Dermoscopy in cutaneous sarcoidosis.

Cutaneous sarcoidosis has a wide variety of manifestations and can be challenging to diagnose clinically. Dermoscopy is a useful tool to support the clinical diagnosis. Herein, we report an elderly woman with pruritic facial plaques. Dermoscopy showed translucent orange globules with shiny white lines, and microscopic examination showed non-necrotizing granulomas with perigranulomatous fibrosis. Shiny white structures on dermoscopy are conventionally associated with basal cell carcinoma, melanoma, and dermatofibroma, and have not yet been reported in sarcoidosis. Current descriptions of dermoscopy findings of sarcoidosis in the literature are summarized. Further differential diagnostic entities for this presentation are described and treatment options for cutaneous sarcoidosis are discussed.

Activity-dependent synapse to nucleus signaling.

The unique polarity of neurons requires that synaptic inputs are relayed to the nucleus to trigger changes in gene expression. This long distance signaling process is crucial for the function and survival of neuronal circuits. To that end, neurons have developed multiple modes of signal transmission from the synapse to the nucleus. In this review, we summarize the latest research on activity-dependent movement and nuclear import of postsynaptic proteins that modulate neuronal plasticity. We also focus on the mechanism of active transport as well as the role of importins in mediating nuclear import of the postsynaptic proteins. Finally, we briefly discuss the role of synapse to nucleus signaling in the context of transcription-dependent plasticity and conclude by describing future challenges in this field of research.

Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder.

Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis.

Cutaneous Adverse Reactions and Survival Outcomes of Advanced Melanoma Treated with Immune Checkpoint Inhibitors in an Academic Medical Centre in Singapore.

Programmed cell death-1 (PD1) inhibitors, a form of immune checkpoint inhibitor, are efficacious for metastatic melanoma but are associated with cutaneous adverse reactions (CARs). Studies in Europe and North America showed that CARs are associated with an increased overall survival. However, studies from Asia showed mixed results. There is a paucity of data regarding the efficacy of PD1 inhibitors and the effect of CARs on overall survival from Southeast Asia. A retrospective study of patients in the National Cancer Centre Singapore who were diagnosed with melanoma between 2015 and 2020 was conducted. Patients were included in the study if they had stage IV melanoma (advanced melanoma). Sixty-two patients were included in the study. The median age was 62.5 years and acral melanoma was the commonest subtype. Forty-three patients received PD1 inhibitors. Comparing patients who did not receive PD1 inhibitors to patients who received PD1 inhibitors, the former had a median overall survival of 6 months (95% CI: 5.07, 6.93), whereas the latter had a median overall survival of 21 months (95% CI: 13.33, 28.67; p < 0.001) (Hazard ratio 0.32; 95% CI: 0.16, 0.63; p = 0.001). Amongst patients who received PD1 inhibitors, patients who developed CARs had a greater median overall survival of 33 months (95% CI: 17.27, 48.73) compared to 15 months (95% CI: 9.20, 20.80; p = 0.013) for patients who did not (HR 0.29; 95% CI: 0.098, 0.834; p = 0.022). This study provides insight into the outcomes of metastatic melanoma in Singapore, and adds to the body of evidence supporting the use of PD1 inhibitors in Asians.

The Skin in Cowden Syndrome.

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.

Lichen planus pemphigoides after body tattooing.

Decorative tattooing is very popular worldwide and is associated with cutaneous complications, ranging from infections to localized or generalized skin reactions. We report a case of a patient presenting with generalized violaceous pruritic papular lesions 1 month after obtaining a black ink tattoo. Histological examination of a papular lesion distal to the tattoo site showed focal band-like lymphocytic infiltrate. He subsequently developed bullae over the papular lesions, with elevated serum BP180 antibody levels. A diagnosis of generalized lichen planus and lichen planus pemphigoides was made. He responded to treatment with potent topical corticosteroids and ciclosporin. We also reviewed the presentation and treatment of published cases of lichenoid reactions in the literature. With the increasing popularity of tattoos, awareness of this potential complication and possible treatments is important.

Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells.

The stem cell niche is a complex local signaling microenvironment that sustains stem cell activity during organ maintenance and regeneration. The mammary gland niche must support its associated stem cells while also responding to systemic hormonal regulation that triggers pubertal changes. We find that Gli2, the major Hedgehog pathway transcriptional effector, acts within mouse mammary stromal cells to direct a hormone-responsive niche signaling program by activating expression of factors that regulate epithelial stem cells as well as receptors for the mammatrophic hormones estrogen and growth hormone. Whereas prior studies implicate stem cell defects in human disease, this work shows that niche dysfunction may also cause disease, with possible relevance for human disorders and in particular the breast growth pathogenesis associated with combined pituitary hormone deficiency.

Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs.

The Drosophila Hedgehog receptor functions to regulate the essential downstream pathway component, Smoothened, and to limit the range of signaling by sequestering Hedgehog protein signal within imaginal disc epithelium. Hedgehog receptor function requires both Patched and Ihog activity, the latter interchangeably encoded by interference hedgehog (ihog) or brother of ihog (boi). Here we show that Patched and Ihog activity are mutually required for receptor endocytosis and degradation, triggered by Hedgehog protein binding, and causing reduced levels of Ihog/Boi proteins in a stripe of cells at the anterior/posterior compartment boundary of the wing imaginal disc. This Ihog spatial discontinuity may contribute to classically defined cell segregation and lineage restriction at the anterior/posterior wing disc compartment boundary, as suggested by our observations that Ihog activity mediates aggregation of otherwise non-adherent cultured cells and that loss of Ihog activity disrupts wing disc cell segregation, even with downstream genetic rescue of Hedgehog signal response.

Lipid-Based Therapy for Ocular Surface Inflammation and Disease.

Ocular surface diseases such as dry eye, allergic keratoconjunctivitis, and infection are very prevalent conditions and involve ocular surface stress and inflammation. Recently, various lipid-based therapies have been advocated for the modulation of ocular surface inflammation. Here we review the latest developments and challenges of these strategies. These include administration of essential fatty acids, cyclooxygenase (COX) inhibitors and resolvin analogs. Lipids form part of the tear film and are crucial for tear film stability; loss of tear film stability can aggravate ocular surface inflammation. Strategies to replenish tear film lipids - namely, eyelid warming and eye drops containing natural or synthetic lipids - are evaluated. Recent advances in the use of lipids as ocular drug delivery vehicles, antioxidants, and diagnostic markers are discussed.

Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate.

Branching morphogenesis is thought to be governed by epithelial-stromal interactions, but the mechanisms underlying specification of branch location remain largely unknown. Prompted by the striking absence of Hedgehog (Hh) response at the sites of nascent buds in regenerating tubules of the adult prostate, we investigated the role of Hh signalling in adult prostate branching morphogenesis. We find that pathway activity is localized to stromal cells, and that its attenuation by genetic or pharmacologic manipulation leads to increased branching. Decreased pathway activity correlates with increased stromal production of hepatocyte growth factor (Hgf), and we show that Hgf induces epithelial tubule branching. Regulation of Hgf expression by Hh signalling is indirect, mediated by Hh-induced expression of the microRNAs miR-26a and miR-26b, which in turn downregulate expression of Hgf. Prostate tubule branching thus may be initiated from regions of low Hh pathway activity, with implications for the prostatic hyperplasia commonly observed in late adulthood.

Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors.

Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.

Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma.

Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium. These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma in situ. Shh-expressing basal cells within this precursor lesion become tumour-initiating cells, although Shh expression is lost in subsequent carcinomas. We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.

FDA oversight of cell therapy clinical trials.

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.