Loss of heterozygosity in multistage carcinogenesis of esophageal carcinoma at high-incidence area in Henan Province, China

Aim: Microsatellites are the repeated DNA sequences scattered widely within the genomes and closely linked with many important genes. This study was designed to characterize the changes of microsatellite DNA loss of heterozygosity (LOH) in esophageal carcinogenesis. Methods: Allelic deletions in 32 cases of matched precancerous, cancerous and normal tissues were examined by syringe microdissection under an anatomic microscope and microsatellite polymorphism analysis using 15 polymorphic markers on chromosomes 3p, 5q, 6p, 9p, 13q, 17p, 17q and 18q. Results: Microsatellite DNA LOH was observed in precancerous and cancerous tissues, except D9S1752. The rate of LOH increased remarkably with the lesions progressed from basal cell hyperplasia (BCH) to squamous cell carcinoma (SCC) (P60%). LOH loci were different in precancerous and cancerous tissues. LOH in D3S1234 and TP53 was the common event in different lesions from the same patients. Conclusion: Microsatellite DNA LOH occurs in early stage of human esophageal carcinogenesis, even in BCH. With the lesion progressed, gene instability increases, the accumulation of this change may be one of the important mechanisms driving precancerous lesions to cancer. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

食管癌原發灶與淋巴結轉移灶細胞染色體變化特征的比較

BACKGROUND & OBJECTIVE: Local lymph node and blood metastasis could occur at early stage of esophageal squamous cell carcinoma (ESCC), which may be the key factors of its recurrence and poor prognosis. However, the mechanism of ESCC metastasis is unclear. This study was to analyze the genetic changes in primary lesion and lymph node metastases of ESCC, to screen for and locate ESCC metastasis-related genes. METHODS: Genomic alterations in 15 pairs of primary lesions and matched metastatic lymph nodes of ESCC were analyzed by comparative genomic hybridization (CGH). RESULTS: In the 15 pairs of tissues, the most common chromosomal alterations were the gains of 3q, 8q, 6p, 20p, 5p, 18p, 2p, 2q and 1q, and the losses of 10p, 10q, 17p, 18q, 4p and 13q. Of these changes, the most significant finding was the gain of 6p with a frequency of 47% in metastatic lymph nodes and 13% in primary lesions, and the gain of 20p with a frequency of 73% in metastatic lymph nodes and 33% in primary lesions. The second interesting finding was the loss of 10p with a frequency of 53% in metastatic lymph nodes and 13% in primary lesions, and the loss of 10q with a frequency of 47% in metastatic lymph nodes and 13% in primary lesions. CONCLUSION: The gains of 6p and 20p and the losses of 10p and 10q are common genomic alterations in primary lesion and lymph node metastases of ESCC, which may code ESCC metastasis-related genes.背景與目的:食管癌早期可發生局部淋巴或血行轉移,這是導致復發和預后差的主要原因。但是,食管癌轉移發生的分子機制尚不清楚。本研究旨在分析食管癌原發灶和淋巴結轉移灶腫瘤細胞染色體變化的特征,尋找或定位與食管癌轉移相關基因,加深對其轉移機制的了解。方法:應用比較基因組雜交技術(comparativegenomichybridization,CGH)分析15例食管癌患者原發灶和其對應的淋巴結轉移灶的染色體基因組改變。結果:最常見染色體DNA拷貝數增加的部位是3q,8q,6p,20p,5p,18p,2p,2q,1q;常見的染色體DNA拷貝數丟失的部位是10p,10q,17p,18q,4p,13q。其中,最有意義的發現是6p增加(原發灶:2/15,13%,轉移灶:7/15,47%),20p增加(原發灶:5/15,33.3%,轉移灶:11/15,73.3%)。第二個發現是10p丟失(原發灶:2/15,13.3%,轉移灶:8/15,53%),10q丟失(原發灶:2/15,13.3%,轉移灶:7/15,46.6%)。結論:食管癌原發灶和淋巴結轉移灶細胞染色體基因組改變最顯著的部位是6p,20p的增加和10p,10q的丟失;這些部位可能存在與食管癌細胞淋巴結轉移相關的基因。link_to_subscribed_fulltex

