bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utility of p16 Immunohistochemistry for the Identification of Lynch Syndrome
Authors: Payá Artemio , Alenda Cristina , Pérez-Carbonell Lucía , Rojas Estefanía , Soto José-Luis , Guillén Carmen , Castillejo Adela , Barberá Victor M. , Carrato Alfredo , Castells Antoni , Llor Xavier , Andreu Montserrat , Koh Jim , Enders Greg H. , Benlloch Susana , Jover Rodrigo 
Published: April 2009

Abstract
Purpose: Immunohistochemistry for mismatch repair proteins has shown utility in the identification of Lynch syndrome, but majority of tumors with loss of MLH1 expression are due to sporadic hypermethylation of the MLH1 promoter. These tumors can also show epigenetic silencing of other genes, such as p16. The aim of our study is to evaluate the utility of p16 immunohistochemistry in the prediction of MLH1 germline mutations.
Experimental Design: p16 immunohistochemistry was appropriately evaluated in 79 colorectal cancers with loss of MLH1 expression. Methylation of MLH1 and p16 were quantitatively studied using real-time PCR assay Methylight. BRAF V600E mutation in tumor tissue was also investigated. Genetic testing for germline mutation of MLH1 was made on 52 patients.
Results: Loss of p16 expression was seen in 21 of 79 samples (26.6%). There was found statistically significant association between p16 expression and p16 methylation (P &lt; 0.001), MLH1 methylation (P &lt; 0.001), and BRAF mutation (P &lt; 0.005). All tumors with loss of p16 expression showed hypermethylation of p16 (21 of 21), 95.2% (20 of 21) showed MLH1 methylation, and 71.4% (15 of 21) were mutated for BRAF V600E. Mutational analysis showed pathogenic germline mutations in 8 of the patients, harboring 10 tumors. All 10 of these tumors showed normal staining of p16 in the immunochemical analysis.
Conclusions: p16 immunohistochemistry is a good surrogate marker for p16 and MLH1 epigenetic silencing due to hypermethylation, and is useful as screening tool in the selection of patients for genetic testing in Lynch syndrome.
Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells
Authors: Ceresa Cecilia , Giovannetti Elisa , Voortman Jens , Laan Adrie C. , Honeywell Richard , Giaccone Giuseppe , Peters Godefridus J. 
Published: April 2009

AbstractBortezomib combination with gemcitabine/cisplatin in patients with advanced tumors, predominantly non-small cell lung cancer (NSCLC), showed an unexpected transient drop in the deoxycytidine plasma levels, a marker for gemcitabine activity. This study investigates the pharmacokinetic/pharmacodynamic effect of bortezomib on gemcitabine in NSCLC and peripheral blood mononuclear cells (PBMC). Gemcitabine metabolites, including difluoro-dCTP (dFdCTP), were studied in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients and from volunteers and NSCLC cells (H460 and SW1573) exposed to 4 h simultaneous or sequential treatments of gemcitabine (50 μmol/L, 4 h) and bortezomib (100 nmol/L, 2 h). Gemcitabine total phosphate levels measured by liquid chromatography-tandem mass spectrometry in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients were strongly reduced after 90 min (−82.2%) up to 4 h post-gemcitabine infusion compared with gemcitabine/cisplatin-treated patients. Accordingly, bortezomib/gemcitabine combinations reduced dFdCTP in PBMCs treated ex vivo. Surprisingly, differential effects were observed in NSCLC cells. dFdCTP decreased after 4 h following gemcitabine removal in H460 but continued to increase for 24 h in SW1573. However, dFdCTP significantly increased (2-fold) in both cell lines in the bortezomib→gemcitabine exposure, coinciding with a major reduction in cell growth compared with single drugs, and the highest increase of deoxycytidine kinase expression, possibly mediated via E2F-1. Bortezomib affects differently gemcitabine pharmacokinetics/pharmacodynamics in PBMCs and NSCLC cells, suggesting that PBMCs are not adequate to evaluate the anticancer activity of bortezomib/gemcitabine combinations. The bortezomib→gemcitabine/cisplatin schedule appeared a safe and active combination for the treatment of advanced NSCLC and the bortezomib→gemcitabine was the most cytotoxic combination in NSCLC cells. The increase of deoxycytidine kinase and dFdCTP might contribute to this synergistic interaction and supports its further clinical investigation. [Mol Cancer Ther 2009;8(5):1026–36]
A Mutation in the β3 Subunit of the Cardiac Sodium Channel Associated With Brugada ECG Phenotype
Authors: Hu Dan , Barajas-Martinez Hector , Burashnikov Elena , Springer Michael , Wu Yuesheng , Varro Andras , Pfeiffer Ryan , Koopmann Tamara T. , Cordeiro Jonathan M. , Guerchicoff Alejandra , Pollevick Guido D. , Antzelevitch Charles 
Published: April 2009

