bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes
Authors: Garcia-Manero Guillermo , Yang Hui , Bueso-Ramos Carlos , Ferrajoli Alessandra , Cortes Jorge , Wierda William G. , Faderl Stefan , Koller Charles , Morris Gail , Rosner Gary , Loboda Andrey , Fantin Valeria R. , Randolph Sophia S. , Hardwick James S. , Reilly John F. , Chen Cong , Ricker Justin L. , Secrist J. Paul , Richon Victoria M. , Frankel Stanley R. , Kantarjian Hagop M.
Published: October 2007

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug–related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.
Whole genome linkage disequilibrium maps in cattle
Authors: McKay Stephanie D , Schnabel Robert D , Murdoch Brenda M , Matukumalli Lakshmi K , Aerts Jan , Coppieters Wouter , Crews Denny , Neto Emmanuel Dias , Gill Clare A , Gao Chuan , Mannen Hideyuki , Stothard Paul , Wang Zhiquan , Van Tassell Curt P , Williams John L , Taylor Jeremy F , Moore Stephen S
Published: October 2007

Background

Bovine whole genome linkage disequilibrium maps were constructed for eight breeds of cattle. These data provide fundamental information concerning bovine genome organization which will allow the design of studies to associate genetic variation with economically important traits and also provides background information concerning the extent of long range linkage disequilibrium in cattle.

Results

Linkage disequilibrium was assessed using r2 among all pairs of syntenic markers within eight breeds of cattle from the Bos taurus and Bos indicus subspecies. Bos taurus breeds included Angus, Charolais, Dutch Black and White Dairy, Holstein, Japanese Black and Limousin while Bos indicus breeds included Brahman and Nelore. Approximately 2670 markers spanning the entire bovine autosomal genome were used to estimate pairwise r2 values. We found that the extent of linkage disequilibrium is no more than 0.5 Mb in these eight breeds of cattle.

Conclusion

Linkage disequilibrium in cattle has previously been reported to extend several tens of centimorgans. Our results, based on a much larger sample of marker loci and across eight breeds of cattle indicate that in cattle linkage disequilibrium persists over much more limited distances. Our findings suggest that 30,000–50,000 loci will be needed to conduct whole genome association studies in cattle.
The complete mitochondrial genome of Pseudocellus pearsei (Chelicerata: Ricinulei) and a comparison of mitochondrial gene rearrangements in Arachnida
Authors: Fahrein Kathrin , Talarico Giovanni , Braband Anke , Podsiadlowski Lars
Published: October 2007

Background

Mitochondrial genomes are widely utilized for phylogenetic and population genetic analyses among animals. In addition to sequence data the mitochondrial gene order and RNA secondary structure data are used in phylogenetic analyses. Arachnid phylogeny is still highly debated and there is a lack of sufficient sequence data for many taxa. Ricinulei (hooded tickspiders) are a morphologically distinct clade of arachnids with uncertain phylogenetic affinities.

Results

The first complete mitochondrial DNA genome of a member of the Ricinulei, Pseudocellus pearsei (Arachnida: Ricinulei) was sequenced using a PCR-based approach. The mitochondrial genome is a typical circular duplex DNA molecule with a size of 15,099 bp, showing the complete set of genes usually present in bilaterian mitochondrial genomes. Five tRNA genes (trnW, trnY, trnN, trnL(CUN), trnV) show different relative positions compared to other Chelicerata (e.g. Limulus polyphemus, Ixodes spp.). We propose that two events led to this derived gene order: (1) a tandem duplication followed by random deletion and (2) an independent translocation of trnN. Most of the inferred tRNA secondary structures show the common cloverleaf pattern except tRNA-Glu where the TψC-arm is missing. In phylogenetic analyses (maximum likelihood, maximum parsimony, Bayesian inference) using concatenated amino acid and nucleotide sequences of protein-coding genes the basal relationships of arachnid orders remain unresolved.

Conclusion

Phylogenetic analyses (ML, MP, BI) of arachnid mitochondrial genomes fail to resolve interordinal relationships of Arachnida and remain in a preliminary stage because there is still a lack of mitogenomic data from important taxa such as Opiliones and Pseudoscorpiones. Gene order varies considerably within Arachnida – only eight out of 23 species have retained the putative arthropod ground pattern. Some gene order changes are valuable characters in phylogenetic analysis of intraordinal relationships, e.g. in Acari.
Evaluation of immune response to Hepatitis B vaccine in health care workers at a tertiary care hospital in Pakistan: an observational prospective study
Authors: Zeeshan Mohammad , Jabeen Kauser , Ali Anita Nausheen Akbar , Ali Ailia Wilayat , Farooqui Saadia Z , Mehraj Vikram , Zafar Afia
Published: October 2007

Background

Seroconversion rates reported after Hepatitis B virus (HBV) vaccination globally ranges from 85–90%. Health care workers (HCWs) are at high risk of acquiring HBV and non responders' rates after HBV vaccination were not reported previously in Pakistani HCWs. Therefore we evaluated immune response to HBV vaccine in HCWs at a tertiary care hospital in Karachi, Pakistan.

