bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Gene Expression Profile Associated to Apoptosis Induced by Dexamethasone in CLL Cells According to IGHV/ZAP-70 Status
Authors: Baptista Maria Joao , Muntañola Ana , Calpe Eva , Abrisqueta Pau , Salamero Olga , Fernández Eva , Codony Carles , Giné Eva , Kalko Susana G. , Crespo Marta , Bosch Francesc 
Published: September 2012

Abstract
Purpose: Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia (CLL) where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucorticoids are active in CLL are not well elucidated. We aimed to ascertain the activity of dexamethasone in CLL cells according to prognosis and to identify the molecular mechanisms that are influencing the response to this drug.
Experimental Design: Sensitivity to dexamethasone was analyzed ex vivo in 50 CLL and compared according to IGHV mutational status and/or ZAP-70 expression. The response was further compared by gene expression profiling (GEP) of selected cases. Expression of genes of interest was validated by quantitative reverse transcriptase PCR.
Results: Response to dexamethasone was higher in cases with unmutated IGHV/high ZAP-70 expression, and the levels of induction of the pro-apoptotic Bim protein correlated with the degree of cell death. GEP analysis showed few genes differentially expressed after dexamethasone treatment between mutated and unmutated cases. However, functional annotation analysis showed that unmutated cases had significant enrichment in terms related to apoptosis. Specific analysis of genes of interest conducted in a large series disclosed that in unmutated IGHV cells, FKBP5 expression was higher at baseline and after dexamethasone exposure and that GILZ was more induced by dexamethasone treatment in these cases.
Conclusions: Unmutated IGHV/high ZAP-70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid receptor pathway and by an increased induction of genes related to apoptosis. Clin Cancer Res; 18(21); 5924–33. ©2012 AACR.
Functional, Genetic, and Epigenetic Aspects of Base and Nucleotide Excision Repair in Colorectal Carcinomas
Authors: Slyskova Jana , Korenkova Vlasta , Collins Andrew R. , Prochazka Pavel , Vodickova Ludmila , Svec Jiri , Lipska Ludmila , Levy Miroslav , Schneiderova Michaela , Liska Vaclav , Holubec Lubos , Kumar Rajiv , Soucek Pavel , Naccarati Alessio , Vodicka Pavel 
Published: September 2012

Abstract
Purpose: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis.
Experimental design: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status.
Results: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P &lt; 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P &lt; 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes.
Conclusions: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes. Clin Cancer Res; 18(21); 5878–87. ©2012 AACR.
Dietary Administration of δ- and γ-Tocopherol Inhibits Tumorigenesis in the Animal Model of Estrogen Receptor–Positive, but not HER-2 Breast Cancer
Authors: Smolarek Amanda K. , So Jae Young , Burgess Brenda , Kong Ah-Ng Tony , Reuhl Kenneth , Lin Yong , Shih Weichung Joe , Li Guangxun , Lee Mao-Jung , Chen Yu-Kuo , Yang Chung S. , Suh Nanjoo 
Published: September 2012

Abstract
Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P &lt; 0.01) and 7.1 ± 0.7 g (P &lt; 0.01), respectively. Tumor multiplicity was also reduced in δ- and γ-tocopherol treatment groups by 42% (P &lt; 0.001) and 32% (P &lt; 0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer. Cancer Prev Res; 5(11); 1310–20. ©2012 AACR.
A Randomized Clinical Trial of the Effects of Supplemental Calcium and Vitamin D3 on the APC/β-Catenin Pathway in the Normal Mucosa of Colorectal Adenoma Patients
Authors: Ahearn Thomas U. , Shaukat Aasma , Flanders W. Dana , Rutherford Robin E. , Bostick Roberd M. 
Published: September 2012