Background—Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.Methods and Results—A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 ofSCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression ofSCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a −9.6-mV shift of half-inactivation voltage compared withSCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed thatSCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WTSCN1BandSCN3Bbut remain trapped in intracellular organelles when coexpressed withSCN1B/WT andSCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium.Conclusions—Our results provide support for the hypothesis that mutations inSCN3Bcan lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.
Ambivalent Commitments: Troubles of Morality, Religiosity and Aspiration among Young Egyptians
Authors: Schielke Samuli 
Published: April 2009

AbstractIn contrast to a line of studies that inquire how Muslims try to solve the problem of living piously in a society dominated by materialist tendencies and secular rationality, in this article I turn the question around and problematize the will to live piously and the focus on self-discipline. In everyday lives of young men from the Nile Delta region, the Islamic revivalist project of creating comprehensive moral and civic virtues uneasily coexists with other less total aims and ideals, notably community and family bonds, romantic love, success and self-realization. I attempt to take these contradictions seriously and dwell on the ways people live them and their attempts to make sense of their lives. In particular, I look at the ways people employ the normative registers of religion, love and aspiration in their lives, the promises each of these ideals entail and the options that are available should any of these promises fail.
Spiritual Warfare 101: Preparing the Student for Christian Battle
Authors: Stambach Amy 
Published: April 2009

AbstractTaking its subtitle from a theological college course description, this paper examines the intersections of theological and anthropological ideas of culture, as seen through the eyes of Kenyan evangelists and American missionaries. One of the key concepts developed in the course, and in the broader program of this U.S.-funded nondenominational church in East Africa, is that understanding culture is key to learning and unlocking the spiritual 'personalities' (both godly and satanic) involved in spiritual warfare. Both Kenyans and Americans conceive of warfare as the struggle between secular and Christian worldviews and consider education to be one of the strongest weapons needed to win the battle. However, where U.S. teachers focus on animism and world-religious conflict as evidence of lingering immorality and ungodliness, Kenyans focus on American ethnocentrism and xenophobia as evidence of ongoing cultural misunderstandings and injustice. Analysis is based on examination of mission records and on field research conducted in Nairobi and western Kenya.
The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions
Authors: Kobelt G , Texier-Richard B , Lindgren P 
Published: April 2009

Objective To evaluate the long-term costs and quality of life (QoL) with and without disease-modifying treatments (DMTs) of patients with multiple sclerosis (MS). Methods Data on resource consumption, productivity losses, QoL (utility), and fatigue were collected from 1355 patients registered with a patient association and descriptive analyses was performed. A Markov model was developed to estimate costs and utility over 20 years using the survey data. Disease progression without DMTs was taken from an epidemiological cohort in France (EDMUS cohort, LYON). Progression under DMTs was estimated from the Stockholm MS registry. Results are presented as cost per quality-adjusted life-years (QALYs), from the societal perspective, in EUR2007, discounted at 3%. Results Mean Expanded Disability Status Scale (EDSS) was 4.4 and mean total annual costs per patient were EUR44,400, of which 47% were productivity losses and 11% informal care. Public payers cover an estimated 48% of costs. Mean utility was 0.52, and the loss compared with the normal population was estimated at 0.28. Costs and utility ranged from EUR16,000 and 0.79 at EDSS 1 to EUR76,000 and 0.11 at EDSS 8–9. Over 20 years, costs were estimated at EUR429,000 and QALYs at 8.96 for patients without DMTs and at EUR433,207 and 9.24 QALYs if all patients were starting treated with DMTs at EDSS 1–3. Conclusion Although the data for this analysis come from different sources, the results indicate that the cost increase with DMTs is moderate.
Growing and gaining through caring for a loved one with dementia
Authors: Netto Nicholas Raphael , Jenny Goh Yen Ni , Philip Yap Lin Kiat 
Published: April 2009

Aim: To investigate the gains experienced by family caregivers of persons with dementia. Methods: Twelve respondents were recruited using purposive sampling from three institutions around Singapore. A qualitative design, guided by the grounded theory approach, was adopted and involved semi-structured, in-depth, face-to-face interviews. The interviews were recorded, transcribed and analyzed using open, axial and selective coding. Results: All caregivers interviewed reported having gained from caregiving. The most common gain was that of `personal growth' which comprised being more patient/understanding, becoming stronger/more resilient, having increased self-awareness and being more knowledgeable. Another theme that emerged was `gains in relationships' whereby caregivers experienced an improvement in their relationship with the care recipient, with others in the family or in their ability to interact with other older persons. The third gain experienced was that of `higher-level gains' which encompassed gains in spirituality, deepened relations with God, and a more enlightened perspective in life. Discussion: This research supports a shift from the conventional focus on burdens to a more holistic approach that considers how caregivers can grow and emerge stronger from the caregiving experience. This has implications in the design and delivery of services as utilizing these gains as a coping resource may enable better support for caregivers. It is pertinent that professionals supporting caregivers internalize the perspective of gains so that it becomes a natural way of seeing their clients and in the process help caregivers find meaning and enrichment in their caregiving journey.
IL-7 adjuvant treatment enhances long-term tumor antigen-specific CD8+ T-cell responses after immunization with recombinant lentivector
Authors: Colombetti Sara , Lévy Frédéric , Chapatte Laurence 
Published: April 2009

