Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy.

Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.

The effects of procedural and conceptual knowledge on visual learning.

Even though past research suggests that visual learning may benefit from conceptual knowledge, current interventions for medical image evaluation often focus on procedural knowledge, mainly by teaching classification algorithms. We compared the efficacy of pure procedural knowledge (three-point checklist for evaluating skin lesions) versus combined procedural plus conceptual knowledge (histological explanations for each of the three points). All students then trained their classification skills with a visual learning resource that included images of two types of pigmented skin lesions: benign nevi and malignant melanomas. Both treatments produced significant and long-lasting effects on diagnostic accuracy in transfer tasks. However, only students in the combined procedural plus conceptual knowledge condition significantly improved their diagnostic performance in classifying lesions they had seen before in the pre- and post-tests. Findings suggest that the provision of additional conceptual knowledge supported error correction mechanisms.

Arginine- but not alanine-rich carboxy-termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti.

Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant-negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)-terminus, from poly-glycine to either a poly-arginine or -alanine tail. Previous studies on the type of C-terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C-termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C-terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine-rich C-terminus. However, this was not observed with K10 featuring an alanine-rich C-terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild-type and truncated forms of K10. This study demonstrates that, of the various 3' frameshift variants of KRT10, exclusively arginine-rich C-termini lead to nuclear localization of K10.

Non-infectious granulomatous dermatoses.

Granulomatous dermatoses comprise a wide range of etiologically and clinically distinct skin diseases that share a common histology characterized by the accumulation of histiocytes include macrophages. While the pathogenesis of these disorders is not fully understood, the underlying mechanism is thought to involve a reaction pattern caused by an immunogenic stimulus. Antigen-presenting cells and the effect of various cytokines play a key role. Our understanding of granulomatous reaction patterns has been advanced by insights drawn from observations of such reactions in patients on immunomodulatory therapy and in individuals with genetic immunodeficiency. Traditionally, a distinction is made between infectious and non-infectious granulomatous dermatoses. The present CME article addresses granulomatous skin diseases for which there is no evidence of a causative infectious agent. Common representatives include granuloma annulare, necrobiosis lipoidica and cutaneous sarcoidosis. Granulomatous dermatoses may be part of the clinical spectrum of various systemic disorders or may be associated therewith. Some neoplastic disorders may mimic granulomatous dermatoses histologically. Given the pathogenetic diversity involved, the clinical presentation, too, is quite varied. Overall, however, each disorder is characterized by typical clinical features. The diagnosis always requires thorough clinicopathologic correlation. Treatment is preferably based on the underlying pathogenesis and frequently involves anti-inflammatory agents. In most cases, however, there is insufficient study data. The dermal nature of these disorders frequently poses a therapeutic challenge, especially with respect to topical treatment.

Predictors of readmission and health related quality of life in patients with chronic heart failure: a comparison of different psychosocial aspects.

Psychological distress is common in patients with chronic heart failure. The impact of different psychological variables on prognosis has been shown but the comparative effects of these variables remain unclear. This study examines the impact of depression, anxiety, vital exhaustion, Type D personality, and social support on prognosis in chronic heart failure patients. One hundred eleven patients (mean age 57 ± 14 years) having participated in an exercise based ambulatory cardiac rehabilitation program were enrolled in a prospective cohort study. Psychological baseline data were assessed at program entry. Mortality, readmission, and health-related quality of life were assessed at follow up (mean 2.8 ± 1.1 years). After controlling for disease severity none of the psychological variables were associated with mortality, though severe anxiety predicted readmission [HR = 3.21 (95% CI, 1.04-9.93; P = .042)]. Health-related quality of life was independently explained by vital exhaustion, anxiety and either body mass index (physical dimension) or sex (emotional dimension). As psychological variables have a strong impact on health-related quality of life they should be routinely assessed in chronic heart failure patients` treatment.