Methods

Descriptive observational study conducted at Aga Khan University from April 2003 to July 2004. Newly HBV vaccinated HCWs were evaluated for immune response by measuring serum Hepatitis B surface antibody (HBsAb) levels, 6 weeks post vaccination.

Results

Initially 666 employees were included in the study. 14 participants were excluded due to incomplete records. 271 (41%) participants were females and 381(59%) were males. Majority of the participants were young (<25–39 years old), regardless of gender. Out of 652 HCWs, 90 (14%) remained seronegative after six weeks of post vaccination. The percentage of non responders increased gradually from 9% in participants of <25, 13% in 25–34, 26% in 35–49, and 63% in >50 years of age. Male non responders were more frequent (18%) than female (8%).

Conclusion

Seroconversion rate after HBV vaccination in Pakistani HCWs was similar to that reported in western and neighboring population. HCWs with reduced immune response to HBV vaccine in a high disease prevalent population are at great risk. Therefore, it is crucial to check post vaccination HBsAb in all HCWs. This strategy will ensure safety at work by reducing nosocomial transmission and will have a cost effective impact at an individual as well as at national level, which is very much desired in a resource limited country.
Crystal structures of Leptospira interrogans FAD-containing ferredoxin-NADP+ reductase and its complex with NADP+
Authors: Nascimento Alessandro S , Catalano-Dupuy Daniela L , Bernardes Amanda , Neto Mario de Oliveira , Santos Maria Auxiliadora M , Ceccarelli Eduardo A , Polikarpov Igor
Published: October 2007

Background

Ferredoxin-NADP(H) reductases (FNRs) are flavoenzymes that catalyze the electron transfer between NADP(H) and the proteins ferredoxin or flavodoxin. A number of structural features distinguish plant and bacterial FNRs, one of which is the mode of the cofactor FAD binding. Leptospira interrogans is a spirochaete parasitic bacterium capable of infecting humans and mammals in general. Leptospira interrogans FNR (LepFNR) displays low sequence identity with plant (34% with Zea mays) and bacterial (31% with Escherichia coli) FNRs. However, LepFNR contains all consensus sequences that define the plastidic class FNRs.

Results

The crystal structures of the FAD-containing LepFNR and the complex of the enzyme with NADP+, were solved and compared to known FNRs. The comparison reveals significant structural similarities of the enzyme with the plastidic type FNRs and differences with the bacterial enzymes. Our small angle X-ray scattering experiments show that LepFNR is a monomeric enzyme. Moreover, our biochemical data demonstrate that the LepFNR has an enzymatic activity similar to those reported for the plastidic enzymes and that is significantly different from bacterial flavoenzymes, which display lower turnover rates.

Conclusion

LepFNR is the first plastidic type FNR found in bacteria and, despite of its low sequence similarity with plastidic FNRs still displays high catalytic turnover rates. The typical structural and biochemical characteristics of plant FNRs unveiled for LepFNR support a notion of a putative lateral gene transfer which presumably offers Leptospira interrogans evolutionary advantages. The wealth of structural information about LepFNR provides a molecular basis for advanced drugs developments against leptospirosis.
Evaluation of the intra- and inter-specific genetic variability of Plasmodium lactate dehydrogenase
Authors: Talman Arthur M , Duval Linda , Legrand Eric , Hubert Véronique , Yen Seiha , Bell David , Le Bras Jacques , Ariey Frédéric , Houze Sandrine
Published: October 2007

Background

Malaria diagnosis is vital to efficient control programmes and the recent advent of malaria rapid diagnostic tests (RDTs) provides a reliable and simple diagnostic method. However a characterization of the efficiency of these tests and the proteins they detect is needed to maximize RDT sensitivity.

Methods

Plasmodial lactate dehydrogenase (pLDH) gene of wild isolates of the four human species of Plasmodium from a variety of malaria endemic settings were sequenced and analysed.

Results

No variation in nucleotide was found within Plasmodium falciparum, synonymous mutations were found for Plasmodium malariae and Plasmodium. vivax; and three different types of amino acid sequence were found for Plasmodium ovale. Conserved and variable regions were identified within each species.

Conclusion

The results indicate that antigen variability is unlikely to explain variability in performance of RDTs detecting pLDH from cases of P. falciparum, P. vivax or P. malariae malaria, but may contribute to poor detection of P. ovale.
Are HIV positive patients resistant to statin therapy?
Authors: Johns Kevin W. , Bennett Matthew T. , Bondy Gregory P.
Published: October 2007

Background

Patients with HIV are subject to development of HIV metabolic syndrome characterized by dyslipidemia, lipodystrophy and insulin resistance secondary to highly active antiretroviral therapy (HAART). Rosuvastatin is a highly potent HMG-CoA reductase inhibitor. Rosuvastatin is effective at lowering LDL and poses a low risk for drug-drug interaction as it does not share the same metabolic pathway as HAART drugs. This study sought to determine the efficacy of rosuvastatin on lipid parameters in HIV positive patients with HIV metabolic syndrome.

