and multiple daily injections) and does not appear to be associated with significant adverse outcomes. Additional studies are needed to further examine the relative risks of CSII therapy, including the potential psychosocial impact of this technologically advanced therapy.
Inhibition of Tumorigenicity and Metastasis of Human Melanoma Cells by Anti-Cathepsin L Single Chain Variable Fragment
Authors: Nathalie Rousselet, Lisa Mills, Didier Jean, Carmen Tellez, Menashe Bar-Eli, Raymond Frade
Journal: Cancer Research (2004)

Abstract We demonstrated previously that the switch from nonmetastatic to highly metastatic phenotype of human melanoma cells is directly related to secretion of procathepsin L form. This cysteine proteinase was identified on the basis of its property to cleave human C3, the third component of complement. In an attempt to control procathepsin L secretion, we have recently generated an anti-cathepsin L single chain variable fragment (ScFv) from an anti-cathepsin L monoclonal antibody generated against recombinant cathepsin L. We herein selected clones stably transfected with this anti-cathepsin L ScFv and analyzed them for changes in tumor growth and metastasis. We show that in stably transfected clones, anti-cathepsin L ScFv strongly inhibited the secretion of procathepsin L without modifying the intracellular amount or processing pattern of cathepsin L forms. Confocal analysis demonstrated colocalization of endogenous cathepsin L and anti-cathepsin L ScFv. In addition, expression of this ScFv strongly inhibited generation of tumor and metastasis by these human melanoma clones in nude mice. In vivo, the anti-cathepsin L ScFv-transfected cells produced tumors with decreased vascularization (angiogenesis) concomitant with increased apoptosis of tumor cells. Matrigel assay also demonstrated that melanoma invasiveness was completely abolished. Thus, this is the first demonstration that anti-cathepsin L ScFv could be used to inhibit the tumorigenic and metastatic phenotype of human melanoma, depending on procathepsin L secretion, and could therefore be used as a molecular tool in a therapeutic cellular approach.
Asthma in reaction to two occupational agents in the same workplace
Authors: J.-L. Malo, J. L'Archeveque
Journal: Thorax (2011)

Workers can be simultaneously exposed to several agents that can cause occupational asthma (OA). The frequency of exposure to sensitisers at the workplace is high: more than 50% of workers reported being or having been exposed to such agents.1 In the presence of OA, it is important to avoid further exposure to the causal agent to prevent worsening of asthma.2 This justifies identification of the causal agent by exposing subjects to specific inhalation challenges.3 We describe five subjects, all working at food production companies, with a diagnosis of OA exposed to two different agents present in their workplace.

The methods used in the investigation are described in the online supplement. The characteristics of …
Limited Induction of Tumor Cross-Reactive T Cells without a Measurable Clinical Benefit in Early Melanoma Patients Vaccinated with Human Leukocyte Antigen Class I–Modified Peptides
Authors: Paola Filipazzi, Lorenzo Pilla, Luigi Mariani, Roberto Patuzzo, Chiara Castelli, Chiara Camisaschi, Andrea Maurichi, Agata Cova, Gianluigi Rigamonti, Felicetta Giardino, Annabella Di Florio, Marco Asioli, Paola Frati, Gloria Sovena, Paola Squarcina, Michele Maio, Riccardo Danielli, Vanna Chiarion-Sileni, Antonello Villa, Claudia Lombardo, Gabrina Tragni, Mario Santinami, Giorgio Parmiani, Licia Rivoltini
Journal: Clinical Cancer Research (2012)

The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III).Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201-restricted modified peptides (Melan-A/MART-1([27L]), gp100([210M]), NY-ESO-1([165V]), and Survivin([97M])) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m(2)) and low-dose IL-2 (3 × 10(6) IU). The immune responses were monitored using ex vivo IFN-γ-ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays.Vaccination induced a rapid and persistent increase in specific effector memory CD8(+) T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells.Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8(+) T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease.
Primary Pulmonary Hypertension
Authors: STUART RICH
Journal: Annals of Internal Medicine (1987)

A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (± SD) of 36 ± 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLC0), and hypoxemia with hypocapnia. The mean (± SD) right atrial pressure was 9.7 ± 6 mm Hg; mean pulmonary artery pressure, 60 ± 18 mm Hg; cardiac index, 2.3 ± 0.9 L/min·m2; and pulmonary vascular resistance index, 26 ± 14 mm Hg/L/min·m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.
Expression of interleukin (IL)-1 family members upon stimulation with IL-17 differs in keratinocytes derived from patients with psoriasis and healthy donors
Authors: P. Muhr, J. Zeitvogel, I. Heitland, T. Werfel, M. Wittmann
Journal: British Journal of Dermatology (2011)

