tbuckley/cabot-search huggingface dataset:
Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene
Authors: H. Schumann, W. Roth, C. Has, A. Volz, C. Erfurt-Berge, T.M. Magin, L. Bruckner-Tuderman
Journal: British Journal of Dermatology (2012)

Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling-Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin-2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki-67 were increased and levels of E-cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte-mediated inflammation, possibly via p120-catenin-dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.
The Pharmacokinetic-Pharmacodynamic Relationship for Total and Free Mycophenolic Acid in Pediatric Renal Transplant Recipients
Authors: Lutz T. Weber, Maria Shipkova, Victor W. Armstrong, Natalie Wagner, Ekkehard Schütz, Otto Mehls, Lothar B. Zimmerhackl, Michael Oellerich, Burkhard Tönshoff
Journal: Journal of the American Society of Nephrology (2002)

It is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organ transplantation. This open-label longitudinal study in pediatric renal transplant recipients was designed to investigate the pharmacokinetic (PK)/pharmacodynamic relationship of total and free MPA and to establish PK values for the assessment of an individual's MPA PK parameters. Fifty-four children, aged 2.2 to 17.8 yr, on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and MMF (600 mg/m(2) body surface area twice daily) were investigated 1 wk and 3 wk (initial phase) and 3 mo and 6 mo (stable phase) after renal transplantation. MPA was measured by reverse phase HPLC, free MPA by HPLC after separation by ultrafiltration. There was an association between the risk of acute rejection episodes and MPA-AUC(0-12) values or MPA predose levels; by receiver operating characteristic analysis, an AUC(0-12) of 33.8 mg x h/L in the initial phase posttransplant had a diagnostic sensitivity of 75% and a diagnostic specificity of 64% for discrimination of patients with acute rejections. The respective discrimination threshold for the MPA predose concentration was 1.2 mg/L with a sensitivity of 83% and a specificity of 64%. In contrast, high free, but not total, MPA-AUC(0-12) values were associated with an increased risk of the MMF-related side effects leukopenia and/or infections. These data indicate that therapeutic drug monitoring of MPA has the potential for optimization of MMF efficacy in this patient population by steering patients away from the low values of MPA PK variables that are associated with an increased rejection risk. For the assessment of the toxic risk of MMF regarding leukopenia and/or infections, measurement of free MPA appears to be more appropriate.
A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer.
Authors: M L Slevin, P I Clark, S P Joel, S Malik, R J Osborne, W M Gregory, D G Lowe, R H Reznek, P F Wrigley
Journal: Journal of Clinical Oncology (1989)

Etoposide is an increasingly used and well-tolerated drug in cancer medicine. Its cytotoxic action is phase-specific and it has demonstrated schedule dependency in both in vitro and animal studies, but clinical evidence of the importance of drug scheduling is uncertain. The two administration schedules of etoposide that have been compared in this randomized study of 39 patients with previously untreated extensive small-cell lung cancer treated with single-agent etoposide were 500 mg/m2 as a continuous intravenous (IV) infusion over 24 hours or five consecutive daily 2-hour infusions each of 100 mg/m2. Both regimens were repeated every 3 weeks, for a maximum of six cycles. Patients received combination chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAC) or radiotherapy on failure to respond or at relapse, depending on their Karnofsky performance status. The same therapy was used in both arms of the study. All patients are evaluable for response to etoposide. In the 24-hour arm, two patients achieved a partial remission, resulting in an overall response rate of 10%. In the 5-day schedule, 16 patients had a partial response and one had a complete remission, producing an overall response rate of 89%, which was significantly superior to that in the 24-hour arm (P less than .001). The median duration of remission to etoposide in the 5-day arm was 4.5 months. Bone marrow toxicity was similar in both schedules. Etoposide pharmacokinetics were measured in all patients, and total areas under the concentration versus time curves (AUCs) were equivalent in both regimens. This study has clearly demonstrated the importance of etoposide scheduling in humans, and the superiority of five daily infusions over a 24-hour continuous infusion. The response rate to single-agent etoposide using an efficacious schedule in extensive small-cell lung cancer has been determined to be in excess of 80%.
Repeatability and reproducibility of impulse oscillometry and body plethysmography in healthy, asthmatic and COPD subjects
Authors: Nitin Vanjare, Shweta Rasam, Satish Bhosale, Yogesh Gupta, Sundeep Salvi, Rahul Kodgule
Journal: European Respiratory Journal (2013)