AbstractAPC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on adenomatous polyposis coli (APC), β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2 × 2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months (N = 92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D3-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (Φh APC) increased 21% (P = 0.01), β-catenin decreased 12% (P = 0.18), E-cadherin increased 72% (P = 0.03), and the Φh APC/β-catenin ratio (APC/β-catenin score) increased 31% (P = 0.02). In the calcium-supplemented group Φh APC increased 10% (P = 0.12), β-catenin decreased 15% (P = 0.08), and the APC/β-catenin score increased 41% (P = 0.01). In the calcium/vitamin D3-supplemented group, β-catenin decreased 11% (P = 0.20), E-cadherin increased 51% (P = 0.08), and the APC/β-catenin score increased 16% (P = 0.26). These results support (i) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, (ii) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and (iii) the potential of APC, β-catenin, and E-cadherin expression as modifiable, preneoplastic risk biomarkers for colorectal neoplasms. Cancer Prev Res; 5(10); 1247–56. ©2012 AACR.
A Genetic Snapshot of Small Cell Lung Cancer
Authors: Rosell Rafael , Wannesson Luciano 
Published: September 2012

Abstract
Summary: Overexpression of PARP1 and enhancer of zeste homolog 2 (EZH2) has been identified in an integrated analysis of multiple proteins involved in intracellular signaling pathways in small cell lung cancer (SCLC) cell lines. The knockdown of PARP1 and EZH2 abrogated SCLC growth. These findings provide the basis for novel predictive markers and new treatment strategies in SCLC, for which there is now a paucity of available therapies. Cancer Discov; 2(9); 769–71. ©2012 AACR.
Commentary on Byers et al., p. 798.
Whole-Genome Sequencing and Cancer Therapy: Is Too Much Ever Enough?
Authors: Garraway Levi A. , Baselga José 
Published: September 2012

Abstract
Summary: This issue of Cancer Discovery features an article that describes the use of whole-genome sequencing to discover an actionable genetic alteration that was not detected using a lower resolution diagnostic approach. This finding highlights the growing debate surrounding the optimal deployment of powerful new genomics technologies in the clinical oncology arena. Cancer Discov; 2(9); 766–8. ©2012 AACR.
Commentary on Dahlman et al., p. 791.
Mechanical left ventricular support using a 50 cc 8 Fr fibre-optic intra-aortic balloon technology: a case report
Authors: Mulholland J , Yarham G , Clements A , Morris C , Loja D 
Published: September 2012

Introduction: More than four decades have passed since the first clinical use of an (IABP) to improve the clinical scenario for patients with chronic left ventricular failure. The original IAB catheter size was 15 French (Fr), requiring an open surgical insertion and removal. This therapy has now become the most widely used mechanical device for failure of the left ventricle. The introduction of an 8 Fr fibre-optic IAB catheter with a 50 cc diastolic blood volume displacement has further increased the potential clinical impact of this technology. This new catheter can be used for all patients over 162 cm in height, allowing a broader spectrum of patients to benefit from increased diastolic blood volume displacement and fibre-optic pressure monitoring. The catheter has been designed on an 8 Fr shaft platform, potentially reducing the incidence of vascular complications. We present our case report on the world’s first implant of this 50cc 8 Fr IAB catheter. Case Report: Cardiac investigations on a 53-year-old man showed the patient to have ischaemic dilated cardiomyopathy with a left ventricular ejection fraction (LVEF) of 25%. An 8 Fr 50cc Sensation PlusTM IAB catheter was inserted pre-operatively, prior to coronary artery bypass grafting. Results: The world’s first insertion of this 8 Fr 50 cc IAB catheter was a complete success, with no complications. The patient’s pre-, peri- and post-operative courses were as we expected and event free, underpinned by IABP support. Conclusion: This new 50 cc, 8 Fr IAB expands the patient group that can benefit from greater diastolic blood volume delivery, improved distal perfusion, more accurate monitoring, subsequent better beat-per-beat support and, finally, the reduced complication rates associated with an 8 Fr shaft.
Ten Years’ Follow-Up of a Family With Myokymia and Muscle Cramps Without Ataxia
Authors: Moghimi Narges , Rosen Jennifer Block , Jabbari Bahman 
Published: September 2012

