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BACKGROUND - The aim of this study was to compare patients with PHC with lymph node metastases (LN+) who underwent a resection with patients who did not undergo resection because of locally advanced disease at exploratory laparotomy.
METHODS - Consecutive LN+ patients who underwent a resection for PHC in 12 centers were compared with patients who did not undergo resection because of locally advanced disease at exploratory laparotomy in 2 centers.
RESULTS - In the resected cohort of 119 patients, the median overall survival (OS) was 19 months and the estimated 1-, 3- and 5-year OS was 69%, 27% and 13%, respectively. In the non-resected cohort of 113 patients, median OS was 12 months and the estimated 1-, 3- and 5-year OS was 49%, 7%, and 3%, respectively. OS was better in the resected LN+ cohort (p < 0.001). Positive resection margin (hazard ratio [HR]: 1.54; 95%CI: 0.97-2.45) and lymphovascular invasion (LVI) (HR: 1.71; 95%CI: 1.09-2.69) were independent poor prognostic factors in the resected cohort.
CONCLUSION - Patients with PHC who underwent a resection for LN+ disease had better OS than patients who did not undergo resection because of locally advanced disease at exploratory laparotomy. LN+ PHC does not preclude 5-year survival after resection.
Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted MS platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from ∼0.03 to 1.5 fmol/microgram protein and the parallel reaction monitoring (PRM) data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody. PD-1 was measured at levels up to 20-fold lower than PD-L1, but the abundances were not significantly correlated (r = 0.062, = 0.264). PD-1 abundance was weakly correlated (r = 0.3057, = 0.009) with the fraction of lymphocytes and histiocytes in sections. PD-L2 was measured from 0.03 to 1.90 fmol/microgram protein and the ratio of PD-L2 to PD-L1 abundance ranged from 0.03 to 2.58. In 10 samples, PD-L2 was present at more than half the level of PD-L1, which suggests that PD-L2, a higher affinity PD-1 ligand, is sufficiently abundant to contribute to T-cell downregulation. We also identified five branched mannose and N-acetylglucosamine glycans at PD-L1 position N192 in all 22 samples. Extent of PD-L1 glycan modification varied by ∼10-fold and the melanoma with the highest PD-L1 protein abundance and most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function. Additional PRM analyses quantified immune checkpoint/co-regulator proteins LAG3, IDO1, TIM-3, VISTA, and CD40, which all displayed distinct expression independent of PD-1, PD-L1, and PD-L2. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Glands in frog skin secrete substances that possess broad antimicrobial function. Holthausen et al. mined this soup of natural products and discovered a peptide that destroys diverse human influenza strains (Holthausen et al., 2017). This study points the way to the discovery of novel anti-influenza molecules targeting conserved elements on influenza surface proteins.
Copyright © 2017 Elsevier Inc. All rights reserved.
Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR-31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non-melanoma skin cancer and hair follicle growth. miR-31 is a marker of the hair growth phase, and in our miR-31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR-31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR-31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Histopathological interpretation of proliferative nodules occurring in association with congenital melanocytic nevi can be very challenging due to their similarities with congenital malignant melanoma and malignant melanoma arising in association with congenital nevi. We hereby report a diagnostically challenging case of congenital melanocytic nevus with proliferative nodules and ulcerations, which was originally misdiagnosed as congenital malignant melanoma. Subsequent histopathological examination in consultation by one of the authors (R.L.) and mass spectrometry imaging analysis rendered a diagnosis of congenital melanocytic nevus with proliferative nodules. In this case, mass spectrometry imaging, a novel method capable of distinguishing benign from malignant melanocytic lesions on a proteomic level, was instrumental in making the diagnosis of a benign nevus. We emphasize the importance of this method as an ancillary tool in the diagnosis of difficult melanocytic lesions.
How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA. Noteworthy, rictor-deficient keratinocytes displayed increased lifespan, protection from senescence, and enhanced tolerance to cellular stressors such as growth factors deprivation, epirubicin and X-ray in vitro and radioresistance in vivo. Rictor-deficient keratinocytes exhibited changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of rictor-deficient epidermal cells relies on these ROS increases, indicating stress resistance via mitohormesis. Thus, our findings reveal a new link between metabolic changes and stress adaptation of keratinocytes centered on mTORC2 activity, with potential implications in skin aging and therapeutic resistance of epithelial tumors.