Background : Impulse Oscillometry (IOS) and Body Plethysmography (BP) are highly sensitive but variable tests for lung function. The source of variability is not known. Aim : To study the repeatability and reproducibility (R&R), source of variability and effect of bronchodilator on variability of IOS and BP in healthy, asthmatic and COPD subjects. Methods : Technician 1 (T1) and Technician 2 (T2) conducted three successive IOS, BP and spirometry maneuvers. T1 repeated the 3 maneuvers of all the tests after salbutamol 400 mcg inhalation and again after 14 days. The R&R were analyzed by ANOVA method using Minitab measurement system analysis software. Results : In this ongoing study, 4 healthy, 9 asthma & 10 COPD subjects completed the study so far. Variance for resistance at 5 Hz (R5), 20 Hz (R20), R5-20, specific airway conductances sGawtot & sGaweff, residual volume (RV) and total lung capacity (TLC) were 4.78, 0.45, 2.8, 12.41, 16.9, 61.47 and 71.7 respectively.  The contribution to variance was mainly due to patient related variations (77-95%) rather R(2-10%) & R(0-17%). Repeatability improved after bronchodilation in all the parameters except sGawtot and sGaweff. The inter-day variability was mainly driven by patient-related variance.   Conclusion : IOS and BP have high R&R which further improves after bronchodilation. RV and TLC have lowest R&R.
Increased p130Cas activity induces smooth muscle cell proliferation and migration in idiopathic pulmonary arterial hypertension
Authors: Ly Tu, Frances De Man, Florence Lecerf, Charlene François, Philippe Dartevelle, Gerald Simonneau, Elie Fadel, Marc Humbert, Saadia Eddahibi, Christophe Guignabert
Journal: European Respiratory Journal (2011)

Introduction:  p130 Cas  is a docking protein integrating and regulating extracellular cues and intracellular signaling pathways that controls cell proliferation and motility. Therefore, we hypothesize that p130 Cas  contributes to excessive migration and proliferation of PA-SMCs in idiopathic Pulmonary Arterial Hypertension (iPAH).   Methods:  Protein and phosphorylation levels of p130 Cas  were quantified by Western blot in surgically resected lung specimens from iPAH-patients and normal subjects. To assess the functional role of p130 Cas  in iPAH and controls, we evaluated migration and proliferation of cultured PA-SMCs with and without p130 Cas  inhibition by siRNA.   Results:  We observed significantly elevated p130 Cas  protein expression and activity in iPAH-patients compared to controls. In addition, decreasing p130 Cas  signaling by RNA-interference reduced to similar levels both the migration and proliferative potentials of IPAH and control PA-SMCs. The decreased migration and proliferation are respectively mediated by decreased matrix metalloproteinase (MMP)-2 release and by decreased mitogen-activated protein kinase (MAPK) activation.   Conclusions:  These results demonstrate that p130 Cas  protein expression and activity induces PA-SMC proliferation and migration in iPAH, suggesting p130 Cas  as an attractive drug target for PAH therapy.
Fluorouracil Modulation in Colorectal Cancer: Lack of Improvement With N -Phosphonoacetyl- l -Aspartic Acid or Oral Leucovorin or Interferon, But Enhanced Therapeutic Index With Weekly 24-Hour Infusion Schedule—An Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study
Authors: Peter J. O’Dwyer, Judith Manola, Frank H. Valone, Louise M. Ryan, John D. Hines, Scott Wadler, Daniel G. Haller, Susan G. Arbuck, Louis M. Weiner, Robert J. Mayer, Al B. Benson
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m 2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m 2 day l, 5-FU 2,600 mg/m 2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m 2 with oral leucovorin (LV) 125 mg/m 2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m 2 with intravenous (IV) LV 600 mg/m 2 , weekly; arm E, 5-FU 750 mg/m 2 /d IV by continuous infusion for 5 days, then 750 mg/m 2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P &lt; .001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.
Mechanisms of cell injury with hepatotoxic chemicals.
Authors: J L Farber, R J Gerson
Journal: Pharmacological Reviews (1984)

