bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoplastic Renal Corpuscles in the Dog
Authors: Yoon Young H. , Santamarina Enrique 
Published: September 2009

Hypoplasia of renal corpuscles was studied in 238 dogs ranging in age from 1 to 24 months: 98 purebred beagles, 115 foxhounds and 25 dogs of 10 other breeds. Twenty-six (26.5%) of the beagles had hypoplastic renal corpuscles, comprising approximately 0.3 to 4% of the total number of renal corpuscles counted in each kidney. All beagles which had hypoplastic renal corpuscles appeared to have normal glomerular function as determined by serum creatinine concentration level, and all other histological structures of the kidney appeared normal. Most of the hypoplastic renal corpuscles in these dogs were observed undergoing atrophy, degeneration, necrosis, and occasional calcification. Since these beagles had no noticeable abnormalities in the kidneys and the other organs that might cause secondary atrophy of renal corpuscles, it could be assumed that the small renal corpuscles were the result of true hypoplasia. Calcification of hypoplastic renal corpuscles was seen in 25 of the dogs of all other breeds studied. Suppurative pneumonia was the most common disease in 16 of the 25 animals which had the calcification. Nine of the 16 animals had pneumonia and canine distemper concurrently and the remaining 7 animals had pneumonia only with no other detectable diseases. Since the dog is extensively used for research in animal and human kidney diseases and for testing drugs, the finding of hypoplastic renal corpuscles could be a valuable contribution for pathologists and physiologists dealing with studies on kidney function.
Endocardial Thickening in the Sprague-Dawley Rat
Authors: Zaidi I. , Sullivan D. J. , Seiden D. 
Published: September 2009

Thickening of the endocardium is sometimes observed in rats and other animals as a spontaneous or experimentally induced lesion. However, its nature, pathogenesis, and significance are not well understood. In this study, 480 Sprague-Dawley CD outbred albino rats between the ages of 6 and 25 months were examined grossly and microscopically. Endocardial thickening was observed in six cases. It was diffuse and was caused by proliforation of fibroblast-like cells, most frequently involving the left ventricle. Endocardial thickening in Sprague-Dawley rats appears to be primarily due to endomyocardial fibrosis. It may represent repair of damage to subendocardial myocardium occurring spontaneously or as a consequence of exposure to chemicals or other agents.
Phenotypic Properties of Preneoplastic Rat Liver Lesions and Applications to Detection of Carcinogens and Tumor Promoters
Authors: Williams Gary M. 
Published: September 2009

A variety of cellular lesions arise during liver carcinogenesis by chemicals in rats. The altered focus is a lesion of hepatocytes that occurs early in hepatocarcinogenesis and appears to give rise to both neoplastic nodules and carcinomas. Foci display numerous phenotypic abnormalities which together with nuclear abnormalities indicate that they are truly a new altered population. Using histochemical markers, the induction of foci can be measured as a quantitative index of hepatocarcinogenicity of genotoxic carcinogens. In addition, determination of the effect of agents on foci previously induced by genotoxic carcinogens can be used to assess the capacity of chemicals to act as liver tumor promoters.
Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments
Authors: de la Iglesia Felix A. , Farber Emmanuel 
Published: September 2009

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs. Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity. Thus, hypolipidemics such as gemfibrozil or Clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.
Statistical Support of the Proposed National Toxicology Program Protocol
Authors: Haseman Joseph K. 
Published: September 2009

Statistical issues related to the design, analysis and interpretation of carcinogenicity studies are considered. A proposed modification of the “standard” National Cancer Institute (NCI) design of carcinogenicity studies in rodents is discussed. The primary objective was to obtain a design that maintained the power of the NCI design for detecting carcinogenic effects, while increasing the precision with which the underlying dose-response model could be estimated. “Optimum” three-dose designs are presented and discussed. Data analysis issues are also considered. Comparisons of tumor incidence should include adjustments for survival differences, and, if possible, cause of death determinations should be made for each individual animal. In some instances historical control data can aid an investigator in the overall evaluation of experimental results. Several important problems are discussed that must be overcome before historical control data can be used in a meaningful way. One critical issue in the interpretation of tumor incidence data is the issue of false positives. Data from 25 recent long term feeding studies are used to derive a statistical decision rule that closely approximates the scientific judgment process used in these studies. The overall false positive rate associated with this decision rule was found to be no more than 7-8%.
Use of Historical Control Data in Carcinogenicity Studies in Rodents
Authors: Haseman Joseph K. , Huff James , Boorman Gary A. 
Published: September 2009

