Integrated Genomic and Functional microRNA Analysis Identifies miR-30-5p as a Tumor Suppressor and Potential Therapeutic Nanomedicine in Head and Neck Cancer.

PURPOSE: To identify deregulated and inhibitory miRNAs and generate novel mimics for replacement nanomedicine for head and neck squamous cell carcinomas (HNSCC). EXPERIMENTAL DESIGN: We integrated miRNA and mRNA expression, copy number variation, and DNA methylation results from The Cancer Genome Atlas (TCGA), with a functional genome-wide screen. RESULTS: We reveal that the miR-30 family is commonly repressed, and all 5 members sharing these seed sequence similarly inhibit HNSCC proliferation in vitro. We uncover a previously unrecognized inverse relationship with overexpression of a network of important predicted target mRNAs deregulated in HNSCC, that includes key molecules involved in proliferation (EGFR, MET, IGF1R, IRS1, E2F7), differentiation (WNT7B, FZD2), adhesion, and invasion (ITGA6, SERPINE1). Reexpression of the most differentially repressed family member, miR-30a-5p, suppressed this mRNA program, selected signaling proteins and pathways, and inhibited cell proliferation, migration, and invasion in vitro. Furthermore, a novel miR-30a-5p mimic formulated into a targeted nanomedicine significantly inhibited HNSCC xenograft tumor growth and target growth receptors EGFR and MET in vivo. Significantly decreased miR-30a/e family expression was related to DNA promoter hypermethylation and/or copy loss in TCGA data, and clinically with decreased disease-specific survival in a validation dataset. Strikingly, decreased miR-30e-5p distinguished oropharyngeal HNSCC with poor prognosis in TCGA (P = 0.002) and validation (P = 0.007) datasets, identifying a novel candidate biomarker and target for this HNSCC subset. CONCLUSIONS: We identify the miR-30 family as an important regulator of signal networks and tumor suppressor in a subset of HNSCC patients, which may benefit from miRNA replacement nanomedicine therapy.

CD7 expression and galectin-1-induced apoptosis of immature thymocytes are directly regulated by NF-kappaB upon T-cell activation.

CD7, one of the galectin-1 receptors, has crucial roles in galectin-1-mediated apoptosis of activated T-cells and T-lymphoma progression in peripheral tissues. In this study, we showed that CD7 promoter activity was increased by NF-kappaB and that this activity was synergistic when Sp1 was co-expressed in the immature T-cell line L7. Site-directed mutagenesis analysis of the CD7 promoter indicated that NF-kappaB specifically bound to the NF-kappaE2 site in cooperation with Sp1. Overexpression of E12 or Twist2 proteins negatively regulated NF-kappaB-mediated activity of the CD7 proximal promoter. In addition, CD7 expression was down-regulated by treatment with the p38 MAPK inhibitor SB20358, or the MSK1 inhibitor H-89. These signaling pathway inhibitors prevented galectin-1-mediated apoptosis of immature T-cells. From these results, we concluded that the regulation of CD7 gene expression through NF-kappaB activation induced by TCR/CD28 might have significant implications for T-cell homeostasis.

Assessing the Impact of Video-Based Assignments on Health Professions Students' Social Presence on Web: Case Study.

BACKGROUND: Web-based education is one of the leading learning pedagogies in health professions education. Students have access to a multitude of opinions, knowledge, and resources on Web, but communication among students in Web-based courses is complicated. Technology adds a filter that makes it difficult to decipher the emotions behind words or read nonverbal cues. This is a concern because students benefit more from Web-based classes when they have a high perception of social presence. To enhance social presence on Web, we planned to use video-based assignments (VBAs) that encourage students to interact with each other. OBJECTIVE: This case study examines the impact of VBAs on health professions students and their experiences with the technology. This study aims to provide information to the growing body of literature about strategies to develop social presence on Web. METHODS: A total of 88 students from various nursing programs participated in the study. While the control group comprised 36 students who submitted only written-based assignments (WBAs), the experimental group of 52 students submitted VBAs besides WBAs. No enrolled student had previously participated in the course, and there were no repeaters in either of the groups. Both groups participated in a weekly survey comprising 4 open-ended questions and 3 Likert items on a scale of 1-5 (1=strongly disagree and 5=strongly agree). The social presence questionnaire assessed by the experimental group comprised 16 items and a 5-point Likert scale in which higher scores represented higher levels of social presence. While quantitative data were analyzed using descriptive statistics, qualitative responses were analyzed using content analysis. RESULTS: No significant differences were noted between the groups regarding the program (F1,87=0.36, P=.54). Regarding students' engagement, no statistically significant difference was observed between the 2 groups (t14=0.96, P=.35). However, the experimental group's average score for engagement was slightly higher (4.29 [SD 0.11]) than that of the control group (4.21 [SD 0.14]). Comparison of the total number of responses to the weekly engagement survey revealed 88.0% (287/326) as either strongly agree or agree in the control group, whereas 93.1% (525/564) in the experimental group. No statistically significant difference was observed between VBAs and WBAs weeks (t6=1.40, P=.21) in the experimental group. Most students reported a positive experience using VBAs, but technical issues were barriers to embracing this new approach to learning. CONCLUSIONS: This study reveals that social presence and engagement are positively associated with student learning and satisfaction in Web-based courses. Suggestions are offered to enhance social presence on Web that could generate better learning outcomes and students' experiences.