Results

Mean TC decreased from 6.54 to 4.89 mmol/L (25.0% reduction, p < 0.001). Mean LDL-C decreased from 3.39 to 2.24 mmol/L (30.8% reduction, p < 0.001). Mean HDL rose from 1.04 to 1.06 mmol/L (2.0% increase, p = ns). Mean triglycerides decreased from 5.26 to 3.68 mmol/L (30.1% reduction, p < 0.001). Secondary analysis examining the effectiveness of rosuvastatin monotherapy (n = 70) vs. rosuvastatin plus fenofibrate (n = 43) showed an improvement of 21.3% in TG and a decrease of 4.1% in HDL-C in the monotherapy group. The rosuvastatin plus fenofibrate showed a greater drop in triglycerides (45.3%, p < 0.001) and an increase in HDL of 7.6% (p = 0.08).

Conclusion

This study found that rosuvastatin is effective at improving potentially atherogenic lipid parameters in HIV-positive patients. The lipid changes we observed were of a smaller magnitude compared to non-HIV subjects. Our results are further supported by a small, pilot trial examining rosuvastatin effectiveness in HIV who reported similar median changes from baseline of -21.7% (TC), -22.4% (LDL-C), -30.1% (TG) with the exception of a 28.5% median increase in HDL. In light of the results revealed by this pilot study, clinicians may want to consider a possible resistance to statin therapy when treating patients with HIV metabolic syndrome.
Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort
Authors: Sivakumaran Haran , Wang Bin , Gill M John , Beckholdt Brenda , Saksena Nitin K , Harrich David
Published: October 2007

Here we investigated the nature and functional consequences of mutations in the HIV-1 tat gene within an epidemiologically-linked AIDS transmission cohort consisting of a non-progressing donor (A) and two normal progressing recipients (B and C). Multiple nonsynonymous mutations in the tat first exon were observed across time in all individuals. Some mutations demonstrated striking host specificity despite the cohort being infected with a common virus. Phylogenetic segregation of the tat clones at the time of progression to AIDS was also observed especially in recipient C. Tat clones supporting high levels of transactivation were present at all time points in all individuals, although a number of clones defective for transactivation were observed for recipient C in later time points. Here we show that the tat quasispecies in a linked transmission cohort diversify and evolve independently between hosts following transmission. It supports the belief that quasispecies variation in HIV-1 is a mechanism for selection towards defining a fitter gene variant that is capable of resisting the human immune system.
Transcriptional profiling reveals barcode-like toxicogenomic responses in the zebrafish embryo
Authors: Yang Lixin , Kemadjou Jules R , Zinsmeister Christian , Bauer Matthias , Legradi Jessica , Müller Ferenc , Pankratz Michael , Jäkel Jens , Strähle Uwe
Published: October 2007

Background

Early life stages are generally most sensitive to toxic effects. Our knowledge on the action of manmade chemicals on the developing vertebrate embryo is, however, rather limited. We addressed the toxicogenomic response of the zebrafish embryo in a systematic manner by asking whether distinct chemicals would induce specific transcriptional profiles.

Results

We exposed zebrafish embryos to a range of environmental toxicants and measured the changes in gene-expression profiles by hybridizing cDNA to an oligonucleotide microarray. Several hundred genes responded significantly to at least one of the 11 toxicants tested. We obtained specific expression profiles for each of the chemicals and could predict the identity of the toxicant from the expression profiles with high probability. Changes in gene expression were observed at toxicant concentrations that did not cause morphological effects. The toxicogenomic profiles were highly stage specific and we detected tissue-specific gene responses, underscoring the sensitivity of the assay system.

Conclusion

Our results show that the genome of the zebrafish embryo responds to toxicant exposure in a highly sensitive and specific manner. Our work provides proof-of-principle for the use of the zebrafish embryo as a toxicogenomic model and highlights its potential for systematic, large-scale analysis of the effects of chemicals on the developing vertebrate embryo.
Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization
Authors: Marioni John C , Thorne Natalie P , Valsesia Armand , Fitzgerald Tomas , Redon Richard , Fiegler Heike , Andrews T Daniel , Stranger Barbara E , Lynch Andrew G , Dermitzakis Emmanouil T , Carter Nigel P , Tavaré Simon , Hurles Matthew E
Published: October 2007

Background

Large-scale high throughput studies using microarray technology have established that copy number variation (CNV) throughout the genome is more frequent than previously thought. Such variation is known to play an important role in the presence and development of phenotypes such as HIV-1 infection and Alzheimer's disease. However, methods for analyzing the complex data produced and identifying regions of CNV are still being refined.

Results

We describe the presence of a genome-wide technical artifact, spatial autocorrelation or 'wave', which occurs in a large dataset used to determine the location of CNV across the genome. By removing this artifact we are able to obtain both a more biologically meaningful clustering of the data and an increase in the number of CNVs identified by current calling methods without a major increase in the number of false positives detected. Moreover, removing this artifact is critical for the development of a novel model-based CNV calling algorithm - CNVmix - that uses cross-sample information to identify regions of the genome where CNVs occur. For regions of CNV that are identified by both CNVmix and current methods, we demonstrate that CNVmix is better able to categorize samples into groups that represent copy number gains or losses.

