Therapeutic implications of KIT in melanoma.

Melanoma is a heterogeneous disease representing distinct biologic and genetic subsets. Activating mutations in KIT have been discovered in a significant proportion of melanomas arising from acral, mucosal, and chronically sun-damaged sites and represent an important melanoma genetic subset. Initially, KIT was believed to function as a tumor suppressor, but additional research suggests that, in certain contexts, KIT functions as an oncogene.

Immunologic correlates of the abscopal effect in a patient with melanoma.

The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a monoclonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).

The antitumor immunity of ipilimumab: (T-cell) memories to last a lifetime?

Ipilimumab has shown an overall survival benefit in 2 randomized phase III studies. A minority of patients achieve long-term disease control, highlighting the potential of this immunotherapeutic approach. In ongoing efforts, investigators are continuing to characterize these patients' unique clinical courses and correlate their responses with underlying mechanisms of antitumor immunity.

Beyond cancer vaccines: a reason for future optimism with immunomodulatory therapy.

Despite significant scientific knowledge in the field of cancer immunology, therapeutic strategies using cancer vaccines to generate anti-tumor immunity have historically resulted in only modest clinical benefit. Disappointing results from prior cancer vaccine trials are likely due to multifactorial causes. Perhaps the most important is the role of inherent tumor-induced immune suppression and enhanced immunologic tolerance.

Tumor necrosis factor-alpha prevents desensitization of Galphas-coupled receptors by regulating GRK2 association with the plasma membrane.

We have reported previously that interleukin-1 and tumor necrosis factor (TNF)-alpha increase expression and function of adenosine A2A receptors (A2ARs), although the increased function is disproportionate to the increment in expression. We therefore studied the effect of TNF-alpha on A2A R function and desensitization in human monocytoid THP-1 cells. We observed that TNF-alpha regulates activity of A2A Rs and other G protein-coupled receptors (GPCRs) by altering their ligand-mediated desensitization.

Disruption of the Aspergillus fumigatus gene encoding nucleolar protein CgrA impairs thermotolerant growth and reduces virulence.

Aspergillus fumigatus CgrA is the ortholog of a yeast nucleolar protein that functions in ribosome synthesis. To determine how CgrA contributes to the virulence of A. fumigatus, a Delta cgrA mutant was constructed by targeted gene disruption, and the mutant was reconstituted to wild type by homologous introduction of a functional cgrA gene.