bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-Catenin Activation Is Associated with Specific Clinical and Pathologic Characteristics and a Poor Outcome in Adrenocortical Carcinoma
Authors: Gaujoux Sébastien , Grabar Sophie , Fassnacht Martin , Ragazzon Bruno , Launay Pierre , Libé Rossella , Chokri Ilham , Audebourg Anne , Royer Benedict , Sbiera Silviu , Vacher-Lavenu Marie-Cécile , Dousset Bertrand , Bertagna Xavier , Allolio Bruno , Bertherat Jérôme , Tissier Frédérique 
Published: November 2010

AbstractPurpose: Activation of the Wnt/β-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of β-catenin immunohistochemistry and CTNNB1 (β-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC.Experimental design: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), β-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort).Results: In the Cochin-COMETE cohort, the presence of a β-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. β-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort.Conclusions: Wnt/β-catenin activation, confirmed by the presence of β-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC. Clin Cancer Res; 17(2); 206–11. ©2010 AACR. Clin Cancer Res; 17(2); 328–36. ©2010 AACR.
Carbon Nanotubes Enhance CpG Uptake and Potentiate Antiglioma Immunity
Authors: Zhao Dongchang , Alizadeh Darya , Zhang Leying , Liu Wei , Farrukh Omar , Manuel Edwin , Diamond Don J. , Badie Behnam 
Published: November 2010

Abstract
Purpose: Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. Because TLR9 is located intracellularly, we hypothesized that methods that enhance its internalization may also potentiate its immunostimulatory response. The goal of this study was to evaluate carbon nanotubes (CNT) as a CpG delivery vehicle in brain tumor models.
Experimental Design: Functionalized single-walled CNTs were conjugated with CpG (CNT–CpG) and evaluated in vitro and in mice bearing intracranial GL261 gliomas. Flow cytometry was used to assess CNT–CpG uptake and antiglioma immune response. Tumor growth was measured by bioluminescent imaging, histology, and animal survival.
Results: CNT–CpG was nontoxic and enhanced CpG uptake both in vitro and intracranial gliomas. CNT-mediated CpG delivery also potentiated proinflammatory cytokine production by primary monocytes. Interestingly, a single intracranial injection of low-dose CNT–CpG (but not free CpG or blank CNT) eradicated intracranial GL261 gliomas in half of tumor-bearing mice. Moreover, surviving animals exhibited durable tumor-free remission (&gt;3 months), and were protected from intracranial tumor rechallenge, demonstrating induction of long-term antitumor immunity.
Conclusions: These findings suggest that CNTs can potentiate CpG immunopotency by enhancing its delivery into tumor-associated inflammatory cells. Clin Cancer Res; 17(4); 1–12. ©2010 AACR.
Health Benefits and Cost-Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population
Authors: Dinh Tuan A. , Rosner Benjamin I. , Atwood James C. , Boland C. Richard , Syngal Sapna , Vasen Hans F. A. , Gruber Stephen B. , Burt Randall W. 
Published: November 2010

Abstract
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice. Cancer Prev Res; 4(1): 9–22. ©2010 AACR. Cancer Prev Res; 4(1); 9–22. ©2010 AACR.
Sickle Cell Disease and Transcranial Doppler Imaging
Authors: Krejza Jaroslaw , Chen Rong , Romanowicz Grzegorz , Kwiatkowski Janet L. , Ichord Rebecca , Arkuszewski Michal , Zimmerman Robert , Ohene-Frempong Kwaku , Desiderio Lisa , Melhem Elias R. 
Published: November 2010

Background and Purpose—
To establish reference values of interhemispheric differences and ratios of blood flow Doppler parameters in the terminal internal carotid artery, middle cerebral artery, and anterior cerebral artery in children with sickle cell anemia.

