tbuckley/cabot-search huggingface dataset:
Response to Inhaled Nitric Oxide in Patients with Acute Right Heart Syndrome
Authors: SANGEETA BHORADE, JEFFREY CHRISTENSON, MICHAEL O'CONNOR, ANNICK LAVOIE, ANNE POHLMAN, JESSE B. HALL
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, has been shown to decrease pulmonary artery pressures but not increase cardiac output in hemodynamically stable patients with a variety of causes of pulmonary hypertension. The response to iNO in hemodynamically unstable patients with acute right heart syndrome has not been previously described. We determined the response to iNO in 26 critically ill adult patients with acute right heart failure defined by echocardiographic criteria. Patients received iNO through the inspiratory limb of the ventilator in increments of 10 ppm with hemodynamic and gas-exchange measurements made before and after each level. When maximal effect was seen, iNO was discontinued to compare parameters with baseline. iNO significantly increased cardiac output (5.5 ± 3 to 6.4 ± 4 L/min), stroke volume (54 ± 27 to 65 ± 38 ml), and mixed-venous oxygen saturation (69 ± 8 to 73 ± 10%), all p < 0.01. With discontinuation of iNO, all parameters returned immediately to baseline. These parameters of improved perfusion were related to a decrease in pulmonary vascular pressures and resistance. In a subset of approximately 50% of patients, these changes were substantial ( > 20%) and in approximately 25% of all patients, the improvement in hemodynamic measures permitted a decrease in other vasoactive drug administration. The mean concentration of iNO required to achieve these effects was 35 ppm, and 85% of patients exhibiting a substantial improvement in hemodynamics did so at a concentration of iNO of less than or equal to 40 ppm. Underlying causes of right heart failure and baseline hemodynamics did not predict response to iNO, but the use of α -agonist catecholamines did. We conclude iNO improves hemodynamics in patients with respiratory failure, shock, and right ventricular dysfunction. Although mortality was not a key end point in this pilot study, it was high for both responders and nonresponders to this therapy. Further evaluation of the role of iNO in this patient population is supported by these data.
Cardiac Norepinephrine Stores and the Contractile State of Heart Muscle
Authors: JAMES F. SPANN, EDMUND H. SONNENBLICK, THEODORE COOPER, CHARLES A. CHIDSEY, VALLEE L. WILLMAN, EUGENE BRAUNWALD
Journal: Circulation Research (1966)

In order to assess the role played by endogenous norepinephrine (NE) stores in the intrinsic contractile state of cardiac muscle, the right ventricular papillary muscles from normal cats and cats with cardiac NE depletion produced by chronic cardiac denervation or reserpine pretreatment were studied. The contractile state of NE-depleted ventricular myocardium was found to be normal. The resting and active length-tension curves, the forcevelocity relations, and the augmentation of isometric tension achieved by paired electrical stimulation and by increasing frequency of contraction were not depressed in either group of NE-depleted muscles. Similarly, no changes in the absolute refractory period and electrical excitability were observed. It is concluded that cardiac stores of NE are not fundamental for maintaining the intrinsic contractile state of the myocardium. Further, release of endogenous NE from cardiac muscle does not appear to play an essential role in the mediation of the positive inotropic effects of increasing frequency of contraction or of sustained postextrasystolic potentiation.
P148 Aspirin therapy is associated with reduced mortality in patients with acute lung injury: Abstract P148 Table 1.
Authors: AJB Boyle, SD Digangi, LM Mottram, UH Hamid, LM McNamee, GW White, LJMC Cross, JM McNamee, CO O'Kane, DFM McAuley
Journal: Thorax (2013)

<h3>Introduction</h3> Platelet activation has a role in the pathogenesis of ALI. Observational data suggests aspirin treatment may prevent the development of ALI in critically ill patients. However, it is unknown if aspirin usage alters outcomes in patients with established ALI. <h3>Methods</h3> All patients with ALI were identified prospectively in a single large regional medical and surgical ICU between December 2010 and July 2012. Demographic, clinical, and laboratory variables were recorded. Aspirin usage, both pre-hospital and during Intensive Care Unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate analyses to assess the impact of these variables on ICU mortality. <h3>Results</h3> Two hundred and two patients with ALI were included. 56 (28%) of these received aspirin either pre-hospital, in ICU, or both. Using multivariate logistic regression analysis, aspirin was found to be protective for ICU mortality. Additional factors that predicted ICU mortality for patients with ALI were vasopressor use and APACHE II score (Table). <h3>Conclusion</h3> Aspirin usage is associated with reduced mortality in patients with ALI. Whilst trials are ongoing to assess if aspirin can prevent ALI, these new data support the need for a clinical trial to investigate if aspirin improves outcomes in patients with established ALI.
Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer
Authors: Peng Liu, Ashwani Khurana, Ramandeep Rattan, Xiaoping He, Steve Kalloger, Sean Dowdy, Blake Gilks, Viji Shridhar
Journal: Cancer Research (2009)