Conclusion

Removing artifactual 'waves' (which appear to be a general feature of array comparative genomic hybridization (aCGH) datasets) and using cross-sample information when identifying CNVs enables more biological information to be extracted from aCGH experiments designed to investigate copy number variation in normal individuals.
Simplified ontologies allowing comparison of developmental mammalian gene expression
Authors: Kruger Adele , Hofmann Oliver , Carninci Piero , Hayashizaki Yoshihide , Hide Winston
Published: October 2007

Model organisms represent an important resource for understanding the fundamental aspects of mammalian biology. Mapping of biological phenomena between model organisms is complex and if it is to be meaningful, a simplified representation can be a powerful means for comparison. The Developmental eVOC ontologies presented here are simplified orthogonal ontologies describing the temporal and spatial distribution of developmental human and mouse anatomy. We demonstrate the ontologies by identifying genes showing a bias for developmental brain expression in human and mouse.
Roles of T lymphocytes in pulmonary fibrosis
Authors: Luzina Irina G , Todd Nevins W , Iacono Aldo T , Atamas Sergei P
Published: October 2007

Infiltration of T lymphocytes in the lungs is common in patients with and in animal models of pulmonary fibrosis. The role of these cells in regulating the accumulation of extracellular matrix, particularly collagen, is not understood completely. Research literature provides evidence for a profibrotic, an antifibrotic, or no significant role of T lymphocytes in pulmonary fibrosis. This review offers a discussion of such evidence with the focus on phenotypes of pulmonary T lymphocytes and related profibrotic and antifibrotic mechanisms. It appears unlikely that T lymphocytic infiltration per se is the central driving force in most cases of pulmonary fibrosis. Instead, evidence suggests that T lymphocytes may modulate the inflammatory and healing responses in the lungs in a profibrotic or antifibrotic manner, depending on their phenotype. Phenotypic reshaping, rather than elimination of the infiltrating pulmonary T lymphocytes, may be a promising approach to improving outcomes in patients with pulmonary fibrosis.
Nuclear Exclusion of Forkhead Box O and Elk1 and Activation of Nuclear Factor-κB Are Required for C2C12-RasV12C40 Myoblast Differentiation
Authors: De Alvaro Cristina , Nieto-Vazquez Iria , Rojas Jose Maria , Lorenzo Margarita
Published: October 2007

Activating ras point mutations are frequently found in skeletal muscle tumors such as rhabdomyosarcomas. In this study we investigated the impact of two different H-ras mutants in skeletal muscle differentiation: RasV12, a constitutively active form, and RasV12C40, a mutant deficient in Raf1 activation. Stably transfected C2C12-RasV12 myoblasts actively proliferated as indicated by the sustained expression of proliferating cell nuclear antigen and retinoblastoma at the hyperphosphorylated state and failed to express differentiation markers. This differentiation-defective phenotype was a consequence of the chronic p44/p42MAPK phosphorylation and the inability of the cells to activate AKT. Moreover, we observed that p44/p42MAPK activation in C2C12-RasV12 myoblasts phosphorylated the ETS-like transcription factor (ELK) 1, which translocates to the nuclei and seemed to be involved in maintaining myoblast proliferation. C2C12-RasV12C40 myoblasts cultured in low serum repressed phosphorylation of p44/p42MAPK and ELK1, resulting in cell cycle arrest and myogenic differentiation. Under this condition, activation of AKT, p70S6K, and p38MAPK was produced, leading to formation of myotubes in 3 d, 1 d earlier than in control C2C12-AU5 cells. Moreover, the expression of muscle-specific proteins, mainly the terminal differentiation markers caveolin-3 and myosin heavy chain, also occurred 1 d earlier than in control cells. Furthermore, AKT activation produced phosphorylation of Forkhead box O that led to nuclear exclusion and inactivation, allowing myogenesis. In addition, we found an induction of nuclear factor-κB activity in the nucleus in C2C12-RasV12C40 myotubes attributed to p38MAPK activation. Accordingly, muscle differentiation is associated with a pattern of transcription factors that involves nuclear exclusion ELK1 and Forkhead box O and the increase in nuclear factor-κB DNA binding.
Cell Lineage-Specific Signaling of Insulin and Insulin-Like Growth Factor I in Rabbit Blastocysts
Authors: Navarrete Santos Anne , Ramin Nicole , Tonack Sarah , Fischer Bernd
Published: October 2007

The insulin/IGF system plays a critical role in embryo growth and development. We have investigated the expression of insulin receptor (IR) and IGF-I receptor (IGF-IR) and the activation of their downstream pathways in rabbit 6-d-old blastocysts. IR was expressed in embryoblast (Em, inner cell mass) and trophoblast (Tr) cells, whereas IGF-IR was localized mainly in Em. Isoform A (IR-A) represents the main insulin isoform in blastocysts and was found in Em and Tr cells. IR-B was detectable only in Tr. IR/IGF-IR signaling pathways were analyzed after stimulation with insulin (17 nm) or IGF-I (1.3 nm) in cultured blastocysts. Insulin stimulated Erk1/2 in Em and Tr and Akt in Tr but not in Em. IGF-I activated both kinases exclusively in Em. The target genes c-fos (for MAPK kinase-1/Erk signaling) and phosphoenolpyruvate carboxykinase (PEPCK, for PI3K/Akt signaling) were also specifically regulated. Insulin down-regulated PEPCK RNA amounts in Tr by activation of the phosphatidylinositol 3-kinase/Akt pathway. Expression of c-fos by insulin and IGF-I was different with respect to time and fortitude of expression, mirroring again the specific IR and IGF-IR expression patterns in Em and Tr. Taken together, we show that IGF-I acts primarily mitogenic, an effect that is cell lineage-specifically restricted to the Em. By contrast, insulin is the growth factor of the Tr stimulating mitogenesis and down-regulating metabolic responses. As soon as blastocyst differentiation in Em and Tr has been accomplished, insulin and IGF-I signaling is different in both cell lineages, implying a different developmental impact of both growth factors.
Ghrelin Prevents Cisplatin-Induced Mechanical Hyperalgesia and Cachexia
Authors: Garcia José M. , Cata Juan P. , Dougherty Patrick M. , Smith Roy G.
Published: October 2007

