tbuckley/cabot-search huggingface dataset:
Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation of therapeutic trials
Authors: Josep M. Llovet, Javier Bustamante, Antoni Castells, Ramon Vilana, Maria Del Carmen Ayuso, Margarita Sala, Concepció Brú, Joan Rodés, Jordi Bruix
Journal: Hepatology (1999)

This study analyzed the natural history and prognostic factors of patients with nonsurgical hepatocellular carcinoma (HCC). Twenty variables from 102 cirrhotic patients with HCC who were not treated within prospective randomized controlled trials (RCT) were investigated through uni– and multivariate analyses. None of them was suitable for radical therapies (surgical resection, liver transplantation, or ethanol injection) or presented end–stage disease as reflected by an Okuda stage 3 or a Performance Status ≥3. Sixty–five patients were Child–Pugh A, 34 were B, and 3 were C. Most of them exhibited a preserved Performance Status Test (PST) (0 = 56; 1 = 38; 2 = 8). Tumor was solitary in 26 (≤5 cm in 16) and multinodular/massive in 76. After a median follow–up of 17 months, 79 patients died, the 1–, 2–, and 3–year survival being 54%, 40%, and 28%. The multivariate study identified PST ( P = .01), constitutional syndrome ( P = .04), vascular invasion ( P = .001), and extrahepatic spread ( P = .04) as independent predictors for mortality. The 1–, 2–, and 3–year survival for the 48 patients without adverse factors (Stage 0) was 80%, 65%, and 50%, respectively, and 29%, 16%, and 8% in the 54 patients with at least one adverse parameter (Stage I). Therefore, Stage 0 would correspond to an intermediate stage, while Stage I would represent an advanced status, before reaching an end–stage phase. In conclusion, the outcome of nonsurgical HCC is not homogeneously grim and may be predicted by assessing the presence of symptoms and of an invasive tumoral pattern. Therapeutic trials should be designed and evaluated considering these characteristics.
Heading in a New Direction: Drug Permeability in Breast Cancer Brain Metastasis
Authors: George W. Sledge
Journal: Clinical Cancer Research (2010)

Systemic therapies for breast cancer brain metastasis are largely unsuccessful. Mouse models of brain metastasis show significant heterogeneity in uptake of paclitaxel and doxorubicin, with average levels more than those seen in normal brain tissue, but significantly less than in metastases to other organs.
Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C
Authors: T Asselah, I Bieche, S Narguet, A Sabbagh, I Laurendeau, M-P Ripault, N Boyer, M Martinot-Peignoux, D Valla, M Vidaud, P Marcellin
Journal: Gut (2007)

