- 作者列表："Kumar S","Xie H","Shi H","Gao J","Juhlin CC","Björnhagen V","Höög A","Lee L","Larsson C","Lui WO
:Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T-antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T-antigens induce miR-375, miR-30a-3p and miR-30a-5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV-positive tumors. Ectopic expression of MCPyV small T-antigen and truncated large T-antigen (LT), but not the wild-type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV-mediated tumorigenesis. Torin-1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan-caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV-mediated tumorigenesis and potential MCC treatment.
: 病毒可以通过多种机制抑制宿主自噬，而逃避自噬在免疫抑制和病毒致癌中起重要作用。默克尔 (angela Merkel细胞多瘤病毒 (MCPyV) T-t igens表达和参与t他pa t hogenesis大型比例t离子Merkel细胞癌 (MCC).然而，MCPyV如何诱导肿瘤发生尚不完全清楚。在此，我们展示了t ha t MCPyV T-an t-igens诱导miR-375 、miR-30a-3p和miR-30a-5p表达，t arge t mul t iple关键基因参与au t自噬，包括A T G7 、SQS T M1 (p62) 和becn1。在MCC肿瘤中，ATG7 和p62 的低表达与MCPyV阳性肿瘤相关。Ec t opic MCPyV小T-an t igen和t runca t ed大T-an t igen (L T) 的表达，bu t no t t he wild-t type L T，resul t ed in au t自噬抑制，建议t荷兰国际集团 (ing) t他对于t性能au t ophagy逃避在MCPyV媒体t ed t umorigenesis.Torin-1 治疗诱导细胞死亡，而自噬抑制剂而不是泛半胱天冬酶抑制剂可减弱细胞死亡，提示自噬在促进MCC细胞死亡中的潜在作用。从概念上讲，我们的研究表明，MCPyV癌蛋白抑制自噬以保护癌细胞免受细胞死亡，这有助于更好地理解MCPyV介导的肿瘤发生和潜在的MCC治疗。
METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.
METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.