A number of studies have challenged the T-cell-centred pathogenetic view of psoriasis by the finding that epithelium-expressed genes are intimately involved in the inflammatory process. Interleukin (IL)-17 is an important inflammatory mediator in skin psoriasis.IL-17 is known to act on keratinocytes and we were interested in its impact on the expression of pro- and anti-inflammatory IL-1 family members.We compared human keratinocytes derived from epidermal stem cells of hair follicles plucked from patients with psoriasis and healthy individuals using quantitative reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assays.In the presence of IL-17, psoriasis-derived keratinocytes showed a significantly higher induction of the proinflammatory IL-1 family members IL-1F6 and IL-1F9, but not of anti-inflammatory members IL-1F5, IL-1F7 or IL-1F3 compared with keratinocytes from healthy individuals. Both basal and IL-17-induced levels of IL-1F2 and IL-1F1 were found to be significantly lower in psoriasis keratinocytes.As keratinocytes were derived from epidermal stem cells of the hair follicles and were obtained from nonlesional sites, differences found are likely to present an intrinsic feature of psoriasis epithelium. Our data support the significance of IL-1 family members as therapeutic targets in psoriasis conditions.
Dietary Fat and Breast Cancer: Contributions From a Survival Trial
Authors: Anne C. M. Thiébaut, Arthur Schatzkin, Rachel Ballard-Barbash, Victor Kipnis
Journal: JNCI Journal of the National Cancer Institute (2006)

EDITORIALS 1753 The relation between dietary fat and breast cancer incidence and survival remains one of the most controversial hypotheses in nutritional epidemiology, with mostly observational studies showing rather inconsistent results ( 1 – 3 ) . In this ongoing debate, results of a pertinent intervention trial are potentially highly informative. In this issue of the Journal, Chlebowski et al. ( 4 ) report interim results of the Women’s Intervention Nutrition Study (WINS), a low-fat dietary intervention trial among women diagnosed with breast cancer. The WINS fi ndings, however, raise several concerns that complicate drawing etiologic conclusions about dietary fat and breast cancer as well as making defi nitive recommendations for survivors. Results of the interim analysis ( 4 ) suggest a benefi t of dietary fat reduction on relapse-free survival: the log-rank test was of borderline statistical signifi cance ( P = .07), and exploratory multivariable Cox regression analysis showed a statistically signifi cant decrease in the risk of relapse in the group assigned to the low-fat dietary eating plan ( P = .03). A key concern is whether the improved survival could have been confounded by the higher frequency of mastectomy in the intervention group than in the control group, given that a recent pooled analysis ( 5 ) showed that breast-conserving therapy was associated with a greater risk of locoregional recurrence than mastectomy. The authors note that adjustment for the surgical procedure did not eliminate the outcome advantage observed in women randomly assigned to the low-fat dietary eating plan. Moreover, among WINS patients who underwent lumpectomy, those in the intervention group also experienced lower ipsilateral breast recurrence (11 events out of 624, compared with 31 out of 1018 in the control group) [tables 2 and 4, ( 4 ) ]. A post hoc covariate adjustment, however, is not as inferentially strong as an analysis that is based on baseline equivalence across the two groups. The treatment imbalance thus lends
Virtual bronchoscopic navigation combined with endobronchial ultrasound to diagnose small peripheral pulmonary lesions: a randomised trial
Authors: T. Ishida, F. Asano, K. Yamazaki, N. Shinagawa, S. Oizumi, H. Moriya, M. Munakata, M. Nishimura
Journal: Thorax (2011)

