bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11
Authors: Sepulveda Fernando E. , Debeurme Franck , Ménasché Gaël , Kurowska Mathieu , Côte Marjorie , Pachlopnik Schmid Jana , Fischer Alain , de Saint Basile Geneviève 
Published: November 2012

Abstract
Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.
Incremental value in outcome prediction with gene expression–based signatures in diffuse large B-cell lymphoma
Authors: Hong Fangxin , Kahl Brad S. , Gray Robert 
Published: November 2012

AbstractMultiple gene expression–based signatures have been identified in diffuse large B-cell lymphoma that are predictive for survival outcomes. Most studies assess predictive significance based on P values from multivariable Cox regression. Few investigations have evaluated the incremental usefulness of these signatures. Recent developments in statistical methodology extend the use of concordance measures on censored survival data. We applied these methods to evaluate the added value in survival risk prediction from 3 published gene-based signatures on 2 sets of patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Our results indicate these gene-based signatures are inferior to clinical factors and provide little added value in risk assessment. To develop highly discriminating risk prediction models, we need to use appropriate approaches and consider more than gene expression. However, the study of gene expression and clinical outcomes retains considerable potential to enhance understanding of disease mechanisms and uncover new therapeutic targets.
Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas
Authors: Gaudio Eugenio , Paduano Francesco , Ngankeu Apollinaire , Lovat Francesca , Fabbri Muller , Sun Hui-Lung , Gasparini Pierluigi , Efanov Alexey , Peng Yong , Zanesi Nicola , Shuaib Mohammed A. , Rassenti Laura Z. , Kipps Thomas J. , Li Chenglong , Aqeilan Rami I. , Lesinski Gregory B. , Trapasso Francesco , Croce Carlo M. 
Published: November 2012

AbstractT-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.
Some Hermite-Hadamard type inequalities for n-time differentiable "Equation missing" -convex functions
Authors: Bai Shu-Ping , Wang Shu-Hong , Qi Feng 
Published: November 2012

Abstract
In the paper, the famous Hermite-Hadamard integral inequality for convex functions is generalized to and refined as inequalities for n-time differentiable functions which are

(
α
,
m
)

-convex.

MSC: 26D15, 26A51, 41A55.
A standard numbering scheme for thiamine diphosphate-dependent decarboxylases
Authors: Vogel Constantin , Widmann Michael , Pohl Martina , Pleiss Jürgen 
Published: November 2012

Abstract

Background
Standard numbering schemes for families of homologous proteins allow for the unambiguous identification of functionally and structurally relevant residues, to communicate results on mutations, and to systematically analyse sequence-function relationships in protein families. Standard numbering schemes have been successfully implemented for several protein families, including lactamases and antibodies, whereas a numbering scheme for the structural family of thiamine-diphosphate (ThDP) -dependent decarboxylases, a large subfamily of the class of ThDP-dependent enzymes encompassing pyruvate-, benzoylformate-, 2-oxo acid-, indolpyruvate- and phenylpyruvate decarboxylases, benzaldehyde lyase, acetohydroxyacid synthases and 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase (MenD) is still missing.
Despite a high structural similarity between the members of the ThDP-dependent decarboxylases, their sequences are diverse and make a pairwise sequence comparison of protein family members difficult.

Results
We developed and validated a standard numbering scheme for the family of ThDP-dependent decarboxylases. A profile hidden Markov model (HMM) was created using a set of representative sequences from the family of ThDP-dependent decarboxylases. The pyruvate decarboxylase from S. cerevisiae (PDB: 2VK8) was chosen as a reference because it is a well characterized enzyme. The crystal structure with the PDB identifier 2VK8 encompasses the structure of the Sc PDC mutant E477Q, the cofactors ThDP and Mg2+ as well as the substrate analogue (2S)-2-hydroxypropanoic acid. The absolute numbering of this reference sequence was transferred to all members of the ThDP-dependent decarboxylase protein family. Subsequently, the numbering scheme was integrated into the already established Thiamine-diphosphate dependent Enzyme Engineering Database (TEED) and was used to systematically analyze functionally and structurally relevant positions in the superfamily of ThDP-dependent decarboxylases.