Abstract : Toxic chemicals can be broadly divided into two classes. The first requires metabolism by the target cells, and the cell killing is dependent on this metabolism. The second group does not require metabolism by the target cells. Compounds that require metabolism can be further subdivided into those that are metabolized by the cytochrome P-450 mixed function oxidases, and those that are not. Much of the work on the mechanisms of action of toxic chemicals has dealt with compounds that are metabolized by mixed function oxidation, and the present discussion will focus principally on the results of these studies. There are three consequences of the metabolism of toxic chemicals by mixed function oxidases that may be responsible for the genesis of membrane alterations that may in turn relate to the genesis of lethal cell injury: 1) the formation of free radicals, 2) the formation of electrophilic products, and 3) the generation of activated oxygen species.
Atopic sensitization in Maldivian childhood asthmatics
Authors: Sukhbir Shahid
Journal: European Respiratory Journal (2013)

Background: Evaluation of various triggers of childhood asthma aids better management. There is to date no data on common allergens in childhood asthma in Maldives.  Objective: We aimed to evaluate atopic sensitization in allergic children attending our clinic.  Methods: Demography and allergy patterns of children with specific symptoms of allergy were noted. Total serum IgE, and specific IgE to 29 common food and aeroallergens were determined in each child. The values were compared in asthmatic and non-asthmatic allergic children.  Results: 205 out of 255 allergic children had childhood asthma. Their mean age, sex, total IgE did not differ from those with non-asthma allergies. Atopic dermatitis, allergic rhinitis and allergic conjunctivitis were seen in 75.1, 73.7 and 46.8% of these children. 88.2% of asthmatic children were positive to atleast one allergen. Higher sensitization was to house dust mites, egg white, wheat, cow’s milk and banana. Number and type of atopic sensitization did not differ in wheezing and non-wheezing children; except for mugwort grass sensitization which was significantly more in those with wheeze. Children with asthma alone (n=20) tended to be less atopic compared to those with asthma and other allergies (Atopy index of 4.92±1.42 vs 9.09± 0.67 respectively, p=0.06).  Conclusion: Atopic sensitization is common in asthma in Maldivian children. Children with sole asthma tended to be less atopic compared to asthmatics with other allergies. Genes, environmental pollutants and developmental causes to varying extent could be plausible reasons for non-atopic wheeze.
Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve
Authors: Rihab Bouchareb, Ablajan Mahmut, Mohamed Jalloul Nsaibia, Marie-Chloé Boulanger, Abdellaziz Dahou, Jamie-Lee Lépine, Marie-Hélène Laflamme, Fayez Hadji, Christian Couture, Sylvain Trahan, Sylvain Pagé, Yohan Bossé, Philippe Pibarot, Corey A. Scipione, Rocco Romagnuolo, Marlys L. Koschinsky, Benoît J. Arsenault, André Marette, Patrick Mathieu
Journal: Circulation (2015)

Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve.We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD.ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.
Administration of &lt;italic&gt;N&lt;/italic&gt;-Nitrosodimethylamine, &lt;italic&gt;N&lt;/italic&gt;-Nitrosopyrrolidine, or &lt;italic&gt;N′&lt;/italic&gt;-Nitrosonornicotine to Nursing Rats: Their Interactions With Liver and Kidney Nucleic Acids From Sucklings&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M I Díaz Gómez, D Tamayo, J A Castro
Journal: JNCI Journal of the National Cancer Institute (1986)

When nursing Sprague-Dawley rats were treated with [14C]N-nitrosodimethylamine [(NDMA) CAS: 62-75-9], N-nitrosopyrrolidine (CAS:930-55-2), or N'-nitrosonornicotine (CAS: 16543-55-8), the liver and kidney DNA from their 14-day-old offspring that had been nursed over a 24-hour period became labeled. Upon analysis, liver DNA from sucklings whose nursing mothers were treated with [14C]NDMA showed N7-methylguanine- and O6-methylguanine-altered bases. The results suggest that these nitrosamines, which are present in food, tobacco smoke, and in different environmental sources, are a risk not only for lactating mothers but also for the nursing infants.
Toxoplasma pneumonitis: fatal presentation of disseminated toxoplasmosis in a patient with AIDS
Authors: C Bergin, M Murphy, D Lyons, E Gaffney, FM Mulcahy
Journal: European Respiratory Journal (1992)

