Assessing potential mechanisms of arsenic-induced skin lesions and cancers: Human and in vitro evidence.
- 作者列表："Zeng Q","Zhang A
:Environmental exposure to arsenic is a major public health challenge worldwide. In detailing the hallmark signs of chronic arsenic exposure, previous studies have shown that epigenetic and immune dysfunction are associated with arsenic-induced skin lesions; however, knowledge regarding interactions between the mechanisms listed above is limited. In this study, a total of 106 skin samples were collected over the past 20 years. Based on the presence or absence of high arsenic exposure, the participants were divided into arsenic exposure (72) and reference (34) groups. Additionally, the arsenic exposure group was further divided into the non-cancer group (31, including skin hyperpigmentation and hyperkeratosis) and the skin cancer group (41, including Bowen's disease, basal cell carcinoma and squamous cell carcinoma) according to a skin histopathological examination. First, the associations among miR-155, NF-AT1 with immunological dysfunction and arsenic-induced skin lesions and carcinogenesis were confirmed using these skin samples. In the arsenic-exposed group, miR-155-5p, keratin 1(Krt1), keratin 10 (Krt10), and keratin 6c (Krt6c) were significantly increased in the skin (p < 0.05), while NF-AT1, interleukin-2 (IL-2), and interferon-γ (IFN-γ) were significantly decreased (p < 0.05). Clear correlations were observed among these factors (p < 0.05). In immortalized human keratinocytes, silencing and overexpression of NF-AT1 could alter the expression and secretion of immunological dysfunction indicators (IL-2 and IFN-γ) that are induced by arsenic exposure (p < 0.05); however, miR-155-5p levels did not change significantly (p > 0.05). The miR-155-5p mimic and inhibitor could regulate the NF-AT1-mediated immunological dysfunction caused by arsenic (p < 0.05). Our study provides some limited evidence that miR-155-5p regulates the NF-AT1-mediated immunological dysfunction that is involved in the pathogenesis and carcinogenesis of arsenic. The second major finding was that Krt1 and Krt10 are markers of hyperkeratosis caused by arsenic, and Krt6c is a potential biomarker that can reflect arsenic carcinogenesis.
: 砷的环境暴露是全球范围内的重大公共卫生挑战。在详细描述慢性砷暴露的标志性标志时，先前的研究表明表观遗传和免疫功能障碍与砷诱导的皮肤病变相关; 然而，关于上述机制之间相互作用的知识有限。在这项研究中，在过去的 20 年中共收集了 106 个皮肤样本。根据是否存在高砷暴露，将参与者分为砷暴露 (72) 和参考 (34) 组。此外，砷暴露组进一步分为非癌症组 (31 例，包括皮肤色素沉着和角化过度) 和皮肤癌组 (41 例，包括Bowen病，基底细胞癌和鳞状细胞癌) 根据皮肤组织病理学检查。首先，使用这些皮肤样本证实了miR-155 、NF-AT1 与免疫功能障碍和砷诱导的皮肤病变和致癌的相关性。砷暴露组皮肤miR-155-5p、角蛋白 1(Krt1) 、角蛋白 10 (Krt10) 和角蛋白 6c (Krt6c) 均显著升高 (p <0.05)。而NF-AT1 、interleukin-2 (IL-2) 、 γ-干扰素 (IFN-γ) 则显著降低 (p <0.05)。在这些因素之间观察到明确的相关性 (p <0.05)。在永生化的人角质形成细胞中，沉默和过表达NF-AT1 可改变砷暴露诱导的免疫功能障碍指标 (IL-2 和IFN-γ) 的表达和分泌 (p < 0.05); 但miR-155-5p水平变化不明显 (p> 0.05)。MiR-155-5p模拟物和抑制剂对砷引起的NF-AT1-mediated免疫功能障碍具有调节作用 (p <0.05)。我们的研究提供了一些有限的证据，miR-155-5p调节参与砷的发病和致癌的NF-AT1-mediated免疫功能障碍。第二个主要发现是Krt1 和Krt10 是砷引起的角化过度的标志物，Krt6c是一个潜在的生物标志物，可以反映砷致癌作用。
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.