We report 10 years’ follow-up of the previously described family with a novel mutation of the KCNA1 gene. The family consisted of 3 affected boys (first seen at ages 3, 11, and 12) and their affected mother and asymptomatic father and sister. They clinically presented with diffuse myokymia, muscle cramps, and lower limb spasticity without ataxia, but episodic ataxia developed later during adolescence and early adulthood. Long-term follow-ups of families with known KCNA1 gene mutation are rarely mentioned in the literature. Treatment with carbamazepine, 600 to 800 mg daily resulted in cessation of muscle cramps and marked improvement of lower leg symptoms. In the youngest child, after 2 years carbamazepine had to be changed to oxcarbazepine because of side effects. Carbamazepine and oxcarbazepine are both effective in treatment of symptoms related to KCNA1 gene mutation. Symptoms will reoccur if treatment is stopped and there is variability of symptom severity between family members.
A numerical control algorithm for a B-double truck–trailer with steerable trailer wheels and active hitch angles. Part 2: Reversing
Authors: Percy Andrew , Spark Ian 
Published: September 2012

The authors have previously proposed a solution to the twin problems of wheel scuffing and off-tracking of B-double truck–trailer vehicles thereby reducing tyre wear and environmental damage as well as improving maneuverability. The solution to the scuffing problem requires that trailer axles in excess of one per trailer must have steerable wheels. However, if all trailer wheels are steerable, then the off-tracking problem can also be solved. The previous work devised an algorithm for a B-double in forward motion, whereby an on-board computer would be used to calculate the correct wheel and hitch angles and a control system would implement these angles. The purpose of the present technical note is to complete the study of a numerical algorithm for navigating a B-double truck–trailer vehicle by considering travel in the reverse direction. In this case the angle of the front wheels of the truck must also be controlled by the on-board computer. The algorithm for determining the effective angle of the truck’s steerable wheels is derived using an innovative combination of vector geometry and calculus and completes the total control system for these B-double vehicles. The paper concludes with a simulation study of the control algorithm demonstrating its versatility for reversing along twisting paths and effectiveness in reducing off-tracking.
Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease
Authors: Bean Christopher J. , Boulet Sheree L. , Ellingsen Dorothy , Pyle Meredith E. , Barron-Casella Emily A. , Casella James F. , Payne Amanda B. , Driggers Jennifer , Trau Heidi A. , Yang Genyan , Jones Kimberly , Ofori-Acquah Solomon F. , Hooper W. Craig , DeBaun Michael R. 
Published: September 2012

AbstractSickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.
In vitro and clinical studies examining the expression of osteopontin in cigarette smoke-exposed endothelial cells and cigarette smokers
Authors: Bishop Emma , Theophilus Eugenia H , Fearon Ian M 
Published: September 2012

Abstract

Background
Cigarette smoking is a leading cause of mortality and morbidity and is associated with cardiovascular disease via contributory processes such as endothelial dysfunction, inflammation and thrombosis. Cigarette smoke both contains and stimulates the production of cellular oxidants and it may also promote vascular inflammation. Osteopontin is a non-collagenous matrix protein first identified in bone and there is increasing evidence for its role in inflammation and cardiovascular disease via its action as a soluble cytokine.

Methods
In this study we have examined the mechanisms underlying the expression of osteopontin in human vascular endothelial cells in vitro following exposure to cigarette smoke particulate matter (PM), using PCR, electrochemiluminescence, immunostaining and Western blotting. We further determined if serum osteopontin levels changed in humans who quit smoking.

Results
Non-cytotoxic concentrations of PM increased osteopontin levels in cultured human endothelial cells and this effect was reduced in the presence of ascorbate, suggesting a role for oxidants in the response to PM. However, oxidant production played no role in the PM-evoked induction MMP-3, an enzyme which cleaves osteopontin. In smokers who quit smoking for 5 days, serum osteopontin levels were significantly lowered compared to those measured prior to smoking cessation.

