tbuckley/cabot-search huggingface dataset:
Nomograms for Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection
Authors: Hwai-I Yang, Morris Sherman, Jun Su, Pei-Jer Chen, Yun-Fan Liaw, Uchenna H. Iloeje, Chien-Jen Chen
Journal: Journal of Clinical Oncology (2010)

Purpose Counseling patients with chronic hepatitis B virus (HBV) on their individual risk of liver disease progression is challenging. This study aimed to develop nomograms for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B. Patients and Methods Two thirds of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer–Hepatitis B Virus (REVEAL-HBV) study cohort was allocated for model derivation (n = 2,435), and the remaining third was allocated for model validation (n = 1,218). Previously confirmed independent risk predictors included in three Cox proportional hazards regression models were sex, age, family history of hepatocellular carcinoma, alcohol consumption habit, serum ALT level, hepatitis B envelope antigen (HBeAg) serostatus, serum HBV DNA level, and HBV genotype. Regression coefficients were rounded into integer risk scores, and predicted risk over 5- and 10-year periods for each risk score was calculated and depicted in nomograms. The predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC) and the correlation between predicted and observed hepatocellular carcinoma risk. Results All selected risk predictors were statistically significant in all models. In each model, either HBeAg seropositivity or HBeAg seronegativity with high viral load (HBV DNA level ≥ 100,000 copies/mL) and genotype C infection had the highest risk scores. All AUROCs for risk prediction nomogram were ≥ 0.82 in both model derivation and validation sets. The correlation coefficients between the observed hepatocellular carcinoma risk and the nomogram-predicted risk were greater than 0.90 in all model derivation and validation sets. Conclusion These easy-to-use nomograms based on noninvasive clinical characteristics can accurately predict the risk of hepatocellular carcinoma in patients with chronic hepatitis B. They may facilitate risk communication between patients and clinicians.
Sulfasalazine reduces bile acid induced apoptosis in human hepatoma cells and perfused rat livers
Authors: C Rust
Journal: Gut (2005)

<b>Background:</b> Bile acid induced apoptosis in hepatocytes can be antagonised by nuclear factor κB (NFκB) dependent survival pathways. Sulfasalazine modulates NFκB in different cell types. We aimed to determine the effects of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid (5-ASA) on bile acid induced apoptosis in hepatocytes. <b>Methods:</b> Apoptosis was determined by caspase assays and immunoblotting, NFκB activation by electrophoretic mobility shift assay and reporter gene assays, generation of reactive oxygen species (ROS) fluorometrically, bile secretion gravimetrically, and bile acid uptake radiochemically and by gas chromatography in HepG2-Ntcp cells and isolated perfused rat livers. <b>Results:</b> Glycochenodeoxycholic acid (GCDCA 75 µmol/l) induced apoptosis was reduced by sulfasalazine dose dependently (1–1000 µmol/l) in HepG2-Ntcp cells whereas its metabolites 5-ASA and sulfapyridine had no effect. Sulfasalazine significantly reduced GCDCA induced activation of caspases 9 and 3. In addition, sulfasalazine activated NFκB and decreased GCDCA induced generation of ROS. Bile acid uptake was competitively inhibited by sulfasalazine. In perfused rat livers, GCDCA (25 µmol/l) induced liver injury and extensive hepatocyte apoptosis were significantly reduced by simultaneous administration of 100 µmol/l sulfasalazine: lactate dehydrogenase and glutamate-pyruvate transaminase activities were reduced by 82% and 87%, respectively, and apoptotic hepatocytes were observed only occasionally. GCDCA uptake was reduced by 45 (5)% when sulfasalazine was coadministered. However, when 50% of GCDCA (12.5 µmol/l) was administered alone, marked hepatocyte apoptosis and liver injury were again observed, questioning the impact of reduced GCDCA uptake for the antiapoptotic effect of sulfasalazine. <b>Conclusion:</b> Sulfasalazine is a potent inhibitor of GCDCA induced hepatocyte apoptosis in vitro and in the intact liver.
TRAIL Induces Receptor-Interacting Protein 1–Dependent and Caspase-Dependent Necrosis-Like Cell Death under Acidic Extracellular Conditions
Authors: Olivier Meurette, Amélie Rebillard, Laurence Huc, Gwenaëlle Le Moigne, Delphine Merino, Olivier Micheau, Dominique Lagadic-Gossmann, Marie-Thérèse Dimanche-Boitrel
Journal: Cancer Research (2007)

