tbuckley/cabot-search huggingface dataset:
Contribution of stem-like cells to angioproliferative pulmonary arterial hypertension in the SU5416/chronic hypoxia model
Authors: Laszlo Farkas, Daniela Farkas, Donatas Kraskauskas, Aysar Alhussaini, Vita Kraskauskiene, Harm Bogaard, Norbert Voelkel
Journal: European Respiratory Journal (2012)

Severe pulmonary arterial hypertension (PAH) is a disease with high mortality and no curative treatment. The goal of our study was to investigate the potential contribution of stem-like cells to the angioobliteration in the SU5416/chronic hypoxia (SuHx) model of severe PAH.  Animals were treated according to the SuHx protocol and underwent sequential labeling with two halogenated thymidine analogues to investigate asymmetrical cell division, and treatment with the CXCR4 inhibitor AMD3100 (day 1-21) or recombinant human G-CSF (day 14-21).  After three weeks, we identified by immunofluorescence/confocal microscopy in the angioproliferative lesions of the SuHx rat model of severe PAH cells expressing markers of pluripotent stem cells and multipotent differentiation. We also showed that lesion cell division in SuHx animals was asymmetrical. The CXCR4 inhibitor AMD3100 reduced pulmonary artery muscularization and obliteration of medium size vessels in the animal model without greatly impacting PAH. This was associated with a reduction in the numbers of c-kit+ cells in the vessel.  We further show that G-CSF-induced cell mobilization from the bone marrow did not affect the PAH, but caused enhanced pulmonary artery muscularization together with pulmonary neovascularization instead, associated with an augmented accumulation of c-kit+ cells in and around the vessels.  In conclusion, our data indicate that putative stem-like cells, which express pluri- and multipotency markers, contribute to the pulmonary angioproliferation. Successful treatment of severe angioobliterative PAH will likely require a better knowledge of the role of such cells in the pathobiology of PAH.
Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein
Authors: Ali Salanti, Thomas M. Clausen, Mette Ø. Agerbæk, Nader Al Nakouzi, Madeleine Dahlbäck, Htoo Z. Oo, Sherry Lee, Tobias Gustavsson, Jamie R. Rich, Bradley J. Hedberg, Yang Mao, Line Barington, Marina A. Pereira, Janine LoBello, Makoto Endo, Ladan Fazli, Jo Soden, Chris K. Wang, Adam F. Sander, Robert Dagil, Susan Thrane, Peter J. Holst, Le Meng, Francesco Favero, Glen J. Weiss, Morten A. Nielsen, Jim Freeth, Torsten O. Nielsen, Joseph Zaia, Nhan L. Tran, Jeff Trent, John S. Babcook, Thor G. Theander, Poul H. Sorensen, Mads Daugaard
Journal: Cancer Cell (2015)
Sputum cells apoptosis by different asthma phenotypes in children
Authors: Alla Nakonechna, Jurij Antipkin, Tatjana Umanets, Vladimir Lapshyn, Tamara Zadorozhnaja, Olga Pustovalova
Journal: European Respiratory Journal (2012)

Background:  Reduced apoptosis is one important mechanism for cell accumulation and maintenance of airway inflammation by asthma. However the role of death factors and their receptors in the regulation of granulocyte apoptosis in childhood asthma is still unclear.  The aim was to determine the expression of apoptosis receptors in sputum cells by different asthma phenotypes in children.   Methods:  Seventy eight asthma children aged 6-12 years and 25 age-matched healthy controls were assessed including skin prick testing (SPT), lung function, total and antigen specific IgE, induced sputum analysis. Expression of pro-apoptotic Apo-1/Fas and Bax and anti-apoptotic Bcl-2 antigens in sputum cells were assessed using immunocytochemistry.   Results:  Among investigated children 69.2% had atopic asthma with increased total and specific IgE, positive SPT at least to one allergen. These children had mild-to-moderate asthma and sputum eosinophilia. They demonstrated decreased apoptotic ratio(AR) in sputum eosinophils that directly correlated with Apo-1/Fas and Bax expression and inversely with Bcl-2 expression and these parameters were more significant in moderate asthma than those in mild(p  In contrast 30.8% children with non-atopic asthma had moderate-to-severe asthma and induced sputum neutrophilia. Their sputum neutrophils showed decreased Apo-1/Fas and Bax and elevated Bcl-2 expression that was more significant in severe asthma group(p   Conclusion:  Our findings indicated that sputum cell apoptosis vary in different asthma phenotypes in children.  The identification of differences in the apoptosis regulation may help to define new medicines that allow specific induction of either eosinophil or neutrophil apoptosis.
Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.
Authors: M J Ratain, G Rosner, S L Allen, M Costanza, D A Van Echo, I C Henderson, R L Schilsky
Journal: Journal of Clinical Oncology (1995)