Surveillance of Schistosoma japonicum Infection in Domestic Ruminants in the Dongting Lake Region, Hunan Province, China

Background: Schistosomiasis japonica is prevalent in Asian countries and it remains a major public health problem in China. The major endemic foci are the marsh and lake regions of southern China, particularly the Dongting Lake region bordering Hunan and Hubei provinces, and the Poyang Lake region in Jiangxi province. Domestic ruminants, especially bovines, have long been considered to play a major role in the transmission of Schistosoma japonicum to humans. Methods and Findings: A miracidial hatching technique was used to investigate the prevalence of S. japonicum infections in domestic ruminants and field feces collected from two towns located to the south and east of Dongting Lake, Hunan province, between 2005 and 2010. The overall prevalence of infection was not significantly reduced from 4.93 % in 2005 to 3.64 % in 2008, after which it was maintained at this level. Bovines comprised 23.5–58.2 % of the total infected ruminants, while goats comprised 41.8–76.5%. Infection rates in cattle and goats were significantly higher than those found in buffalo in most study years. The prevalence in buffalo younger than three years was significantly higher than that in those aged over three years. All the positive field samples of feces were derived from bovines in Nandashan. In Matang Town, 61.22 % of the positive field feces were from bovines, while the rest were from goats. The positive rates for field feces were approximately the same in April and November/October. Conclusions: The present study found that bovines and goats are major sources of S. japonicum infection in the Dongtin

Requirement of the CXXC Motif of Novel Francisella Infectivity Potentiator Protein B FipB, and FipA in Virulence of F. tularensis subsp. tularensis

The lipoprotein encoded by the Francisella tularensis subsp. tularensis locus FTT1103 is essential for virulence; an FTT1103 deletion mutant is defective in uptake and intracellular survival, and mice survive high dose challenges of greater than 108 bacteria. This protein has two conserved domains; one is found in a class of virulence proteins called macrophage infectivity potentiator (Mip) proteins, and the other in oxidoreductase Disulfide Bond formation protein A (DsbA)-related proteins. We have designated the protein encoded by FTT1103 as FipB for Francisella infectivity potentiator protein B. The locus FTT1102 (fipA), which is upstream of fipB, also has similarity to same conserved Mip domain. Deletion and site-specific mutants of fipA and fipB were constructed in the Schu S4 strain, and characterized with respect to intracellular replication and in vivo virulence. A nonpolar fipA mutant demonstrated reduced survival in host cells, but was only slightly attenuated in vivo. Although FipB protein was present in a fipA mutant, the abundance of the three isoforms of FipB was altered, suggesting that FipA has a role in post-translational modification of FipB. Similar to many DsbA homologues, FipB contains a cysteine-any amino acid-any amino acid-cysteine (CXXC) motif. This motif was found to be important for FipB's role in virulence; a deletion mutant complemented with a gene encoding a FipB protein in which the first cysteine was changed to an alanine residue (AXXC) failed to restore intracellular survival or in vivo virulence. Complementation with a gene that encoded a CXXA containing FipB protein was significantly defective in intracellular growth; however, only slightly attenuated in vivo

Assessment of left ventricular function by three-dimensional echocardiography.

Accurate determination of LV volume, ejection fraction and segmental wall motion abnormalities is important for clinical decision-making and follow-up assessment. Currently, echocardiography is the most common used method to obtain this information. Three-dimensional echocardiography has shown to be an accurate and reproducible method for LV quantitation, mainly by avoiding the use of geometric assumptions. In this review, we describe various methods to acquire a 3D-dataset for LV volume and wall motion analysis, including their advantages and limitations. We provide an overview of studies comparing LV volume and function measurement by various gated and real-time methods of acquisition compared to magnetic resonance imaging. New technical improvements, such as automated endocardial border detection and contrast enhancement, will make accurate on-line assessment with little operator interaction possible in the near future

Genomic imbalances in esophageal squamous cell carcinoma identified by molecular cytogenetic techniques

