tbuckley/cabot-search huggingface dataset:
Preclinical Differentiation between Apparently Safe and Potentially Hepatotoxic Applications of TRAIL Either Alone or in Combination with Chemotherapeutic Drugs
Authors: Tom M. Ganten, Ronald Koschny, Jaromir Sykora, Henning Schulze-Bergkamen, Peter Büchler, Tobias L. Haas, Manuela B. Schader, Andreas Untergasser, Wolfgang Stremmel, Henning Walczak
Journal: Clinical Cancer Research (2006)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) exhibits potent antitumor activity on systemic administration in nonhuman primates without deleterious side effects for normal tissue. However, there is a controversy about the potential toxicity of TRAIL on human hepatocytes. The use of different recombinant TRAIL forms only partially explains the contradicting reports on TRAIL sensitivity in primary human hepatocytes (PHH).To clarify this issue, we comprehensively tested four different recombinant forms of TRAIL for their apoptosis-inducing capacity on PHH obtained from a total of 55 human livers between day 1 and day 8 of in vitro culture.One day after single-cell isolation, all but one recombinant form of TRAIL [i.e., an untagged form of TRAIL (TRAIL.0)] induced apoptosis in PHH. Apoptosis induction by TRAIL in these cells could only be fully inhibited by concomitant blockade of TRAIL receptor 1 and TRAIL receptor 2. At day 4 of in vitro culture, when surrogate markers indicated optimal hepatocyte in vitro function, only high doses of cross-linked FLAG-TRAIL killed PHH whereas the other three recombinant TRAIL forms did not. Strikingly, cotreatment of day 4 PHH with cisplatin sensitized for TRAIL-induced apoptosis whereas 5-fluorouracil, etoposide, gemcitabine, irinotecan, or oxaliplatin, which are commonly used in the treatment of gastrointestinal cancers, did not.Our data show that whereas TRAIL alone or together with selected chemotherapeutic drugs seems to be safe, the combination of TRAIL with cisplatin is toxic to PHH.
Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development
Authors: Ugur Sahin, Michael Koslowski, Karl Dhaene, Dirk Usener, Gunda Brandenburg, Gerhard Seitz, Christoph Huber, Özlem Türeci
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Antibody-based cancer therapies have emerged as the most promising therapeutics in oncology. The purpose of this study was to discover novel targets for therapeutic antibodies in solid cancer. Experimental Design: We combined data mining and wet-bench experiments to identify strictly gastrocyte lineage–specific cell surface molecules and to validate them as therapeutic antibody targets. Results: We identified isoform 2 of the tight junction molecule claudin-18 (CLDN18.2) as a highly selective cell lineage marker. Its expression in normal tissues is strictly confined to differentiated epithelial cells of the gastric mucosa, but it is absent from the gastric stem cell zone. CLDN18.2 is retained on malignant transformation and is expressed in a significant proportion of primary gastric cancers and the metastases thereof. In addition to its orthotopic expression, we found frequent ectopic activation of CLDN18.2 in pancreatic, esophageal, ovarian, and lung tumors, correlating with distinct histologic subtypes. The activation of CLDN18.2 depends on the binding of the transcription factor cyclic AMP–responsive element binding protein to its unmethylated consensus site. Most importantly, we were able to raise monoclonal antibodies that bind to CLDN18.2 but not to its lung-specific splice variant and recognize the antigen on the surface of cancer cells. Conclusions: Its highly restricted expression pattern in normal tissues, its frequent ectopic activation in a diversity of human cancers, and the ability to specifically target this molecule at the cell surface of tumor cells qualify CLDN18.2 as a novel, highly attractive pan-cancer target for the antibody therapy of epithelial tumors.
Women's compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study
Authors: H. M Inskip, S. R Crozier, K. M Godfrey, S. E Borland, C. Cooper, S. M Robinson
Journal: BMJ (2009)