Abstract We recently identified HSulf-1 as a down-regulated gene in ovarian carcinomas. Our previous analysis indicated that HSulf-1 inactivation in ovarian cancers is partly mediated by loss of heterozygosity and epigenetic silencing. Here, we show that variant hepatic nuclear factor 1 (vHNF1), encoded by transcription factor 2 gene (TCF2, HNF1β), negatively regulates HSulf-1 expression in ovarian cancer. Immunoblot assay revealed that vHNF1 is highly expressed in HSulf-1–deficient OV207, SKOV3, and TOV-21G cell lines but not in HSulf-1–expressing OSE, OV167, and OV202 cells. By short hairpin RNA–mediated down-regulation of vHNF1 in TOV-21G cells and transient enhanced vHNF1 expression in OV202 cells, we showed that vHNF1 suppresses HSulf-1 expression in ovarian cancer cell lines. Reporter assay and chromatin immunoprecipitation experiments showed that vHNF1 is specifically recruited to HSulf-1 promoter at two different vHNF1-responsive elements in OV207 and TOV-21G cells. Additionally, down-regulation of vHNF1 expression in OV207 and TOV-21G cells increased cisplatin- or paclitaxel-mediated cytotoxicity as determined by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays and this effect was reversed by down-regulation of HSulf-1. Moreover, nude mice bearing TOV-21G cell xenografts with stably down-regulated vHNF1 were more sensitive to cisplatin- or paclitaxel-induced cytotoxicity compared with xenografts of TOV-21G clonal lines with nontargeted control short hairpin RNA. Finally, immunohistochemical analysis of 501 ovarian tumors including 140 clear-cell tumors on tissue microarrays showed that vHNF1 inversely correlates to HSulf-1 expression. Collectively, these results indicate that vHNF1 acts as a repressor of HSulf-1 expression and might be a molecular target for ovarian cancer therapy. [Cancer Res 2009;69(11):4843–50]
O54 SPONTANEOUS RESOLUTION OF HEPATITIS C VIRUS INFECTION IS ASSOCIATED WITH THE PRESENCE OF ANTI-RECEPTOR ANTIBODIES IN A COHORT OF SINGLE-SOURCE OUTBREAK
Authors: R.G. Tawar, M. Roggendorf, H. Meisel, F.-L. Cosset, T. Berg, M.B. Zeisel, T.F. Baumert
Journal: Journal of Hepatology (2014)
MicroRNA-200a Promotes Anoikis Resistance and Metastasis by Targeting YAP1 in Human Breast Cancer
Authors: San-Jian Yu, Jing-Ying Hu, Xia-Ying Kuang, Jian-Min Luo, Yi-Feng Hou, Gen-Hong Di, Jiong Wu, Zhen-Zhou Shen, Hou-Yan Song, Zhi-Ming Shao
Journal: Clinical Cancer Research (2013)

The process of metastases involves the dissociation of cells from the primary tumor, penetration into the basement membrane, invasion, and exiting from the vasculature to seed and colonize distant tissues. miR-200a is involved in this multistep metastatic cascade. This study aimed to test the hypothesis that miR-200a promotes metastasis through increased anoikis resistance in breast cancer.Breast cancer cells transfected with mimic or inhibitor for miR-200a were assayed for anoikis in vitro. miR-200a expression was assessed by quantitative real-time PCR (qRT-PCR). Luciferase assays, colony formation assays, and animal studies were conducted to identify the targets of miR-200a and the mechanism by which it promotes anoikis resistance.We found that overexpression of miR-200a promotes whereas inhibition of miR-200a suppresses anoikis resistance in breast cancer cells. We identified Yes-associated protein 1 (YAP1) as a novel target of miR-200a. Our data showed that targeting of YAP1 by miR-200a resulted in decreased expression of proapoptotic proteins, which leads to anoikis resistance. Overexpression of miR-200a protected tumor cells from anoikis and promoted metastases in vivo. Furthermore, knockdown of YAP1 phenocopied the effects of miR-200a overexpression, whereas restoration of YAP1 in miR-200a overexpressed breast cancer cells reversed the effects of miR-200a on anoikis and metastasis. Remarkably, we found that YAP1 expression was inversely correlated with miR-200a expression in breast cancer clinical specimens, and miR-200a expression was associated with distant metastasis in patients with breast cancer.Our data suggest that miR-200a functions as anoikis suppressor and contributes to metastasis in breast cancer.
Haploinsufficiency in DNA Polymerase β Increases Cancer Risk with Age and Alters Mortality Rate
Authors: Diane C. Cabelof, Yuji Ikeno, Abraham Nyska, Rita A. Busuttil, Njwen Anyangwe, Jan Vijg, Larry H. Matherly, James D. Tucker, Samuel H. Wilson, Arlan Richardson, Ahmad R. Heydari
Journal: Cancer Research (2006)

