Summary Insulin-resistant syndromes such as type II diabetes mellitus (T2DM) involve disrupted temporal coordination of hepatic metabolism such that synthesis and secretion of lipid and glucose are inappropriately engaged concurrently. Here we test the hypothesis that a combination of direct and indirect actions of insulin on liver can lead to the metabolic phenotype exhibited in T2DM without a defect in proximal hepatic insulin signaling. First, we show that the insulin-dependent inhibition of Foxo1 and activation of mTorc1 by Akt is both necessary and sufficient for the induction of lipogenesis and the lipogenic gene program. In marked contrast, insulin, acting in vivo independent of hepatocyte insulin signaling can suppress glucose production by reducing serum free fatty acids. These studies support the hypothesis that under conditions of obesity and diabetes, intact hepatic insulin signaling can maintain lipogenesis while excess circulating FFAs become a dominant positive regulator of HGP.

The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53 mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53 exons 4-9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53 mutational status in both VSCC and vulvar in situ lesions.

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10−11 discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10−8 discovery group; P=4.4 × 10−6 replication group), HLA-DQB1*02:01 (P=1.3 × 10−8 discovery group; P=7.2 × 10−6 replication group), and HLA-DQA1*05:01 (P=1.4 × 10−8 discovery group; P=7.6 × 10−6 replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.

Intersecting minority identities may confer unique risks for stress and trauma. In this article, we reviewed extant research on the processes and outcomes of racial and sexual/gender identity-related (i.e., "intersectional") stress and trauma among the understudied population of lesbian, gay, bisexual, transgender, and queer (LGBTQ) Asian Americans. Specifically, we proposed a model of intersectional stress and trauma in LGBTQ Asian Americans that builds upon elements of minority stress theory for sexual minorities. Method: We used PsycINFO and other online databases and search engines to search for information in developing and describing our model. We included 84 peer-reviewed empirical, qualitative, and review/theoretical articles, as well as books, book chapters, unpublished data, and organization reports from 1970 to 2016. Results: In the model, we detail how structural oppression, cultural norms and stigma, interpersonal discrimination, internalized minority stress cognitions, and maladaptive coping and poor social support interact in contributing to negative mental and sexual health outcomes in LGBTQ Asian Americans, as a function of their intersecting racial and sexual/gender identities. Conclusions: LGBTQ Asian Americans face unique stressors that can lead to traumatization. Future research should empirically validate our model of intersectional stress and trauma, increase scientific representation of all LGBTQ Asian American subgroups, and emphasize the LGBTQ Asian American identity as multifaceted and intersectional. Finally, components of our model appear to be promising areas for intervention. However, we urge clinicians to consider the utility of treatments from the perspective of indigenous practices and healing, compared with adaptation from Western, heteronormative treatment approaches.

This study provides new evidence of deficient auditory cortical processing of speech in noise in autism spectrum disorders (ASD). Speech-evoked responses (~100-300 ms) in quiet and background noise were evaluated in typically-developing (TD) children and children with ASD. ASD responses showed delayed timing (both conditions) and reduced amplitudes (quiet) compared to TD responses. As expected, TD responses in noise were delayed and reduced compared to quiet responses. However, minimal quiet-to-noise response differences were found in children with ASD, presumably because quiet responses were already severely degraded. Moreover, ASD quiet responses resembled TD noise responses, implying that children with ASD process speech in quiet only as well as TD children do in background noise.

BackgroundThe urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain.ResultsWe identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16–3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74–2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07–3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28–2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48–1.94, p < 0.92) although data was limited.Materials and MethodsWe undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS).ConclusionsWe conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.

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Preterm infants were just as likely to be monitored for withdrawal as term infants, but their Finnegan scores were lower and fewer preterm infants were treated for NAS. Whether this indicates decreased NAS severity or physiological immaturity is uncertain. Other means of evaluating NAS in preterm infants are warranted, especially long-term outcomes.