Conclusions

In vitro cigarette smoke extract exposure induced osteopontin expression in human endothelial cells in an oxidative stress-dependent manner, which may involve MMP-3 cleavage. In humans, serum osteopontin was decreased with short-term smoking cessation. Endothelial-derived osteopontin may contribute to inflammation in smokers, and may also contribute to atherosclerosis and cardiovascular disease-related processes.
Lactobacillus plantarum possesses the capability for wall teichoic acid backbone alditol switching
Authors: Bron Peter A , Tomita Satoru , van Swam Iris I , Remus Daniela M , Meijerink Marjolein , Wels Michiel , Okada Sanae , Wells Jerry M , Kleerebezem Michiel 
Published: September 2012

Abstract

Background
Specific strains of Lactobacillus plantarum are marketed as health-promoting probiotics. The role and interplay of cell-wall compounds like wall- and lipo-teichoic acids (WTA and LTA) in bacterial physiology and probiotic-host interactions remain obscure. L. plantarum WCFS1 harbors the genetic potential to switch WTA backbone alditol, providing an opportunity to study the impact of WTA backbone modifications in an isogenic background.

Results
Through genome mining and mutagenesis we constructed derivatives that synthesize alternative WTA variants. The mutants were shown to completely lack WTA, or produce WTA and LTA that lack D-Ala substitution, or ribitol-backbone WTA instead of the wild-type glycerol-containing backbone. DNA micro-array experiments established that the tarIJKL gene cluster is required for the biosynthesis of this alternative WTA backbone, and suggest ribose and arabinose are precursors thereof. Increased tarIJKL expression was not observed in any of our previously performed DNA microarray experiments, nor in qRT-PCR analyses of L. plantarum grown on various carbon sources, leaving the natural conditions leading to WTA backbone alditol switching, if any, to be identified. Human embryonic kidney NF-κB reporter cells expressing Toll like receptor (TLR)-2/6 were exposed to purified WTAs and/or the TA mutants, indicating that WTA is not directly involved in TLR-2/6 signaling, but attenuates this signaling in a backbone independent manner, likely by affecting the release and exposure of immunomodulatory compounds such as LTA. Moreover, human dendritic cells did not secrete any cytokines when purified WTAs were applied, whereas they secreted drastically decreased levels of the pro-inflammatory cytokines IL-12p70 and TNF-α after stimulation with the WTA mutants as compared to the wild-type.

Conclusions
The study presented here correlates structural differences in WTA to their functional characteristics, thereby providing important information aiding to improve our understanding of molecular host-microbe interactions and probiotic functionality.
Capsid protein expression and adeno-associated virus like particles assembly in Saccharomyces cerevisiae
Authors: Backovic Ana , Cervelli Tiziana , Salvetti Alessandra , Zentilin Lorena , Giacca Mauro , Galli Alvaro 
Published: September 2012

Abstract

Background
The budding yeast Saccharomyces cerevisiae supports replication of many different RNA or DNA viruses (e.g. Tombusviruses or Papillomaviruses) and has provided means for up-scalable, cost- and time-effective production of various virus-like particles (e.g. Human Parvovirus B19 or Rotavirus). We have recently demonstrated that S. cerevisiae can form single stranded DNA AAV2 genomes starting from a circular plasmid. In this work, we have investigated the possibility to assemble AAV capsids in yeast.

Results
To do this, at least two out of three AAV structural proteins, VP1 and VP3, have to be simultaneously expressed in yeast cells and their intracellular stoichiometry has to resemble the one found in the particles derived from mammalian or insect cells. This was achieved by stable co-transformation of yeast cells with two plasmids, one expressing VP3 from its natural p40 promoter and the other one primarily expressing VP1 from a modified AAV2 Cap gene under the control of the inducible yeast promoter Gal1. Among various induction strategies we tested, the best one to yield the appropriate VP1:VP3 ratio was 4.5 hour induction in the medium containing 0.5% glucose and 5% galactose. Following such induction, AAV virus like particles (VLPs) were isolated from yeast by two step ultracentrifugation procedure. The transmission electron microscopy analysis revealed that their morphology is similar to the empty capsids produced in human cells.

Conclusions
Taken together, the results show for the first time that yeast can be used to assemble AAV capsid and, therefore, as a genetic system to identify novel cellular factors involved in AAV biology.