<b>Objective</b> To examine the extent to which women planning a pregnancy comply with recommendations for nutrition and lifestyle. <b>Design</b> Prospective cohort study. <b>Setting</b> Southampton, United Kingdom. <b>Participants</b> 12 445 non-pregnant women aged 20-34 recruited to the Southampton Women's Survey through general practices, 238 of whom became pregnant within three months of being interviewed. <b>Main outcome measures</b> Folic acid supplement intake, alcohol consumption, smoking, diet, and physical activity before pregnancy. <b>Results</b> The 238 women who became pregnant within three months of the interview were only marginally more likely to comply with recommendations for those planning a pregnancy than those who did not become pregnant in this period. Among those who became pregnant, 2.9% (95% confidence interval 1.2% to 6.0%) were taking 400 μg or more of folic acid supplements a day and drinking four or fewer units of alcohol a week, compared with 0.66% (0.52% to 0.82%) of those who did not become pregnant. 74% of those who became pregnant were non-smokers compared with 69% of those who did not become pregnant (P=0.08). Women in both groups were equally likely to consume five or more portions of fruit and vegetables a day (53% in each group, P=1.0), but only 57% of those who became pregnant had taken any strenuous exercise in the past three months compared with 64% in those who did not become pregnant (P=0.03). <b>Conclusion</b> Only a small proportion of women planning a pregnancy follow the recommendations for nutrition and lifestyle. Greater publicity for the recommendations is needed, but as many pregnancies are unplanned, improved nutrition and lifestyles of women of childbearing age is also required.
Evaluation of angiopoietin-2 and thrombomodulin as biomarkers for pulmonary hypertension
Authors: Svenja Lena Tiede, Insa Randaxhe, Thomas Schmidt, Henning Tiede, Friedrich Grimminger, Werner Seeger, Hossein Ardeschir Ghofrani, Ralph Theo Schermuly
Journal: European Respiratory Journal (2013)

Introduction: Angiopoietin-2 (Ang-2) was shown to be increased in plasma of idiopathic pulmonary arterial hypertension (IPAH) patients (Kumpers, P et al. European Heart Journal 2010; 31:2291–2300). On the other hand, thrombomodulin (TM) is significantly decreased in patients with IPAH and with associated forms of pulmonary arterial hypertension (Sakamaki, F et al. Circulation 2000; 102:2720-25).  Aims and objectives: To investigate whether Ang-2 and TM have potential as biomarkers for clinical use in Pulmonary Hypertension (PH).  Methods: Blood samples from patients with IPAH (n=40), PH associated with collagen vascular disease (CVD, n=40), pulmonary venous hypertension (PVH, n=40), chronic thromboembolic PH (n=40), and non-PH controls (n=40) were taken during right heart catheterization. Ang-2 and TM level was measured by ELISA in plasma and correlated with survival and hemodynamics.  Results: Ang-2 is significantly higher in plasma from CVD patients (median 4.8, IQR 10.2 ng/ml) compared to non-PH controls (median 3.3, IQR 1.7 ng/ml, p  Conclusions: TM is not a biomarker for diagnosis, prognosis or severity of disease in our cohort. Ang-2 plasma levels are associated with disease severity and prognosis.
New Frontiers in Patient-Reported Outcomes: Adverse Event Reporting, Comparative Effectiveness, and Quality Assessment
Authors: Ethan Basch
Journal: Annual Review of Medicine (2013)

Patient-reported outcomes (PROs) are data elements directly reported by patients or their surrogates about experiences with care, including symptoms, functional status, or quality of life. PROs have commonly been evaluated in clinical trials for drug and medical device development. Interest is growing in the ability to integrate PROs into additional contexts, particularly product safety evaluation, comparative effectiveness research, and measurement of care quality. This interest reflects a growing focus on patient-centeredness in health care broadly and on provisions of the US Patient Protection and Affordable Care Act of 2010. Multiple initiatives demonstrate the feasibility and value of patient reporting in these areas. Inclusion of PROs in electronic health records and hospital patient portals, as well as longitudinal registries, can facilitate use of these data for multiple analytic purposes as well as enhance delivery of care and patient-provider communication. Challenges include the logistics and cost of implementing PRO programs; missing data, particularly from hard-to-reach and ill patients; and the need for standardization of outcome measures and electronic data representation. These challenges have been surmounted in limited initiatives and now must be translated to larger implementations.
AMPK Potentiates Hypertonicity-induced Apoptosis by Suppressing NFκB/COX-2 in Medullary Interstitial Cells
Authors: Qifei Han, Xiaoyan Zhang, Rui Xue, Hang Yang, Yunfeng Zhou, Xiaomu Kong, Pan Zhao, Jing Li, Jichun Yang, Yi Zhu, Youfei Guan
Journal: Journal of the American Society of Nephrology (2011)