Methods—

Fifty-seven out of 74 recruited children (mean age, 7.8±3.4 years; range limits, 3–14 years), who were free of neurological deficits and intracranial narrowing detectable by MRA and had flow velocities <170 cm/s by conventional transcranial Doppler ultrasound, underwent transcranial color-coded duplex ultrasonography. Reference limits of flow parameters corrected and uncorrected for the angle of insonation were estimated using tolerance intervals, with
P
=0.90 for all possible data values from 95% of a population.

Results—
Reference limits for left-to-right differences in cm/s in the mean angle-corrected and uncorrected flow velocities were −56 to 53 and −72 to 75 for middle cerebral artery, −49 to 57 and −81 to 91 for anterior cerebral artery, and −55 to 64 and −73 to 78 for terminal internal carotid artery, respectively. Respective reference limits for left-to-right velocity ratios were 0.31 to 1.84 and 0.38 to 1.75 for middle cerebral artery, 0.48 to 2.99 and 0.46 to 2.89 for anterior cerebral artery, and 0.61 to 2.56 and 0.56 to 2.23 for terminal internal carotid artery.

Conclusions—
The study provides reference limits of interhemispheric differences and ratios of blood flow Doppler parameters that may be helpful in identification of intracranial arterial narrowing in children with sickle cell disease undergoing ultrasound screening for stroke prevention.
Effect of Baseline CT Scan Appearance and Time to Recanalization on Clinical Outcomes in Endovascular Thrombectomy of Acute Ischemic Strokes
Authors: Goyal Mayank , Menon Bijoy K. , Coutts Shelagh B. , Hill Michael D. , Demchuk Andrew M. 
Published: November 2010

Background and Purpose—
The Penumbra Pivotal Stroke Trial reported a 25% good outcome (modified Rankin scale score ≤2) despite an 81% recanalization rate. We evaluated the association of a favorable initial noncontrast CT and a short time to recanalization in predicting good outcome.

Methods—
Data were from the Penumbra Pivotal Stroke Trial. Baseline scans were evaluated by 2 experienced readers blinded to outcomes using ASPECTS. ASPECTS scores were dichotomized into >7 and ≤7 for primary analysis. Data on degree of recanalization based on thrombolysis in myocardial infarction scores, stroke onset to recanalization, and CT to recanalization times were obtained. Primary outcome was modified Rankin scale score ≤2 at 3 months.

Results—

Median baseline NIHSS was 18 (range, 8–34) and median baseline ASPECTS score was 6 (range, 0–10); 81.2% achieved recanalization (thrombolysis in myocardial infarction, 2–3) and (27.7%) achieved good outcome. Good outcome was significantly higher in the ASPECTS score >7 group when compared to the ASPECTS score ≤7 group (50% vs 15%; RR, 3.3; 95% CI, 1.6–6.8;
P
=0.0001). No patient with an ASPECTS score ≤4 (n=28) or without recanalization (n=16) had a good outcome. There was an interaction between baseline ASPECTS score (>7 and ≤7) and onset to recanalization time (≤300 minutes and >300 minutes) in predicting good outcome (
P
=0.06).

Conclusion—
Patients with baseline CT ASPECTS score ≤4 do not benefit from recanalization. Fast recanalization may benefit patients with evident damage on the CT scan (ASPECTS score >4). Overall, patients benefit the most with early recanalization and a favorable baseline CT scan (ASPECTS score >7).
Overweight, obesity, and strong attitudes
Authors: Magoc Dejan , Tomaka Joe , Thompson Sharon 
Published: November 2010