Abstract Tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pHe), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pHe (7.4), could be sensitized to TRAIL at acidic pHe (6.5). However, at this acidic pHe, cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pHe in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pHe (7.4), it was not cleaved following TRAIL treatment at acidic pHe (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pHe, showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pHe conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pHe. [Cancer Res 2007;67(1):218–26]
Genetic Engineering of Hematopoiesis for Targeted IFN-α Delivery Inhibits Breast Cancer Progression
Authors: Giulia Escobar, Davide Moi, Anna Ranghetti, Pinar Ozkal-Baydin, Mario Leonardo Squadrito, Anna Kajaste-Rudnitski, Attilio Bondanza, Bernhard Gentner, Michele De Palma, Roberta Mazzieri, Luigi Naldini
Journal: Science Translational Medicine (2014)

The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγ(null)) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression. By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.
Allergenic pollen records (15 years) and sensitization in patients with respiratory allergy in Thessaloniki, Greece
Authors: D. Gioulekas, D. Papakosta, A. Damialis, F. Spieksma, P. Giouleka, D. Patakas
Journal: Allergy (2004)

Very limited allergenic pollen records exist in Greece so far; moreover, there is a lack of investigation on patient sensitization. The above data are necessary for respiratory allergy diagnosis and treatment worldwide.Daily records and identification of 16 airborne pollen species were made using a Burkard trap (1987-2001). Skin sensitivity to 13 most common pollen extracts was investigated, in a sample of 1311 asthmatics with atopy, admitted to the Out-Patient Clinic for Asthma (1990-2001). Skin sensitivity to 55 allergens, including 13 pollen extracts, was detected by skin prick test.The following pollen concentrations were recorded: cypress (24.9% of the total), oak (20.8%), wall pellitory (13.6%), olive (9.1%), pine (8.9%), grasses (6.3%), plane (5.4%), hazel (3%), goosefoot (2.5%) and poplar (1.4%). The respective percentages of birch, ragweed, mugwort, willow, alder and elm were lower than 1%. The highest counts of airborne pollen grains were detected from March to June. Regarding patient sensitization, sensitivity was detected to: grasses in 530 patients (40.4%), olive 417 (31.8%), goosefoot 240 (18.3%), wall pellitory 201 (15.3%), mugwort 198 (15.1%), plantain 194 (14.6%), cypress 166 (12.7%), hazel 126 (9.6%), pine 122 (9.3%), poplar 111 (8.4%), plane 107 (8,2%), oak 99 (7.6%) and to birch 89 patients (6.8%). The sensitivity to pollen grains displays preponderance (57.9%) to males.For the first time in Thessaloniki, Greece, 15-year allergenic pollen records were conducted. Clinical observations confirm that the pollen mainly implicated in respiratory allergy symptoms are grasses, olive and wall pellitory.
Peak expiratory flow (PEF) as a predictive factor of elevated fraction exhaled nitric oxide (FENO) in young healthy swimmers in indoor chlorinated pools
Authors: Sotiria Peletidou, George Vavougios, Stavrou Vasileios, Eleni Karetsi, Konstantinos Gourgoulianis, Zoe Daniil
Journal: European Respiratory Journal (2013)

