Single nucleotide polymorphism rs11614913 associated with CC genotype in miR-196a2 is overrepresented in laryngeal squamous cell carcinoma, but not salivary gland tumors in Polish population

Abstract

The miRNA-196a2 has shown significance in the development of various neoplasms, including head and neck squamous cell carcinoma (HNSCC). The oncogenic functionality of this miRNA is mediated via its potential to target annexin A1 mRNA, a tumor suppressor gene involved in inhibition of the NF-κB pathway. Interestingly, recent data indicate a susceptibility for aforementioned neoplasms in patients with the CC genotype vs the CT and TT genotypes of the rs11614913 SNP located within the DNA sequence of the miR-196a2 that results in elevated expression of the gene. To further investigate this phenomenon, we genotyped this SNP in 40 patients with laryngeal squamous cell carcinoma (LSCC), the most common tumor of the head and neck region and 60 patients with salivary gland tumors (SGT) that show a yet unexplained incidence increase in the last two decades. In agreement with previous reports, we have identified a statistically significant (p < 0.05) overrepresentation of the CC genotype in LSCC patients and demonstrated in LSCC cell lines that it results in elevated expression of miR-196a2 as compared to cell lines with the TT genotype of the respective SNP. Importantly, none of these correlations was found in patients with SGT. These findings underline the importance of the SNP rs11614913 for LSCC development in the Polish population and moreover highlight the different genetic background of the two studied neoplasms of the head and neck region.

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A Health Profile and Overview of Healthcare Experiences of Cambodian American Refugees and Immigrants Residing in Southern California

Abstract

Asian Americans are understudied in health research and often aggregated into one homogenous group, thereby disguising disparities across subgroups. Cambodian Americans, one of the largest refugee communities in the United States, may be at high risk for adverse health outcomes. This study compares the health status and healthcare experiences of Cambodian American refugees and immigrants. Data were collected via questionnaires and medical records from two community clinics in Southern California (n = 308). Chi square and t-tests examined the socio-demographic differences between immigrants and refugees, and ANCOVA models compared the mean differences in responses for each outcome, adjusting for age at immigration, education level, and clinic site. Cambodian American refugees reported overall lower levels of health-related quality of life (all p's < 0.05 in unadjusted models) and self-rated health [unadjusted means (SD) = 18.2 (16.8) vs. 21.7 (13.7), p < 0.05], but either similar or more positive healthcare experiences than Cambodian American immigrants. In adjusted analyses, refugees had higher rates of diabetes and cardiovascular disease risk (e.g. heart condition and hypertension; p's < 0.05) compared to Cambodian American immigrants. There were minimal differences in self-reported health behaviors between the two groups. There is a need for more health promotion efforts among Cambodian American refugees and immigrants to improve their health outcomes and perceived wellbeing.

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Diminutive intramucosal invasive (Tis) sigmoid colon carcinoma

Abstract

A 60-year-old woman underwent colonoscopy, which revealed a red, 5-mm protruded lesion in the sigmoid colon, surrounded by white spots in white-light imaging. Indigo carmine spray indicated endoscopic morphological type Is + IIc. The vessel pattern was diagnosed as JNET-type 2B in magnifying narrow-band imaging, and magnified crystal violet-stained images revealed a VI low-grade pit pattern. We endoscopically diagnosed this lesion as an intramucosal or slightly invasive submucosal carcinoma with low confidence, and performed endoscopic mucosal resection to obtain a total biopsy. Hematoxylin and eosin staining of the resected specimen showed that the surface of the lesion was well-differentiated adenocarcinoma. The muscularis mucosae was identified by desmin immunostaining. There was no lymphovascular infiltration. Structural atypia was notable in the invasive front, indicating well-to-moderately differentiated adenocarcinoma, which invaded the lamina muscularis mucosae. In addition, desmoplastic reaction was recognized to be present. The lesion was, therefore, diagnosed as an intramucosal invasive (Tis) carcinoma, rather than high-grade dysplasia, according to the World Health Organization definition.

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High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation

Abstract

While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.

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A Cloning-Free Method for CRISPR/Cas9-Mediated Genome Editing in Fission Yeast

The CRISPR/Cas9 system, which relies on RNA-guided DNA cleavage to induce site-specific DNA double-strand breaks, is a powerful tool for genome editing. This system has been successfully adapted for the fission yeast Schizosaccharomyces pombe by expressing Cas9 and the single-guide RNA (sgRNA) from a plasmid. In the procedures published to date, the cloning step that introduces a specific sgRNA target sequence into the plasmid is the most tedious and time-consuming. To increase the efficiency of applying the CRISPR/Cas9 system in fission yeast, we here developed a cloning-free procedure that uses gap repair in fission yeast cells to assemble two linear DNA fragments, a gapped Cas9-encoding plasmid and a PCR-amplified sgRNA insert, into a circular plasmid. Both fragments contain only a portion of the ura4 or bsdMX marker so that only the correctly assembled plasmid can confer uracil prototrophy or blasticidin resistance. We show that this gap-repair-based and cloning-free CRISPR/Cas9 procedure permits rapid and efficient point mutation knock-in, endogenous N-terminal tagging, and genomic sequence deletion in fission yeast.

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Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes

Apoptotic cell death is a type of eukaryotic cell death. In animals, it regulates development, is involved in cancer suppression, and causes cell death during pathological aging of neuronal cells in neurodegenerative diseases such as Alzheimer's. Mitochondrial apoptotic-like cell death, a form of primordial apoptosis, also occurs in unicellular organisms. Here, we ask the question why the apoptosis machinery has been acquired and maintained in unicellular organisms and attempt to answer it by performing ancestral state reconstruction. We found indications of an ancient evolutionary arms race between protomitochondria and host cells, leading to the establishment of the currently existing apoptotic pathways. According to this reconstruction, the ancestral protomitochondrial apoptosis machinery contained both caspases and metacaspases, four types of apoptosis induction factors (AIFs), both fungal and animal OMI/HTR proteases, and various apoptotic DNases. This leads to the prediction that in extant unicellular eukaryotes, the apoptotic factors are involved in mitochondrial respiration and their activity is needed exclusively in aerobic conditions. We test this prediction experimentally using yeast and find that a loss of the main apoptotic factors is beneficial under anaerobic conditions yet deleterious under aerobic conditions in the absence of lethal stimuli. We also point out potential medical implications of these findings.

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A High-Quality Reference Genome for the Invasive Mosquitofish Gambusia affinis Using a Chicago Library

The western mosquitofish, Gambusia affinis, is a freshwater poecilid fish native to the southeastern United States but with a global distribution due to widespread human introduction. Gambusia affinis has been used as a model species for a broad range of evolutionary and ecological studies. We sequenced the genome of a male G. affinis to facilitate genetic studies in diverse fields including invasion biology and comparative genetics. We generated Illumina short read data from paired-end libraries and in vitro proximity-ligation libraries. We obtained 54.9x coverage, N50 contig length of 17.6 kb, and N50 scaffold length of 6.65 Mb. Compared to two other species in the Poeciliidae family, G. affinis has slightly fewer genes that have shorter total, exon, and intron length on average. Using a set of universal single-copy orthologs in fish genomes, we found 95.5% of these genes were complete in the G. affinis assembly. The number of transposable elements in the G. affinis assembly is similar to those of closely related species. The high-quality genome sequence and annotations we report will be valuable resources for scientists to map the genetic architecture of traits of interest in this species.

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