Complications induced by the chemotherapeutic agent cisplatin, such as neuropathy and cachexia, occur frequently, are often dose limiting, and have an impact on quality of life and survival in cancer patients. The recently discovered hormone ghrelin is a potent GH secretagogue with orexigenic and neuroprotective properties that may prevent or ameliorate these complications. The objective of this study was to determine the effects of ghrelin administration on mechanical hyperalgesia, anorexia, and cachexia induced by cisplatin. Adult male Sprague-Dawley rats were given cisplatin, ghrelin, ghrelin-cisplatin, or vehicle ip. Food intake and body weight were measured daily. Behavioral tests to assess the development of hyperalgesia were conducted by measuring mechanical and thermal sensitivity. Plasma ghrelin and IGF-I levels were also measured. Our results indicate that ghrelin coadministration inhibited the development of cisplatin-induced mechanical hyperalgesia, anorexia, and cachexia induced by cisplatin. Although ghrelin treatment had no effect on plasma IGF-I levels in control rats, it prevented the decrease in IGF-I levels induced by cisplatin. The attenuation of cisplatin-induced mechanical hyperalgesia induced by ghrelin was correlated with the prevention of cisplatin-induced lowering of IGF-I. In conclusion, ghrelin administration may be useful in the treatment or prevention of chemotherapy induced neuropathy and cachexia. Attenuation of mechanical hyperalgesia in the rat by the hormone ghrelin provides a unique model for elucidating the mechanisms involved, which are essential toward our understanding of these complications.
Cell Proliferation and Expression of Cell Cycle Regulatory Proteins that Control the G1/S Transition Are Age Dependent and Lobe Specific in the Brown Norway Rat Model of Prostatic Hyperplasia
Authors: Yan Jinchun , Brown Terry R.
Published: October 2007

Age-dependent epithelial cell hyperplasia in the dorsal and lateral lobes of Brown Norway rats is analogous to benign prostatic hyperplasia in aging men. A major question is whether differential lobe-specific and age-dependent proliferation of cells, rather than cell survival, contributes to the hyperplasia. Although serum testosterone (T) levels decline in aged rats, active cell proliferation was detected as Ki67-positive cells in the dorsal and lateral lobes. We determined whether androgens differentially affect cell proliferation and cell-cycle regulatory proteins in the prostate lobes of young and aged rats. Castrated rats were treated with different doses of T to restore serum levels to those of intact young or aged rats. Rates of cell proliferation, measured by 5-bromodeoxyuridine labeling, peaked after 3-d T treatment in all lobes. 5-bromodeoxyuridine-labeling indices were higher in the dorsal and lateral lobes of aged than of young rats with equivalent serum T levels. No age-dependent difference was seen in the ventral lobe. Cell proliferation was marked by increased levels of cyclins D1 and E and cyclin-dependent kinases 4 and 6, decreased p27 and increased phosphorylation of Rb. Levels of cyclins D1 and E were higher in the dorsal and lateral lobes of intact and T-treated aged than young rats. Confocal immunofluorescent microscopy documented changes in cyclin-dependent kinase 4 and cyclin D1 subcellular localization. Cyclin D1 nuclear localization correlated with the time frame for cell proliferation. In conclusion, rates of cell proliferation and levels of cell-cycle regulatory proteins that control the G1/S transition exhibit lobe-specific and age-dependent differences in response to androgens.
IL18 Haplotypes Are Associated with Serum IL-18 Concentrations in a Population-Based Study and a Cohort of Individuals with Premature Coronary Heart Disease
Authors: Thompson Simon R , McCaskie Pamela A , Beilby John P , Hung Joseph , Jennens Michelle , Chapman Caroline , Thompson Peter , Humphries Steve E
Published: October 2007

Background: Interleukin (IL)-18 is a proinflammatory cytokine that has been implicated in several diseases, including atherosclerosis, and increased circulating IL-18 concentrations increase risk of future coronary heart disease (CHD). We evaluated the effect of common variation within the IL18 gene on concentrations of circulating IL-18.

Methods: We measured IL-18, by ELISA, in the population-based study group [Carotid Ultrasound Disease Assessment Study (CUDAS)] and a predominantly male cohort with premature cardiovascular disease [Carotid Ultrasound in Patients with Ischaemic Heart Disease (CUPID)]. Using a tagging single-nucleotide polymorphism (SNP) approach that captured >90% of genetic variation, we identified 4 common (>10%) haplotypes.

