Genodermatoses associated with melanocytic nevi.

Though melanocytic nevi are ubiquitous in the general population, they can also be key cutaneous manifestations of genetic syndromes. We describe genodermatoses associated with melanocytic nevi and discuss their clinical characteristics, cutaneous manifestations, underlying genetics, and, if applicable, guidelines for when genetic testing should be performed. We categorized these genodermatoses based on their association with congenital nevi, acquired nevi, or nevi whose first appearance is unknown. In many cases, the distinctive morphology or distribution of melanocytic nevi can be an important clue that an underlying genetic syndrome is present, allowing both the patient as well as family members to be screened for the more serious complications of their genetic disorder and receive education on potential preventative measures. As we continue to advance our understanding of how various genotypes give rise to the wide spectrum of phenotypes observed in these genodermatoses, we shall be able to better stratify risk and tailor our screening methods to clinically manage the heterogeneous manifestations of genodermatoses among these patients.

Dermatologic toxicities associated with radiation therapy in women with breast cancer.

Breast-conserving surgery with adjuvant radiation therapy has become the standard of care for women with early stage breast cancer, and as a result, a large number of patients are affected by the cutaneous sequelae of radiation therapy. These dermatologic toxicities may present during treatment or years later and can significantly impact patients' quality of life. In this review, we discuss the clinical presentation, prevention, and management of radiation-induced cutaneous toxicities in women with breast cancer, including radiation dermatitis, radiation recall, radiation-induced morphea, radiation-induced fibrosis, and cutaneous malignancies in irradiated skin.

Development and Application of the Metalloprotease Activity Multiplexed Bead-Based Immunoassay (MAMBI).

Metalloproteinases (MMPs) are zinc-dependent endopeptidases that cleave various proteins to regulate normal and diseased cellular functions, and as such, they play significant roles in human tissue development, homeostasis, and the pathogenesis of many diseases, including cancers, endometriosis, arthritis, etc. Most MMPs are produced as zymogenic latent enzymes that must be cleaved to activate their catalytic regions, and localized endogenous protein inhibitors further regulate activity. Accordingly, they operate within recursive networks to degrade extracellular matrix proteins and regulate cell signaling by cleaving growth factors and receptors at the cell surface and in the local pericellular environment. Thus, high-resolution information about the concentrations of specific active MMPs, revealing their intricate regulatory networks, may improve disease diagnosis and treatment. Here, we introduce a new and readily mastered method for measuring MMP activities in a multiplex fashion. We integrate aspects of activity-based enzyme labeling with commercial high-throughput, multiplexed protein quantification to yield the metalloproteinase activity multiplexed bead-based immunoassay (MAMBI). Assays of recombinant active MMP-1, -2, -3, -7, -8, -9, -12, and -13 establish the sensitivity and selectivity of MAMBI detection. Levels of active native MMPs are similarly characterized in conditioned cell culture medium, menstrual effluent, and uterine tissue. In a single MAMBI (5 µL), we achieve sensitivities equal to those from leading single-plex MMP activity detection strategies (e.g., 10-15 M for MMP-1). We also demonstrate high-throughput inhibitor screening via the MAMBI approach in complex, patient-derived samples.

Dermatologic conditions in women receiving systemic cancer therapy.

As advances in cancer therapies have improved cancer-related survival, novel therapeutics have also introduced a variety of dermatologic toxicities, and an increased number of patients are living with these sequalae. Women with cancer in particular experience a spectrum of dermatologic conditions that affect their skin, hair, nail, and mucosal surfaces. Studies have shown that these toxic effects can significantly affect quality of life and alter a woman's self-image, cultural identity, femininity, sexuality, and mental health. In severe instances, dermatologic toxicities may even disrupt cancer therapy and can therefore affect overall survival and treatment response. In this article, we review the dermatologic adverse effects from traditional chemotherapy, targeted therapy, immune checkpoint inhibitors, and endocrine therapy that disproportionately affect women. The timely diagnosis and management of these dermatologic conditions is crucial in the multidisciplinary care of women with cancer.

Chemoproteomics of matrix metalloproteases in a model of cartilage degeneration suggests functional biomarkers associated with posttraumatic osteoarthritis.

Active matrix metalloproteases (MMPs) play a significant role in the pathogenesis of many diseases including osteoarthritis (OA), which involves progressive proteolytic degradation of cartilage. Clinical success of OA interventions that target MMPs has been limited by a lack of information about the presence and activity of specific disease-related proteases. We therefore developed a chemoproteomics approach based on MS to characterize the release and activity of MMPs in an in vitro model of the early inflammatory phase of posttraumatic OA (PTOA). We designed and synthesized chemical activity-based probes (ABPs) to identify active MMPs in bovine cartilage explants cultured for 30 days with the proinflammatory cytokine, interleukin-1α. Using these probes in an activity-based protein profiling-multidimensional identification technology (ABPP-MudPIT) approach, we identified active MMP-1, -2, -3, -7, -9, -12, and -13 in the medium after 10 days of culture, the time at which irreversible proteolysis of the collagen network in the explant was detected using proteolytic activation of FRET-quenched MMP substrates. Total MMP levels were quantified by shotgun proteomics, which, taken with ABPP-MudPIT data, indicated the presence of predominantly inactive MMPs in the culture medium. The selectivity of the ABPP-MudPIT approach was further validated by detection of specific endogenous MMPs activated de novo with 4-aminophenylmurcuric acetate. The utility of the new ABPP-MudPIT approach for detecting molecular biomarkers of PTOA disease initiation and potential targets for therapeutics motivates possible application in other diseases involving MMP activity.