PURPOSE To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability. PATIENTS AND METHODS Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined. RESULTS The primary determinant of toxicity at a fixed dose of amonafide was the extent of N-acetylation. Fast acetylators (36% of patients) had significantly greater toxicity than slow acetylators (64% of patients), with median WBC nadirs of 500/microL and 3,400/microL, respectively (P &lt; or = .001). In a multivariate analysis, lower pretreatment WBC count, lower albumin level, and nonwhite race were also independently associated with toxicity. Further analysis of interracial differences demonstrated that minority women had slower clearance of amonafide (P = .026) and a higher incidence of grade 4 leukopenia (P = .042). CONCLUSION The highly variable toxicity of amonafide is primarily due to genetic differences in N-acetylation. Other genetic (race) and acquired factors (baseline WBC count and albumin level) also appear to influence the extent of toxicity observed following administration of this agent.
Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.
Authors: F B Stehman, B N Bundy, G Thomas, H M Keys, G d'Ablaing, W C Fowler, R Mortel, W T Creasman
Journal: Journal of Clinical Oncology (1993)

Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported.Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death.There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen.In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.
Multivariate quality of life (QoL) prognostic factor analysis in hepatocellular carcinoma (HCC)
Authors: F. Bonnetain, M. Doeffel, O. Bouche, D. Vetter, A. Abergel, S. Fratté, J. P. Grangé, J. C. Barbare, F. Masskouri, L. Bedenne
Journal: Journal of Clinical Oncology (2005)

4162 Background: The aim of this study was to explore whether pre-treatment quality of life (QoL) predicts survival in patients with non-operable HCC. Methods: Between 1995 and 2002, 123 eligible cirrhotic patients of Child-Pugh class A or B with unresectable HCC of Okuda stage I or II were included in a randomized multicentric phase III trial (FFCD 9402). At baseline, the clinician measured QoL ranging from 0 to 10 with Spitzer index. The overall survival (OS) was calculated until death or last follow-up using the Kaplan-Meier method. A univariate assessment of the prognostic effect of each baseline factor using Cox model was performed to calculated hazard ratio (HR) with 95% CI. Multivariate analysis was performed using backward stepwise Cox proportional hazards regression modeling (p = 0.05 to add and 0.10 to sort). Results: According to Spitzer QoL Index (N= 94) the median of OS ranged from 2.4 (Spitzer = 6) to 21.8 (Spitzer =10) months. It was respectively 3.9 and 18.6 months among patients with QoL < 9 (N=36) and ≥ 9 (N=58). Relevant or univariate significant factors included for multivariate analyses were: Spitzer (ordinal score, p< 0.0001), WHO performance status > 0 (p =0.015), sex (women vs men, NS), Okuda stage (II vs I, p< 0.0001), included patients by center < 6 (NS), treatment (Chemoembolization vs Tamoxifen, NS), alcohol cirrhosis (NS), Child-Pugh class (B vs A, p< 0.0001), hepatomegaly (p =0.03), hepatalgia (p< 0.0001), age ≥ 65 years, (NS), AFP ≥ 400 ng/ml (p< 0.0001), icterus (p=0.01), Diameter of the main nodule ≥ 5cm (p=0.14), tumor stage multinodular (p =0.014), and portal vein thrombosis (NS). Seven independent prognostic factors were retained by multivariate analysis: Spitzer QoL Index (HR = 0.79 [0.6 - 0.97]), Hepatalgia (HR = 2.31 [1.3 - 4.3], sex (HR = 0.49 [0.2 - 0.97], Child-Pugh (HR = 2.01 [1.2 - 3.44], AFP (HR = 2.47 [1.5 - 4.11], Center (HR = 2.46 [1.3 - 4.60]) and hepatomegaly (HR = 1.92 [1.2 - 3.12]). Conclusions: QoL could help individual HCC patient risk stratification and to plan future phase III trials. No significant financial relationships to disclose.
Therapeutic management of non-small cell lung cancers in Tunisia
Authors: Hamida Kwas, Imen Elmjendel, Ines Zendah, Amel Khattab, Habib Ghedira
Journal: European Respiratory Journal (2013)