Results: A common SNP was associated with differences in IL-18 concentrations; in CUDAS individuals carrying 2 copies of the rare allele, concentrations were 13% higher than in those with no copies (P = 0.002). Haplotypes were also associated with significant differences in IL-18 concentrations in CUDAS and CUPID. Haplotype GTATA (frequency 23%) was associated with significantly lower IL-18 than others. In CUDAS, those carrying 2 copies had IL-18 concentrations 15% lower than those carrying no copies (P = 0.002); in CUPID, the difference was 22% (P = 0.004). These associations remained significant after adjustment for age, sex, hypertension, HDL cholesterol, waist-to-hip ratio, and alcohol consumption. Despite being associated with differences in IL-18 concentrations, the haplotypes did not occur at different frequencies in those with or without carotid atherosclerotic plaques.

Conclusions: Variation within IL18 affects IL-18 concentrations in healthy and diseased individuals and thus may influence the pathophysiology of plaques at all stages of CHD progression.
MS-FLAG, a Novel Real-Time Signal Generation Method for Methylation-Specific PCR
Authors: Bonanno Cinzia , Shehi Erlet , Adlerstein Daniel , Makrigiorgos G Mike
Published: October 2007

Background: Aberrant promoter methylation is a major mechanism for silencing tumor suppressor genes in cancer. Detection of hypermethylation is used as a molecular marker for early cancer diagnosis, as a prognostic index, or to define therapeutic targets for reversion of aberrant methylation. We report on a novel signal generation technology for real-time PCR to detect gene promoter methylation.

Methods: FLAG (fluorescent amplicon generation) is a homogeneous signal generation technology based on the exceptionally thermostable endonuclease PspGI. FLAG provides real-time signal generation during PCR by PspGI-mediated cleavage of quenched fluorophores at the 5′ end of double-stranded PCR products. Methylation-specific PCR (MSP) applied on bisulfite-treated DNA was adapted to a real-time format (methylation-specific FLAG; MS-FLAG) for quantifying methylation in the promoter of CDKN2A (p16), GATA5, and RASSF1. We validated MS-FLAG on plasmids and genomic DNA with known methylation status and applied it to detection of methylation in a limited number of clinical samples. We also conducted bisulfite sequencing on these samples.

Results: Real-time PCR results obtained via MS-FLAG agreed with results obtained via conventional, gel-based MSP. The new technology showed high specificity, sensitivity (2–3 plasmid copies), and selectivity (0.01% of methylated DNA) on control samples. It enabled correct prediction of the methylation status of all 3 gene promoters in 21 lung adenocarcinoma samples, as confirmed by bisulfite sequencing. We also developed a multiplex MS-FLAG assay for GATA5 and RASSF1 promoters.

Conclusion: MS-FLAG provides a new, quantitative, high-throughput method for detecting gene promoter methylation and is a convenient alternative to agarose gel-based MSP for screening methylation. In addition to methylation, FLAG-based real-time signal generation may have broad applications in DNA diagnostics.
Remediating Basement Leaks
Authors: Henshell Justin
Published: October 2007

This paper discusses and reviews several of the more common causes of water infiltration into basementsThe terms “basement” and “cellar” are defined in building codes, but long-term use seems to have rendered them interchangeable. In this paper, the term “basement” is used for below-grade and partially below-grade habitable spaces, including such locations under plazas (but excluding vehicular tunnels). such as: failure of the waterproofing system, structural failure of the foundation or slab, and an increase in hydrostatic pressure. Recommendations are offered for alleviating water pressure by modifying above grade building components, altering topographical elements and the use of internal and external drains. Techniques are described for stopping water infiltration by applying negative side waterproofing materials, injecting grouts and chemicals in the soil around the foundation walls, under slabs, behind walls, and into leaking cracks and joints. The paper concludes with a review of the various materials and systems that are used for repairing leaking basements together with their pros and cons.
Autoregulation of Cerebral Blood Flow
Authors: Greisen Gorm
Published: October 2007

Autoregulation is a result of an intrinsic character of vascular smooth muscle cells. Other factors interact with pressure to define the degree of contraction of the smooth muscle cell. The final common pathway involves plasma membrane potassium conductance, smooth cell membrane potential, and cytoplasmatic calcium concentration. The molecular mechanisms are too complex to allow quantitative predictions. Autoregulation operates in most newborn infants (even the most immature), although the cerebral blood flow (CBF)-pressure relation is not likely to be strictly flat. In severely asphyxiated neonates, in preterm neonates who eventually develop major intracranial hemorrhage, and in hypotensive preterm infants treated with dopamine, the CBF-pressure relation is significantly above zero and may be as high as 4% per millimeter of mercury, corresponding to complete pressure passiveness. The lower threshold for cerebral autoregulation can be assumed to be 30 mm Hg or below. When blood pressure falls below this threshold, CBF decreases more than in proportion to pressure due to the elastic reduction in vascular diameter, but significant blood flow can be assumed to continue until the blood pressure is well below 20 mm Hg. The clinical relevance of autoregulation of CBF is the ability of cerebral arteries and arterioles to dilate to compensate for low blood pressure and protect against ischemic brain injury. The importance of the ability to constrict to protect against cerebral hemorrhage is not supported by clinical research.
Genetic Syndromes Determined by Alterations in Genomic Imprinting Pathways
Authors: Jonas Jessica M. , Demmer Laurie A.
Published: October 2007

