tbuckley/cabot-search huggingface dataset:
Phospholipase D2 acts as an essential adaptor protein in the activation of Syk in antigen-stimulated mast cells
Authors: Jun Ho Lee, Young Mi Kim, Nam Wook Kim, Jie Wan Kim, Erk Her, Bo Kyung Kim, Jong Hyun Kim, Sung Ho Ryu, Jong Woo Park, Dong Wan Seo, Jeung Whan Han, Michael A. Beaven, Wahn Soo Choi
Journal: Blood (2006)
The Notch/Hes1 Pathway Sustains NF-κB Activation through CYLD Repression in T Cell Leukemia
Authors: Lluis Espinosa, Severine Cathelin, Teresa D'Altri, Thomas Trimarchi, Alexander Statnikov, Jordi Guiu, Veronica Rodilla, Julia Inglés-Esteve, Josep Nomdedeu, Beatriz Bellosillo, Carles Besses, Omar Abdel-Wahab, Nicole Kucine, Shao-Cong Sun, Guangchan Song, Charles C. Mullighan, Ross L. Levine, Klaus Rajewsky, Iannis Aifantis, Anna Bigas
Journal: Cancer Cell (2010)
Generation of a Stable Antioxidant Response Element–Driven Reporter Gene Cell Line and Its Use to Show Redox-Dependent Activation of Nrf2 by Cancer Chemotherapeutic Agents
Authors: Xiu Jun Wang, John D. Hayes, C. Roland Wolf
Journal: Cancer Research (2006)

Abstract The NF-E2 p45-related factor 2 (Nrf2) regulates cytoprotective genes that contain an antioxidant response element (ARE) in their promoters. To investigate whether anticancer drugs can induce ARE-driven gene expression, we have developed a stable human mammary MCF7-derived reporter cell line called AREc32, which contains a luciferase gene construct controlled by eight copies of the cis-element. In these cells, luciferase activity was increased up to 50-fold following treatment with 50 μmol/L tert-butylhydroquinone (t-BHQ). Basal and inducible luciferase activities in AREc32 cells were increased by forced overexpression of Nrf2 and reduced by knockdown of endogenous Nrf2 expression with RNA interference. Depletion of cellular reduced glutathione (GSH) by treatment of AREc32 cells with l-buthionine-S,R-sulfoximine (BSO) did not influence basal levels of luciferase activity, but pretreatment with BSO augmented induction of luciferase activity by t-BHQ. Induction of reporter activity by t-BHQ in AREc32 cells was suppressed markedly by the antioxidants N-acetylcysteine and GSH but only modestly by vitamins C or E, suggesting that ARE-luciferase expression is induced primarily by thiol-active electrophiles rather than free radicals. The anticancer drugs cisplatin, etoposide, mitoxantrone, chlorambucil, melphalan, and carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] weakly induced luciferase activity in AREc32 cells. Moreover, treatment of AREc32 cells with BSO immediately before exposure to anticancer drugs enhanced induction of ARE-driven luciferase activity by cisplatin, BCNU, chlorambucil, and melphalan and also induced endogenous AKR1C (AKR1C refers to AKR1C1 and AKR1C2), a target gene of Nrf2. Our findings show that Nrf2 can be activated by certain anticancer agents, and this will influence the effectiveness of chemotherapy. (Cancer Res 2006; 66(22): 10983-94)
Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane–Anthracycline Containing Chemotherapy—DAFNE (GBG-70)
Authors: Claus Hanusch, Andreas Schneeweiss, Sibylle Loibl, Michael Untch, Stefan Paepke, Sherko Kümmel, Christian Jackisch, Jens Huober, Jörn Hilfrich, Bernd Gerber, Holger Eidtmann, Carsten Denkert, Serban Costa, Jens Uwe Blohmer, Knut Engels, Nicole Burchardi, Gunter von Minckwitz
Journal: Clinical Cancer Research (2015)

Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pathologic complete response (pCR) rates of up to 60% in HER2-positive breast cancer. The DAFNE (Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment) phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting.Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20 mg/d) and trastuzumab [(8) 6 mg/kg/3 weeks] alone; followed by 12-week treatment with paclitaxel (80 mg/m(2)/1 week), trastuzumab, and afatinib; followed by 12 weeks with epirubicin (90 mg/m(2)/3 weeks), cyclophosphamide (600 mg/m(2)/3 weeks), and trastuzumab before surgery. Primary objective was pCR rate, defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of ≤55%.pCR rate was 49.2% [90% confidence interval (CI), 38.5-60.1] in 65 treated patients. Patients with hormone receptor-negative (N = 19) or hormone receptor-positive (N = 46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P = 0.153). Patients with (N = 9) or without (N = 56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P < 0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P = 0.363). Clinical responses were seen in 96.3% of 54 evaluable patients, and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent nonhematologic grade 3-4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure.Neoadjuvant treatment with afatinib, trastuzumab, and chemotherapy showed acceptable tolerability, and a pCR rate comparable with that of other anti-HER2 doublets but below challenging expectations.
Electrolyte Alterations in Acute Myocardial Ischemic Injury
Authors: ROBERT B. JENNINGS, HERBERT M. SOMMERS, JOHN P. KALTENBACH, JOEL J. WEST
Journal: Circulation Research (1964)

The electrolyte shifts occurring in myocardial cells irreversibly injured by ischemia were compared in two groups of dogs; one given 40 minutes of transient ischemia followed by 20, 50, 80, and 200 minutes of restored coronary arterial flow and the other 30, 60, 90, 130, and 240 minutes of permanent ischemia. Each interval of restored arterial flow in the transient ischemia group was associated with marked changes in the electrolyte content of the injured myocardium. Sodium, chloride, and water were increased and potassium and phosphorus were decreased. These changes occurred much more quickly in dogs exposed to transient ischemia than in dogs with comparable periods of permanent ischemia. These data indicate that objective chemical evidence of the death of myocardial cells develops slowly in areas of permanent ischemia primarily because of the reduced flow of blood through the ischemic injured tissue.
Non-cardiomyocyte microRNAs in heart failure
Authors: A. J. Tijsen, Y. M. Pinto, E. E. Creemers
Journal: Cardiovascular Research (2011)

Multiple structural changes are known to occur in a failing heart. Myocyte hypertrophy, cardiomyocyte apoptosis, interstitial fibrosis, reduced capillary density, and activation of the immune system are all involved in the pathogenesis and progression of heart failure (HF). The molecular mechanisms underlying these changes of the myocardium have been extensively studied, and many pathways involved in these processes have been uncovered. Recently, it has become evident that a novel class of small non-coding RNAs, called miRNAs, also plays a key role in these structural changes of the heart. This review summarizes the current insights on the role of miRNAs outside myocytes in the heart. Specifically, we will discuss miRNA function in fibroblasts, endothelial cells and immune cells in response to myocardial stress as occurs after myocardial infarction and in the pathogenesis of HF.
SIRT1 Pathway Dysregulation in the Smoke-Exposed Airway Epithelium and Lung Tumor Tissue
Authors: Jennifer Beane, Luis Cheng, Raffaella Soldi, Xiaohui Zhang, Gang Liu, Christina Anderlind, Marc E. Lenburg, Avrum Spira, Andrea H. Bild
Journal: Cancer Research (2012)

Cigarette smoke produces a molecular field of injury in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly upregulated in cytologically normal bronchial airway epithelial cells from active smokers compared with nonsmokers. In contrast, this activity is strikingly downregulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and downregulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Furthermore, our findings suggest that the airway gene expression signatures derived in this study can provide novel insights into signaling pathways altered in the "field of injury" induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.
Progression-Free Survival: Meaningful or Simply Measurable?
Authors: Christopher M. Booth, Elizabeth A. Eisenhauer
Journal: Journal of Clinical Oncology (2012)