Cells residing in the hypertonic, hypoxic renal medulla depend on dynamic adaptation mechanisms to respond to changes in energy supply and demand. The serine/threonine kinase 5'-AMP protein kinase (AMPK) is a sensor of cellular energy status, but whether it contributes to the survival of cells in the renal medulla is unknown. Here, hypertonic conditions induced a decrease in AMPK phosphorylation within 12 hours in renal medullary interstitial cells (RMIC), followed by a gradual return to baseline levels. Activation of AMPK markedly increased hypertonicity-induced apoptosis of RMICs and suppressed both hypertonicity-induced NFκB nuclear translocation and cyclooxygenase-2 (COX-2) activation; overexpression of COX-2 significantly attenuated these effects. AMPK activation also markedly reduced generation of reactive oxygen species and nuclear expression of tonicity-responsive enhancer-binding protein, which prevented upregulation of osmoprotective genes. In vivo, pharmacologic activation of AMPK led to massive apoptosis of RMICs and renal dysfunction in the setting of water deprivation in mice. Taken together, these results identify a critical role for AMPK in the maintenance of RMIC viability and suggest that AMPK modulates the NFκB-COX-2 survival pathway in the renal medulla. Furthermore, this study raises safety concerns for the development of AMPK activators as anti-diabetic drugs, especially for patients prone to dehydration.
513 CCL20 AS POTENTIAL MEDIATOR OF INFLAMMATION AND FIBROSIS IN PATIENTS WITH ALCOHOLIC HEPATITIS: EVIDENCES OF A TRANSLATIONAL STUDY
Authors: S. Affò, O. Morales-Ibanez, D. Rodrigo-Torres, J. Altamirano, D.H. Dapito, J.M. Caviglia, V. Arroyo, P. Ginès, J. Caballería, R.F. Schwabe, R. Bataller, P. Sancho-Bru
Journal: Journal of Hepatology (2013)
Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort
Authors: Trine Tramm, Hayat Mohammed, Simen Myhre, Marianne Kyndi, Jan Alsner, Anne-Lise Børresen-Dale, Therese Sørlie, Arnoldo Frigessi, Jens Overgaard
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into “high LRR risk” and “low LRR risk” groups. PMRT significantly reduced risk of LRR in “high LRR risk” patients, whereas “low LRR risk” patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. Clin Cancer Res; 20(20); 5272–80. ©2014 AACR.
Microalbuminuria and Coronary Heart Disease Risk in an Ethnically Diverse UK Population
Authors: Therese Tillin, Nita Forouhi, Paul McKeigue, Nish Chaturvedi
Journal: Journal of the American Society of Nephrology (2005)

Microalbuminuria (MA) is a strong risk factor for subsequent chronic disease, both renal and coronary heart disease (CHD), in European origin populations, but CHD risks differ by ethnicity, and it was hypothesized that prevalence of MA and relations with CHD may also differ. Combined analyses of two population-based cohorts started in 1988 and consisted of 1460 Europeans (70% male), 946 South Asians (78% male), and 559 African Caribbeans (51% male) who resided in London and were aged 40 to 69. Baseline fasting blood, overnight urine collection, and clinical measurements were performed. Prevalent CHD was defined by clinical history or major electrocardiogram changes. Age-adjusted albumin excretion rates (AER; geometric means, mug/min) were significantly higher in African Caribbeans (men: 6.1, 95% confidence interval [CI] 5.5 to 6.7; women: 5.7, 95% CI 5.2 to 6.2) than in South Asians (men: 4.3, 95% CI 4.0 to 4.5; women 3.4, 95% CI 3.0 to 3.8) and Europeans (men: 4.5, 95% CI 4.3 to 4.8; women: 3.3, 95% CI 3.1 to 3.6). MA was associated with both prevalent CHD and CHD mortality in South Asian men (hazard ratio 2.5; 95% CI 1.3 to 4.8) and in European women (hazard ratio 13.0; 95% CI 2.6 to 64.2) but not in any other group. Greater AER in African Caribbeans and the absence of association with CHD contrast with lower AER in South Asian men and European women, both strongly associated with CHD prevalence and mortality. These differences suggest that the pathogenesis of kidney disease and its link with CHD differ by ethnicity and gender.
Insulin Sensitivity, Vascular Function, and Iron Stores in Voluntary Blood Donors
Authors: Haoyi Zheng, Milan Patel, Ritchard Cable, Lawrence Young, Stuart D. Katz
Journal: Diabetes Care (2007)

