Melanoma genotypes and phenotypes get personal.

Traditionally, the diagnosis of metastatic melanoma was terminal to most patients. However, the advancements towards understanding the fundamental etiology, pathophysiology, and treatment have raised melanoma to the forefront of contemporary medicine. Indeed, the evidence of durable remissions are being heard ever more frequently in clinics around the globe. Despite having more gene mutations per cell than any other type of cancer, investigators are overcoming complex genomic landscapes, signaling pathways, and immune checkpoints by generating novel technological methods and clinical protocols with breath-taking speed. Significant progress in deciphering molecular genetics, epigenetics, kinase-driven networks, metabolomics, and immune-enhancing pathways to achieve personalized and positive outcomes has truly provided new hope for melanoma patients. However, obstacles requiring breakthroughs include understanding the influence of sunlight exposure on melanoma etiology, and overcoming all too frequently acquired drug resistance, complicating targeted therapy. Pathologists continue to have critically important roles in advancing the field, particularly in the area of transitioning from microscope-based diagnostic reports to pharmacogenomics through molecularly informed tumor boards. Although melanoma is no longer considered just 'one disease', pathologists will continue this rapidly progressing and exciting journey to identify tumor subtypes, to utilize tumorgraft or so-called patient-derived xenograft (PDX) models, and to develop companion diagnostics to keep pace with the bewildering breakthroughs occurring on a regular basis. Exactly which combination of drugs will ultimately be required to eradicate melanoma cells remains to be determined. However, it is clear that pathologists who are as dedicated to melanoma as the pioneering pathologist Dr Sidney Farber was committed to childhood cancers, will be required as the battle against melanoma continues. In this review, we describe what sets melanoma apart from other tumors, and demonstrate how lessons learned in the melanoma clinic are being transferred to many other types of aggressive neoplasms.

Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88.

Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88(-/-) mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)- α, interferon (IFN)-γ, interleukin (IL)-1ß, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay, and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kB-driven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-α and IL-1ß production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication.

Inhibition of toxic shock by human monoclonal antibodies against staphylococcal enterotoxin B.

BACKGROUND: Staphylococcus aureus is implicated in many opportunistic bacterial infections around the world. Rising antibiotic resistance and few alternative methods of treatment are just two looming problems associated with clinical management of S. aureus. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value. METHODOLOGY/PRINCIPAL FINDINGS: The inhibitory and biophysical properties of ten human monoclonal antibodies, isolated from a recombinant library by panning against SEB vaccine (STEBVax), were examined as bivalent Fabs and native full-length IgG (Mab). The best performing Fabs had binding affinities equal to polyclonal IgG, low nanomolar IC(50)s against SEB in cell culture assays, and protected mice from SEB-induced toxic shock. The orthologous staphylococcal proteins, SEC1 and SEC2, as well as streptococcal pyrogenic exotoxin C were recognized by several Fabs. Four Fabs against SEB, with the lowest IC(50)s, were converted into native full-length Mabs. Although SEB-binding kinetics were identical between each Fab and respective Mab, a 250-fold greater inhibition of SEB-induced T-cell activation was observed with two Mabs. CONCLUSIONS/SIGNIFICANCE: Results suggest that these human monoclonal antibodies possess high affinity, target specificity, and toxin neutralization qualities essential for any therapeutic agent.