The last few years have seen an increase in the number of randomized controlled trials (RCTs) of new agents in metastatic solid tumors using progression-free survival (PFS) as the primary end point. Some trials showing improvement in PFS, without a correspondingincreaseinoverallsurvival(OS),haveledtoapprovalofnew drugs and/or changes in standard of care. This suggests a growing belief in the oncology community that delaying progression in metastaticdiseaseisaworthygoal,evenifOSisnotimproved.Butisanew treatment that improves PFS really an advance for patients? Or is it only lowering the bar to declare active some of our much-heralded new molecular targeted therapies? We believe that as a community, this trend requires discussion and debate.
Salt-sensitive hypertension is associated with dysfunctional Cyp4a10 gene and kidney epithelial sodium channel
Authors: Kiyoshi Nakagawa, Vijaykumar R. Holla, Yuan Wei, Wen-Hui Wang, Arnaldo Gatica, Shouzou Wei, Shaojun Mei, Crystal M. Miller, Dae Ryong Cha, Edward Price, Roy Zent, Ambra Pozzi, Matthew D. Breyer, Youfei Guan, John R. Falck, Michael R. Waterman, Jorge H. Capdevila
Journal: Journal of Clinical Investigation (2006)

Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-/- mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.
Should we abandon standard forceps biopsy to diagnose an endobronchial lesion?
Authors: C. Dooms
Journal: European Respiratory Journal (2012)

The diagnostic yield of flexible bronchoscopy with direct standard forceps biopsy ranges from 72% to 82% in large (>200 patients) case series of patients with endobronchial visible tumours presenting as an exophytic mass or submucosal lesion [1]. At least three endobronchial forceps biopsy samples are recommended at the risk of mild self-limiting (10%) or severe life-threatening ( 90% [3, 4].

A flexible cryoprobe (ERBE USA, Inc., Marietta, GA, USA) for use within a flexible bronchoscope was introduced in 1994. Shortly thereafter, Mathur et al. [5] and Vergnon et al . [6] described its application in the treatment of malignant airway obstruction (palliation) and radio-occult early-stage lung cancer (cure) applying multiple …
Prevention of Nonvertebral Fractures by Alendronate
Authors: David B. Karpf
Journal: JAMA (1997)

<h3>Objective.</h3> —To evaluate the effect of treatment with alendronate sodium, a potent aminobisphosphonate, on the incidence of nonvertebral fractures in postmenopausal women with osteoporosis. <h3>Data Sources.</h3> —Published data and data on file at Merck Research Laboratories. <h3>Study Selection.</h3> —All completed prospective, randomized, placebo-controlled alendronate trials of at least 2 years' duration (5 studies). <h3>Data Extraction.</h3> —All subjects were women with osteoporosis between the ages of 42 and 85 years, postmenopausal at least 4years with lumbar spine bone mineral density (measured using dual-energy x-ray absorptiometry) at least 2.0 SD below the mean for young adult women. All women randomized to treatment with placebo or alendronate at a dose higher than 1 mg per day for at least 2 years were included. <h3>Data Synthesis.</h3> —In the placebo group (n=590), 60 women reported nonvertebral fractures during 1347 patient-years at risk (overall rate, 4.45 women with fractures per 100 patient-years at risk). In the alendronate group (n=1012), 73 women reported nonvertebral fractures during 2240 patient-years at risk (overall rate, 3.26 women with fractures per 100 patient-years at risk). The estimated cumulative incidence of nonvertebral fractures after 3 years was 12.6% in the placebo group and 9.0% in alendronate group. The relative risk for nonvertebral fracture estimated using the Cox proportional hazards model was 0.71 (95% confidence interval,0.502-0.997) (<i>P</i>=.048). A reduction in risk was consistent across each of the studies and at each major site of osteoporotic fracture, including the hip and wrist. <h3>Conclusion.</h3> —In postmenopausal women with osteoporosis, treatment with alendronate reduces the risk of nonvertebral fractures over at least 3 years.
Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells
Authors: Fulvio Mavilio, Graziella Pellegrini, Stefano Ferrari, Francesca Di Nunzio, Enzo Di Iorio, Alessandra Recchia, Giulietta Maruggi, Giuliana Ferrari, Elena Provasi, Chiara Bonini, Sergio Capurro, Andrea Conti, Cristina Magnoni, Alberto Giannetti, Michele De Luca
Journal: Nature Medicine (2006)
Lessons from the central Hampshire electronic health record pilot project: issues of data protection and consent
Authors: Trina Adams, Martin Budden, Chris Hoare, Hugh Sanderson
Journal: BMJ (2004)