<h3>Background</h3> Bronchoscopy using endobronchial ultrasound (EBUS) can help to diagnose small peripheral pulmonary lesions. However, although biopsy sites can be confirmed, a bronchoscope cannot be guided in EBUS. Virtual bronchoscopic navigation (VBN) can guide a bronchoscope with virtual images, but its value has not been confirmed. <h3>Methods</h3> This prospective multicentre study examines the value of VBN-assisted EBUS for diagnosing small peripheral pulmonary lesions. 199 patients with small peripheral pulmonary lesions (diameter ≤30 mm) were randomly assigned to VBN-assisted (VBNA) or non-VBN-assisted (NVBNA) groups. A bronchoscope was introduced into the target bronchus of the VBNA group using the VBN system. Sites of specimen sampling were verified using EBUS with a guide sheath under fluoroscopy. <h3>Results</h3> The diagnostic yield was higher for the VBNA than for the NVBNA group (80.4% vs 67.0%; p=0.032). The duration of the examination and time elapsed until the start of sample collection were reduced in the VBNA compared with the NVBNA group (median (range), 24.0 (8.7–47.0) vs 26.2 (11.6–58.6) min, p=0.016) and 8.1 (2.8–39.2) vs 9.8 (2.3–42.3) min, p=0.045, respectively). The only adverse event was mild pneumothorax in a patient from the NVBNA group. <h3>Conclusions</h3> The diagnostic yield for small peripheral pulmonary lesions is increased when VBN is combined with EBUS. <h3>Clinical trial number</h3> UMIN000000569.
Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non–high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol
Authors: Gunnar Cario, Martin Zimmermann, Renja Romey, Stefan Gesk, Inga Vater, Jochen Harbott, André Schrauder, Anja Moericke, Shai Izraeli, Takashi Akasaka, Martin J. S. Dyer, Reiner Siebert, Martin Schrappe, Martin Stanulla
Journal: Blood (2010)
PharmGKB Submission Update: IX. ADRB1 Gene Summary
Authors: Michael A. Pacanowski, Julie A. Johnson
Journal: Pharmacological Reviews (2007)

Pharmacological Reviews periodically publishes summaries of new information available from the PharmGKB database ([www.pharmgkb.org][1]) as a service to our readers. Full information with references for this summary is available at [www.pharmgkb.org/search/annotatedGene/adrb1][2]. Gene HGNC Name:
Cyclooxygenase 2 Expression in Colorectal Cancer with DNA Mismatch Repair Deficiency
Authors: Antoni Castells, Artemio Payá, Cristina Alenda, Francisco Rodríguez-Moranta, Rubén Agrelo, Montserrat Andreu, Virgínia Piñol, Sergi Castellví-Bel, Rodrigo Jover, Xavier Llor, Elisenda Pons, J. Ignasi Elizalde, Xavier Bessa, Javier Alcedo, Joan Saló, Enrique Medina, Antonio Naranjo, Manel Esteller, Josep M. Piqué
Journal: Clinical Cancer Research (2006)

Abstract Background: Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors. Aim: To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting. Patients and Methods: MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated. Results: One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P &amp;lt; 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04). Conclusions: Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.
A New Melanoma Antigen Fatty Acid–Binding Protein 7, Involved in Proliferation and Invasion, Is a Potential Target for Immunotherapy and Molecular Target Therapy
Authors: Yasufumi Goto, Yuriko Matsuzaki, Sachiko Kurihara, Ayako Shimizu, Tsutomu Okada, Kazuhiko Yamamoto, Hiroshi Murata, Minoru Takata, Hiroyuki Aburatani, Dave S.B. Hoon, Toshiaki Saida, Yutaka Kawakami
Journal: Cancer Research (2006)

Abstract The identification of molecules that are preferentially expressed in melanoma cells and involved in their malignant phenotypes is important for understanding melanoma biology and the development of new diagnostic and therapeutic methods. By comparing the expression profile of a melanoma cell line with those of various normal tissues using GeneChip and by confirming the actual expression of the selected genes by reverse transcription-PCR and Northern and Western blot analyses, fatty acid–binding protein 7 (FABP7), which is frequently expressed in melanomas, was identified. Immunohistochemical examination revealed that FABP7 was expressed in 11 of 15 melanoma tissues. By down-regulating the FABP7 expression with FABP7-specific small interfering RNAs, in vitro cell proliferation and Matrigel invasion were suppressed in two of six melanoma cell lines. Overexpression of FABP7 in a FABP7-negative embryonic kidney cell line 293T by transfecting with the FABP7 cDNA resulted in enhanced cell proliferation and Matrigel invasion, indicating that FABP7 plays a role in the malignant phenotype of some melanoma cell lines. IgG antibodies specific for the phage or bacterial recombinant FABP7 protein were detected in 14 of 25 (56%) or in 8 of 31 (26%) sera from melanoma patients, respectively, but not in sera from healthy individuals, indicating that FABP7 is an immunogenic antigen in melanoma patients. These results showed that FABP7 is frequently expressed in melanoma, may be involved in cell proliferation and invasion, and may be a potential target for development of diagnostic and therapeutic methods. (Cancer Res 2006; 66(8): 4443-9)