This paper considers the use of historical control data in the evaluation of tumor incidences from carcinogenicity studies in rodents. Although the most appropriate control group for interpretative purposes is always the concurrent control, there are instances in which the use of historical control information can aid an investigator in the overall evaluation of tumor incidence data. One example is rare tumors; another is a tumor that shows a marginally significant result relative to concurrent controls. However, before historical control data can be used in a formal testing framework, a number of important issues must first be considered. The nomenclature conventions and diagnostic criteria for each study should be identical to insure unambiguous identification of all relevant tumors in the historical control database. Criteria should be established that will aid in determining whether a particular study should be included in the database. This will assure a homogeneous set of studies upon which to base statistical comparisons. Since study-to-study variability in tumor rates may exceed what would be expected by chance alone, these sources of variability should be identified and controlled. Finally, statistical procedures should be employed that adjust for extra-binomial variability. This paper also summarizes tumor incidence data from untreated Fischer 344 rats and B6C3F1 mice in the National Toxicology Program (NTP) historical control database. All studies in the database are of two years duration, and all neoplasms occurring with a frequency of 0.5% or more are reported.
Multinucleated Hepatocytes Induced by Rifabutin in Rats
Authors: Scampini Giovanna , Nava Alberto , Newman Arthur John , Torre Paola Delia , Mazuéa Guy 
Published: September 2009

Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose- and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery (12 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors. MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.
A pre-S gene chip to detect pre-S deletions in hepatitis B virus large surface antigen as a predictive marker for hepatoma risk in chronic hepatitis B virus carriers
Authors: Shen Fan-Ching , Su Ih-Jen , Wu Han-Chieh , Hsieh Yi-Hsuan , Yao Wei-Jen , Young Kung-Chia , Chang Tsung-Chuan , Hsieh Hui-Chuan , Tsai Han-Ni , Huang Wenya 
Published: September 2009

Abstract

Background
Chronic hepatitis B virus (HBV) infection is an important cause of hepatocellular carcinoma (HCC) worldwide. The pre-S1 and -S2 mutant large HBV surface antigen (LHBS), in which the pre-S1 and -S2 regions of the LHBS gene are partially deleted, are highly associated with HBV-related HCC.

Methods
The pre-S region of the LHBS gene in two hundred and one HBV-positive serum samples was PCR-amplified and sequenced. A pre-S oligonucleotide gene chip was developed to efficiently detect pre-S deletions in chronic HBV carriers. Twenty serum samples from chronic HBV carriers were analyzed using the chip.

Results
The pre-S deletion rates were relatively low (7%) in the sera of patients with acute HBV infection. They gradually increased in periods of persistent HBV infection: pre-S mutation rates were 37% in chronic HBV carriers, and as high as 60% in HCC patients. The Pre-S Gene Chip offers a highly sensitive and specific method for pre-S deletion detection and is less expensive and more efficient (turnaround time 3 days) than DNA sequencing analysis.

Conclusion
The pre-S1/2 mutants may emerge during the long-term persistence of the HBV genome in carriers and facilitate HCC development. Combined detection of pre-S mutations, other markers of HBV replication, and viral titers, offers a reliable predictive method for HCC risks in chronic HBV carriers.
Exploratory and inferential analysis of gene cluster neighborhood graphs
Authors: Scharl Theresa , Voglhuber Ingo , Leisch Friedrich 
Published: September 2009

Abstract

Background
Many different cluster methods are frequently used in gene expression data analysis to find groups of co-expressed genes. However, cluster algorithms with the ability to visualize the resulting clusters are usually preferred. The visualization of gene clusters gives practitioners an understanding of the cluster structure of their data and makes it easier to interpret the cluster results.

Results
In this paper recent extensions of package gcExplorer are presented. gcExplorer is an interactive visualization toolbox for the investigation of the overall cluster structure as well as single clusters. The different visualization options including arbitrary node and panel functions are described in detail. Finally the toolbox can be used to investigate the quality of a given clustering graphically as well as theoretically by testing the association between a partition and a functional group under study.

Conclusion
It is shown that gcExplorer is a very helpful tool for a general exploration of microarray experiments. The identification of potentially interesting gene candidates or functional groups is substantially accelerated and eased. Inferential analysis on a cluster solution is used to judge its ability to provide insight into the underlying mechanistic biology of the experiment.
Inhibition of eIF2α dephosphorylation inhibits ErbB2-induced deregulation of mammary acinar morphogenesis
Authors: Sequeira Sharon J , Wen Huei Chi , Avivar-Valderas Alvaro , Farias Eduardo F , Aguirre-Ghiso Julio A 
Published: September 2009

Abstract

Background
The ErbB2/Her2/Neu receptor tyrosine kinase is amplified in ~30% of human breast cancers. Phosphorylation of the translation initiation factor, eIF2α inhibits global protein synthesis and activates a stress signaling and growth suppressive program. We have shown that forced phosphorylation of eIF2α can suppress head and neck, colorectal carcinoma and multiple myeloma tumor growth and/or survival. Here we explore whether ErbB2 modulates eIF2α phosphorylation and whether forced phosphorylation of the latter can antagonize ErbB2 deregulation of mammary acinar morphogenesis.