Background: Obesity is the leading cause of preventable death and conveys risk for diabetes, hypertension, heart disease, and stroke. Overweight and obesity are common among college students with surveys showing 35 per cent of college students to be overweight (National College Health Risk Behavioral Survey (NCHRBS), 1995). Unhealthy diets and low physical activity are the major causes. Objective: To examine rates of obesity, participation in exercise, and predictors of exercise among a predominantly Hispanic (72 per cent) college student sample. Methods: Three hundred and ninety two students completed questionnaires as part of a general health screening. Results: General participation in exercise is high (61 per cent), but the majority (69 per cent) do not meet the Centers for Disease Control and Prevention (CDC) recommendations for physical activity (PA). Also, exercise importance and gender were strong predictors of participation in physical activity and exercise in this sample. Conclusion: Strong attitudes are an important determinant of participation in PA in this sample. Future studies might explore these relationships among other ethnic/demographic groups, as well as test the effectiveness of attitude change interventions for increasing PA.
Examining differences in the stigma of depression and schizophrenia
Authors: Norman Ross M.G. , Windell Deborah , Manchanda Rahul 
Published: November 2010

Background: Although there is evidence of greater stigmatization of schizophrenia in comparison to depression, there has been little investigation of the reasons for this difference. Aims: To examine the role of beliefs about depression and schizophrenia in mediating the difference in preferred social distance towards individuals with these two disorders. Methods: In Study I, 200 undergraduates completed questionnaires concerning beliefs about depression or schizophrenia and willingness to interact with an individual who has one of the two disorders. In Study II, 103 members of a community service club completed similar measures. Results: For both samples, beliefs about likely appropriateness of social behaviour showed evidence of mediating differences in preferred level of social distance. In addition, differences in perceived danger may have been a mediator for the undergraduate sample and perceived prognosis for the service club respondents. Conclusions: Beliefs about social appropriateness, danger and prognosis, which have implications for likely costs and benefits of interaction, are more likely to mediate differences in social distance towards the disorders than beliefs concerning causation or continuity with normal experience.
Burden of care among relatives of patients with schizophrenia in midwestern Nigeria
Authors: Igberase Osayi O. , Morakinyo Olufemi , Lawani Ambrose O. , James Bawo O. , Omoaregba Joyce O. 
Published: November 2010

Background: Schizophrenia is a devastating mental disorder which places immense burden on family members. There are few studies that have explored the enormity of burden experienced by caregivers in sub-Saharan Africa. Method: Two hundred caregivers who were relatives of 200 consecutive outpatients with a diagnosis of schizophrenia and undergoing treatment at the Federal Psychiatric Hospital, Uselu, Benin, between August and November 2008, were studied. The degree of burden experienced by the caregivers was assessed using the Burden Questionnaire (BQ). The patients’ symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). Results: Mean financial burden score was significantly greater than the mean scores for burden of disruption of family routine and interaction, social stigma and subjective distress. Caregivers of unemployed patients had significantly higher mean burden scores compared to those of employed patients. Level of burden showed significant associations with caregivers’ educational level, age of patient, employment status of patients and global rating of difficulty in coping with caregiving. Conclusion: Caregivers of patients with schizophrenia experience immense burden. Public health education as well as targeted interventions in the area of employment, financial and other support for persons with mental disorders would help to ameliorate this burden.
Ron receptor deficient alveolar myeloid cells exacerbate LPS-induced acute lung injury in the murine lung
Authors: Nikolaidis Nikolaos M , Kulkarni Rishikesh M , Gray Jerilyn K , Collins Margaret H , Waltz Susan E 
Published: November 2010

Previous studies have shown that the Ron receptor tyrosine kinase is an important regulator of the acute lung inflammatory response induced by intranasal administration of bacterial LPS. Compared to wild-type mice, complete loss of the Ron receptor in all cell types in vivo was associated with increased lung damage as determined by histological analyses and several markers of lung injury including increases in pro-inflammatory cytokines such as TNF-α. Tumor-necrosis factor-α is a multifunctional cytokine secreted by macrophages, which plays a major role in inflammation and is a central mediator of several disease states including rheumatoid arthritis and sepsis. Based on increased TNF-α production observed in the Ron-deficient mice, we hypothesized that Ron receptor function in the inflammatory cell compartment is essential for the regulating lung injury in vivo. To test this hypothesis, we generated myeloid lineage-specific Ron-deficient mice. In this study, we report that loss of Ron signaling selectively in myeloid cells results in increased lung injury following intranasal administration of LPS as measured by increases in TNF-α production, ensuing neutrophil accumulation and increased lung histopathology. These findings corroborate the role of Ron receptor tyrosine kinase as a negative regulator of inflammation and further demonstrate the in vivo significance of Ron signaling selectively in myeloid cells as a major regulator of this response in vivo. These data authenticate Ron as a potential target in innate immunity and TNF-α-mediated pathologies.
Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes
Authors: Grisouard Jean , Bouillet Elisa , Timper Katharina , Radimerski Tanja , Dembinski Kaethi , Frey Daniel M , Peterli Ralph , Zulewski Henryk , Keller Ulrich , Müller Beat , Christ-Crain Mirjam 
Published: November 2010

