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.

The Skin in Cowden Syndrome.

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog () 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.

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.

Stromal 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 , 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.

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.

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.

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.

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.

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.

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.

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.