Results
We tested whether ErbB2 signaling influenced eIF2α signaling and whether enhanced phosphorylation of the latter affected ErbB2-deregulated mammary acinar development. We obtained stable MCF10A cells overexpressing wild-type (Wt) Neu/ErbB2 or a constitutively active (CA) variant via retroviral delivery or mammary tumor cells from MMTV-Neu tumors. Western blotting, RT-PCR and confocal microscopy were used to analyze the effects of ErbB2 activation on eIF2α signaling and the effect of the GADD34-PP1C inhibitor salubrinal. Wt- and MMTV-Neu cells formed aberrant acini structures resembling DCIS, while CA-ErbB2 overexpression induced invasive lesions. In these structures we found that CA-ErbB2 but not the Wt variant significantly down-regulated the pro-apoptotic gene CHOP. This occurred without apparent modulation of basal phosphorylation of PERK and eIF2α or induction of its downstream target ATF4. However, inhibition of eIF2α dephosphorylation with salubrinal was sufficient to inhibit Wt- and CA-ErbB2- as well as MMTV-Neu-induced deregulation of acinar growth. This was linked to enhanced CHOP expression, inhibition of proliferation, induction of apoptosis and luminal clearing in Wt-ErbB2 and to inhibition of cyclin D1 levels and subsequent proliferation in CA-ErbB2 cells.

Conclusion
Depending on the strength of ErbB2 signaling there is a differential regulation of CHOP and eIF2α phosphorylation. ErbB2 uncouples in basal conditions eIF2α phosphorylation from CHOP induction. However, this signal was restored by salubrinal treatment in Wt-ErbB2 expressing MCF10A cells as these DCIS-like structures underwent luminal clearing. In CA-ErbB2 structures apoptosis is not induced by salubrinal and instead a state of quiescence with reduced proliferation was achieved. Treatments that stabilize P-eIF2α levels may be effective in treating ErbB2 positive cancers without severely disrupting normal tissue function and structure.
Conserved repertoire of orthologous vomeronasal type 1 receptor genes in ruminant species
Authors: Ohara Hiromi , Nikaido Masato , Date-Ito Atsuko , Mogi Kazutaka , Okamura Hiroaki , Okada Norihiro , Takeuchi Yukari , Mori Yuji , Hagino-Yamagishi Kimiko 
Published: September 2009

Abstract

Background
In mammals, pheromones play an important role in social and innate reproductive behavior within species. In rodents, vomeronasal receptor type 1 (V1R), which is specifically expressed in the vomeronasal organ, is thought to detect pheromones. The V1R gene repertoire differs dramatically between mammalian species, and the presence of species-specific V1R subfamilies in mouse and rat suggests that V1R plays a profound role in species-specific recognition of pheromones. In ruminants, however, the molecular mechanism(s) for pheromone perception is not well understood. Interestingly, goat male pheromone, which can induce out-of-season ovulation in anestrous females, causes the same pheromone response in sheep, and vice versa, suggesting that there may be mechanisms for detecting "inter-species" pheromones among ruminant species.

Results
We isolated 23 goat and 21 sheep intact V1R genes based on sequence similarity with 32 cow V1R genes in the cow genome database. We found that all of the goat and sheep V1R genes have orthologs in their cross-species counterparts among these three ruminant species and that the sequence identity of V1R orthologous pairs among these ruminants is much higher than that of mouse-rat V1R orthologous pairs. Furthermore, all goat V1Rs examined thus far are expressed not only in the vomeronasal organ but also in the main olfactory epithelium.