High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold ( P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level ( P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.
PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model
Authors: Reilly Michael P. , Sinha Uma , André Pierrette , Taylor Scott M. , Pak Yvonne , DeGuzman Francis R. , Nanda Nisha , Pandey Anjali , Stolla Moritz , Bergmeier Wolfgang , McKenzie Steven E. 
Published: November 2010

AbstractHeparin-induced thrombocytopenia (HIT) is a major cause of morbidity and mortality resulting from the associated thrombosis. Extensive studies using our transgenic mouse model of HIT have shown that antibodies reactive with heparin-platelet factor 4 complexes lead to FcγRIIA-mediated platelet activation in vitro as well as thrombocytopenia and thrombosis in vivo. We tested PRT-060318 (PRT318), a novel selective inhibitor of the tyrosine kinase Syk, as an approach to HIT treatment. PRT318 completely inhibited HIT immune complex-induced aggregation of both human and transgenic HIT mouse platelets. Transgenic HIT model mice were treated with KKO, a mouse monoclonal HIT-like antibody, and heparin. The experimental group received orally dosed PRT318, whereas the control group received vehicle. Nadir platelet counts of PRT318-treated mice were significantly higher than those of control mice. When examined with a novel thrombosis visualization technique, mice treated with PRT318 had significantly reduced thrombosis. The Syk inhibitor PRT318 thus prevented both HIT immune complex-induced thrombocytopenia and thrombosis in vivo, demonstrating its activity in HIT.
Lymphomas differ in their dependence on Epstein-Barr virus
Authors: Vereide David T. , Sugden Bill 
Published: November 2010

AbstractEpstein-Barr virus (EBV) encodes oncogenic information and, oftentimes concomitant with host immunosuppression, gives rise to malignancies in all major categories of lymphoma defined by the World Health Organization.1 Here, we conditionally evicted the viral extrachromosomal genome from tumor cells in vitro to examine the role of EBV in different lymphomas, including Burkitt lymphoma (BL) and posttransplant lymphoproliferative disorder. Cells derived from 2 canonical BLs were found to have the least dependence on the virus; some required EBV to prevent the inefficient induction of apoptosis. In contrast, cells derived from a subset of BL, Wp-restricted BL, required EBV to block a robust apoptotic program that involves the up-regulation of the proapoptotic protein Bim. Wp-restricted BL cells also relied on the virus to promote efficient proliferation, a distinction that highlights the multiple contributions EBV makes to affect proliferation of its host cells. Like Wp-BL cells, posttransplant lymphoproliferative disorder cells depended on the virus to inhibit apoptosis. They furthermore required the virus to drive them out of G1/G0. Together, these results reveal a graded dependence on EBV among tumor cells that directly correlates with the number of viral genes expressed in the tumor cell.
B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice
Authors: Chu Yuanyuan , Vahl J. Christoph , Kumar Dilip , Heger Klaus , Bertossi Arianna , Wójtowicz Edyta , Soberon Valeria , Schenten Dominik , Mack Brigitte , Reutelshöfer Miriam , Beyaert Rudi , Amann Kerstin , van Loo Geert , Schmidt-Supprian Marc 
Published: November 2010

Abstract
The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose–dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.