Introduction:  Lung cancer is a public health problem in Tunisia. Its incidence in 2010 was 27.4 per 100,000 inhabitants.   Aim:  To study therapeutic strategies of NSCLC in our patients.   Patients and Methods:  Retrospective study including 106 patients treated for non small cell lung cancer (NSCLC) between January 2003 and December 2011.   Results:  The adenocarcinoma was the predominating histologic type (39 %), followed by non small cell cancer whose type was difficult to determine (29 %), squamous carcinoma (28 %) and sarcomatoid carcinoma (4 %). The cancer was classified: stage IV (60 %), stage III (24 %), stage II (8 %) and stage I (8 %). Two patients underwent surgical resection alone. Eleven patients underwent surgery with neoadjuvant or adjuvant chemotherapy. Fifteen patients were treated by radiotherapy associated with chemotherapy. Chemotherapy was administered alone in 54 cases. The other patients had only symptomatic treatment. Chemotherapy was based on cisplatin plus Gemcitabin (46 cases), plus Vinorelbine (28 cases) and plus Pemetrexed (6 cases). For patients not operated on, tumor has regressed (6 cases), remained stable (16 cases) and progressed (32 cases). Eighteen patients received second-line chemotherapy. The third line chemotherapy was indicated in 8 patients. Median survival was 7 months for patients without surgery and 30 months for those who had surgery.   Conclusion:  Lung cancer is diagnosed at an advanced stage in more than 50% of cases, which limits treatment options. This makes us insist on the importance of anti-smoking strike.
Interleukin-18 system plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions
Authors: D.V. Do, C.T. Ong, Y.T. Khoo, A. Carbone, C.P. Lim, S. Wang, A. Mukhopadhyay, X. Cao, D.H. Cho, X.Q. Wei, G. Bellone, I. Lim, T.T. Phan
Journal: British Journal of Dermatology (2011)