Conclusion
Our results suggest that, compared with rodents, the repertoire of orthologous V1R genes is remarkably conserved among the ruminants cow, sheep and goat. We predict that these orthologous V1Rs can detect the same or closely related chemical compound(s) within each orthologous set/pair. Furthermore, all identified goat V1Rs are expressed in the vomeronasal organ and the main olfactory epithelium, suggesting that V1R-mediated ligand information can be detected and processed by both the main and accessory olfactory systems. The fact that ruminant and rodent V1Rs have distinct features suggests that ruminant and rodent V1Rs have evolved distinct functions.
Sequenced BAC anchored reference genetic map that reconciles the ten individual chromosomes of Brassica rapa
Authors: Kim HyeRan , Choi Su Ryun , Bae Jina , Hong Chang Pyo , Lee Seo Yeon , Hossain Md Jamil , Van Nguyen Dan , Jin Mina , Park Beom-Seok , Bang Jea-Wook , Bancroft Ian , Lim Yong Pyo 
Published: September 2009

AbstractBackgroundIn view of the immense value ofBrassica rapain the fields of agriculture and molecular biology, the multinationalBrassica rapaGenome Sequencing Project (BrGSP) was launched in 2003 by five countries. The developing BrGSP has valuable resources for the community, including a reference genetic map and seed BAC sequences. Although the initialB. rapalinkage map served as a reference for the BrGSP, there was ambiguity in reconciling the linkage groups with the ten chromosomes ofB. rapa. Consequently, the BrGSP assigned each of the linkage groups to the project members as chromosome substitutes for sequencing.ResultsWe identified simple sequence repeat (SSR) motifs in theB. rapagenome with the sequences of seed BACs used for the BrGSP. By testing 749 amplicons containing SSR motifs, we identified polymorphisms that enabled the anchoring of 188 BACs onto theB. rapareference linkage map consisting of 719 loci in the 10 linkage groups with an average distance of 1.6 cM between adjacent loci. The anchored BAC sequences enabled the identification of 30 blocks of conserved synteny, totaling 534.9 cM in length, between the genomes ofB. rapaandArabidopsis thaliana. Most of these were consistent with previously reported duplication and rearrangement events that differentiate these genomes. However, we were able to identify the collinear regions for seven additional previously uncharacterized sections of the A genome. Integration of the linkage map with theB. rapacytogenetic map was accomplished by FISH with probes representing 20 BAC clones, along with probes for rDNA and centromeric repeat sequences. This integration enabled unambiguous alignment and orientation of the maps representing the 10B. rapachromosomes.ConclusionWe developed a second generation reference linkage map forB. rapa, which was aligned unambiguously to theB. rapacytogenetic map. Furthermore, using our data, we confirmed and extended the comparative genome analysis betweenB. rapaandA. thaliana. This work will serve as a basis for integrating the genetic, physical, and chromosome maps of the BrGSP, as well as for studies on polyploidization, speciation, and genome duplication in the genusBrassica.
malT knockout mutation invokes a stringent type gene-expression profile in Actinobacillus pleuropneumoniae in bronchoalveolar fluid
Authors: Lone Abdul G , Deslandes Vincent , Nash John HE , Jacques Mario , MacInnes Janet I 
Published: September 2009

AbstractBackgroundActinobacillus pleuropneumoniaecauses contagious pleuropneumonia, an economically important disease of commercially reared pigs throughout the world. To cause this disease,A. pleuropneumoniaemust rapidly overcome porcine pulmonary innate immune defenses. Since bronchoalveolar fluid (BALF) contains many of the innate immune and other components found in the lungs, we examined the gene expression of a virulent serovar 1 strain ofA. pleuropneumoniaeafter exposure to concentrated BALF for 30 min.ResultsIn reverse transcription PCR differential display (RT-PCR DD) experiments,A. pleuropneumoniaeCM5 exposed to BALF up-regulated, among other genes, a gene predicted to encode LamB, an outer-membrane transport protein of the maltose regulon. To determine the role of thelamBand other genes of the maltose regulon in the pathogenesis ofA. pleuropneumoniae, knockout mutations were created in thelamBandmalTgenes, the latter being the positive transcriptional regulator of the maltose regulon. Relative to thelamBmutant and the wild type, themalTmutant had a significant (P< 0.05) decrease in growth rate and an increased sensitivity to fresh porcine serum and high concentrations (more than 0.5 M) of sodium chloride. In DNA microarray experiments, the BALF-exposedmalTmutant exhibited a gene-expression profile resembling that of a stringent type gene-expression profile seen in bacteria facing amino acid or carbon starvation. Genes encoding proteins for protein synthesis, energy metabolism, and DNA replication were down-regulated, while genes involved in stringent response (e.g.,relA), amino acid and nucleotide biosynthesis, biofilm formation, DNA transformation, and stress response were up-regulated.ConclusionThese results suggest that MalT may be involved in protection against some stressors and in the transport of one or more essential nutrients in BALF. Moreover, if MalT is directly or indirectly linked to the stringent response, an important global mechanism of bacterial persistence and virulence in many bacterial pathogens, it might play a role inA. pleuropneumoniaepathogenesis.