Towards the identification of a tumor suppressor gene on chromosome 3p12: Physical mapping and candidate gene screening

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Characterization of RCC tumors indicates that the most frequent genetic event associated with the initiation of tumor formation involves a loss of heterozygosity or cytogenetic aberration on the short arm of human chromosome 3. A tumor suppressor locus Nonpapillary Renal Carcinoma-1 (NRC-1, OMIM ID 604442) has been previously mapped to a 5–7 cM region on chromosome 3p12 and shown to induce rapid tumor cell death in vivo, as demonstrated by functional complementation experiments. ^ To identify the gene that accounts for the tumor suppressor activities of NRC-1, fine-scale physical mapping was conducted with a novel real-time quantitative PCR based method developed in this study. As a result, NRC-1 was mapped within a 4.6-Mb region defined by two unique sequences within UniGene clusters Hs.41407 and Hs.371835 (78,545Kb–83,172Kb in the NCBI build 31 physical map). The involvement of a putative tumor suppressor gene Robo1/Dutt1 was excluded as a candidate for NRC-1. Furthermore, a transcript map containing eleven candidate genes was established for the 4.6-Mb region. Analyses of gene expression patterns with real-time quantitative RT-PCR assays showed that one of the eleven candidate genes in the interval (TSGc28) is down-regulated in 15 out of 20 tumor samples compared with matched normal samples. Three exons of this gene have been identified by RACE experiments, although additional exon(s) seem to exist. Further gene characterization and functional studies are required to confirm the gene as a true tumor suppressor gene. ^ To study the cellular functions of NRC-1, gene expression profiles of three tumor suppressive microcell hybrids, each containing a functional copy of NRC-1, were compared with those of the corresponding parental tumor cell lines using 16K oligonucleotide microarrays. Differentially expressed genes were identified. Analyses based on the Gene Ontology showed that introduction of NRC-1 into tumor cell lines activates genes in multiple cellular pathways, including cell cycle, signal transduction, cytokines and stress response. NRC-1 is likely to induce cell growth arrest indirectly through WEE1. ^

Neurocognitive impairment in relation to glutathione S-transferase enzyme polymorphisms among medulloblastoma patients

Background. Medulloblastoma is a type of brain cancer that accounts for approximately 7-8% of all intracranial tumors and 20-30% of pediatric brain tumors. It is the most common type of malignant brain tumor in childhood. It was reported that majority of survivors with medulloblastoma have social problems, endocrine deficits, and neurological complications. Furthermore, all had significant deficits in neurocognitive functioning. Glutathione S-transferases belong to a family of isoenzymes that catalyze the glutathione conjugation of a variety of electrophilic compounds. ^ Objective. We aimed to determine whether the development of neurocognitive impairment is associated with GST polymorphisms among children and adolescents diagnosed with medulloblastoma (MB) after radiation therapy. ^ Methods. A pilot study composing of 16 children and adolescents diagnosed with MB at Texas Children's Cancer Center was conducted. The t-test was used to determine if the GST polymorphisms were related to neurocognitive impairment and logistic regression was performed to explore association between GST polymorphisms and gender, age at diagnosis, race/ethnicity, and risk group. ^ Results. An association was observed between GSTT1 polymorphism and cognitive impairment one year after radiation and GSTM1 polymorphism two years after radiation. It was observed that patients with GSTT1 null genotype have lower performance IQ (p=0.03) and full scale IQ (p=0.02) one year after radiation and patients with GSTM1 null genotype have lower verbal IQ (p=0.02) two years after radiation. Patients under age 8 have a statistically non-significant higher risk of having not null genotypes compared to those older than age 8 (OR= 7.5, 95%CI: 0.62-90.65 and OR= 2.63, 95%CI: 0.30-23.00 for GSTT1 and GSTM1 respectively). ^ Conclusion. There was a significant association between GSTT1 polymorphism and cognitive impairment one year after radiation and between GSTM1 polymorphism and cognitive impairment two years after radiation. Further large scale studies may be needed to confirm this finding and to examine the underlying mechanism of neurocognitive impairments after treatment of medulloblastoma patients.^

Use of tabletop exercises for disaster preparedness training

Background. In public health preparedness, disaster preparedness refers to the strategic planning of responses to all types of disasters. Preparation and training for disaster response can be conducted using different teaching modalities, ranging from discussion-based programs such as seminars, drills and tabletop exercises to more complex operation-based programs such as functional exercises and full-scale exercises. Each method of instruction has its advantages and disadvantages. Tabletop exercises are facilitated discussions designed to evaluate programs, policies, and procedures; they are usually conducted in a classroom, often with tabletop props (e.g. models, maps or diagrams). ^ Objective. The overall goal of this project was to determine whether tabletop exercises are effective teaching modalities for disaster preparedness, with an emphasis on intentional chemical exposure. ^ Method. The target audience for the exercise was the Medical Reserve Brigade of the Texas State Guard, a group of volunteer healthcare providers and first responders who prepare for response to local disasters. A new tabletop exercise was designed to provide information on the complex, interrelated organizations within the national disaster preparedness program that this group would interact with in the event of a local disaster. This educational intervention consisted of a four hour multipart program that included a pretest of knowledge, lecture series, an interactive group discussion using a mock disaster scenario, a posttest of knowledge, and a course evaluation. ^ Results. Approximately 40 volunteers attended the intervention session; roughly half (n=21) had previously participated in a full scale drill. There was an 11% improvement in fund of knowledge between the pre- and post-test scores (p=0.002). Overall, the tabletop exercise was well received by those with and without prior training, with no significant differences found between these two groups in terms of relevance and appropriateness of content. However, the separate components of the tabletop exercise were variably effective, as gauged by written text comments on the questionnaire. ^ Conclusions. Tabletop exercises can be a useful training modality in disaster preparedness, as evidenced by improvement in knowledge and qualitative feedback on its value. Future offerings could incorporate recordings of participant responses during the drill, so that better feedback can be provided to them. Additional research should be conducted, using the same or similar design, in different populations that are stakeholders in disaster preparedness, so that the generalizability of these findings can be determined.^