Description: Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS–associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085–97. ©2018 AACR .

Description: [1]  The primary objective of this work is to synthesize components of benthic flux in the Patos Lagoon coastal zone, Rio Grande do Sul, Brazil. Specifically, the component of benthic discharge flux forced by the terrestrial hydraulic gradient is 0.8 m 3 d −1 ; components of benthic discharge and recharge flux associated with the groundwater tidal prism are both 2.1 m 3 d −1 ; components of benthic discharge and recharge flux forced by surface-gravity wave setup are both 6.3 m 3 d −1 ; the component of benthic discharge flux that transports radium-228 is 350 m 3 d −1 ; and components of benthic discharge and recharge flux forced by surface-gravity waves propagating over a porous medium are both 1400 m 3 d −1 . (All models are normalized per meter shoreline.) Benthic flux is a function of components forced by individual mechanisms and nonlinear interactions that exist between components. Constructive and destructive interference may enhance or diminish the contribution of benthic flux components. It may not be possible to model benthic flux by summing component magnitudes. Geochemical tracer techniques may not accurately model benthic discharge flux or submarine groundwater discharge (SGD). A conceptual model provides a framework on which to quantitatively characterize benthic discharge flux and SGD with a multifaceted approach.

Description: The primary objective of this work is to synthesize components of benthic flux in the Patos Lagoon coastal zone, Rio Grande do Sul, Brazil. Specifically, the component of benthic discharge flux forced by the terrestrial hydraulic gradient is 0.8 m3 d−1; components of benthic discharge and recharge flux associated with the groundwater tidal prism are both 2.1 m3 d−1; components of benthic discharge and recharge flux forced by surface-gravity wave setup are both 6.3 m3 d−1; the component of benthic discharge flux that transports radium-228 is 350 m3 d−1; and components of benthic discharge and recharge flux forced by surface-gravity waves propagating over a porous medium are both 1400 m3 d−1. (All models are normalized per meter shoreline.) Benthic flux is a function of components forced by individual mechanisms and nonlinear interactions that exist between components. Constructive and destructive interference may enhance or diminish the contribution of benthic flux components. It may not be possible to model benthic flux by summing component magnitudes. Geochemical tracer techniques may not accurately model benthic discharge flux or submarine groundwater discharge (SGD). A conceptual model provides a framework on which to quantitatively characterize benthic discharge flux and SGD with a multifaceted approach.

Description: Attack by the white pine weevil has notably reduced Sitka spruce productivity in British Columbia (BC) (Canada) and western US. By the 1970s, the BC Ministry of Forests established provenance trials of Sitka spruce with the objective of detecting usable genetic resistance to weevil. These early trials reported significant weevil resistance and allowed the production of the first (F1) controlled-cross progeny generation with demonstrable weevil resistance (R) or susceptibility (S). This study reports results of the screening for weevil resistance and the levels of constitutive defenses of this F1 Sitka spruce progeny. Progeny from resistant parents (R x R progeny) sustained significantly fewer weevil attacks than progeny from susceptible parents (S x S progeny) or progeny with one resistant and one susceptible parent (R x S progeny). Individual and family heritability estimates of the weevil resistance were 0.5 and 0.9, respectively. Constitutive defenses, measured by resin canal and sclereid cell density in the cortex, were significantly higher in R x R progeny than in R x S or S x S progeny. We observed a negative correlation between the percentage of trees attacked in each cross and the average density of the resin canals or sclereid cells for each cross.

Description: Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor–initiating cells (BTIC) that confer resistance to conventional therapies. Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically. Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro , and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation). Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings. Clin Cancer Res; 22(15); 3860–75. ©2016 AACR .