Genomic imprinting appears to be a mammal-specific phenomenon whereby differential gene expression according to parent of origin has evolved as a means to regulate many complex pathways related to growth, metabolism, and neurologic development. Imprinting is accomplished by an epigenetic mechanism involving, for example, methylation of specific sequences, without changing the underlying genetic code. This process occurs with very specific timing in relation to development of an embryo and is reset in the sex-specific gametes of each individual. Epigenetic deregulation of the imprinting process is the cause of specific genetic syndromes, many of which show alterations in growth, metabolism, and neurologic development. In fact, it has been demonstrated that alterations of a single imprinting control region (IGF2/H19) can lead to opposite disorders of congenital growth (Beckwith-Wiedemann syndrome and Silver-Russell syndrome). Recently, it has been suggested that the use of assisted reproductive techniques such as in vitro fertilization may heighten the susceptibility of embryos to epigenetic deregulation, leading to increased risk for certain imprinting disorders. Also, the knowledge that imprinted genes are involved in pathways of fetal and placental growth has prompted researchers to look into the role of imprinting in intrauterine growth restriction. This may have consequences well beyond the newborn period because epidemiologic studies have shown a strong link between poor fetal growth and the susceptibility to glucose intolerance and insulin resistance syndrome in adults.
Long-chain Polyunsaturated Fatty Acid (LCPUFA) Supplementation for Infants Born Preterm
Authors: Smithers Lisa G. , Gibson Robert A. , Makrides Maria
Published: October 2007

During gestation, the placenta actively enriches the fetal circulation with long-chain polyunsaturated fatty acids (LCPUFA), and significant quantities are concentrated in brain and retinal tissues. Preterm infants are denied the usual gestational accretion of LCPUFA, prompting the addition of these fatty acids to preterm formula. Electrophysiologic assessment of visual maturation has shown improved retinal sensitivity and visual acuity with LCPUFA formula supplementation, although the optimal dose has not been determined. Developmental assessment trials of infants fed LCPUFA-supplemented formulas have shown varied results, as have trials assessing the growth of infants fed such formulas. Comparative trials have shown no increased incidence of sepsis, necrotizing enterocolitis, or bronchopulmonary dysplasia among preterm infants fed LCPUFA-supplemented formulas. Further research is required to determine the overall balance of LCPUFA in the diets of preterm infants fed either human milk or infant formula.
Marine Oil Supplements for Pregnant Women
Authors: Makrides Maria , Gibson Robert A.
Published: October 2007

Prenatal supplements containing n-3 long-chain polyunsaturated fatty acids (LCPUFA) are becoming popular with pregnant women, primarily because of the suggestion that an increased supply of docosahexaenoic acid (DHA), a key n-3 LCPUFA, may be important to fetal brain development. Current research data suggest that routine use of marine oil supplements in pregnancy probably has little benefit in preventing pre-eclampsia, preterm birth, and low birthweight, although its use is safe during pregnancy. There is a suggestion that dietary DHA insufficiency may be associated with symptoms of postnatal depression; randomized, controlled studies are needed to investigate this possibility. The effect of a DHA-rich marine oil intervention in pregnancy on long-term development of children is under investigation. The possibility that maternal marine oil supplementation may modify neonatal immune function requires further investigation.
Neonatal Nasal Obstruction
Authors: Krakovitz Paul R. , Koltai Peter J.
Published: October 2007

Neonatal nasal obstruction is a true emergency. It is preferable to establish an airway initially, which allows full evaluation of the problem. The newborn should be stabilized prior to embarking on definitive treatment, especially if other congenital anomalies involving multiple organ systems are present. Once the infant's situation is controlled, appropriate tests, such as diagnostic endoscopy and radiologic imaging, can be undertaken. Medical options should be considered initially. When appropriate, surgical therapy can be curative.
Pharmacology Review
Authors: Steinhorn Robin H. , Kinsella John P.
Published: October 2007

Studies have shown that inhaled nitric oxide (iNO) improves ventilation/perfusion matching, decreases lung inflammation and oxidant stress, and restores more normal patterns of angiogenesis and parenchymal growth in the immature lung. Such findings suggest a potential role for this therapy in preterm newborns at risk for bronchopulmonary dysplasia. Early clinical trials have shown that iNO can benefit larger preterm infants (>1,000 g) who have early respiratory failure and preterm infants who continue to require positive pressure support after the first postnatal week. Debate continues as to whether iNO increases the rate of intracerebral hemorrhage. Additional trials are needed to discern benefits to specific forms and durations of iNO therapy in both the short and long term.
Current Issues in Human Milk Banking
Authors: Cohen Ronald S.
Published: October 2007

