tbuckley/cabot-search huggingface dataset:
Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group.
Authors: S Amadori, A M Testi, M Aricò, A Comelli, M Giuliano, E Madon, G Masera, R Rondelli, L Zanesco, F Mandelli
Journal: Journal of Clinical Oncology (1993)

PURPOSE This study was conducted to assess the comparative values of allogeneic bone marrow transplantation (BMT) and autologous bone marrow transplantation (ABMT) with sequential postremission chemotherapy (SPC) in children with acute myelogenous leukemia (AML) in first remission. PATIENTS AND METHODS From March 1987 to March 1990, 161 assessable patients younger than 15 years of age with newly diagnosed AML were treated uniformly with two courses of daunorubicin and standard-dose cytarabine. After initial consolidation with a course of daunorubicin, cytarabine, and thioguanine (DAT), patients in complete remission (CR) were randomized to receive either ABMT or SPC, except for those with an HLA-matched sibling who were assigned to undergo BMT. SPC consisted of three additional courses of DAT, followed by three pairs of drugs administered sequentially for a total of six cycles. RESULTS Overall, 127 of 161 patients attained CR (79%). The estimated probabilities of survival and event-free survival (EFS) at 5 years for all patients were 42% and 25%, respectively (median follow-up, 28 months). For the 127 complete responders, the 5-year probability of disease-free survival (DFS) was 31%, with a cumulative risk of relapse of 64%. For the purpose of this study, all complete responders were evaluated for analysis of disease outcome according to the intent-to-treat principle, regardless of whether they actually received the intended therapy. The 5-year DFS was 51% for the BMT group (n = 24), significantly higher (P = .03) than that observed for the other cohorts: 21% for ABMT (n = 35), 27% for SPC (n = 37), and 34% for a group of 31 nonrandomized (NR) patients. Bone marrow relapse was the most frequent cause of postremission failure in all therapeutic subgroups, including the BMT cohort, in which no deaths attributable to the toxicity of the procedure were recorded. CONCLUSION The results of this study show that BMT is more effective than ABMT or SPC in preventing leukemia relapse and extending DFS duration in children with AML in first remission.
A molecular assay to predict survival in resected non-squamous non-small-cell lung cancer
Authors: Tin Myo Hlaing, Jeng-Shing Wang
Journal: Thorax (2012)

A molecular assay to predict survival in resected non-squamous non-small-cell lung cancer This 14-gene expression assay that uses quantitative PCR on formalin-fixed paraffin-embedded tissue samples was developed and validated and compared with conventional staging.This assay was developed in patients with resected non-squamous non-small-cell lung cancer (NSCLC) at one centre, and then validated in patients with resected stage I non-squamous NSCLC and on patients with resected stage I-III nonsquamous NSCLC in two further centres.This assay was the strongest predictor of 5-year mortality compared with clinical risk factors such as sex, age, smoking status, tumour size and even disease stage.It also outperformed criteria used to identify high-risk patients with stage I disease and differentiated low-risk, intermediate-risk and high-risk patients within all disease stages.However, this assay did not take account of the relationship between genes, nor redundancy of information, and the combination of top-ranked features might not be optimal.Additionally, lung cancers with different amounts of cancer stem cells should be considered.Although most studies focus on the prediction of signatures, the biological relevance of genes in the signature is important.More detailed clinical risk factors, such as high-tech imaging studies or cardiopulmonary exercise testing might be an option for prognosis and prediction.Prognostic and predictive markers will allow personalised medicine for patients.Further studies will tell whether this assay is of functional relevance.
Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non–Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment
Authors: Tan Min Chin, Margaret P. Quinlan, Anurag Singh, Lecia V. Sequist, Thomas J. Lynch, Daniel A. Haber, Sreenath V. Sharma, Jeffrey Settleman
Journal: Clinical Cancer Research (2008)

Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been Food and Drug Administration-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically.In a cell culture model of an erlotinib-sensitive EGFR-mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib.Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the phosphatidylinositol 3-kinase/AKT survival pathway.These preclinical findings suggest that first-line chemotherapy treatment of EGFR-mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.
Immune Checkpoint Blockade in Cancer Therapy
Authors: Michael A. Postow, Margaret K. Callahan, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2015)