INTRODUCTION: FENO testing is used in everyday clinical practice as a supplementary diagnostic and treatment monitoring tool in asthma. Furthermore, it contributes to the identification of patients at risk of exacerbation. Several epidemiological studies have pointed out that childhood indoor swimming pool attendance is implicated in the onset or triggering of asthma. Exposure to chlorine and its by-products is thought to be a key event in the development of the aforementioned pathology. However, FENO testing usefulness may vary depending on the clinical context.  OBJECTIVE:The aim of the present study is to identify FENO subgroups in a population of young healthy swimmers and assess possible predictive factors that would determine group allocation.  METHODS: We examined 77 children and young healthy adolescents, 10 to 18 yrs old, who had attended indoor swimming pools. FENO measurements and spirometry were performed both before and after exercise.  RESULTS: Cluster analysis identified two distinct groups regarding post exercise FENO measurements: Group A and B, with mean FENO 23.11±1.7 and 5.52±4.2 respectively. Baseline PEF was the most important determinant of cluster membership (F=4.4, p=0.040). Clusters differed significantly regarding baseline FEV1/FVC (p=0.007), PEF (p=0.007), FEF25-75 (p=0.032) and post exercise PEF (P=0.041).  CONCLUSIONS: The preliminary findings of our study, suggest that baseline PEF may be a significant determinant of post exercise FENO in healthy indoor swimmers.
Human Ehrlichioses: Newly Recognized Infections Transmitted by Ticks
Authors: J. Stephen Dumler, Johan S. Bakken
Journal: Annual Review of Medicine (1998)

Human ehrlichioses are tick-borne infections caused by bacteria in the genus Ehrlichia. Human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis and human granulocytic ehrlichiosis is caused by an agent similar to Ehrlichia equi. E. chaffeensis infects mononuclear phagocytes and is transmitted by Lone Star ticks (Amblyomma americanum) found in the south central and eastern United States. The agent of human granulocytic ehrlichiosis infects mostly neutrophils, is transmitted by Ixodes species ticks, and occurs mostly in the upper midwest and northeast United States. Despite the undifferentiated presentation of both ehrlichioses with fever, headache, myalgias, leukopenia, thrombocytopenia, and elevated liver enzyme activities, the diagnostic methods are distinct. Occasional severe complications include meningoencephalitis, adult respiratory distress syndrome, shock, and opportunistic infections. Immunocompromised patients are at high risk for death. An adverse outcome is associated with delayed diagnosis and therapy; thus, empirical treatment is advocated. Treatment with doxycycline usually results in prompt defervescence and cure.
The pathogenic consequences of a single mutated CFTR gene
Authors: U. Griesenbach, D. M. Geddes, E. W. Alton
Journal: Thorax (1999)

Background.Cystic fibrosis is a recessive disorder mainly characterized by lung disease.We tested the hypothesis that individuals heterozygous for the common cystic fibrosis F508 mutation are at risk of obstructive pulmonary disease.Methods.We studied a cross-sectional sample from the general population of Copenhagen, Denmark, aged 20 years and older.We did spirometry to measure forced expiratory volume in 1s (FEV 1 ) and forced vital capacity (FVC), and did genotyping on blood samples of 9141 individuals.We asked for information on smoking and other factors that could have contributed to obstructive pulmonary disease.Findings.We identified 250 carriers of the F508 mutation (2.7% [95% CI 2.5 to 3.1]).9% of carriers reported having asthma compared with 6% of non-carriers (p= 0.04).The odds ratio for asthma in participants heterozygous for F508 mutations was 2.0 (1.2 to 3.5, p=0.02).Furthermore, among individuals with airway obstruction, the percentage predicted FEV 1 and FVC were significantly lower in participants heterozygous for F508 than in non-carriers (49 vs 58%, p=0.004; and 70 vs 82%, p<0.001, respectively), mainly due to an effect in those with self-reported asthma.Interpretation.Cystic fibrosis F508 heterozygosity may be over-represented among people with asthma and seems to be associated with decreased pulmonary function in people with airway obstruction who also have asthma.(
Respiratory Effects of Relocating to Areas of Differing Air Pollution Levels
Authors: EDWARD L. AVOL, W. JAMES GAUDERMAN, SYLVIA M. TAN, STEPHANIE J. LONDON, JOHN M. PETERS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We studied 110 children (59 boys and 51 girls, who were 10 yr of age at enrollment and 15 yr of age at follow-up) who had moved from communities participating in a 10-yr prospective study of respiratory health (The Children's Health Study [CHS]) to determine whether changes in air quality caused by relocation were associated with changes in annual lung function growth rates. The subjects were given health questionnaires and underwent spirometry in their homes across six western states, according to a protocol identical to evaluations performed annually on the CHS cohort in school. Changes in annual average exposure to particulate matter with a mean diameter of 10 μ m (PM10) were associated with differences in annual lung function growth rates for FEV1, maximal midexpiratory flow, and peak expiratory flow rate. As a group, subjects who had moved to areas of lower PM10 showed increased growth in lung function and subjects who moved to communities with a higher PM10 showed decreased growth in lung function. A stronger trend was found for subjects who had migrated at least 3 yr before the follow-up visit than for those who had moved in the previous 1 to 2 yr. We conclude that changes in air pollution exposure during adolescent growth years have a measurable and potentially important effect on lung function growth and performance.
ECT2 regulates the Rho/ERK signalling axis to promote early recurrence in human hepatocellular carcinoma
Authors: Jianxiang Chen, Hongping Xia, Xiaoqian Zhang, Sekar Karthik, Seshachalam Veerabrahma Pratap, London Lucien Ooi, Wanjin Hong, Kam M. Hui
Journal: Journal of Hepatology (2015)
Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods
Authors: C. D. van Ginkel, B. M. J. Flokstra-de Blok, B. J. Kollen, J. Kukler, G. H. Koppelman, A. E. J. Dubois
Journal: Allergy (2015)

