Journal Of Investigative Dermatology

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Updated: 2 hours 51 min ago

Normalization Cancer Immunotherapy for Melanoma

Fri, 2020-02-21 00:00
Today, we are witnessing a revolution in the treatment of cancer through the use of immunotherapy. In the last decade, work from many laboratories and clinicians have unequivocally demonstrated that the immune system can eradicate established cancers and enhance patient survival. However, immunotherapies have distinct tumor response-to-toxicity profiles due to distinct mechanisms of action. We have previously termed immunotherapies that activate a general, systemic immune response as “enhancement cancer immunotherapy” and those that target a specific dysfunctional immune response, especially within the tumor microenvironment, as “normalization cancer immunotherapy”.

TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors

Thu, 2020-02-20 00:00
Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes.We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, and TERT-124C>T and TERT-146C>T mutations.

A Randomized Placebo Controlled Trial of Secukinumab on Aortic Vascular Inflammation in Moderate to Severe Plaque Psoriasis (VIP-S)

Thu, 2020-02-20 00:00
Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has demonstrated high efficacy with a favorable safety profile in various psoriatic disease manifestations.

Response to Ring: In silico predictive metagenomic analyses highlight key metabolic pathways impacted in the HS skin microbiome

Thu, 2020-02-20 00:00
The metagenomics analysis performed in Schneider et al provided the first investigation into the functional role of microbial dysbiosis in Hidradenitis Suppurativa (HS). This study included a predictive analysis which utilized a publically-available dataset (Ring et al. 2017) and our dataset that was generated from a prospectively recruited cohort of HS subjects and normal controls (Schneider et al. 2019). These two datasets were generated using the same sequencing method (16S rRNA V3-V4), although the patient demographics, sampling procedures, and body sites sampled varied between them (Table 1a).

Staphylococcus aureus bloodstream infection in patients with atopic dermatitis - or: Think twice before placing a venous catheter into lesional atopic skin

Tue, 2020-02-18 00:00
Due to the high rate of colonization, patients with atopic dermatitis are at risk of S. aureus bloodstream infection, the most severe manifestation of S. aureus infections. Intravascular devices and the skin are the major portals of entry for S. aureus in AD. With prompt and adequate diagnostic and therapeutic management, mortality is lower than in Non-AD patients with SAB and severe sequelae can be averted. Important preventive strategies include AD treatment to reduce S. aureus colonization and meticulous care of intravascular catheters, which should not be placed in/on lesional atopic skin.

Next generation sequencing in myeloid neoplasm-associated Sweet’s syndrome demonstrates clonal relation between malignant cells and skin-infiltrating neutrophils

Tue, 2020-02-18 00:00
Sweet's syndrome (SS) is a neutrophilic dermatoses (ND) that may occur in the context of malignancy, inflammatory disease or drug exposure (von den Driesch 1994). Approximately 20% of the reported SS patients have an associated cancer (Cohen et al. 1988), which is a myeloid neoplasm (MN) in half of the cases, predominantly an acute myeloid leukemia (AML) (Nelson et al. 2018). Although the association between MN and SS has been reported for a long time (Vignon-Pennamen and Wallach 1991), the pathophysiological link between these diseases remains unclear.

Lesional inflammatory profile in Hidradenitis Suppurativa is not solely driven by IL-1

Tue, 2020-02-18 00:00
Immune dysregulation is strongly implicated in the pathogenesis of hidradenitis suppurativa (HS).(Vossen et al., 2018) This is demonstrated by the presence of inflammation in both lesional and perilesional HS skin (Kelly et al., 2015; Van der Zee et al., 2012; Witte-Händel et al., 2019). However, our current understanding of HS pathophysiology, with follicular occlusion and rupture as the primary events, is under scrutiny. A complex immune driven pathogenesis, initiated by an initial aberrant immune response to a possibly dysbiotic cutaneous microbiome, is suspected, with follicular occlusion occurring as a secondary phenomenon.(Frew, 2019) It is presumed that commensal bacterial products like lipopolysaccharide, peptidoglycan, and bacterial DNA and RNA as well as complex keratin filaments released after follicular rupture promote the simultaneous activation of multiple auto-inflammatory pathways such as membrane and cytosolic innate receptors, complement and the NLRP inflammasome.

Loss of both CDKN2A and CDKN2B allows for centrosome overduplication in melanoma.

Fri, 2020-02-14 00:00
Centrosomes duplicate only once in coordination with the DNA replication cycle and have an important role in segregating genetic material. In contrast, the majority of cancer cells have centrosome aberrations including supernumerary centrosomes and this correlates with aneuploidy and genetic instability. The tumour suppressors p16 (CDKN2A) and p15 (CDKN2B) (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p16 is also associated with suppressing centrosomal aberrations in breast cancer; however, the role of p15 in centrosome amplification is unknown.

NK cell and fibroblast-mediated regulation of skin squamous cell carcinoma invasion by CLEC2A is compromised in Xeroderma Pigmentosum

Thu, 2020-02-13 01:05
The ability of cancer cells to invade and disseminate can be affected by components of the surrounding microenvironment. To identify dermal components regulating the growth of epidermal carcinomas, we studied the xeroderma pigmentosum genetic disease that bears mutations in genes involved in nucleotide excision DNA repair. Xeroderma pigmentosum patients are more prone to develop cutaneous tumors compared to the general population and their dermal fibroblasts display features of dermal cancer-associated fibroblasts, promoting keratinocyte invasion.