Summary Background Keloid scarring is a dermal fibroproliferative disorder characterized by increased fibroblast proliferation and excessive production of collagen and extracellular matrix (ECM) components. To date, the role of cytokines in keloid pathogenesis has not been completely unravelled. Interleukin (IL)-18 is a pro-inflammatory cytokine that plays important roles in wound healing, fibrogenesis and carcinogenesis. Objectives Our aim was to study the role of the IL-18 system in keloid pathogenesis. Materials and methods Expression and localization of IL-18 and its receptor (IL-18R) were investigated in normal skin and keloid tissues using Western blot and immunohistochemistry. We further studied the expression of the IL-18 system in normal and keloid-derived cell lines in a coculture model. Results Results from Western blot and immunohistochemistry revealed that IL-18, IL-18Rα and IL-18Rβ expression was elevated in keloid tissue compared with normal skin tissue. Studies on the expression of IL-18 and its antagonist, IL-18 binding protein (IL-18BP), using a coculture model demonstrated severe IL-18/IL-18BP imbalance in keloid keratinocyte/keloid fibroblast (KK/KF) cocultures with significant elevation of bioactive IL-18 whereas IL-18BP levels remained the same. This overproduction of bioactive IL-18 in keloid cocultures could be due to increased caspase-1 and decreased caspase-3 expression in keloid tissue, as well as decreased soluble IL-10 levels observed in keloid cocultures. The important inductive effects of IL-18 on KFs were further underscored by the observation that exposure of KF to IL-18 resulted in increased collagen and ECM component synthesis, and increased secretion of profibrotic cytokines such as IL-6 and IL-8. Finally, the addition of phosphatidylinositol 3-kinase (PI3K), mitogen activation protein kinase (MAPK), specificity protein 1 (Sp1) and mammalian target of rapamycin (mTOR) inhibitors inhibited IL-18 secretion in keloid cocultures. Conclusions The present study has proven that the IL-18 system plays an important role in keloid pathogenesis via epithelial–mesenchymal interactions. It also suggests a therapeutic potential of PI3K, MAPK, Sp1 and mTOR inhibitors in the treatment of keloid scarring.
Impact of the Expression Levels of Fluoropyrimidine Pathway Genes on Treatment Outcomes from Adjuvant S-1 Therapy in Gastric Cancer
Authors: J. Kim, E. Shin, J.W. Kim, H.S. Lee, Y.J. Kim, J.H. Kim, D.J. Park, H. Kim, J. Lee, K. Lee
Journal: Annals of Oncology (2014)
Risk Factors for Frequent Severe Exacerbations in Late-Onset Eosinophilic Asthma
Authors: Jantina C. de Groot, Marijke Amelink, Selma B. de Nijs, Robin Plaat, Bennie H. Reitsma, Huib Storm, Elisabeth H. D. Bel, Anneke ten Brinke
Journal: American Journal of Respiratory and Critical Care Medicine (2015)
General remodeling in the rehabilitation process through salt mine speleotherapy
Authors: Neli Claudia Bilha, Iuri Simionca
Journal: European Respiratory Journal (2013)

Introduction. Little is known about speleotherapy in salt mines from a scientific viewpoint.  Aims. To analyze the immediate and long-term clinical and biological effects of speleotherapy.  Methods. Experimental longitudinal prospective direct observed study during 3 weeks on a lot of selected volunteers and followup after 1 year. We made a complex clinical, para-clinical and biologic assessment (over 50 inflammatory, immunological and endocrinological parameters were tested). The patients also passed the SGRQ. We descended by stairs in a salt mine in our county with an organized eclectic group of 20 patients (mean age 43) with mild respiratory disease and in average shape. A multitude of factors were involved: salt mine gallery underground environment with specific micro-climate, traces of undesirable hydrocarbons, physical exercise, prayer therapy, relaxation, psychotherapy, changes in the daily routine, group interaction and friendship etc.  Results. There was an improvement in everyone9s fitness level. Respiratory symptoms were ameliorated, even for the 2 patients that did not tolerate well the conditions. The laboratory tests showed immunological, inflammatory and endocrinological benefits. The quality of life was ameliorated over a prolonged period of time. The relations between the group members continued after the end of the study.  Conclusions. The study cannot separately asses the involvement of each factor, but despite this shortcoming, the salt mine speleotherapy proves it9s potential. We confirmed that a successful rehabilitation process harmonizes body, mind and soul, thus realizing a general remodeling (a concept that I previously described).
The concept of boundaries in clinical practice: theoretical and risk- management dimensions
Authors: T G Gutheil, G O Gabbard
Journal: American Journal of Psychiatry (1993)

The authors systematically examine the concept of boundaries and boundary violations in clinical practice, particularly as they relate to recent sexual misconduct litigation. They selectively review the literature on the subject and identify critical areas that require explication in terms of harmful versus nonharmful boundary issues short of sexual misconduct. These areas include role; time; place and space; money; gifts, services, and related matters; clothing; language; self-disclosure and related matters; and physical contact. While broad guidelines are helpful, the specific impact of a particular boundary crossing can only be assessed by careful attention to the clinical context. Heightened awareness of the concepts of boundaries, boundary crossings, and boundary violations will both improve patient care and contribute to effective risk management.
Acceleration of Neutrophil Apoptosis by Glucose-Containing Peritoneal Dialysis Solutions
Authors: MARINA PENÉLOPE CATALAN, ANA REYERO, JESÚS EGIDO, ALBERTO ORTIZ
Journal: Journal of the American Society of Nephrology (2001)

