Shikonin enhances efficacy of a gene-based cancer vaccine via induction of RANTES

<p>Abstract</p> <p>Background</p> <p>Shikonin, a phytochemical purified from <it>Lithospermum erythrorhizon</it>, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation.</p> <p>Method</p> <p>The mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model.</p> <p>Results</p> <p>Among various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells.</p> <p>Conclusion</p> <p>Together, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.</p

Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: Replication and functional characterization of non-coding regions

Common genetic variants 3′ of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 309 LD block (farther from MC4R ) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression. © 2014 Evans et al

The Relationship Between Brand Repositioning and Management Performance: The Role of Transformational Leadership

本研究以平衡計分卡分析架構為基礎，論述轉換型領導在品牌重定位過程中對經營績效的影響，以A飯店為個案研究對象，發現A飯店業者採取品牌重定位的行為策略，此策略包括：重新選擇目標市場、改變產品與服務及調整訂價政策，最後完成A飯店的品牌重定位。本研究也發現，A飯店業者在品牌重定位的過程中，轉換型領導對經營績效有正面的影響。Based on the frameworks of the balanced scorecard (BSC), this study discusses the brand repositioning strategy of Taiwan's hot spring hotel industry and further illustrates the transformational leadership and performance of brand repositioning. This study conducts case analysis method and puts forward the research proposition based on the findings. This research explores the brand repositioning strategy in Taiwan's hot spring hotel industry, and further examines how the brand repositioning strategy influences performance. In addition, this study examines the role of transformational leadership in the process of brand repositioning. The concrete strategies of brand repositioning will include re-selecting target market, re-adjusting product and service, and implementing of pricing strategy. This research use balanced scorecard to evaluate the performance of brand repositioning and finds that transformational leadership influence management performance positively

Designing and Pricing Commercial Stroke Insurance: An Application of Taiwan NHIRD

由於近年日益升高的腦中風危害，本研究依據全民健保資料庫，估計國人腦中風發生機率與相關醫療成本，設計腦中風保單，並進行保費精算。研究追蹤全民健保資料庫自1996年至2012年，共99,165位40歲以上投保人之資料，分別以追蹤羅吉斯迴歸模型（panel logit model）推估腦中風機率，與追蹤負二項迴歸模型（panel negative binomial model）推估因腦中風就醫／住院次數。研究發現，年齡、性別、月薪資、居住地區、職業別與疾病史，對腦中風機率和就醫／住院次數有顯著的影響。其中年齡、男性、糖尿病、高血壓、牙周病、腎病、心房顫動、弱勢族群、地區人口對於中風機率影響皆為正向；而月薪資較高、職業為軍公教或農漁民者，影響為負向。居住於南部、東部或離島地區者，中風機率均較北部居民低。邊際效果來看，年齡每增加1歲，中風機率平均增加0.14%，男性中風機率平均較女性高出0.60%。此外，罹患糖尿病、高血壓、腎病、心房顫動的患者，中風機率皆增加超過1%。最後，本文為台灣保險公司與民眾設計一張腦中風商業保單，根據此實證模型，預估腦中風機率和次數進行保費估算，藉此提高國人因腦中風而遭受危害的財務保障。Given the increasing incidence of stroke, we design and price a commercial stroke insurance using National Health Insurance Research Database (NHIRD) for insurance companies and customers in Taiwan. We collect 99,165 people over 40 years old during the period from 1996 to 2012 to perform the empirical study. In the study, the panel logit model and panel negative binomial model are employed to estimate the probability of stroke and the frequency of outpatient visits or inpatient days due to stroke respectively. We find that age, gender, monthly income, place of residence, occupation, and disease history have significant effects on the probability of stroke and the frequency of outpatient visits or inpatient days due to stroke

Hepatic Resection and Transplantation for Primary Carcinoid Tumors of the Liver

OBJECTIVE: To discuss the diagnosis and management of primary carcinoid tumors of the liver in light of our experience and a literature review. SUMMARY BACKGROUND DATA: Carcinoid tumors of the liver are rare and pose a diagnostic and management dilemma. This series is the largest reported and the only one to include liver transplantation as a treatment option. METHODS: Between March 1994 and May 2002, we treated 8 patients (4 male, 4 female) with primary hepatic carcinoid tumors. Carcinoid syndrome complicated only 1 of the cases. Treatment was by liver resection in 6 patients and orthotopic liver transplantation in 2. RESULTS: The diagnosis was confirmed histologically with light microscopy and immunohistochemistry in the absence of an alternative primary site. Six patients remain alive and disease free after follow-up of more than 3 years: 39, 43, 45, 50, 50, and 95 months. Two patients are recently postoperative. CONCLUSIONS: Active exclusion of an extrahepatic primary site is essential for the diagnosis of primary carcinoid of the liver. The mainstay of treatment should be liver resection, although liver transplantation may be considered in patients with widespread hepatic involvement. A radical surgical approach is warranted as this disease carries a better prognosis than for other primary hepatic tumors and for secondary hepatic carcinoids