The gold standard treatment of chronic hepatitis C (CHC) is combined pegylated interferon and ribavirin. Considering side effects and treatment cost, prediction of treatment response before therapy is important. The aim of this study was to identify a liver gene signature to predict sustained virological response in patients with CHC.Group A (training set) comprised 40 patients with CHC including 14 non-responders (NRs) and 26 sustained virological responders (SVRs). Group B (validation set) comprised 29 patients including 9 NRs and 20 SVRs. Eleven responder-relapsers were also included. A total of 58 genes associated with liver gene expression dysregulation during CHC were selected from the literature. Real-time quantitative RT-PCR assays were used to analyse the mRNA expression of these 58 selected genes in liver biopsy specimens taken from the patients before treatment.From the Group A data, three genes whose expression was significantly increased in NRs compared with SVRs were identified: IFI-6-16/G1P3, IFI27 and ISG15/G1P2. These three genes also showed significant differences in their expression profiles between NRs and SVRs in the independent sample (Group B). Supervised class prediction analysis identified a two-gene (IFI27 and CXCL9) signature, which accurately predicted treatment response in 79.3% (23/29) of patients from the validation set (Group B), with a predictive accuracy of 100% (9/9) and of 70% (14/20) in NRs and SVRs, respectively. The expression profiles of responder-relapsers did not differ significantly from those of NRs and SVRs, and 73% (8/11) of them were predicted as SVRs with the two-gene classifier.NRs and SVRs have different liver gene expression profiles before treatment. The most notable changes occurred mainly in interferon-stimulated genes. Treatment response could be predicted with a two-gene signature (IFI27 and CXCL9).
9-<i>cis</i>-Retinoic Acid Treatment Increases Serum Concentrations of α-Tocopherol in Former Smokers
Authors: Ji-Youn Han, Diane D. Liu, J. Jack Lee, Jonathan Kurie, Reuben Lotan, Waun K. Hong, Ho-Young Lee
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Low serum concentrations of antioxidants may be associated with an increased risk of cancer. Based on the accumulated evidence, we hypothesized that retinoids would elevate serum α-tocopherol. This study was designed to determine whether 9-cis-retinoic acid (9-cis-RA), the most common chemopreventive agent, could alter serum α-tocopherol in former smokers. Because hyperlipidemia is a known side effect of retinoids, we also evaluated the association between serum α-tocopherol and lipids in the same population. Experimental Design: Subjects who had stopped smoking at least 12 months before the study were randomly assigned to receive oral 9-cis-RA or placebo daily for 3 months. Clinical information and blood samples were obtained monthly; serum α-tocopherol concentrations were measured by high-performance liquid chromatography and lipid levels by enzymatic assays before treatment and every month during the treatment. Results: Of the 149 subjects in the study, 113 completed 3 months of treatment and provided samples for evaluation of serum α-tocopherol. Serum α-tocopherol levels in the 9-cis-RA group (n = 52) were higher after treatment (r = 0.445, P &amp;lt; 0.01) than before. The incidences of grade ≥2 hypertriglyceridemia and hypercholesterolemia were higher in the 9-cis-RA group than in the placebo group (P = 0.0005 and P = 0.01, respectively), but there were no serious complications related to hyperlipidemia. Conclusions: Treatment of former smokers with 9-cis-RA significantly increased their serum α-tocopherol levels, and this could be a benefit. In addition, serum α-tocopherol could serve as a biomarker for 9-cis-RA treatment.
Cytokine profile in quadriceps muscles of patients with severe COPD
Authors: E Barreiro, A M W J Schols, M I Polkey, J B Galdiz, H R Gosker, E B Swallow, C Coronell, J Gea
Journal: Thorax (2007)

<h3>Background:</h3> Systemic proinflammatory cytokines and oxidative stress have been described in association with peripheral muscle wasting and weakness of patients with severe chronic obstructive pulmonary disease (COPD), but their expression in skeletal muscle is unknown. The objectives of the present study were to determine muscle protein levels of selected cytokines in patients with COPD and to study their relationships with protein carbonylation as a marker of oxidative stress, quadriceps function and exercise capacity. <h3>Methods:</h3> We conducted a cross sectional study in which 36 cytokines were detected using a human antibody array in quadriceps specimens obtained from 19 patients with severe COPD and seven healthy controls. Subsequently, selected cytokines (tumour necrosis factor (TNF)α, TNFα receptors I and II, interleukin (IL) 6, interferon γ, transforming growth factor (TGF) β and vascular endothelial growth factor (VEGF)), as well as protein carbonylation (oxidative stress index) were determined using an enzyme linked immunosorbent assay (ELISA) in all muscles. <h3>Results:</h3> Compared with controls, the vastus lateralis of patients with COPD showed significantly lower protein ELISA levels of TNFα, which positively correlated with their quadriceps function, TNFα receptor II and VEGF. Protein ELISA levels of IL6, interferon γ and TGFβ did not differ between patients and controls. Quadriceps protein carbonylation was greater in patients and inversely correlated with quadriceps strength among them. <h3>Conclusions:</h3> These findings do not support the presence of a proinflammatory environment within the quadriceps muscles of clinically and weight stable patients with severe COPD, despite evidence for increased oxidative stress and the presence of muscle weakness.
Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival
Authors: Gwendaline Guidicelli, Florent Guerville, Sébastien Lepreux, Chris Wiebe, Olivier Thaunat, Valérie Dubois, Jonathan Visentin, Thomas Bachelet, Emmanuel Morelon, Peter Nickerson, Pierre Merville, Jean-Luc Taupin, Lionel Couzi
Journal: Journal of the American Society of Nephrology (2015)