Conclusions
The numbering scheme serves as a tool for the reliable sequence alignment of ThDP-dependent decarboxylases and the unambiguous identification and communication of corresponding positions. Thus, it is the basis for the systematic and automated analysis of sequence-encoded properties such as structural and functional relevance of amino acid positions, because the analysis of conserved positions, the identification of correlated mutations and the determination of subfamily specific amino acid distributions depend on reliable multisequence alignments and the unambiguous identification of the alignment columns. The method is reliable and robust and can easily be adapted to further protein families.
PHB granules are attached to the nucleoid via PhaM in Ralstonia eutropha
Authors: Wahl Andreas , Schuth Nora , Pfeiffer Daniel , Nussberger Stephan , Jendrossek Dieter 
Published: November 2012

Abstract

Background
Poly(3-hydroxybutyrate) (PHB) granules are important storage compounds of carbon and energy in many prokaryotes which allow survival of the cells in the absence of suitable carbon sources. Formation and subcellular localization of PHB granules was previously assumed to occur randomly in the cytoplasm of PHB accumulating bacteria. However, contradictionary results on subcellular localization of PHB granules in Ralstonia eutropha were published, recently.

Results
Here, we provide evidence by transmission electron microscopy that PHB granules are localized in close contact to the nucleoid region in R. eutropha during growth on nutrient broth. Binding of PHB granules to the nucleoid is mediated by PhaM, a PHB granule associated protein with phasin-like properties that is also able to bind to DNA and to phasin PhaP5. Over-expression of PhaM resulted in formation of many small PHB granules that were always attached to the nucleoid region. In contrast, PHB granules of ∆phaM strains became very large and distribution of granules to daughter cells was impaired. Association of PHB granules to the nucleoid region was prevented by over-expression of PhaP5 and clusters of several PHB granules were mainly localized near the cell poles.

Conclusion
Subcellular localization of PHB granules is controlled in R. eutropha and depends on the presence and concentrations of at least two PHB granule associated proteins, PhaM and PhaP5.
PTENgenomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity
Authors: Choucair Khalil , Ejdelman Joshua , Brimo Fadi , Aprikian Armen , Chevalier Simone , Lapointe Jacques 
Published: November 2012

Abstract

Background
Prostate cancer (PCa), a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3), is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR) signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up.

Methods
Fluorescence In Situ Hybridization (FISH) was done on formalin fixed paraffin embedded (FFPE) PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC).

Results
Using FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03). Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (P<0.05). To validate these observations we interrogated a copy number alteration and gene expression profiling dataset of 64 PCa samples, 17 of which were PTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03). PTEN deletion was also linked to diminished expression of PTEN (P<0.01) and AR (P=0.02). Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors.

Conclusions
Altogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.
Use of and factors associated with self-treatment in China
Authors: Yuefeng Li , Keqin Rao , Xiaowei Ren 
Published: November 2012

Abstract

Background
When an individual is ill or symptomatic, they have the options of seeking professional health care, self-treating or doing nothing. In China, some studies suggest that the number of individuals opting to self-treat has been rapidly increasing in recent years. Therefore, the aim of this study was to analyze the trends of and factors related to self-treatment in China.

Methods
Self-treatment was measured based the concept and data of the China National Health Survey (CNHS), which covers 802,454 individuals. We used CNHS data from 1993, 1998, 2003, and 2008, and a Multinomial Logit Selection Model to estimate the factors influencing the decision to self-treat.

Results
The prevalences of self-treatment with a recall period of two-weeks were significantly higher in urban compared with rural areas (31.2% vs 14.9% in 1993, 43.5% vs 21.4% in 1998, 47.2% vs 31.4% in 2003, 31.0% vs 25.3% in 2008) in China. Economic (per capita income, TV, sanitary water) and individual (education, profession, family members, exercise) factors, as well as accessibility to drugs had a positive association with the probability of self-treating. Different illness symptoms, severity, and duration show a negative association with the probability of self-treating, showing a degree of rationality in decision-making. Different insurance systems were also found to have an effect on self-treatment decision-making.