Immunologic checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have demonstrated promise in a variety of malignancies. Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US Food and Drug Administration for the treatment of advanced melanoma, and additional regulatory approvals are expected across the oncologic spectrum for a variety of other agents that target these pathways. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to determine whether they enhance the efficacy of either approach alone. Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as new immunologic checkpoint blocking antibodies begin clinical investigation.
Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study
Authors: J. Menne, M. Nitschke, R. Stingele, M. Abu-Tair, J. Beneke, J. Bramstedt, J. P. Bremer, R. Brunkhorst, V. Busch, R. Dengler, G. Deuschl, K. Fellermann, H. Fickenscher, C. Gerigk, A. Goettsche, J. Greeve, C. Hafer, F. Hagenmuller, H. Haller, S. Herget-Rosenthal, B. Hertenstein, C. Hofmann, M. Lang, J. T. Kielstein, U. C. Klostermeier, J. Knobloch, M. Kuehbacher, U. Kunzendorf, H. Lehnert, M. P. Manns, T. F. Menne, T. N. Meyer, C. Michael, T. Munte, C. Neumann-Grutzeck, J. Nuernberger, H. Pavenstaedt, L. Ramazan, L. Renders, J. Repenthin, W. Ries, A. Rohr, L. C. Rump, O. Samuelsson, F. Sayk, B. M. W. Schmidt, S. Schnatter, H. Schocklmann, S. Schreiber, C. U. von Seydewitz, J. Steinhoff, S. Stracke, S. Suerbaum, A. van de Loo, M. Vischedyk, K. Weissenborn, P. Wellhoner, M. Wiesner, S. Zeissig, J. Buning, M. Schiffer, T. Kuehbacher
Journal: BMJ (2012)

<b>Objective</b> To evaluate the effect of different treatment strategies on enterohaemorrhagic <i>Escherichia coli</i> O104:H4 induced haemolytic uraemic syndrome. <b>Design</b> Multicentre retrospective case-control study. <b>Setting</b> 23 hospitals in northern Germany. <b>Participants</b> 298 adults with enterohaemorrhagic <i>E coli</i> induced haemolytic uraemic syndrome. <b>Main outcome measures</b> Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. <b>Results</b> 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% <i>v</i> 15%, P=0.03), fewer deaths (0% <i>v</i> 5%, p=0.029), required no abdominal surgery, and excreted <i>E coli</i> for a shorter duration. <b>Conclusions</b> Enterohaemorrhagic <i>E coli</i> induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.
High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects
Authors: T. F. Galvao, B. H. Brown, P. A. Hecker, K. A. O'Connell, K. M. O'Shea, H. N. Sabbah, S. Rastogi, C. Daneault, C. Des Rosiers, W. C. Stanley
Journal: Cardiovascular Research (2011)

The impact of a high-fat diet on the failing heart is unclear, and the differences between polyunsaturated fatty acids (PUFA) and saturated fat have not been assessed. Here, we compared a standard low-fat diet to high-fat diets enriched with either saturated fat (palmitate and stearate) or PUFA (linoleic and α-linolenic acids) in hamsters with genetic cardiomyopathy. Male δ-sarcoglycan null Bio TO2 hamsters were fed a standard low-fat diet (12% energy from fat), or high-fat diets (45% fat) comprised of either saturated fat or PUFA. The median survival was increased by the high saturated fat diet (P< 0.01; 278 days with standard diet and 361 days with high saturated fat)), but not with high PUFA (260 days) (n = 30–35/group). Body mass was modestly elevated (∼10%) in both high fat groups. Subgroups evaluated after 24 weeks had similar left ventricular chamber size, function, and mass. Mitochondrial oxidative enzyme activity and the yield of interfibrillar mitochondria (IFM) were decreased to a similar extent in all TO2 groups compared with normal F1B hamsters. Ca2+-induced mitochondrial permeability transition pore opening was enhanced in IFM in all TO2 groups compared with F1B hamsters, but to a significantly greater extent in those fed the high PUFA diet compared with the standard or high saturated fat diet. These results show that a high intake of saturated fat improves survival in heart failure compared with a high PUFA diet or low-fat diet, despite persistent mitochondrial defects.
Restorative proctocolectomy with ileal reservoir: a pathophysiological assessment.
Authors: R J Nicholls, P Belliveau, M Neill, M Wilks, S Tabaqchali
Journal: Gut (1981)