C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.
Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein–Induced Vascular Injury
Authors: Thomas Thum, Jürgen Borlak
Journal: Circulation Research (2003)

Oxidized low-density lipoprotein (oxLDL) is an important risk factor for vascular injury. Its role on coronary vasoconstriction remains speculative. Endothelial monooxygenases (cytochrome P450s [CYPs]) are regulators of vascular tonus through production of epoxy fatty acids. We investigated the effects of oxLDL on CYP monooxygenases in human arterial coronary endothelial cells and explanted healthy and atherosclerotic aortae. We found oxLDL to induce radical oxygen species production via the action of NADPH oxidase NOX4. Intracellular radical oxygen species production prompted reduced protein expression of the transcriptional regulator nuclear factor 1 (NF-1). We identified novel DNA binding sites for NF-1 in promoter regions of CYPs. DNA binding of NF-1 was confirmed by electromobility shift assays. OxLDL repressed DNA binding of NF-1 and diminished transcript level of CYP genes targeted by this factor. The production of endothelial-derived hyperpolarization factor, a key regulator of vascular tonus, was also reduced. Repression of CYP monooxygenases was reversed, and production of endothelial-derived hyperpolarization factor was normalized after treatment of endothelium with the lectin-like oxLDL receptor antagonist κ-carrageenan or blocking of LOX-1 with a specific antibody. This suggests a mechanistic role of CYP monooxygenases in oxLDL-induced vascular injury. Therapy of endothelial dysfunction through LOX-1 receptor antagonism will be an interesting avenue to explore. The full text of this article is available online at http://www.circresaha.org.
Football incident analysis: a new video based method to describe injury mechanisms in professional football
Authors: T E Andersen, Ø Larsen, A Tenga, L Engebretsen, R Bahr
Journal: British Journal of Sports Medicine (2003)

To develop and test a new video based method for match analysis that combines football specific and medical information to achieve a better understanding of the injury mechanisms and events leading up to high risk situations.Football incident analysis (FIA) is a video based method describing incidents that may result in an injury using 19 variables and categories modified from match analysis. Videos from 35 of 76 (46%) official Norwegian under 21 matches played from 1994 to 1998 were analysed. Two football experts classified each incident on the basis of predetermined criteria, and their results were compared using interobserver and intraobserver reliability tests.kappa correlation coefficients for interobserver and intraobserver agreement were very good for 63% and 95% and good for 37% and 5% of the variables respectively. Fifty two incidents were recorded (1.6 incidents per team per match or 94 per 1000 player hours), and 16 (31%) led to injuries (0.5 injuries per match or 29 injuries per 1000 player hours). FIA results showed that 28 incidents occurred while attacking in midfield zone 2 or the attacking zone, and 24 took place while defending in the defensive zone or midfield zone 1. Midfielders were exposed in 67% of the incidents, mainly in breakdown attacks or during long attacks by the opposing team. Of the 28 incidents during offence, only one was classified as having great potential to score a goal. Most incidents (70%) were the result of tackling duels both in the offensive and defensive playing phases. Of the 21 offensive incidents resulting from tackling duels, in 19 cases the exposed player was unaware of the tackling (passive duellist).This study shows that football incident analysis is a potentially valuable tool for understanding the events leading up to injuries in football.
Intestinal phase of gastric secretion in patients with duodenal ulcer
Authors: S. J. Konturek, N. Kwiecien, W. Obtulowicz, E. Sito, J. Oleksy
Journal: Gut (1978)

