No abstract

New methods for long-lasting protection against sexually transmitted disease, such as the human immunodeficiency virus (HIV), are needed to help reduce the severity of STD epidemics, especially in developing countries. Intravaginal delivery of therapeutics has emerged as a promising means to provide women with local protection, but residence times of such agents are greatly reduced by the protective mucus layer, fluctuating hormone cycle, and complex anatomical structure of the reproductive tract. Polymeric nanoparticles (NPs) capable of encapsulating the desired cargo, penetrating through the mucosal surfaces, and delivering agents to the site of action have been explored. However, prolonged retention of polymer carriers and their enclosed materials may also be needed to ease adherence and confer longer-lasting protection against STDs. Here, we examined the fate of two poly(lactic acid)-hyperbranched polyglycerols (PLA-HPG) NP formulations – 1) nonadhesive PLA-HPG NPs (NNPs) and 2) surface-modified bioadhesive NPs (BNPs) – loaded with the antiretroviral elvitegravir (EVG) after intravaginal administration. BNP distribution was widespread throughout the reproductive tract, and retention was nearly 5 times higher than NNPs after 24h. Moreover, BNPs were found to be highly associated with submucosal leukocytes and epithelial cell populations for up to 48h after topical application, and EVG was retained significantly better in the vaginal lumen when delivered with BNPs as opposed to NNPs over a 24h period. Our results suggest that bioadhesive PLA-HPG NPs can greatly improve and prolong intravaginal delivery of agents, which may hold potential in providing sustained protection over longer durations.

Detection of individual cytokines in routine biopsies from patients with inflammatory skin diseases has the potential to personalize diagnosis and treatment selection, but this approach has been limited by technical feasibility. We evaluate whether a chromogen-based RNA in situ hybridization approach can be used to detect druggable cytokines in psoriasis and atopic dermatitis. A series of psoriasis (n ¼ 20) and atopic dermatitis (n ¼ 26) biopsies were stained using RNA in situ hybridization for IL4, IL12B (IL-12/23 p40), IL13, IL17A, IL17F, IL22, IL23A (IL-23 p19), IL31, and TNF (TNF-a). NOS2 and IFNG, canonical psoriasis biomarkers, were also included. All 20 of the psoriasis cases were positive for IL17A, which tended to be the predominant cytokine, although some cases had relatively higher levels of IL12B, IL17F, or IL23A. The majority of cytokine expression in psoriasis was epidermal. A total of 22 of 26 atopic dermatitis cases were positive for IL13, also at varying levels; a subset of cases had significant IL4, IL22, or IL31 expression. Patterns were validated in independent bulk RNA-sequencing and single-cell RNA-sequencing datasets. Overall, RNA in situ hybridization for cytokines appears highly specific with virtually no background staining and may allow for individualized evaluation of treatment-relevant cytokine targets in biopsies from patients with inflammatory skin disorders.

We present the case of a 31‐year‐old female with a 1.5 cm pigmented nodule on the scalp. Histopathological examination revealed a proliferation of relatively bland spindle cells and pigmented dendritic cells, with interspersed lymphoid follicles diffusely infiltrating the adipose tissue. The microscopic differential diagnosis included pigmented dermatofibrosarcoma protuberans (DFSP). The spindle cells showed S‐100 and CD34 labeling but were negative for SOX‐10. Immunohistochemical stain for pan‐TRK was positive, while fluorescence in‐situ hybridization for PDGFB gene rearrangement was negative. Targeted RNA sequencing revealed an LMNA‐NTRK1 (exon2/exon10) fusion. This molecular result coupled with the histopathological findings and immunohistochemical profile supported the diagnosis of the recently characterized NTRK‐rearranged spindle cell neoplasm termed “lipofibromatosis‐like neural tumor (LPF‐NT).” These neoplasms typically occur in superficial soft tissue and are characterized by a distinctive immunoprofile (CD34+, S‐100+, SOX10−). Histopathological differential diagnosis for LPF‐NT tumors includes lipofibromatosis, DFSP, low‐grade malignant peripheral nerve sheath tumor, and spindle cell/desmoplastic melanoma. The pigmented dendritic cells reminiscent of pigmented DFSP and lymphoid follicles noted in our case have not been previously reported in LPF‐NT, thus expanding the morphological spectrum of this entity. LMNA‐NTRK1 fusion serves both as a diagnostic and therapeutic biomarker, as cases with advanced disease may be amenable to targeted therapy using tyrosine kinase inhibitors.

Aims Pseudomelanocytic nests or “pseudonests” arising in lichenoid dermatoses can be a diagnostic pitfall for melanoma in situ (MIS), especially on sun‐damaged skin. We sought to evaluate histopathological features that may be helpful in distinguishing this benign process from inflamed MIS. Methods Ten biopsy specimens containing pseudomelanocytic nests within lichenoid dermatoses and twenty cases of inflamed MIS were retrospectively reviewed. Cases with pseudomelanocytic nests represented either a rash (n = 6) or a discrete non‐melanocytic lesion, such as lichenoid keratosis (n = 4). Results All cases with pseudomelanocytic nests showed nests of microphthalmia‐associated transcription factor‐positive cells at the dermoepidermal junction (DEJ) with interface changes and lichenoid inflammation. Pagetoid scatter, confluence of solitary melanocytes at the DEJ and significant cytologic atypia was not seen in any of these cases. In contrast, all cases of inflamed MIS demonstrated confluence of single melanocytes at the DEJ with cytologic atypia (P < 0.001) and 18/20 cases showed pagetoid scatter of melanocytes (P = 0.001). Conclusions Our results show that, of the different histopathological features assessed, confluent growth and pagetoid scatter of atypical melanocytes were seen in most cases of inflamed MIS but were absent in all cases with pseudomelanocytic nests. Therefore, in addition to clinicopathological correlation, these features may be useful in differentiating pseudomelanocytic nests arising in lichenoid dermatoses from inflamed MIS.