Reduced iron stores after blood donation are associated with improved vascular function and decreased cardiovascular risk. We sought to determine whether iron-dependent changes in glucose metabolism may contribute to improved vascular function in blood donors.We conducted a prospective cross-sectional study in 21 high-frequency blood donors (more than eight donations in the last 2 years) and 21 low-frequency blood donors (one to two donations in the last 2 years) aged 50-75 years. Serum markers of iron stores, whole-body insulin sensitivity index (WBISI) during oral glucose tolerance testing, and flow-mediated dilation in the brachial artery were determined in all subjects.Serum ferritin was decreased (median values 23 vs. 36 ng/ml, P < 0.05) and flow-mediated dilation in the brachial artery was increased (median values 5.9 vs. 5.3%, P < 0.05) in high-frequency donors compared with low-frequency donors, respectively, but WBISI (median values 4.8 vs. 4.7) and related measures of glucose tolerance did not differ between groups. Flow-mediated dilation significantly decreased at 1 h after oral glucose loading in both groups, but the decrease in flow-mediated dilation at 1 h did not differ between high- and low-frequency donors.High-frequency blood donation reduced serum ferritin and increased flow-mediated dilation compared with low-frequency donation but did not improve insulin sensitivity or protect the vascular endothelium from the adverse effects of acute hyperglycemia after oral glucose loading. These findings suggest that the mechanisms linking blood donation to improved vascular function are not likely related to changes in glucose metabolism.
Dose response curve of allergen and histamine in skin prick tests
Authors: R. I. Harris, M. A. Stern, H. K. Watson
Journal: Allergy (1988)

Twenty‐six Dermatophagoides pteronyssinus (D.pt.) sensitive subjects were skin prick tested in duplicate with 15 concentrations of D.pt. ranging from 0.0018 to 17.8 mg/ml, 15 concentrations of the major allergen of D.pt., antigen P 1 , ranging from 0.0002 to 1.88 mg/ml and 15 concentrations of histamine dihydrochloride solution ranging from 0.048 to 114.0 mg/ml. Weal areas and concentrations were transformed by taking logs and linear and non‐linear regression curves fitted, allowing for confounding variables, such as subject, and interactions. The weal areas over all concentrations fitted “S” shaped curves with essentially straight central portions, parallel between materials, with differences between subjects but parallel within subjects. The dose response curves of P 1 and D.pt. were coincident when the concentrations were adjusted to allow for differences in potency. The concentrations of allergen and histamine commonly used for standardisation purposes will give weals that can be plotted along a straight line, but at higher and lower concentrations the response will tail off. This accounts for previously ambiguous results. Standardisation of allergens using 10 mg/ml histamine is preferable to 1 mg/mg.
Prenatal Nicotine Exposure Blunts the Cardiorespiratory Response to Hypoxia in Lambs
Authors: Ola Hafström, Joseph Milerad, Håkan W. Sundell
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Because smoking during pregnancy is a major risk factor for late fetal death and the sudden infant death syndrome, we investigated cardiorespiratory defense mechanisms to hypoxia in 7 prenatally nicotine-exposed (N) lambs (approximate maternal dose: 0.5 mg/kg/day) and 11 control (C) lambs all at an average age of 5 days. The ventilatory response to 10% oxygen (hyperpnea) was significantly attenuated during quiet sleep in N lambs compared with C lambs and in N lambs aroused from sleep later compared with C lambs (161 +/- 90 versus 75 +/- 66 seconds, p < 0.05). The ventilatory response to hypoxia was similar in the two groups during wakefulness (W), whereas the heart rate response (tachycardia) was significantly lower in N lambs compared with C lambs during both activity states. The ventilatory response to hyperoxia was significantly lower in N lambs compared with C lambs during both activity states. Transition from W to quiet sleep was associated with a significant decrease in ventilation in C lambs but not in N lambs. In conclusion, prenatal nicotine exposure, at a dose comparable with moderate smoking, blunts major elements of the cardiorespiratory defense to hypoxia, i.e., the heart rate and ventilatory and arousal responses, and abolishes the normal decrease in ventilation during sleep compared with W.
The Wives of Drug Addicts
Authors: SUSAN D. TAYLOR, MARY WILBUR, ROBERT OSNOS
Journal: American Journal of Psychiatry (1966)