Clinical features of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a study of 25 patients in Korea.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare adverse drug reaction. This study aimed to evaluate the incidence of association with individual drugs, clinical manifestations, disease course, and outcomes of DRESS. METHODS: Using the criteria of the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR), the medical records of 25 patients diagnosed with DRESS between 2006 and 2015 were retrospectively reviewed. Demographic data, culprit drugs, latency periods, clinical and laboratory findings, and outcomes were investigated. RESULTS: The study group comprised 11 men (44%) and 14 women (56%) with an age range of 13-93 years (mean, 58 ± 19.86 years). The drugs most commonly implicated were carbamazepine (28%), allopurinol (16%), and antituberculosis drugs (12%). Individual latency periods ranged from 4 to 40 days (mean, 17.6 ± 9.95 days). Latency periods for anticonvulsants were significantly longer than those for other drugs (P < 0.05). However, no statistical differences were found between the RegiSCAR scores for anticonvulsants and those for other drugs. Disease severity, based on RegiSCAR score, was correlated with blood count abnormalities (P < 0.05). CONCLUSIONS: The results of our study revealed that anticonvulsants were the leading culprit drugs for DRESS, and carbamazepine was the individual drug most commonly associated with DRESS in Korea. Further studies of the mechanisms of action of these drugs are required in order to facilitate prompt diagnosis and effective management, which can affect prognosis and clinical outcome, of DRESS.

Stevens-Johnson syndrome induced by acetazolamide.

Acetazolamide is a sulfonamide derivative and carbonic anhydrase inhibitor used to lower intraocular pressure in glaucomatous patients. Stevens-Johnson syndrome (SJS) toxic epidermal necrolysis (TEN) associated with acetazolamide treatment has been diagnosed in Japanese, Japanese-American and Indian patients. Herein, we report the second Korean case of SJS-TEN associated with acetazolamide treatment. The result of human leukocyte antigen (HLA) typing of our patient was positive for HLA-B59. According to recent research, HLA-B59 has been detected in SJS caused by metazolamide, which is analogous to acetazolamide. This suggests a possible relationship between genetic background and SJS-TEN-associated acetazolamide treatment. Theretofore, acetazolamide should be prescribed to Korean patients with the same discreet caution.

Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach.

Environmental and genetic factors are important both in affecting life span and neoplastic transformation. We have shown previously that mice, which are homozygous for full-length breast cancer-associated gene-1 (Brca1) deletion and heterozygous for a p53-null mutation (Brca1(Delta11/Delta11)p53(+/-)), display premature aging and high frequency of spontaneous lymphoma and mammary tumor formation. To investigate the role of Brca1 in regulation of organ homeostasis and susceptibility of Brca1 deficiency to environmental carcinogens, we examined biological function of Brca1 in maintaining organ homeostasis and carcinogen-induced tumorigenesis. Brca1(Delta11/Delta11)p53(+/-) mice showed altered gastrointestinal tract homeostasis, including hyperkeratosis in the esophagus and forestomach. At 6 months of age, most mutant mice displayed hyperplasia in their forestomach and esophagus, leading to dysplasia and carcinoma formation in older animals. Brca1 mutant mice exhibited increased expression of Redd1, elevated reactive oxygen species and are more sensitive to oxidative stress induced lethality. Upon methyl-N-amylnitrosamine (MNAN) treatment, 70% Brca1 mutant mice developed tumors within 4 months whereas only 14% control animals developed tumor at the same period of the time. Our further analysis revealed that the tumorigenesis is accompanied by the loss of p53 and increased expression of a number of oncogenes, including Cyclin D1, phosphorylated form of Akt, beta-catenin, Runx-2 and c-Myc. These results suggest that Brca1 is involved in renewable organ homeostasis, linking the environmental and genetic factors in carcinogenesis and aging, and providing new insights into genomic instability in organism maintenance and tumorigenesis.