Transcription factor AP-1 in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection

<p>Abstract</p> <p>Background</p> <p>Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (J&K) region of India. A substantial proportion of esophageal carcinoma is associated with infection of high-risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Activator Protein-1 (AP-1). We, therefore, have investigated the role of DNA binding and expression pattern of AP-1 in esophageal cancer with or without HPV infection.</p> <p>Methods</p> <p>Seventy five histopathologically-confirmed esophageal cancer and an equal number of corresponding adjacent normal tissue biopsies from Kashmir were analyzed for HPV infection, DNA binding activity and expression of AP-1 family of proteins by PCR, gel shift assay and immunoblotting respectively.</p> <p>Results</p> <p>A high DNA binding activity and elevated expression of AP-1 proteins were observed in esophageal cancer, which differed between HPV positive (19%) and HPV negative (81%) carcinomas. While JunB, c-Fos and Fra-1 were the major contributors to AP-1 binding activity in HPV negative cases, Fra-1 was completely absent in HPV16 positive cancers. Comparison of AP-1 family proteins demonstrated high expression of JunD and c-Fos in HPV positive tumors, but interestingly, Fra-1 expression was extremely low or nil in these tumor tissues.</p> <p>Conclusion</p> <p>Differential AP-1 binding activity and expression of its specific proteins between HPV - positive and HPV - negative cases indicate that AP-1 may play an important role during HPV-induced esophageal carcinogenesis.</p

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

AIMS: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. METHODS: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. RESULTS: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. CONCLUSIONS: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development

Clondalkin Drug Task Force strategic plan 2008.

Clondalkin Drugs Task Force: The Clondalkin Drug Task Force is one of 14 LDTFs located mainly in the greater Dublin region. Their overall role is to prepare and implement action plans which identify existing and emerging gaps in services in relation to education/prevention, treatment, rehabilitation and curbing local supply. To date the Clondalkin Drug Task Force The Task Forces has drawn up two Area Actions Plans based on intensive consultations (1997/8 and 2001). The plans represent a consensus on the priority issues to be addressed in the community in terms of problematic drug use. Each plan included a range of measures in terms of treatment, rehabilitation, education and prevention, and curbing the local supply of drugs. The initial Action Plan focused on education and prevention strategies and actions in response to the identified need for innovative community based education programmes in Clondalkin. CDTF’s most recent Area Action Plan was developed in 2001 and entitled ‘Making Progress’. In the development of the this Action Plan, the Task Force reflected on the lessons learned from implementing the initial plan and developed a number of strategies and actions that focused on Treatment & Rehabilitation. Prevalence of Drug Problems in Clondalkin: The research shows that drug use in Clondalkin is perceived to have become more problematic. The prevalence survey suggested that there are greater quantities and varieties of drugs available and there has been an increase in the proportion of younger people using drugs than was the case in the past. The respondents to the survey feel that drug dealing has become more visible in the locality. Drug consumption mostly occurs in the user’s place of residence and the first encounter with illicit drugs typically occurred in the company of friends. Heroin is the overwhelming primary problematic drug of use. Yet, there has been a notable increase in the problematic use of cocaine, alcohol and prescription drugs. Cocaine has become a frequently used recreational drug in Clondalkin. There is some indication in the survey that crack cocaine is an emerging problem drug. The survey highlights how polydrug use is the norm. There are a wide variety of polydrug use patterns: heroin combined with either cannabis, cocaine, benzodiazepines, alcohol or crack cocaine, are the most common patterns of use. The typical pattern for recreational drug users was cocaine combined with either cannabis or alcohol. The injection of cocaine by injecting heroin users was another emerging trend. This research suggests there are 1,591 opiate users in the area. Heroin was overwhelmingly the main problem drug for this cohort. The typical problematic drug user (especially opiates) in Clondalkin is most commonly a male, Irish, single, unemployed, early school leaver between the ages of 15 and 24 years. The MQI research indicates that in contrast to heroin users, recreational cocaine users come from all age groups and all social strata. The majority of problem drug users do not seek treatment until their late twenties and early thirties. This research suggests that there is an obvious lack of data available on drug use among ethnic minorities. This emerges through the lack of engagement by those from new communities with existing treatment services and also lack of general knowledge on the part of community and statutory services of the profile of new communities in Clondalkin. This report reveals that the causes of drug problems were perceived as wide, differed depending on the respondent’s relationship with drugs and ranged across a number of factors such as contact with problematic drug use; family dysfunction; lack of education, low self-esteem and peer influences; curiosity, adolescent experimentation and an awareness of the pleasurable aspects of drug use. Hepatitis C is quite prevalent among Injecting Drug Users (IDUs) according to the survey. In addition, one fifth of those interviewed had been diagnosed with a psychiatric illness and have accessed mental health services. A significant minority of IDUs reported not being aware of needle exchange services in Clondalkin. MQI also show that there was a marginal decrease in the numbers of individuals accessing drug treatment services over the three year period, 2004-2007. It is perceived that services have improved over the past 5 years, due to the increase of facilities. Criticisms of current services included the lack of a ‘moving on’ or progression mechanism as well as the lack of input of clients to their drug treatment. There was widespread agreement that there is a lack of drug treatment services in the Clondalkin area and insufficient numbers of detoxification programmes available. The research also suggests that there is a clear need for a local homeless service in order to provide suitable facilities for homeless drug users. There was a perception that drug related violence has increased significantly in recent years. There was a notable increase in simple possession and possession for sale and supply incidents from 2005 to 2006. Participants in the research perceived that there is a lack of Garda personnel dedicated to tackling drug related crime in Clondalkin. The effects of drug problems on families include: physical and psychological stress; financial burden of payment of drug debts; grandparents who are taking care of their grandchildren; and, concerns for children of drug users in relation to their early exposure to drug addiction. The effects of drug problems on the community include: the crime element of drug use and the openness of dealing; fear of using public amenities; and that community anti-drug activism appears to have diminished due to fatigue