The aim of this study was to assess the genetic association of Filaggrin loss-of-function (FLG LOF) genetic variants with food allergy, and to investigate the added value of this test in diagnosing food allergy. Clinical reactivity to foods was diagnosed by the gold standard, the double-blind, placebo-controlled food challenge. Of 155 children, 33 (21.3%) children had at least one FLG LOF variant, and of these, 29 (87.9%) were clinically reactive to at least one food, compared to 73 of 122 children (59.8%) carrying wild-type alleles. The odds ratio for having at least one FLG LOF variant and clinical reactivity to at least one food was 4.9 (CI = 1.6-14.7, P = 0.005), corresponding to a relative risk of 1.5, compared to carriers of wild-type alleles. Prediction of food allergy improved when FLG LOF variants were included in the model. Therefore, genetic markers may be useful as an addition to clinical assessment in the diagnosis of food allergy.
Comparing structural variations and performance of heart in regular practice and longtime practice lack
Authors: Maesoomeh Khorshidi Mehr, Seyed Ziae Moeini, Hossein Sepasi
Journal: British Journal of Sports Medicine (2010)

The purpose of this research was to compare structural variations and performance of left ventricle heart of athletes in regular practice and long time practice lack. In this research, 30 female athletes were selected. Two groups of 15 females playing basketball and aged 18–29 years in regular and long time practice lack groups were formed in Khuzestan. Some variables in these two stages of test were stroke volume, ejection fraction, heart rate and end systolic diameter that were evaluated by 1D, 2D and Doppler methods in rest situation. The main result of this article is positive effect of regular practice for basketball in performance of left ventricle paid and analysed in the paper.
p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis
Authors: Rubeta N. Matin, Anissa Chikh, Stephanie Law Pak Chong, David Mesher, Manuela Graf, Paolo Sanza’, Valentina Senatore, Maria Scatolini, Francesca Moretti, Irene M. Leigh, Charlotte M. Proby, Antonio Costanzo, Giovanna Chiorino, Rino Cerio, Catherine A. Harwood, Daniele Bergamaschi
Journal: The Journal of Experimental Medicine (2013)

The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.
Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial
Authors: Samuel A. Wells, Bruce G. Robinson, Robert F. Gagel, Henning Dralle, James A. Fagin, Massimo Santoro, Eric Baudin, Rossella Elisei, Barbara Jarzab, James R. Vasselli, Jessica Read, Peter Langmuir, Anderson J. Ryan, Martin J. Schlumberger
Journal: Journal of Clinical Oncology (2011)

There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC.Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).