A metabolic and physiological assessment was carried out in 14 patients who had undergone restorative proctocolectomy with ileal reservoir more than six months previously. The haemoglobin was normal in all but one and plasma electrolytes and serum albumin, calcium, phosphorus, and red cell folate estimations were normal in all. Five patients had low serum iron levels of whom one had an iron deficiency anaemia. The 24 hour faecal fat output was normal in all patients and there was no case of vitamin B12 malabsorption as judged by the Schilling test, although four patients had marginally low values. These were not associated with increased bacterial counts in the faeces within the reservoir and there was no evidence to support a diagnosis of stagnant loop syndrome. Inflammation of the reservoir mucosa was, however, associated with higher counts of aerobic bacteria than in cases where inflammation was absent. Subtotal villous atrophy or inflammation was seen in biopsies of the reservoir in six patients. The mean faecal output per 24 hours was 659 +/- 259 g and the mean reservoir volume was 330 +/- 78 ml. Mean resting anal canal pressure was significantly lower in patients with a mucous leakage per anum than in those without, while manometry of the reservoir showed no alteration of pressure over a period of one hour before and after a meal. A positive rectosphincteric reflex was observed in nine patients.
Cavitating pulmonary nodules growing in a favourable medium
Authors: Cristiano Carbonelli, Francesca Prati, Edoardo Carretto, Alberto Cavazza, Lucia Spaggiari, Giacomo Magnani
Journal: Thorax (2013)

A 76-year-old man, non-smoker, former bricklayer, was admitted to the Infectious Diseases Unit for cough and mild fever persisting for more than 1 month. The patient had no other significant medical problems and had not recently travelled abroad. There were no significant findings on physical examination.

Biochemical examinations showed an increase in inflammatory markers (CRP 7.9 mg/dl) and neutrophilic leukocytosis (14×109/l). Quantiferon test was negative, as were the autoimmune and the oncological markers. Nodular opacities were seen in both lungs on chest x-ray, and a subsequent CT scan showed multiple nodules located in all areas, but particularly in the subpleural location. Some of these nodules had features of cavitation. No ground-glass opacities were present (figure 1A). Mediastinal lymph nodes were slightly enlarged with a maximum diameter of 20 mm. Two ultrasound-guided percutaneous biopsies of the peripheral subpleural nodules were performed, with histological evidence of a suppurative inflammatory infiltrate with negative culture results. A bronchoscopy with bronchoalveolar lavage and transbronchial biopsy showed an intra-alveolar proteinaceous material and no microorganisms (figure 1B); microbiological cultures …
Chemopreventive Effects of a Selective Nitric Oxide Synthase Inhibitor on Carcinogen-Induced Rat Esophageal Tumorigenesis
Authors: Tong Chen, Ronald G. Nines, Sarah M. Peschke, Laura A. Kresty, Gary D. Stoner
Journal: Cancer Research (2004)

Abstract The inducible nitric oxide synthase (iNOS) generates a high concentration of nitric oxide (NO) in tissues. Increased NO production is associated with many disorders including esophageal cancer. Previous studies in our laboratory demonstrated an association between increased iNOS expression and the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. On the basis of these observations, we initiated a bioassay to evaluate the ability of S,S′-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, to prevent the progression of esophageal tumors in rats preinitiated with NMBA. Rats were given s.c. injections of NMBA (0.25 mg/kg body weight) three times per week for 5 weeks. One week later, they were fed a synthetic diet containing either 50 or 100 ppm PBIT until the end of the bioassay (25 weeks). PBIT reduced the incidence of esophageal cancer from 96% in NMBA-treated rats to 83% and 77% (P &amp;lt; 0.05) in rats treated with 50 and 100 ppm PBIT, respectively. Tumor multiplicity was reduced from 3.64 ± 0.42 tumors per esophagus in NMBA-treated rats to 1.79 ± 0.25 (P &amp;lt; 0.001) and 1.50 ± 0.24 (P &amp;lt; 0.0001) in rats treated with 50 and 100 ppm PBIT, respectively. PBIT reduced the production of NO in NMBA-induced preneoplastic and papillomatous esophageal lesions when compared with comparable lesions in rats treated with NMBA only. iNOS mRNA expression was not modulated by PBIT. These observations suggest that iNOS plays a role in tumor development and that its selective inhibitor, PBIT, significantly inhibits esophageal tumor progression presumably through reducing the production of NO.
Identification and MS-assisted interpretation of genetically influenced NMR signals in human plasma
Authors: Johannes Raffler, Werner Römisch-Margl, Ann-Kristin Petersen, Philipp Pagel, Florian Blöchl, Christian Hengstenberg, Thomas Illig, Christa Meisinger, Klaus Stark, H-Erich Wichmann, Jerzy Adamski, Christian Gieger, Gabi Kastenmüller, Karsten Suhre
Journal: Genome Medicine (2013)