In 10 healthy subjects and 10 duodenal ulcer patients the intestinal phase of gastric acid secretion was studied by intraduodenal infusion of a 10% liver extract meal (pH 7) at 400 ml/h for three hours. A gastroduodenal double lumen tube with two balloons was used to block the pylorus and to prevent duodenogastric reflux. Gastric acid response to a duodenal meal of liver extract reached a peak at the end of the first hour of infusion of the extract and was then followed by a relatively well-sustained plateau. When the figure was normalised as a percentage of peak response to pentagastrin it was about 45% in healthy subjects and 63% in duodenal ulcer patients. Serum gastrin concentration increased significantly during a duodenal meal of liver extract only in duodenal ulcer patients and not in healthy subjects. The combination of the duodenal meal of liver extract with pentagastrin infusion resulted in a significantly greater increase in acid output in duodenal ulcer patients than in healthy controls. Duodenal perfusion with a liver extract meal in which the pH was gradually decreased caused a pH-dependent reduction in acid output, but not in serum gastrin, both in the duodenal ulcer patients and in healthy subjects. This study shows that the intestinal phase in man results in a potent gastric acid stimulation which is pH-dependent, greatly augmented by pentagastrin, and more vigorous in duodenal ulcer patients than in healthy controls.
Chemical Pleurodesis for Malignant Pleural Effusions
Authors: Pamela B. Walker-Renard
Journal: Annals of Internal Medicine (1994)

Purpose: To provide information about available agents for chemical pleurodesis. Data Sources: A MEDLINE search (1966 to October 1992) was conducted using the terms malignant pleural effusion and pleurodesis. Study Selection: All articles containing references to patients with recurrent, symptomatic, malignant pleural effusions treated with chemical pleurodesis were selected and reviewed for pleurodesis regimen, number of patients treated, success rate (complete response), and adverse effects. The agents studied included doxycycline, minocycline, tetracycline, bleomycin, cisplatin, doxorubicin, etoposide, fluorouracil, interferon-β, mitomycin-c, Corynebacterium parvum, methylprednisolone, and talc. Data Extraction: Independent extraction by three observers. Results: Studies including a total of 1168 patients with malignant pleural effusions were reviewed for efficacy of the pleurodesis agent and studies including 1140 patients were reviewed for toxicity. Chemical pleurodesis produced a complete response in 752 (64%) of 1168 patients. The success rate of the pleurodesis agents varied from 0% with etoposide to 93% with talc. Corynebacterium parvum, the tetracyclines, and bleomycin had success rates of 76%, 67%, and 54%, respectively. The most commonly reported adverse effects were pain (265 of 1140, 23%) and fever (220 of 1140, 19%). Conclusions: Doxycycline and minocycline, with success rates of 72% and 86%, respectively, appear to be effective tetracycline-replacement agents in the few patients studied. Talc appears to be the most effective and least expensive agent; however, insufflation has the disadvantages of the expense of thoracoscopy and the usual need for general anesthesia. Bleomycin appears to be less effective than talc and the tetracyclines and is substantially more expensive.
Dysregulation of bacterial proteolytic machinery by a new class of antibiotics
Authors: Heike Brötz-Oesterhelt, Dieter Beyer, Hein-Peter Kroll, Rainer Endermann, Christoph Ladel, Werner Schroeder, Berthold Hinzen, Siegfried Raddatz, Holger Paulsen, Kerstin Henninger, Julia E Bandow, Hans-Georg Sahl, Harald Labischinski
Journal: Nature Medicine (2005)
Impact of Formal Continuing Medical Education
Authors: D Davis, M A O'Brien, N Freemantle, F M Wolf, P Mazmanian, A Taylor-Vaisey
Journal: JAMA (1999)