Commercial, glucose-containing peritoneal dialysis (PD) solutions have deleterious effects on leukocytes and mesothelial cells that contribute to an impaired peritoneal defense. However, the molecular mechanisms of these deleterious effects are poorly understood. The effect of PD solutions on neutrophil viability, the molecular mechanisms of cell death, its functional consequences, and the possibilities for pharmacologic modulation have now been studied. The effect of newly available, bicarbonate-buffered PD solutions were further investigated. Lactate-buffered, glucose-containing PD solutions increased the apoptosis rate of cultured neutrophils (control media versus 4.25% glucose PD solution: 31 ± 3% versus 52 ± 3% apoptosis at 24 h, P < 0.001). Bicarbonate-buffered, 4.25% glucose—containing PD solutions with low concentration of glucose degradation products did not increase the rate of apoptosis. Apoptosis induced by lactate-buffered, 4.25% glucose PD solutions was not related to hyperosmolality or acidic pH and was not reproduced by increasing the glucose concentration by the addition of glucose to a commercial, lactate-buffered fluid. Neutrophil apoptosis was associated with caspase-3 activation. Inhibition of caspase-3 by the use of the caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-fmk or the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (zVAD-fmk) prevented features of apoptosis, such as morphologic changes, internucleosomal DNA degradation, and the appearance of hypodiploid cells and increased the number of viable, trypan blue—excluding neutrophils. Furthermore, zVAD-fmk increased neutrophil phagocytosis of bacteria. However, the caspase-1 inhibitor acetyl-Tyr-Val-Ala-Asp-aldehyde did not prevent cell death. These data suggest that unidentified components in commercial, lactate-buffered, high-glucose PD fluid accelerate the rate of neutrophil apoptosis. Glucose degradation products may be such unidentified components. Acceleration of neutrophil apoptosis may contribute to the impaired local defense system of patients undergoing PD.
Cardiovascular Effects of Incretin-Based Therapies
Authors: William B. White, William L. Baker
Journal: Annual Review of Medicine (2016)

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.
The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals
Authors: None Goulden, None Mcgeown, None Cunliffe
Journal: British Journal of Dermatology (1999)

Acne is principally a disorder of adolescence but persists into middle age in a small minority of individuals. There is some evidence, primarily from twin studies, to suggest that acne may be an inherited disease. We have carried out an investigation of the familial risk of persistent adult acne by studying the occurrence of this condition in first-degree relatives of patients with adult persistent acne compared with the relatives of unaffected matched controls. Two hundred and four patients over the age of 25, referred to our department with facial acne which had persisted from adolescence, were included in the study. For each patient, a detailed pedigree which included all first-degree relatives was drawn up. For all relatives over the age of 25, demographic details and the presence or absence of facial acne was recorded. One hundred and forty-four unaffected controls were recruited. These were matched with the patient group in terms of age, social class and ethnic origin. The same questions were asked of controls as of the cases, and they provided the same information on their first-degree relatives. In total, 204 acne cases and 144 non-acne control volunteers were studied, contributing 1203 and 856 first-degree relatives, respectively. Two hundred and three first-degree relatives of cases were affected with facial acne, compared with 42 first-degree relatives of volunteers. The risk of adult acne occurring in a relative of a patient with adult acne was significantly greater than for the relative of an unaffected individual (odds ratio 3.93, 95% confidence interval 2.79-5.51; P < 0.001). Our study suggests that familial factors are important in determining individual susceptibility to adult persistent facial acne. Genetic factors may determine the failure of acne-prone follicles to evolve into acne-resistant follicles in early adult life.