Conclusions
Self-treatment and professional medical services have shared the incremental medical needs of residents in recent years in China. Self-perceived illness status, economic circumstances, and education play important roles in health care decision-making.
Specialist trainees on rotation cannot replace dedicated consultant clinicians for antimicrobial stewardship of specialty disciplines
Authors: Yeo Chay Leng , Wu Jia En , Chung Gladys Wei-Teng , Chan Douglas Su-Gin , Fisher Dale , Hsu Li Yang 
Published: November 2012

Abstract
Our prospective-audit-and-feedback antimicrobial stewardship (AS) program for hematology and oncology inpatients was switched from one led by dedicated clinicians to a rotating team of infectious diseases trainees in order to provide learning opportunities and attempt a “de-escalation” of specialist input towards a more protocol-driven implementation. However, process indicators including the number of recommendations and recommendation acceptance rates fell significantly during the year, with accompanying increases in broad-spectrum antibiotic prescription. The trends were reversed only upon reverting to the original setup. Dedicated clinicians play a crucial role in AS programs involving immunocompromised patients. Structured training and adequate succession/contingency planning is critical for sustainability.
HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation
Authors: Liao Yi-Hsiang , Lin Yi-Chieh , Tsao Shih-Ting , Lin Ying-Cing , Yang Ai-Jen , Huang Chen-Tsung , Huang Kuo-Chin , Lin Wan Wan 
Published: November 2012

Abstract
Statin-induced caspase-1 activation and IL-1β release are due to unmask the anti-inflammatory action of isoprenoids by activating P2X7.
Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1β secretion in monocytes and suggest a crucial role for isoprenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K+ efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1β production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1β secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by LysoTracker staining. Statins also increase intracellular ATP secretion and IL-1β release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1β release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP release, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation.
Mitotane Therapy in Adrenocortical Cancer Induces CYP3A4 and Inhibits 5α-Reductase, Explaining the Need for Personalized Glucocorticoid and Androgen Replacement
Authors: Chortis Vasileios , Taylor Angela E. , Schneider Petra , Tomlinson Jeremy W. , Hughes Beverly A. , O'Neil Donna M. , Libé Rossella , Allolio Bruno , Bertagna Xavier , Bertherat Jérôme , Beuschlein Felix , Fassnacht Martin , Karavitaki Niki , Mannelli Massimo , Mantero Franco , Opocher Giuseppe , Porfiri Emilio , Quinkler Marcus , Sherlock Mark , Terzolo Massimo , Nightingale Peter , Shackleton Cedric H. L. , Stewart Paul M. , Hahner Stefanie , Arlt Wiebke 
Published: November 2012

Abstract

Context:
Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane] is the first-line treatment for metastatic adrenocortical carcinoma (ACC) and is also regularly used in the adjuvant setting after presumed complete removal of the primary tumor. Mitotane is considered an adrenolytic substance, but there is limited information on distinct effects on steroidogenesis. However, adrenal insufficiency and male hypogonadism are widely recognized side effects of mitotane treatment.

Objective:
Our objective was to define the impact of mitotane treatment on in vivo steroidogenesis in patients with ACC.

Setting and Design:
At seven European specialist referral centers for adrenal tumors, we analyzed 24-h urine samples (n = 127) collected from patients with ACC before and during mitotane therapy in the adjuvant setting (n = 23) or for metastatic ACC (n = 104). Urinary steroid metabolite excretion was profiled by gas chromatography/mass spectrometry in comparison with healthy controls (n = 88).