Nuclear magnetic resonance spectroscopy (NMR) provides robust readouts of many metabolic parameters in one experiment. However, identification of clinically relevant markers in (1)H NMR spectra is a major challenge. Association of NMR-derived quantities with genetic variants can uncover biologically relevant metabolic traits. Using NMR data of plasma samples from 1,757 individuals from the KORA study together with 655,658 genetic variants, we show that ratios between NMR intensities at two chemical shift positions can provide informative and robust biomarkers. We report seven loci of genetic association with NMR-derived traits (APOA1, CETP, CPS1, GCKR, FADS1, LIPC, PYROXD2) and characterize these traits biochemically using mass spectrometry. These ratios may now be used in clinical studies.
Diabetes and Cardiovascular Disease
Authors: Helaine E. Resnick, Barbara V. Howard
Journal: Annual Review of Medicine (2002)

▪ Abstract This review focuses on several topics related to the epidemiology of diabetes and cardiovascular disease (CVD). These include the CVD risk factors common in the metabolic syndrome, behavioral risk factors and diabetes, gender differences in the association between diabetes and CVD risk, and how the clinical definition of diabetes influences the association of diabetes and CVD. Nontraditional risk factors potentially linking diabetes and CVD are also discussed, including chronic inflammation, advanced glycation endpoints, autonomic neuropathy, sleep-disordered breathing, and genetic susceptibility to diabetes-associated CVD risk.
Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.
Authors: L Staerk Laursen, M Stokholm, K Bukhave, J Rask-Madsen, K Lauritsen
Journal: Gut (1990)

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.
Central Sleep Apnea in Left Ventricular Dysfunction
Authors: Paola A. Lanfranchi, Virend K. Somers, Alberto Braghiroli, Ugo Corra, Ermanno Eleuteri, Pantaleo Giannuzzi
Journal: Circulation (2003)

The prevalence and characteristics of sleep-disordered breathing in patients with asymptomatic left ventricular (LV) dysfunction are unknown. Therefore, we evaluated the prevalence of sleep-disordered breathing in patients with LV dysfunction without overt heart failure and tested the hypothesis that sleep-disordered breathing is linked to greater hemodynamic and autonomic impairment.We studied 47 patients with LV ejection fractions <or=40% without any history of heart failure. Central sleep apnea (CSA), as defined by an apnea-hypopnea index >or=15/h, was present in 26 patients (55%), 17 (36%) of whom had severe CSA (apnea-hypopnea index >or=30/h). Obstructive sleep apnea was evident in 5 patients (11%). The prevalence and severity of CSA were higher in patients with ischemic cardiomyopathy than in patients with nonischemic cardiomyopathy (P<0.05). Exercise tolerance and echocardiographic indices of systolic and diastolic function were similar in patients without CSA, with mild CSA, and with severe CSA. Heart rate variability was markedly depressed in patients with CSA (P<0.05). Patients with severe CSA also had a higher incidence of nonsustained ventricular tachycardia (P=0.05).CSA is highly prevalent in patients with asymptomatic LV dysfunction. The severity of CSA may not be related to the severity of hemodynamic impairment. Severe CSA is associated with impaired cardiac autonomic control and with increased cardiac arrhythmias.