Atypical Cutaneous Manifestation of Mycosis Fungoides: A Case Report.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) that is characterized by atypical CD4+ T-cell aggregates in the epidermis. It is typically divided into three clinical phases, which consist of the patches, plaques, and tumor stages. There have been atypical manifestations of MF described in the literature, and it is hypothesized that the skin microbiota plays a role in the skin phenotype of MF patients. Here, we describe an MF patient with multiple, large, ulcerated, and purulent lesions that developed after she swam in the ocean. Our patient was found to have a unique set of bacteria isolated from the wound.

Resistance to Checkpoint Inhibition in Cancer Immunotherapy.

The interaction of the host immune system with tumor cells in the tissue microenvironment is essential in understanding tumor immunity and development of successful cancer immunotherapy. The presence of lymphocytes in tumors is highly correlated with an improved outcome. T cells have a set of cell surface receptors termed immune checkpoints that when activated suppress T cell function. Upregulation of immune checkpoint receptors such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) occurs during T cell activation in an effort to prevent damage from an excessive immune response. Immune checkpoint inhibitors allow the adaptive immune system to respond to tumors more effectively. There has been clinical success in different types of cancer blocking immune checkpoint receptors such as PD-1 and CTLA. However, relapse has occurred. The innate and acquired/therapy induced resistance to treatment has been encountered. Aberrant cellular signal transduction is a major contributing factor to resistance to immunotherapy. Combination therapies with other co-inhibitory immune checkpoints such as TIM-3, LAG3 and VISTA are currently being tested to overcome resistance to cancer immunotherapy. Expression of TIM-3 has been associated with resistance to PD-1 blockade and combined blockade of TIM-3 and PD-1 has demonstrated improved responses in preclinical models. LAG3 blockade has the potential to increase the responsiveness of cytotoxic T-cells to tumors. Furthermore, tumors that were found to express VISTA had an increased rate of growth due to the T cell suppression. The growing understanding of the inhibitory immune checkpoints' ligand biology, signaling mechanisms, and T-cell suppression in the tumor microenvironment continues to fuel preclinical and clinical advancements in design, testing, and approval of agents that block checkpoint molecules. Our review seeks to bridge fundamental regulatory mechanisms across inhibitory immune checkpoint receptors that are of great importance in resistance to cancer immunotherapy. We will summarize the biology of different checkpoint molecules, highlight the effect of individual checkpoint inhibition as anti-tumor therapies, and outline the literatures that explore mechanisms of resistance to individual checkpoint inhibition pathways.

Accuracy of Canine Scent Detection of Non-Small Cell Lung Cancer in Blood Serum.

CONTEXT: Early detection provides the best opportunity for lung cancer survival; however, lung cancer is difficult to detect early because symptoms do not often appear until later stages. Current screening methods such as x-ray and computed tomographic imaging lack the sensitivity and specificity needed for effective early diagnosis. Dogs have highly developed olfactory systems and may be able to detect cancer in its primary stages. Their scent detection could be used to identify biomarkers associated with various types of lung cancer. OBJECTIVE: To determine the accuracy of trained beagles' ability to use their olfactory system to differentiate the odor of the blood serum of patients with lung cancer from the blood serum of healthy controls. METHODS: Over the course of 8 weeks, operant conditioning via clicker training was used to train dogs to use their olfactory system to distinguish blood serum from patients with malignant lung cancer from blood serum from healthy controls in a double-blind study. After training, non-small cell lung cancer and healthy control blood serum samples were presented to the dogs, and the sensitivity and specificity of each dog were analyzed. RESULTS: Four dogs were trained for the study, but 1 was unmotivated by training and removed from the study. Three dogs were able to correctly identify the cancer samples with a sensitivity of 96.7%, specificity of 97.5%, positive predictive value of 90.6%, and negative predictive value of 99.2%. CONCLUSION: Trained dogs were able to identify non-small cell lung cancer samples from healthy controls. The findings of this study provide a starting point for a larger-scale research project designed to explore the use of canine scent detection as a tool for cancer biomarkers.

Structural and biochemical properties of an extreme 'salt-loving' proteasome activating nucleotidase from the archaeon Haloferax volcanii.

In eukaryotes, the 26S proteasome degrades ubiquitinylated proteins in an ATP-dependent manner. Archaea mediate a form of post-translational modification of proteins termed sampylation that resembles ubiquitinylation. Sampylation was identified in Haloferax volcanii, a moderate halophilic archaeon that synthesizes homologs of 26S proteasome subunits including 20S core particles and regulatory particle triple-A ATPases (Rpt)-like proteasome-associated nucleotidases (PAN-A/1 and PAN-B/2). To determine whether sampylated proteins associate with the Rpt subunit homologs, PAN-A/1 was purified to homogeneity from Hfx. volcanii and analyzed for its subunit stoichiometry, nucleotide-hydrolyzing activity and binding to sampylated protein targets. PAN-A/1 was found to be associated as a dodecamer (630 kDa) with a configuration in TEM suggesting a complex of two stacked hexameric rings. PAN-A/1 had high affinity for ATP (K m of ~0.44 mM) and hydrolyzed this nucleotide with a specific activity of 0.33 ± 0.1 µmol Pi/h per mg protein and maximum at 42 °C. PAN-A1 was stabilized by 2 M salt with a decrease in activity at lower concentrations of salt that correlated with dissociation of the dodecamer into trimers to monomers. Binding of PAN-A/1 to a sampylated protein was demonstrated by modification of a far Western blotting technique (derived from the standard Western blot method to detect protein-protein interaction in vitro) for halophilic proteins. Overall, our results support a model in which sampylated proteins associate with the PAN-A/1 AAA+ ATPase in proteasome-mediated proteolysis and/or protein remodeling and provide a method for assay of halophilic protein-protein interactions.