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Insulin activates sterol regulatory element-binding protein-1c in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitopetagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This system allows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than do mouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1c mRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP-1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6-kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states. T he liver plays a unique role in lipid metabolism because it is the only organ that synthesizes fatty acids (FAs) and triglycerides (TGs) for export to other tissues. These synthetic processes are controlled reciprocally by insulin and glucagon, which are secreted by the pancreas and delivered directly to the liver via the portal vein. Precise control is important because excess FA synthesis leads to elevated FAs in muscle, thereby contributing to the peripheral insulin resistance and lipotoxicity seen in type 2 diabetes. Excess FA synthesis also causes fatty liver, which sometimes leads to cirrhosis and liver failure (1, 2).Insulin stimulates FA synthesis in liver by increasing the mRNA and the processed nuclear form of sterol regulatory elementbinding protein-1c (SREBP-1c), a transcription factor that activates all the genes needed to produce FAs and TGs in liver (3). Of the three SREBP isoforms, SREBP-1c is the one whose expression is highest in liver, and it is the only one that is controlled primarily by insulin. For this reason, definitive studies of insulin-mediated activation of SREBP-1c must be performed with liver cells.Studies of insulin action on liver cells are difficult because none of the established hepatocyte cell lines responds to insulin with the robustness observed in the livers of living animals. Moreover, freshly isolated hepatocytes lose their insulin responsiveness within 48-72 h after isolation. Therefore, studies must be performed in living animals or with freshly isolated hepatocytes that are less than 72 h old. Even more perplexing are species differences. Although mouse and rat livers manifest robust elevations in SREBP-1c mRNA...

disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE To develop recommendations for the care of adults with EMPD.EVIDENCE REVIEW A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGSThe key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. ( 5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.CONCLUSIONS AND RELEVANCE Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

IMPORTANCE Microcystic adnexal carcinoma (MAC) occurs primarily in older adults of white race/ethnicity on sun-exposed skin of the head and neck. There are no formal guiding principles based on expert review of the evidence to assist clinicians in providing the highest-quality care for patients. OBJECTIVE To develop recommendations for the care of adults with MAC.EVIDENCE REVIEW A systematic review of the literature (1990 to June 2018) was performed using MEDLINE, Embase, Web of Science, and the Cochrane Library. The keywords searched were microcystic adnexal carcinoma, sclerosing sweat gland carcinoma, sclerosing sweat duct carcinoma, syringomatous carcinoma, malignant syringoma, sweat gland carcinoma with syringomatous features, locally aggressive adnexal carcinoma, and combined adnexal tumor. A multidisciplinary expert committee critically evaluated the literature to create recommendations for clinical practice. Statistical analysis was used to estimate optimal surgical margins.

Patients with atopic dermatitis (AD) have increased penetration of allergens, immune dysregulation (including shared cytokine pathways), and frequent use of emollients and topical medications, all of which may predispose toward developing allergic contact dermatitis (ACD). Recent systematic reviews have suggested that ACD is a significant clinical problem in both children and adults with AD. While this remains controversial, ACD remains an important comorbidity and potential exacerbant of AD in clinical practice. Common relevant allergens, include lanolin, neomycin, formaldehyde, sesquiterpene lactone mix, compositae mix, and fragrances that are commonly found in AD patients' personal care products. We herein review the clinical scenarios where patch testing is indicated in AD. In addition, we review the contraindications, preferred patch-testing series, pitfalls, and challenges determining the relevance of positive patch-test reactions in AD patients.