AbstractImmunization with recombinant lentivector elicits higher frequencies of tumor antigen-specific memory CD8+ T cells than peptide-based vaccines. This finding correlates with our observation that, upon recombinant lentivector immunization, a higher fraction of antigen-specific effector CD8+ T cells does not down-regulate the expression of the survival/memory marker interleukin-7 receptor α chain (IL-7Rα). Here we show that, surprisingly, higher expression of IL-7Rα on recombinant lentivector-induced effector CD8+ T cells does not result in the up-regulation of survival molecules, such as Bcl-2. We thus hypothesized that physiologic levels of IL-7 might be limiting in vivo for delivering survival signals to the expanding population of effector cells. To test this hypothesis, we administered recombinant IL-7 during the effector phase of the response. We observed an up-regulation of Bcl-2 and a strong expansion of antigen-specific effector CD8+ T cells, and of naive CD8+ T cells. Strikingly, IL-7 treatment elicited also a significant increase in the number of antigen-specific memory CD8+ T cells in recombinant lentivector-immunized mice, but not in peptide-immunized mice. Altogether, these data show that IL-7 adjuvant treatment can enhance long-term antigen-specific CD8+ T-cell responses. However, its efficacy depends on the expression of IL-7Rα at the surface of effector CD8+ T cells.
The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy
Authors: Ellis Leigh , Bots Michael , Lindemann Ralph K. , Bolden Jessica E. , Newbold Andrea , Cluse Leonie A. , Scott Clare L. , Strasser Andreas , Atadja Peter , Lowe Scott W. , Johnstone Ricky W. 
Published: April 2009

AbstractLAQ824 and LBH589 (panobinostat) are histone deacetylase inhibitors (HDACi) developed as cancer therapeutics and we have used the Eμ-myc lymphoma model to identify the molecular events required for their antitumor effects. Induction of tumor cell death was necessary for these agents to mediate therapeutic responses in vivo and both HDACi engaged the intrinsic apoptotic cascade that did not require p53. Death receptor pathway blockade had no effect on the therapeutic activities of LAQ824 and LBH589; however, overexpression of Bcl-2 or Bcl-XL protected lymphoma cells from HDACi-induced killing and suppressed their therapeutic activities. Deletion of Apaf-1 or Caspase-9 delayed HDACi-induced lymphoma killing in vitro and in vivo, associated with suppression of many biochemical indicators of apoptosis, but did not provide long-term resistance to these agents and failed to inhibit their therapeutic activities. Eμ-myc lymphomas lacking a functional apoptosome displayed morphologic and biochemical features of autophagy after treatment with LAQ824 and LBH589, indicating that, in the absence of a complete intrinsic apoptosis pathway involving apoptosome formation, these HDACi can still mediate a therapeutic response. Our data indicate that damage to the mitochondria is the key event necessary for LAQ824 and LBH589 to mediate tumor cell death and a robust therapeutic response.
Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases
Authors: Del Giudice Ilaria , Chiaretti Sabina , Tavolaro Simona , De Propris Maria Stefania , Maggio Roberta , Mancini Francesca , Peragine Nadia , Santangelo Simona , Marinelli Marilisa , Mauro Francesca Romana , Guarini Anna , Foà Robin 
Published: April 2009