Toxoplasma gondii infection is an uncommon cause of pneumonitis in patients with acquired immune deficiency syndrome (AIDS). We report a case of fatal pulmonary toxoplasmosis, which clinically resembled Pneumocystis carinii pneumonia (PCP). Conventional diagnostic methods for toxoplasmosis lack sensitivity. Bronchoscopy and histological evaluation of transbronchial biopsy specimens failed to identify the infecting organism. At autopsy there was evidence of disseminated infection.
Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial
Authors: George D. Demetri, Margaret von Mehren, Robin L. Jones, Martee L. Hensley, Scott M. Schuetze, Arthur Staddon, Mohammed Milhem, Anthony Elias, Kristen Ganjoo, Hussein Tawbi, Brian A. Van Tine, Alexander Spira, Andrew Dean, Nushmia Z. Khokhar, Youn Choi Park, Roland E. Knoblauch, Trilok V. Parekh, Robert G. Maki, Shreyaskumar R. Patel
Journal: Journal of Clinical Oncology (2015)

This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen.Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring.A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm.Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.
The effect of equipment dead space on lung clearance index
Authors: Anouk Benseler, Sanja Stanojevic, Renee Jensen, Felix Ratjen
Journal: European Respiratory Journal (2014)

Background: Functional residual capacity (FRC) measured by sulfur hexafluoride (SF 6 ) multiple breath washout (MBW) is lower than FRC measured by either nitrogen (N 2 ) MBW or body plethysmography. A lower FRC should result in a higher lung clearance index (LCI); however we found SF 6 LCI to be consistently lower than N 2 LCI (PloS One 2013). In health, the difference was most pronounced in younger children. We designed a series of experiments to investigate the potential effects of equipment dead space (Vd), which is higher with N 2 MBW, on LCI measurements.  Methods: MBW was measured in triplicate in 10 healthy adults (median age 22 years) by both SF 6 MBW (Amis 2000, Innovision, Odense, Denmark) and N 2 MBW (Exhalyzer D ® , EcoMedics AG, Durnten, Switzerland) using standard Vd conditions. SF 6 MBW Vd was then increased to match that of the N 2 MBW. In 11 healthy adults we also increased N 2 MBW Vd in steps approximating 1ml/kg to mimic the spectrum of Vd to weight ratios observed in preschool children.  Results: As previously described, N 2 LCI was higher than SF 6 LCI (mean difference ± SD: 0.137 ± 0.58). When SF 6 MBW Vd was increased to be equivalent to N 2 MBW Vd, SF 6 LCI increased to be higher than standard N 2 LCI (0.273 ± 0.54). When Vd was added to the N 2 MBW system, N 2 LCI increased linearly by 0.4 units for each unit increase in weight adjusted Vd.  Conclusion: Differences in equipment Vd explain differences in LCI observed between SF 6 MBW and N 2 MBW. Furthermore, added Vd in the N 2 MBW system increases N 2 LCI to the same degree observed in preschool children where N 2 LCI is disproportionately higher. These findings have important implications for the interpretation of MBW data in young children.  Supported by NHLBI and The Irwin Family Foundation.
Serial Transplantation of Chemical Carcinogen-Induced Mouse Mammary Ductal Dysplasias&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: D Medina
Journal: JNCI Journal of the National Cancer Institute (1979)

Serial Transplantation of Chemical Carcinogen-Induced Mouse Mammary Ductal Dysplasias Get access Daniel Medina Daniel Medina Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 62, Issue 2, February 1979, Pages 397–405, https://doi.org/10.1093/jnci/62.2.397 Published: 01 February 1979 Article history Received: 12 May 1978 Accepted: 22 August 1978 Published: 01 February 1979