BACKGROUND - Recent data suggest that sodium (Na ) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na accumulation would be associated with abnormalities in peripheral insulin action.
METHODS - Eleven MHD patients and eight controls underwent hyperinsulinemic-euglycemic-euaminoacidemic clamp studies to measure glucose (GDR) and leucine disposal rates (LDR), as well as lower left leg Na magnetic resonance imaging to measure Na concentration in the muscle and skin tissue.
RESULTS - The median GDR and LDR levels were lower, and the median muscle Na concentration was higher in MHD patients compared with controls. No significant difference was found regarding skin Na concentration between group comparisons. Linear regression revealed inverse relationships between muscle Na concentration and GDR and LDR in MHD patients, whereas no relationship was observed in controls. There was no association between skin Na content and GDR or LDR in either MHD patients or controls.
CONCLUSIONS - These data suggest that excessive muscle Na content might be a determinant of IR in MHD patients, although the causality and mechanisms remain to be proven.
© 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.
The aim of this work was to investigate possible sex differences in the patterns of sodium deposition between muscle and skin using sodium MRI. A total of 38 subjects were examined for comparisons: 20 males, aged 25-79years with a median age of 51; 18 females, aged 38-66years, median age 53. All subjects underwent sodium MRI scans of the calf muscles together with cross sections through four calibration standards containing known sodium contents (10mM, 20mM, 30mM, and 40mM). Tissue sodium concentrations (TSC) in muscle and skin were then calculated by comparing signal intensities between tissues and reference standards using a linear analysis. A Wilcoxon rank sum test was applied to the ΔTSC (=TSC-TSC) series of males and females to examine if they were significantly different. Finally, a multiple linear regression was utilized to account for the effects from two potential confounders, age and body mass index (BMI). We found that sodium content appears to be higher in skin than in muscle for men, however women tend to have higher muscle sodium than skin sodium. This sex-relevant sodium deposition is statistically significant (P=3.10×10) by the Wilcoxon rank sum test, and this difference in distribution seems to be more reliable with increasing age. In the multiple linear regression, gender still has a statistically significant effect (P<1.0×10) on the difference between sodium deposition in muscle and skin, while taking the effects of age and BMI into account.
Copyright © 2016 Elsevier Inc. All rights reserved.
Data on cutaneous human papillomavirus (HPV) seroprevalence are primarily derived from skin cancer case-control studies. Few studies have reported the seroprevalence of cutaneous HPV among healthy men. This study investigated the seroprevalence of cutaneous HPV types and associated risk factors among men residing in Brazil, Mexico and the USA. Six hundred men were randomly selected from the HPV Infection in Men study. Archived serum specimens were tested for antibodies against 14 cutaneous HPV genotypes, β-HPV types (5/8/12/14/17/22/23/24/38/48), α-HPV 27, γ-HPV 4, µ-HPV1 and ν-HPV 41 using a glutathione S-transferase L1-based multiplex serology assay. Risk factor data were collected by a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression to examine factors associated with seropositivity. Overall, 65.4 % of men were seropositive to ≥1 of the 14 cutaneous HPV types, and 39.0 % were positive for ≥1 β-HPV types. Seroprevalence was 8.9, 30.9, 28.6 and 9.4 % for α-HPV 27, γ-HPV 4, µ-HPV 1 and ν-HPV 41, respectively. In multivariate analyses, seropositivity for any cutaneous HPV type was associated with higher education [adjusted odds ratio (AOR) 1.75; 95 % confidence interval (CI) 1.08-2.83], and seropositivity of any β-HPV type was significantly associated with increasing age (AOR 1.72; 95 % CI 1.12-2.63, for men aged 31-44 years vs men aged 18-30 years). Other factors associated with various type-specific cutaneous HPV seropositivity included country, circumcision and lifetime number of male sexual partners. These data indicate that exposure to cutaneous HPV is common. Future studies are needed to assess the role of cutaneous HPV in diseases.