Although physicians report spending a considerable amount of time in continuing medical education (CME) activities, studies have shown a sizable difference between real and ideal performance, suggesting a lack of effect of formal CME.To review, collate, and interpret the effect of formal CME interventions on physician performance and health care outcomes.Sources included searches of the complete Research and Development Resource Base in Continuing Medical Education and the Specialised Register of the Cochrane Effective Practice and Organisation of Care Group, supplemented by searches of MEDLINE from 1993 to January 1999.Studies were included in the analyses if they were randomized controlled trials of formal didactic and/or interactive CME interventions (conferences, courses, rounds, meetings, symposia, lectures, and other formats) in which at least 50% of the participants were practicing physicians. Fourteen of 64 studies identified met these criteria and were included in the analyses. Articles were reviewed independently by 3 of the authors.Determinations were made about the nature of the CME intervention (didactic, interactive, or mixed), its occurrence as a 1-time or sequenced event, and other information about its educational content and format. Two of 3 reviewers independently applied all inclusion/exclusion criteria. Data were then subjected to meta-analytic techniques.The 14 studies generated 17 interventions fitting our criteria. Nine generated positive changes in professional practice, and 3 of 4 interventions altered health care outcomes in 1 or more measures. In 7 studies, sufficient data were available for effect sizes to be calculated; overall, no significant effect of these educational methods was detected (standardized effect size, 0.34; 95% confidence interval [CI], -0.22 to 0.97). However, interactive and mixed educational sessions were associated with a significant effect on practice (standardized effect size, 0.67; 95% CI, 0.01-1.45).Our data show some evidence that interactive CME sessions that enhance participant activity and provide the opportunity to practice skills can effect change in professional practice and, on occasion, health care outcomes. Based on a small number of well-conducted trials, didactic sessions do not appear to be effective in changing physician performance.
Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy
Authors: Takuro Arimura, Natsuko Inagaki, Takeharu Hayashi, Daisuke Shichi, Akinori Sato, Kunihiko Hinohara, Matteo Vatta, Jeffrey A Towbin, Taishiro Chikamori, Akira Yamashina, Akinori Kimura
Journal: Cardiovascular Research (2009)

Z-band alternatively spliced PDZ-motif protein (ZASP)/Cypher is a Z-disc component of which several dilated cardiomyopathy (DCM)-associated mutations have been reported. Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3 and both exons were expressed preferentially in the heart. The aim of this study was to investigate the functional alteration of ZASP/Cypher caused by the DCM-associated mutations.The yeast-two-hybrid method was used to identify the protein bound to a domain encoded by exon 4 of LDB3. Interaction of ZASP/Cypher with the binding protein was investigated in relation to the functional alterations caused by LDB3 mutations. Localization of the ZASP/Cypher-binding protein was examined at the cellular level in rat cardiomyocytes. Phosphoglucomutase 1 (PGM1), a metabolic enzyme involved in glycolysis and gluconeogenesis, was identified as a protein interacting with ZASP/Cypher. PGM1 bound to ZASP/Cypher at the domains encoded by exons 4 and 10. Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another mutation in exon 10 (Ile345Met) reduced the binding to PGM1. PGM1 showed diffuse localization in the cytoplasm of rat cardiomyocytes under standard culture conditions, and distribution at the Z-discs was observed under stressed culture conditions. Binding of endogenous PGM1 and ZASP/Cypher was found to be enhanced by stress in rat cardiomyocytes.ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The impaired binding of PGM1 to ZASP/Cypher might be involved in the pathogenesis of DCM.
Landmark article April 25, 1925: Tularemia. By Edward Francis
Authors: E. Francis
Journal: JAMA (1983)

Tularemia occurs in nature as a very fatal bacteremia of various rodents (especially rabbits) and is due to<i>Bacterium tularense</i>; it is transmissible to man as an accidental infection by the bite of an infected bloodsucking insect or tick, or by the lodgment on his hands of the blood or internal organs of an infected rodent, as in the case of market men, cooks, hunters or laboratory workers. Among the few diseases of man that have been discovered in the last fifteen years is tularemia. It is the only disease of man that has been elucidated from beginning to end by American investigators alone. These investigators have worked in widely separated states, and in most instances each made his first contribution while in ignorance of the work of the others. The first observations of each were characterized by the nature of the work for which he was especially trained; thus,