One of the key elements of the NHS information strategy of 1998 was the development of electronic patient records.1 These were expected to be developed within organisations and to be capable of being linked into a patient focused electronic health record, which would form a lifetime record of health and health care for each patient within the NHS.1 This vision has been modified slightly by updates of the strategy, and the electronic health record has been renamed and redefined as the NHS Care Record Service, but in many ways the original concept has remained the same.2

The purpose of the electronic health record—now the NHS Care Record Service—is twofold. Firstly, to provide support for the clinical team to help them recall and communicate health status and treatments for patients in a coordinated way, and, secondly, to act as the source of statistical information on types of patients seen and the process and outcomes of their treatment. Although there was much expectation that these goals could be achieved, there was little evidence to prove that this was the case for the original strategy and its subsequent refreshes.2 For that reason, the NHS Information Authority sponsored 18 pilot projects which ran from April 2000 to March 2003 to test the concepts in several locations.

The central Hampshire electronic health record pilot project was supported from September 2000 to March 2003. During that time it evaluated the practicality of linking records from a wide range of organisations to support emergency and out of hours care, as well as providing information that could support data analysis and clinical governance.

The project, originally based at North and Mid-Hampshire Health Authority, linked with several key organisations within the area, which included three general practices (one in Eastleigh and Test Valley South primary …
An update on antenatal screening for Down’s syndrome and specific implications for assisted reproduction pregnancies
Authors: Boaz Weisz, Charles H. Rodeck
Journal: Human Reproduction Update (2006)

Since the introduction of antenatal serum screening for Down’s syndrome (DS) more than two decades ago, several screening approaches have been utilized in routine clinical practice. The current DS screening strategies involve mid-trimester serum biochemistry tests, first trimester tests combining sonographic markers and serum biochemistry and integration of first and second trimester markers. In this review, we evaluate the performance of DS screening strategies according to the Serum, Urine and Ultrasound Screening Study (SURUSS), the First and Second Trimester Evaluation of Risks (FASTER) Trial and the Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study. We also evaluate the performance of first trimester screening in studies and meta-analyses by other groups. Specific issues related to assisted reproduction technology (ART) pregnancies are also addressed in this review.
ROLE OF ENDOTHELIUM IN THROMBOSIS AND HEMOSTASIS
Authors: K. K. Wu, M.D, P. Thiagarajan, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Vascular endothelium is strategically located at the interface between tissue and blood. It is pivotal for protecting against vascular injury and maintaining blood fluidity. Normal endothelium releases prostacyclin and nitric oxide, potent inhibitors of platelet and monocyte activation and vasodilators. Their syntheses are governed by isoforms of enzymes. Normal endothelial surface expresses ecto-adenosine diphosphatase, which degrades adenosine diphosphate and inhibits platelet aggregation; thrombomodulin, which serves as a binding site for thrombin to activate protein C; and heparin-like molecules, which serve as a cofactor for antithrombin III. Normal endothelium secretes tissue plasminogen activator, which activates the fibrinolysis system. Endothelium produces and secretes von Willebrand factor, which mediates platelet adhesion and shear-stress-induced aggregation. Injury to endothelium is accompanied by loss of protective molecules and expression of adhesive molecules, procoagulant activities, and mitogenic factors, leading to development of thrombosis, smooth muscle cell migration, and proliferation and atherosclerosis.
Self-control: Beyond commitment
Authors: Howard Rachlin
Journal: Behavioral and Brain Sciences (1995)