This review summarizes the chromosomal changes detected by molecular cytogenetic approaches in esophageal squamous cell carcinoma (ESCC), the ninth most common malignancy in the world. Whole genome analyses of ESCC cell lines and tumors indicated that the most frequent genomic gains occurred at 1, 2q, 3q, 5p, 6p, 7, 8q, 9q, 11q, 12p, 14q, 15q, 16, 17, 18p, 19q, 20q, 22q and X, with focal amplifications at 1q32, 2p16-22, 3q25-28, 5p13-15.3, 7p12-22, 7q21-22, 8q23-24.2, 9q34, 10q21, 11p11.2, 11q13, 13q32, 14q13-14, 14q21, 14q31-32, 15q22-26, 17p11.2, 18p11.2-11.3 and 20p11.2. Recurrent losses involved 3p, 4, 5q, 6q, 7q, 8p, 9, 10p, 12p, 13, 14p, 15p, 18, 19p, 20, 22, Xp and Y. Gains at 5p and 7q, and deletions at 4p, 9p, and 11q were significant prognostic factors for patients with ESCC. Gains at 6p and 20p, and losses at 10p and 10q were the most significant imbalances, both in primary carcinoma and in metastases, which suggested that these regions may harbor oncogenes and tumor suppressor genes. Gains at 12p and losses at 3p may be associated with poor relapse-free survival. The clinical applicability of these changes as markers for the diagnosis and prognosis of ESCC, or as molecular targets for personalized therapy should be evaluated

Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11

BACKGROUND: Alternative splicing across exon 11 produces several BRCA1 isoforms. Their proportion varies during the cell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymous substitutions (silent nucleotide variations that do not alter the amino acid residue sequence) in a critical region of BRCA1 exon 11 has been reported to be associated with the necessity to maintain regulatory sequences. METHODOLOGY/PRINCIPAL FINDINGS: Here we have designed a specific minigene to investigate the possibility that this bias in synonymous codon usage reflects the need to preserve the BRCA1 alternative splicing program. We report that in-frame deletions and translationally silent nucleotide substitutions in the critical region affect splicing regulation of BRCA1 exon 11. CONCLUSIONS/SIGNIFICANCE: Using a hybrid minigene approach, we have experimentally validated the hypothesis that the need to maintain correct alternative splicing is a selective pressure against translationally silent sequence variations in the critical region of BRCA1 exon 11. Identification of the trans-acting factors involved in regulating exon 11 alternative splicing will be important in understanding BRCA1-associated tumorigenesis

Does physical activity modify the risk of obesity for type 2 diabetes: a review of epidemiological data

Obesity and physical inactivity are both risk factors for type 2 diabetes. Since they are strongly associated, it has been suggested that they might interact. In this study, we summarized the evidence on this interaction by conducting a systematic review. Two types of interaction have been discerned, statistical and biological interaction, which could give different results. Therefore, we calculated both types of interaction for the studies in our review. Cohort studies, published between 1999 and 2008, that investigated the effects of obesity and physical activity on the risk of type 2 diabetes were included. We calculated both biological and statistical interaction in these studies. Eight studies were included of which five were suitable to calculate interaction. All studies showed positive biological interaction, meaning that the joint effect was more than the sum of the individual effects. However, there was inconsistent statistical interaction; in some studies the joint effect was more than the product of the individual effects, in other studies it was less. The results show that obesity and physical inactivity interact on an additive scale. This means that prevention of either obesity or physical inactivity, not only reduces the risk of diabetes by taking away the independent effect of this factor, but also by preventing the cases that were caused by the interaction between both factors. Furthermore, this review clearly showed that results can differ depending on what method is used to assess interaction

Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism

ACE I/D Gene Polymorphism Can't Predict the Steroid Responsiveness in Asian Children with Idiopathic Nephrotic Syndrome: A Meta-Analysis

The results from the published studies on the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the treatment response to steroid in Asian children with idiopathic nephrotic syndrome (INS) is still conflicting. This meta-analysis was performed to evaluate the relation between ACE I/D gene polymorphism and treatment response to steroid in Asian children and to explore whether ACE D allele or DD genotype could become a predictive marker for steroid responsiveness. = 0.85; respectively), however, the result for the association of II genotype with SRNS risk was not stable.Our results indicate that D allele or DD homozygous can't become a significant genetic molecular marker to predict the treatment response to steroid in Asian children with INS