Abstract
In chronic lymphocytic leukemia (CLL), spontaneous regressions are an exceptional phenomenon, whose biologic features are unknown. We describe 9 CLL patients who underwent a spontaneous clinical regression over an 11-year follow-up, despite a residual neoplastic clone detected by flow cytometry. CD38 and ZAP-70 were negative in all cases. Immunoglobulin heavy chain variable region (IgVH) genes, mutated in all 7 evaluable patients, were restricted to the VH3 family in 6, with the usage of VH3-30 gene in 2. The light chain variable region genes were mutated in 6 of 8 cases, with the use of Vκ4-1 gene in 3. Microarray analysis of CLL cells showed a distinctive genomic profile with an overrepresentation of BCR-related and ribosomal genes, regulators of signal transduction and transcription. The number of activated T lymphocytes expressing IFN-γ, TNF-α, and IL-4 was similar between CLL in spontaneous regression and healthy persons. In conclusion, spontaneous clinical regressions can occur in CLL despite the persistence of the neoplastic clone, and the biologic features include negative CD38 and ZAP-70, mutated VH3-30 and Vκ4-1 genes. The peculiar gene profile suggests that BCR signaling may play an important role in this scenario as the most significant feature of the leukemic clone in regression.
On the edge of Bantu expansions: mtDNA, Y chromosome and lactase persistence genetic variation in southwestern Angola
Authors: Coelho Margarida , Sequeira Fernando , Luiselli Donata , Beleza Sandra , Rocha Jorge 
Published: April 2009

Abstract

Background
Current information about the expansion of Bantu-speaking peoples is hampered by the scarcity of genetic data from well identified populations from southern Africa. Here, we fill an important gap in the analysis of the western edge of the Bantu migrations by studying for the first time the patterns of Y-chromosome, mtDNA and lactase persistence genetic variation in four representative groups living around the Namib Desert in southwestern Angola (Ovimbundu, Ganguela, Nyaneka-Nkumbi and Kuvale). We assessed the differentiation between these populations and their levels of admixture with Khoe-San groups, and examined their relationship with other sub-Saharan populations. We further combined our dataset with previously published data on Y-chromosome and mtDNA variation to explore a general isolation with migration model and infer the demographic parameters underlying current genetic diversity in Bantu populations.

Results
Correspondence analysis, lineage sharing patterns and admixture estimates indicate that the gene pool from southwestern Angola is predominantly derived from West-Central Africa. The pastoralist Herero-speaking Kuvale people were additionally characterized by relatively high frequencies of Y-chromosome (12%) and mtDNA (22%) Khoe-San lineages, as well as by the presence of the -14010C lactase persistence mutation (6%), which likely originated in non-Bantu pastoralists from East Africa. Inferred demographic parameters show that both male and female populations underwent significant size growth after the split between the western and eastern branches of Bantu expansions occurring 4000 years ago. However, males had lower population sizes and migration rates than females throughout the Bantu dispersals.

Conclusion
Genetic variation in southwestern Angola essentially results from the encounter of an offshoot of West-Central Africa with autochthonous Khoisan-speaking peoples from the south. Interactions between the Bantus and the Khoe-San likely involved cattle herders from the two groups sharing common aspects of their social organization. The presence of the -14010C mutation in southwestern Angola provides a link between the East and Southwest African pastoral scenes that might have been established indirectly, through migrations of Khoe herders across southern Africa. Differences in patterns of mtDNA and Y-chromosome intrapopulation diversity and interpopulation differentiation may be explained by contrasting demographic histories underlying the current female and male genetic variation.
Bos taurus genome assembly
Authors: Liu Yue , Qin Xiang , Song Xing-Zhi Henry , Jiang Huaiyang , Shen Yufeng , Durbin K James , Lien Sigbjørn , Kent Matthew Peter , Sodeland Marte , Ren Yanru , Zhang Lan , Sodergren Erica , Havlak Paul , Worley Kim C , Weinstock George M , Gibbs Richard A 
Published: April 2009

Abstract

Background
We present here the assembly of the bovine genome. The assembly method combines the BAC plus WGS local assembly used for the rat and sea urchin with the whole genome shotgun (WGS) only assembly used for many other animal genomes including the rhesus macaque.

Results
The assembly process consisted of multiple phases: First, BACs were assembled with BAC generated sequence, then subsequently in combination with the individual overlapping WGS reads. Different assembly parameters were tested to separately optimize the performance for each BAC assembly of the BAC and WGS reads. In parallel, a second assembly was produced using only the WGS sequences and a global whole genome assembly method. The two assemblies were combined to create a more complete genome representation that retained the high quality BAC-based local assembly information, but with gaps between BACs filled in with the WGS-only assembly. Finally, the entire assembly was placed on chromosomes using the available map information.
Over 90% of the assembly is now placed on chromosomes. The estimated genome size is 2.87 Gb which represents a high degree of completeness, with 95% of the available EST sequences found in assembled contigs. The quality of the assembly was evaluated by comparison to 73 finished BACs, where the draft assembly covers between 92.5 and 100% (average 98.5%) of the finished BACs. The assembly contigs and scaffolds align linearly to the finished BACs, suggesting that misassemblies are rare. Genotyping and genetic mapping of 17,482 SNPs revealed that more than 99.2% were correctly positioned within the Btau_4.0 assembly, confirming the accuracy of the assembly.

Conclusion
The biological analysis of this bovine genome assembly is being published, and the sequence data is available to support future bovine research.