The demand for banked human milk has been increasing, in large part due to the benefits associated with its use. Multiple levels of safeguarding built into the current milk banking process have resulted in an unblemished safety record for banked milk in North America. Holder pasteurization destroys many pathogens in human milk while preserving much of the biologically active content. Among the potential benefits of using banked human milk in the neonatal intensive care unit are promotion of breastfeeding, reduced incidence of necrotizing enterocolitis and sepsis, and possible support of long-term positive neurodevelopmental outcomes in very low- and extremely-low birthweight infants.
About the infrequent thrombotic events during erythropoietin therapy of anemic ovarian cancer patients with chemotherapy
Authors: Lehoczky Ottó , Pulay Tamás
Published: October 2007

Bevezetés:
A daganatos betegek kemoterápiája kapcsán fellépő anémia miatt adott erythropoetin-kezelések ritka velejárója a trombózis. Az epoetint gyártó cégek valamennyi ilyen készítmény ismertetőjében felhívják a figyelmet erre az esetleges mellékhatásra.
Cél:
A petefészekrákos betegek kemoterápiája kapcsán adott epoetinkezelések során fellépő thromboticus események áttekintése.
Anyag és módszer:
Az Országos Onkológiai Intézet Nőgyógyászati osztályán a 2000 és 2006 közötti időszakban 275 petefészekrákos beteg közül 52 kapott epoetin-alfa, 157 epoetin-béta, 66 beteg pedig darbepoetin-alfa-kezelést. A betegek életkora medián 60 (szélső értékek 22, 84) év volt.
Eredmény:
A 275 közül 1 betegben epoetin-alfa-, 2 betegben pedig epoetin-béta-kezelés kapcsán figyeltek meg thromboticus eseményt (3/275 = 1,1%). A kialakult trombózisok és az epoetinkezelés közötti egyértelmű okozati összefüggést igazolni nem sikerült.
Következtetés:
A nagy irodalmi metaanalízisekkel megegyezően a szerzők beteganyagában is csak igen ritka a kezelés kapcsán fellépett trombózis.
Cardiovascular Reserve and Risk Profile of Postmenopausal Women After Chemoendocrine Therapy for Hormone Receptor–Positive Operable Breast Cancer
Authors: Jones Lee W. , Haykowsky Mark , Pituskin Edith N. , Jendzjowsky Nick G. , Tomczak Corey R. , Haennel Robert G. , Mackey John R.
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Discuss cardiorespiratory fitness and cardiac functional reserve in postmenopausal women treated with chemoendocrine therapy.List the cardiovascular risk factors in this study that were found to be less favorable among patients than among controls.Explain the significance of peak aerobic power as a predictor of cardiovascular disease.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Localized Palmar–Plantar Epidermal Hyperplasia: A Previously Undefined Dermatologic Toxicity to Sorafenib
Authors: Beldner Matthew , Jacobson Michael , Burges Gene E. , Dewaay Deborah , Maize John C. , Chaudhary Uzair B.
Published: October 2007

The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar–plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature.
The Role of Bevacizumab in the Treatment of Non-Small Cell Lung Cancer: Current Indications and Future Developments
Authors: Gridelli Cesare , Maione Paolo , Rossi Antonio , De Marinis Filippo
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Describe the main clinical trials of bevacizumab combined with chemotherapy in the treatment of advanced NSCLC.Describe the main clinical trials of bevacizumab combined with other targeted therapies in the treatment of advanced NSCLC.Describe some ongoing trials of bevacizumab in the treatment of NSCLC and try to define future developments of bevacizumab in this clinical setting.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Low-Dose Computed Tomography Screening for Lung Cancer and Pleural Mesothelioma in an Asbestos-Exposed Population: Baseline Results of a Prospective, Nonrandomized Feasibility Trial—An Alpe-Adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002)
Authors: Fasola Gianpiero , Belvedere Ornella , Aita Marianna , Zanin Tina , Follador Alessandro , Cassetti Paolo , Meduri Stefano , De Pangher Vincenzo , Pignata Giusto , Rosolen Valentina , Barbone Fabio , Grossi Francesco
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Describe the current status of LDCT screening for lung cancer among high-risk individuals.Discuss the potential and drawbacks of LDCT for the early detection of lung cancer in asbestos-exposed individuals.Describe the limits and possibilities of LDCT for detecting pleural abnormalities and malignant pleural mesothelioma in asbestos workers and former workers.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Perceptions of Motives in Intimate Partner Violence: Expressive Versus Coercive Violence
Authors: Hamel John , Desmarais Sarah L. , Nicholls Tonia L.
Published: October 2007

This study examined perceptions of motives in the perpetration of intimate partner violence. Respondents (N = 401) of diverse professions read three vignettes and indicated their perception of the aggressor’s motive (from 1 = Exclusively Expressive; 5 = Exclusively Coercive). Half of respondents read vignettes describing male-perpetrated violence against a female partner; the other half, female-perpetrated violence against a male partner. Overall, male-perpetrated aggression was seen as more coercive than female-perpetrated aggression, particularly by shelter workers and victim advocates. Further analyses revealed that men generally gave higher ratings than women, and that women rated female-perpetrated aggression as less coercive than male-perpetrated aggression. In contrast, men did not differ in their ratings of male versus female perpetration. Implications are discussed with respect to the assessment and treatment of partner violence.