UNIPARENTAL ORIGIN OF I(12P) IN HUMAN GERM-CELL TUMORS

We present molecular data to demonstrate that the isochromosome 12p, specific for human germ cell tumors (GCTs), is of uniparental origin. Eight GCT-derived cell lines, containing one or more copies of i(12p) and/or other 12p anomalies, were analyzed with different 12p-derived polymorphic markers. The results from Ma-90, a near-diploid cell line with only one i(12p) in addition to two copies of a normal chromosome 12, clearly show an allelic 12p ratio of approximately 3:1, indicating that both 12p arms are of identical parental origin. These results were further substantiated by data obtained from the other i(12p)-positive GCT-derived cell lines. Therefore, we conclude that the i(12p) in GCTs constitutes a genuine isochromosome with genetically identical arms. The isochromosome most likely originates from a misdivision of the centromere rather than from a translocation or a non-sister chromatid exchange as proposed by others. We also found that supernumerary 12p copies, as observed in i(12p)-negative GCTs, are of uniparental origin. These observations seem to point to an important role for certain 12p-derived sequences in the development of human GCTs

Two cases with partial trisomy 9p:Molecular cytogenetic characterization and clinical follow-up

This paper describes two patients with partial trisomy 9p and partial trisomy 14q due to 3:1 segregation from de novo maternal reciprocal translocations. The breakpoints are different from previously described 9;14 translocations and their 3:1 segregation products. The clinical phenotype of both cases is compatible with the partial trisomy 9p syndrome. We present the follow-up of both patients from birth up to age 7 years. Partial trisomy 9p is a frequently described chromosome abnormality. This does not appear to be related to a breakage sensitive locus on chromosome 9p, since the trisomic fragments of the published cases are heterogeneous. In the two cases described here, GTG-banded karyotyping suggested that the 9p breakpoints were similar; DNA marker analysis, however, showed them to be different. Such DNA studies will be necessary to define the genotype-phenotype relation in partial trisomy 9p syndrome. (C) 2002 Wiley-Liss, Inc