Abstract This study uses a base excision repair (BER)–deficient model, the DNA polymerase β heterozygous mouse, to investigate the effect of BER deficiency on tumorigenicity and aging. Aged β-pol+/− mice express 50% less β-pol transcripts and protein (P &amp;lt; 0.05) than aged β-pol+/+ mice, showing maintenance of the heterozygous state over the life span of the mouse. This reduction in β-pol expression was not associated with an increase in mutation rate but was associated with a 100% increase in the onset of hypoploidy. Aged β-pol+/− mice exhibited a 6.7-fold increase in developing lymphoma (P &amp;lt; 0.01). Accordingly, 38% of β-pol+/− mice exhibited lymphoid hyperplasia, whereas none of the β-pol+/+ exhibited this phenotype. β-pol+/− mice were also more likely to develop adenocarcinoma (2.7-fold increase; P &amp;lt; 0.05) and more likely to develop multiple tumors, as 20% of the β-pol+/− animals died bearing multiple tumors compared with only 5% of the β-pol+/+ animals (P &amp;lt; 0.05). In spite of accelerated tumor development, no gross effect of β-pol heterozygosity was seen with respect to life span. However, the survival curves for the β-pol+/+ and β-pol+/− mice are not identical. A maximum likelihood estimation analysis showed a modest but significant (P &amp;lt; 0.05) acceleration of the age-dependent mortality rate in β-pol+/− mice. Thus, the β-pol+/− mouse represents a model in which mortality rate and tumor development are accelerated and provides evidence supporting the role of genomic maintenance in both aging and carcinogenesis. (Cancer Res 2006; 66(15): 7460-5)
The effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures
Authors: Christian F. Clarenbach, Giovanni Camen, Noriane A. Sievi, Christophe Wyss, John R. Stradling, Malcolm Kohler
Journal: European Respiratory Journal (2013)