Results:
We found a sharp increase in the excretion of 6β-hydroxycortisol over cortisol (P &lt; 0.001), indicative of a strong induction of the major drug-metabolizing enzyme cytochrome P450 3A4. The contribution of 6β-hydroxycortisol to total glucocorticoid metabolites increased from 2% (median, interquartile range 1–4%) to 56% (39–71%) during mitotane treatment. Furthermore, we documented strong inhibition of systemic 5α-reductase activity, indicated by a significant decrease in 5α-reduced steroids, including 5α-tetrahydrocortisol, 5α-tetrahydrocorticosterone, and androsterone (all P &lt; 0.001). The degree of inhibition was similar to that in patients with inactivating 5α-reductase type 2 mutations (n = 23) and patients receiving finasteride (n = 5), but cluster analysis of steroid data revealed a pattern of inhibition distinct from these two groups. Longitudinal data showed rapid onset and long-lasting duration of the observed effects.

Conclusions:
Cytochrome P450 3A4 induction by mitotane results in rapid inactivation of more than 50% of administered hydrocortisone, explaining the need for doubling hydrocortisone replacement in mitotane-treated patients. Strong inhibition of 5α-reductase activity is in line with the clinical observation of relative inefficiency of testosterone replacement in mitotane-treated men, calling for replacement by 5α-reduced androgens.
A proposed protocol for acceptance and constancy control of computed tomography systems: A Nordic Association for Clinical Physics (NACP) work group report
Authors: Kuttner Samuel , Bujila Robert , Kortesniemi Mika , Andersson Henrik , Kull Love , Østerås Bjørn Helge , Thygesen Jesper , Tarp Ivanka Sojat 
Published: November 2012

Background Quality assurance (QA) of computed tomography (CT) systems is one of the routine tasks for medical physicists in the Nordic countries. However, standardized QA protocols do not yet exist and the QA methods, as well as the applied tolerance levels, vary in scope and extent at different hospitals. Purpose To propose a standardized protocol for acceptance and constancy testing of CT scanners in the Nordic Region. Material and Methods Following a Nordic Association for Clinical Physics (NACP) initiative, a group of medical physicists, with representatives from four Nordic countries, was formed. Based on international literature and practical experience within the group, a comprehensive standardized test protocol was developed. Results The proposed protocol includes tests related to the mechanical functionality, X-ray tube, detector, and image quality for CT scanners. For each test, recommendations regarding the purpose, equipment needed, an outline of the test method, the measured parameter, tolerance levels, and the testing frequency are stated. In addition, a number of optional tests are briefly discussed that may provide further information about the CT system. Conclusion Based on international references and medical physicists’ practical experiences, a comprehensive QA protocol for CT systems is proposed, including both acceptance and constancy tests. The protocol may serve as a reference for medical physicists in the Nordic countries.
The Early Detection Research Network: 10-Year Outlook
Authors: Srivastava Sudhir 
Published: November 2012

BACKGROUND
The National Cancer Institute's Early Detection Research Network (EDRN) has made significant progress in developing an organized effort for discovering and validating biomarkers, building resources to support this effort, demonstrating the capabilities of several genomic and proteomic platforms, identifying candidate biomarkers, and undertaking multicenter validation studies. In its first 10 years, the EDRN went from a groundbreaking concept to an operational success.

CONTENTS
The EDRN has established clear milestones for reaching a decision of “go” or “no go” during the biomarker development process. Milestones are established on the basis of statistical criteria, performance characteristics of biomarkers, and anticipated clinical use. More than 300 biomarkers have been stopped from further development. To date, the EDRN has prioritized more than 300 biomarkers and has completed more than 10 validation studies. The US Food and Drug Administration has now cleared 5 biomarkers for various clinical endpoints.

SUMMARY
The EDRN today combines numerous collaborative and multidisciplinary investigator-initiated projects with a strong national administrative and data infrastructure. The EDRN has created a rigorous peer-review system that ensures that preliminary data—analytical, clinical, and quantitative—are of excellent quality. The process begins with an internal review with clinical, biostatistical, and analytical expertise. The project then receives external peer review and, finally, National Cancer Institute program staff review, resulting in an exceptionally robust and high-quality validation trial.