Abstract Self-control, so important in the theory and practice of psychology, has usually been understood introspectively. This target article adopts a behavioral view of the self (as an abstract class of behavioral actions) and of self-control (as an abstract behavioral pattern dominating a particular act) according to which the development of self-control is a molar/molecular conflict in the development of behavioral patterns. This subsumes the more typical view of self-control as a now/later conflict in which an act of self-control is a choice of a larger but later reinforcer over a smaller but sooner reinforcer. If at some future time the smaller-sooner reinforcer will be more valuable than the larger-later reinforcer, self-control may be achieved through a commitment to the largerlater reinforcer prior to that point. According to some, there is a progressive internalization of commitment in the development of self-control. This presents theoretical and empirical problems. In two experiments – one with pigeons choosing between smallersooner and larger-later reinforcers, the other with adult humans choosing between short-term particular and long-term abstract reinforcers – temporal patterning of choices increased self-control.
Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors
Authors: C. Sessa, S. Cresta, T. Cerny, J. Baselga, E. Rota Caremoli, A. Malossi, D. Hess, J. Trigo, M. Zucchetti, M. D'Incalci, A. Zaniboni, G. Capri, B. Gatti, P. Carminati, C. Zanna, S. Marsoni, L. Gianni
Journal: Annals of Oncology (2006)
Depletion of alpha/beta T cells by a monoclonal antibody against the alpha/beta T cell receptor suppresses established adjuvant arthritis, but not established collagen-induced arthritis in rats.
Authors: S Yoshino, L G Cleland
Journal: The Journal of Experimental Medicine (1992)

The effects of treatment with a monoclonal antibody (R73 mAb) against T cell receptor alpha/beta (TCR-alpha/beta) on both established adjuvant arthritis (EAA) and established collagen-induced arthritis (ECIA) in rats have been investigated. Rats were treated with R73 mAb when arthritis reached a peak. Treatment with the anti-TCR-alpha/beta mAb markedly suppressed EAA, whereas ECIA was not affected by the mAb treatment. Histologically, R73 mAb-treated rats with EAA showed mild hyperplasia of synovial tissues, sparse infiltration of inflammatory cells, and minimal erosion of cartilage, whereas arthritic rats treated with PBS and an irrelevant control mAb against Giardia had marked hyperplasia of synovium with pannus, massive inflammatory cell infiltrate, and severe destruction of cartilage and subchondral bone. R73 mAb-treated rats with ECIA exhibited pronounced formation of pannus containing many inflammatory cells and marked cartilage and subchondral damage similar to those in arthritic rats that received the control treatments. Treatment with R73 mAb depleted markedly alpha/beta+ T cells in both peripheral blood and synovial tissues of rats with EAA and ECIA. R73 mAb treatment was associated with marked reduction in arthritogen-specific delayed-type hypersensitivity responses in both EAA and ECIA. The titers of antibodies against type II collagen produced in rats with ECIA were not affected by the mAb. Thus, alpha/beta+ T cells appear to have a central role in EAA, but not in chronic ECIA.
Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling
Authors: Veli-Pekka Ronkainen, Tomi Tuomainen, Jenni Huusko, Svetlana Laidinen, Marjo Malinen, Jorma J. Palvimo, Seppo Ylä-Herttuala, Olli Vuolteenaho, Pasi Tavi
Journal: Cardiovascular Research (2013)

AimsG protein-coupled receptor 35 (GPR35) has been characterized to be one of the genes that are up-regulated in human heart failure. Since mechanisms controlling GPR35 expression are not known, we investigated the regulation of GPR35 gene and protein expression in cardiac myocytes and in the mouse models of cardiac failure.