Background:  Preliminary evidence supports an association between OSA and thoracic aortic dilatation, although potential causative mechanisms are incompletely understood; these may include an increase in aortic wall transmural pressures, induced by obstructive apnoeas and hypopnoeas.  Methods:  In patients undergoing cardiac catheterization mean blood pressure (MBP) in the thoracic aorta and oesophageal pressure were simultaneously recorded by an indwelling aortic pigtail catheter and an oesophageal catheter in randomized order during: normal breathing, simulated obstructive hypopnoea (inspiration through a threshold load), simulated obstructive apnoea (Mueller manoeuvre), and end-expiratory central apnoea. Transmural aortic pressure (aortic MBP minus oesophageal pressure) was calculated as a measure of aortic wall stress.  Results:  10 patients with a median age (range) of 64 (46-75) years were studied. Inspiration through a threshold load, Mueller manoeuvre and end-expiratory central apnoea were successfully performed and recorded in 10, 7 and 9 patients, respectively. The difference between aortic MBP and oesophageal pressure (and thus the extra aortic dilatory force) was median (quartiles) +9.3 (+5.4, +18.6) mmHg, p=0.02 during inspiration through a threshold load, +16.3 (+12.8, +19.4) mmHg, p=0.02 during the Mueller manoeuvre, and +0.4 (-4.5, +4.8) mmHg, p=0.80 during end-expiratory central apnoea.   Conclusions:  Simulated obstructive apnoea and hypopnoea increase aortic wall dilatory transmural pressures because intra-aortic pressures fall less than oesophageal pressures. Thus OSA may mechanically promote thoracic aortic dilatation.
Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study
Authors: Jean-Philippe Spano, Catherine Chodkiewicz, Joan Maurel, Ralph Wong, Harpreet Wasan, Carlo Barone, Richard Létourneau, Emilio Bajetta, Yazdi Pithavala, Paul Bycott, Peter Trask, Katherine Liau, Alejandro D Ricart, Sinil Kim, Olivier Rixe
Journal: The Lancet (2008)
Platelet-derived Growth Factor Expression and Function in Idiopathic Pulmonary Arterial Hypertension
Authors: Frédéric Perros, David Montani, Peter Dorfmüller, Ingrid Durand-Gasselin, Colas Tcherakian, Jérôme Le Pavec, Michel Mazmanian, Elie Fadel, Sacha Mussot, Olaf Mercier, Philippe Hervé, Dominique Emilie, Saadia Eddahibi, Gérald Simonneau, Rogério Souza, Marc Humbert
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Platelet-derived growth factor (PDGF) promotes the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), and may play a role in the progression of pulmonary arterial hypertension (PAH), a condition characterized by proliferation of PASMCs resulting in the obstruction of small pulmonary arteries.To analyze the expression and pathogenic role of PDGF in idiopathic PAH.PDGF and PDGF receptor mRNA expression was studied by real-time reverse transcription-polymerase chain reaction performed on laser capture microdissected pulmonary arteries from patients undergoing lung transplantation for idiopathic PAH. Immunohistochemistry was used to localize PDGF, PDGF receptors, and phosphorylated PDGFR-beta. The effects of imatinib on PDGF-B-induced proliferation and chemotaxis were tested on human PASMCs.PDGF-A, PDGF-B, PDGFR-alpha, and PDGFR-beta mRNA expression was increased in small pulmonary arteries from patients displaying idiopathic PAH, as compared with control subjects. Western blot analysis revealed a significant increase in protein expression of PDGFR-beta in PAH lungs, as compared with control lungs. In small remodeled pulmonary arteries, PDGF-A and PDGF-B mainly localized to PASMCs and endothelial cells (perivascular inflammatory infiltrates, when present, showed intensive staining), PDGFR-alpha and PDGFR-beta mainly stained PASMCs and to a lesser extent endothelial cells. Proliferating pulmonary vascular lesions stained phosphorylated PDGFR-beta. PDGF-BB-induced proliferation and migration of PASMCs were inhibited by imatinib. This effect was not due to PASMC apoptosis.PDGF may play an important role in human PAH. Novel therapeutic strategies targeting the PDGF pathway should be tested in clinical trials.
Goals of Treatment for Type 2 Diabetes
Authors: Piero Marchetti, Roberto Lupi, Silvia Del Guerra, Marco Bugliani, Valentina D'Aleo, Margherita Occhipinti, Ugo Boggi, Lorella Marselli, Matilde Masini
Journal: Diabetes Care (2009)

Type 2 diabetes is the most common form of diabetes in humans and results from a combination of genetic and acquired factors that impair β-cell function and tissue insulin sensitivity (1,2). However, there is growing evidence that β-cell dysfunction is crucial for the development and progression of this form of diabetes (3,4). Reduced β-cell functional mass in diabetes, and other categories of glucose intolerance, has been described by several authors, and decreased islet and/or β-cell volume in the pancreas of type 2 diabetic patients has been consistently reported. In addition, studies conducted in patients, and isolated islets, have shown both quantitative and qualitative defects of glucose-stimulated insulin secretion. Predictably, therefore, much interest is focused on the possibility of preserving the β-cell to prevent the onset of diabetes, or impede the progressive deterioration of glycemic control, observed after diagnosis and developing over the years. In this brief overview, several major features of β-cell dysfunction in different conditions (from normal glucose tolerance [NGT] to overt diabetes) will be described; thereafter, the possibility/feasibility of maintaining or restoring β-cell functional mass in type 2 diabetes, to prevent deterioration of glucose control, will be discussed.

Several cross-sectional and prospective studies showed that β-cell dysfunction plays a major role in determining the onset and progression of type 2 diabetes. When insulin response to an oral glucose tolerance test and insulin sensitivity during euglycemic insulin clamp were measured in 388 individuals (138 with NGT; 49 with impaired glucose tolerance [IGT], and 201 with type 2 diabetes), a progressive decline of β-cell function (with insulin release corrected for glycemic stimulus and degree of insulin resistance) was observed; this decline commenced in normal glucose tolerant subjects (5). Furthermore, in 188 subjects, spanning the range from NGT to IGT or overt diabetes, it was found that …
Phase I Study of Weekly Oxaliplatin in Relapsed or Refractory Pediatric Solid Malignancies
Authors: Birgit Geoerger, François Doz, Jean-Claude Gentet, Michele Mayer, Judith Landman-Parker, Fabienne Pichon, Pascal Chastagner, Hervé Rubie, Didier Frappaz, Anne Le Bouil, Sunil Gupta, Gilles Vassal
Journal: Journal of Clinical Oncology (2008)