Gender differences in cardiac rehabilitation outcomes: do women benefit equally in psychological health?

BACKGROUND: Psychological factors are important in the etiology and prognosis of coronary heart disease (CHD). Cardiac rehabilitation (CR) aims to reduce psychological distress, besides other somatic risk factors. Studies have shown that CR is effective in reducing psychological distress, but little is known about gender-specific outcome differences. Our objective was to examine whether women and men benefit equally from outpatient CR in terms of reduction in psychological distress and whether women show more impaired psychological health at baseline of CR than do men. METHODS: We enrolled 441 CHD patients (mean age 58+/-11 years, 79.8% men) who underwent a 12-week outpatient CR program. Psychological dimensions, namely, anxiety, depression, vital exhaustion, social inhibition, and negative affect, were assessed at baseline and post-CR. Multivariate analysis of variance (MANOVA), controlling for age, disease severity, and exercise capacity, was applied to test for gender-specific differences at baseline and change between baseline and post-CR. In addition, gender-specific effect sizes were calculated for the change on psychological dimensions. RESULTS: Women and men did not differ on any psychological measure at baseline of CR. The effect sizes show small to moderate treatment effects on the psychological dimensions assessed. Gender had a significant impact on change on the dimensions vital exhaustion (F=5.040(df=1), p<0.05) and social inhibition (F=5.74(df=1), p<0.05). Women showed larger change on social inhibition and smaller change on vital exhaustion than men. CONCLUSIONS: Women and men do not differ in the extent of psychological distress at baseline of CR, which could be explained also by the exclusion of highly distressed women from treatment. CR is less effective among women with regard to vital exhaustion and more effective with regard to social inhibition compared with men in a sample of low distressed patients.

PEDANT covers all complete RefSeq genomes.

The PEDANT genome database provides exhaustive annotation of nearly 3000 publicly available eukaryotic, eubacterial, archaeal and viral genomes with more than 4.5 million proteins by a broad set of bioinformatics algorithms. In particular, all completely sequenced genomes from the NCBI's Reference Sequence collection (RefSeq) are covered. The PEDANT processing pipeline has been sped up by an order of magnitude through the utilization of precalculated similarity information stored in the similarity matrix of proteins (SIMAP) database, making it possible to process newly sequenced genomes immediately as they become available. PEDANT is freely accessible to academic users at http://pedant.gsf.de. For programmatic access Web Services are available at http://pedant.gsf.de/webservices.jsp.

Perifollicular protrusions--mid-dermal elastolysis.

Mid-dermal elastolysis is a rare peculiar entity clinically characterized by fine wrinkles and perifollicular protrusions that give the skin an aged or peau d'orange appearance. The histopathologic correlate is a bandlike loss of elastic tissue within the mid-dermis.We present a typical case with prominent perifollicular protrusions.

Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression.

Recent data suggest that individuals with recessive dystrophic epidermolysis bullosa (RDEB) only develop squamous-cell carcinoma (SCC) in the presence of the NC1 domain of type VII collagen. This conclusion was based on experimental work in which cryosections of SCCs from 10 people with RDEB all showed positive type VII collagen immunostaining and observations in a murine model of SCC development in which tumors only occurred using keratinocytes from RDEB subjects that expressed detectable levels of the NC1 domain of the type VII collagen protein. To assess whether the clinical interpretation was valid in another cohort of RDEB patients, we examined expression of type VII collagen in 17 SCC tumors excised from 11 patients. Indirect immunofluorescent staining of SCC cryosections and Western blotting of cultured keratinocyte lysates identified two RDEB individuals who did not express detectable levels of type VII collagen. Mutation analysis revealed that these two patients harbor compound heterozygous nonsense mutations within the region of the COL7A1 gene encoding the NC1 domain. These data suggest that individuals with RDEB can develop SCC regardless of type VII collagen expression and that additional factors have a role in explaining the high incidence of tumors complicating this genodermatosis.