The social and psychological traits of women who marry drug addicts, and the effects of drug addiction and marriage upon each other, were studied among 16 couples seen at a psychiatric outpatient clinic for the treatment of drug users. The personality characteristics of the wives were seen as determinants of their continued involvement with weak men whom they can dominate and who make only minimal adult heterosexual demands upon them.
Transplant Renal Artery Stenosis
Authors: Simona Bruno, Giuseppe Remuzzi, Piero Ruggenenti
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Transplant renal artery stenosis (TRAS) is a recognized, potentially curable cause of posttransplant arterial hypertension, allograft dysfunction, and graft loss. It usually occurs 3 mo to 2 yr after transplantation, but early or later presentations are not uncommon. The prevalence ranges widely from 1 to 23% in different series, reflecting the heterogeneous criteria used to establish the diagnosis, the different manner of preservation of the graft, and surgical expertise. Reported cases are progressively increasing in parallel with the use of non-invasive investigation procedures, such as Doppler ultrasonography and magnetic resonance (MR) angiography, that arouse the suspicion of the disease even in less symptomatic cases. However, definitive diagnosis of hemodynamically significant stenosis rests on the use of invasive angiographic techniques. Percutaneous transluminal angioplasty (PTA) is the treatment of choice and restores kidney perfusion in 60 to 90% of cases. The risk of re-stenosis, the major drawback of the procedure, is prevented by the use of expandable endoprostheses. Surgery is indicated for stenoses that cannot be treated by PTA or that recur after it. Doppler ultrasonography is the procedure of choice to evaluate graft perfusion before and after revascularization. E-mail: [email protected]
Cardiac diastolic function and hypercapnic ventilatory responses in central sleep apnoea
Authors: P. Solin, D.M. Jackson, T. Roebuck, M.T. Naughton
Journal: European Respiratory Journal (2002)

Hyperventilation is the key factor contributing to the development of idiopathic nonhypercapnic central sleep apnoea (ICSA), where left ventricular systolic function is normal. ICSA is reported to occur in 20% of patients with left ventricular diastolic dysfunction, in whom elevated pulmonary vascular pressures and resultant increased pulmonary vagal afferent traffic may contribute to hyperventilation. The contribution of the two potential mechanisms responsible for the hyperventilation seen in the following ICSA was measured: 1) left ventricular diastolic dysfunction-induced pulmonary hypertension; and 2) increased peripheral and central hypercapnic ventilatory responses (HCVR). The pulmonary artery pressure, left ventricular diastolic function and chemosensitivity to hypercapnia were measured during wakefulness in 16 subjects with ICSA. All subjects had systolic pulmonary artery pressures &lt;3.99 kPa (&lt;30 mmHg) and only four had diastolic dysfunction. All subjects had elevated peripheral and central HCVR compared with historical normal control subjects. Diastolic dysfunction correlated with increasing age but not with HCVR or markers of central sleep apnoea severity. Idiopathic nonhypercapnic central sleep apnoea is likely to be dependent upon raised hypercapnic ventilatory responses, and not pulmonary hypertension due to left ventricular diastolic dysfunction.
Role of interleukin 6 in a murine model of Crohn's ileitis: are cytokine/anticytokine strategies the future for IBD therapies?
Authors: T T Pizarro
Journal: Gut (2006)

Although the precise causes of inflammatory bowel disease (IBD) have yet to be discovered, important therapeutic advances have resulted from the manipulation of cytokine function(s) using anticytokine/cytokine therapies, such as targeting of tumor necrosis factor. We discuss the future of this area of investigation in the context of preclinical experimentation using animal models of IBD. In particular, we pinpoint the roles played by interleukin 6 and its intracellular signalling pathways in the SAMP1/Yit murine model of Crohn's-like ileitis.