To explore feasibility, maximum-tolerated dose (MTD), and recommended dose (RD) for phase II studies of weekly oxaliplatin for the treatment of relapsed or refractory pediatric solid malignancies.Eligible patients were 6 months to 21 years old, had a diagnosis of a solid malignancy, and had experienced treatment failure with at least two or more previous lines of therapy. The phase I study was multicentric, open-label, and nonrandomized. It foresaw two phases: a dose-escalation phase (comprising six levels) to find the RD and an extension at the RD to evaluate the cumulative toxicity. Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle.Forty-five patients were enrolled: 29 patients in the dose-escalation phase and 16 patients in the extension at the RD. Median age was 9.5 years (range, 2.8 to 20.0 years) and 7.8 years (range, 1.8 to 19.2 years), respectively. The dose-limiting toxicities during the first treatment cycle were grade 3 (G3) sepsis at 50 mg/m(2), G3 dysesthesia at 90 mg/m(2), and G3 dysesthesia and G3 paresthesia at 110 mg/m(2), thus the MTD and RD was 90 mg/m(2). No case of ototoxicity was reported. Stable disease was reported in seven patients (16.3%), and confirmed partial response was observed in two patients (4.7%), one with neuroblastoma and one with osteosarcoma.Oxaliplatin administered in a weekly schedule has an acceptable safety profile, different from cisplatin and carboplatin, and shows activity in children with relapsed or refractory solid tumors, suggesting further investigation in pediatric malignancies.
Phase II, Open-Label Study of Pazopanib or Lapatinib Monotherapy Compared With Pazopanib Plus Lapatinib Combination Therapy in Patients With Advanced and Recurrent Cervical Cancer
Authors: Bradley J. Monk, Luis Mas Lopez, Juan J. Zarba, Ana Oaknin, Carole Tarpin, Wichai Termrungruanglert, Jacquelyn A. Alber, Jie Ding, Melissa W. Stutts, Lini N. Pandite
Journal: Journal of Clinical Oncology (2010)

Pazopanib and lapatinib are tyrosine kinase inhibitors that target vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit or epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu), respectively. In cervical cancer, EGFR and HER2/neu overexpression and high microvascular density correlate with survival.Patients with measurable stage IVB persistent/recurrent cervical carcinoma not amenable to curative therapy and at least one prior regimen in the metastatic setting were randomly assigned in a ratio of 1:1:1 to pazopanib at 800 mg once daily, lapatinib at 1,500 mg once daily, or lapatinib plus pazopanib combination therapy (lapatinib at 1,000 mg plus pazopanib at 400 mg once daily or lapatinib at 1,500 mg plus pazopanib at 800 mg once daily). Therapy continued until progression or withdrawal because of adverse events (AEs). Primary end point was progression-free survival (PFS), and secondary end points were overall survival (OS), response rate (RR), and safety. The futility boundary was crossed at the planned interim analysis for combination therapy compared with lapatinib therapy, and the combination was discontinued.Of 230 patients enrolled, 152 were randomly assigned to the monotherapy arms: pazopanib (n = 74) or lapatinib (n = 78). Most patients (62%) had recurrent cancer. Pazopanib improved PFS (hazard ratio [HR], 0.66; 90% CI, 0.48 to 0.91; P = .013) and OS (HR, 0.67; 90% CI, 0.46 to 0.99; P = .045). Median OS was 50.7 weeks and 39.1 weeks and RRs were 9% and 5% for pazopanib and lapatinib, respectively. The only grade 3 AE > 10% was diarrhea (11% pazopanib and 13% lapatinib). Grade 4 AEs were 9% (lapatinib) and 12% (pazopanib).This study confirms the activity of antiangiogenesis agents in advanced and recurrent cervical cancer and demonstrates the benefit of pazopanib based on the prolonged PFS and favorable toxicity profile.
Does UV-A potentiate 'short contact' dithranol therapy?
Authors: H. RESHAD, J.H. BARTH, C.R. DARLEY, H. BAKER
Journal: British Journal of Dermatology (1984)

The effect of ultraviolet-A (UV-A) irradiation in combination with ‘short contact’ dithranol treatment was studied in ten patients with chronic plaque psoriasis. Increasing concentrations of dithranol were applied daily to the psoriatic plaques on both sides of the body. One side was irradiated with UV-A daily. There was no difference in the rate of clearance between the two sides. The effectiveness of ‘short contact’ dithranol was confirmed.