Melanoma central nervous system metastases: current approaches,challenges, and opportunities

Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.     

Efficacy of levonorgestrel when administered as an irradiated,slow‐release injectable matrix for feline contraception

Reliable and safe methods of reversible contraception are needed for use in zoo felids. The efficacy of levonorgestrel (LNG) as a contraceptive, when delivered as a cesium‐irradiated, slow‐release, injectable matrix, was tested in domestic cats as a model for exotic cats. An increase (P = 0.0017) in body weight was observed in treated but not control queens (P = 0.2146). All control queens (n = 6), which received injections of matrix only, but none of the LNG‐treated queens (n = 6) became pregnant during the trial. Levonorgestrel was effective in preventing pregnancy for at least 36 weeks after two injections of drug‐loaded formulations (40 mg/kg body weight), administered 68 days apart. Throughout the study, all control queens displayed luteal activity and fluctuating fecal estradiol concentrations, whereas the LNG‐treated queens displayed lower estradiol concentrations and no luteal activity after treatment. We conclude that LNG, when delivered as a cesium‐irradiated, slow‐release, injectable matrix, is an effective contraceptive in domestic cats, reducing follicular activity, and thus, preventing mating and luteal activity. Zoo Biol 20:407–421, 2001. © 2001 Wiley‐Liss, Inc.     

Discovery of novel isothiazole inhibitors of the TrkA kinase: structure-activity relationship, computer modeling, optimization, and identification of highly potent antagonists

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.     

EFFECTS OF FERTILIZATION DISTANCE ON MALE GAIN CURVES IN A FREE‐SPAWNING MARINE INVERTEBRATE: A COMBINED EMPIRICAL AND THEORETICAL APPROACH

Male gain curves describe the relationship between allocation to sperm production and male reproductive success and are central to models of sex allocation in hermaphrodites. Sperm competition is expected to result in more linear gains and select for increased allocation. We hypothesized that high sperm production in passively mating systems may also be the result of selection to enhance the ability to fertilize distant ova. Consequently, we explored the effect of distance on male gain curves in a free‐spawning colonial ascidian. The performance of focal males that varied in sperm production was assayed at three distances via microsatellite markers. An advection‐diffusion model was used to estimate sperm concentration gradients, to predict male reproductive gain integrated across multiple downstream females, and explore effects of hydrodynamic conditions. As distance increased, male reproductive success decreased and empirical gain curves became increasingly linear. Our model predicted that the expected net gain curve is relatively insensitive to variation in flow regime and will saturate much more slowly than if only a single, nearby distance is considered. Thus, high levels of sperm production may enhance fitness both in competitive situations and with increasing fertilization distance, highlighting the need to consider distance effects when evaluating gain curves.     

Rift valley fever virus infection of human cells and insect hosts is promoted by protein kinase C epsilon

As an arthropod-borne human pathogen, Rift Valley fever virus (RVFV) cycles between an insect vector and mammalian hosts. Little is known about the cellular requirements for infection in either host. Here we developed a tissue culture model for RVFV infection of human and insect cells that is amenable to high-throughput screening. Using this approach we screened a library of 1280 small molecules with pharmacologically defined activities and identified 59 drugs that inhibited RVFV infection with 15 inhibiting RVFV replication in both human and insect cells. Amongst the 15 inhibitors that blocked infection in both hosts was a subset that inhibits protein kinase C. Further studies found that infection is dependent upon the novel protein kinase C isozyme epsilon (PKCε) in both human and insect cells as well as in adult flies. Altogether, these data show that inhibition of cellular factors required for early steps in the infection cycle including PKCε can block RVFV infection, and may represent a starting point for the development of anti-RVFV therapeutics.     

Evidence for interleukin-1-independent stimulation of interleukin-12 and down-regulation by interleukin-10 in Helicobacter pylori-infected murine dendritic cells deficient in the interleukin-1 receptor

Helicobacter pylori infection is characterized by infiltration of cells of the immune system, including dendritic cells, into the gastric mucosa. During chronic inflammation with Helicobacter pylori infection, a variety of cytokines are secreted into the mucosa, including interleukin-1beta (IL-1beta). The role of IL-1 in H. pylori infection was investigated using bone-marrow-derived dendritic cells from wild-type and IL-1 receptor-deficient (IL-1R-/-) mice. Dendritic cells were incubated with H. pylori at a multiplicity of infection of 10 and 100, and cytokine production evaluated. Helicobacter pylori SS1, H. pylori SD4, and an isogenic cagE mutant of SD4 stimulated IL-12, IL-6, IL-1beta, IL-10, and tumor necrosis factor-alpha at comparable levels in dendritic cells from both wild-type and IL-1R-/- mice. IL-10 production required the higher inoculum, while IL-12 was decreased at this bacterial load. Pretreatment of dendritic cells with an antibody to IL-10 resulted in an increased production of IL-12, confirming the down-regulation of IL-12 by IL-10. cagE was required for maximum stimulation of IL-12 by H. pylori. We speculate that the down-regulation of IL-12 by IL-10 at the higher multiplicity of infection represents the modulation of the host inflammatory response in vivo by H. pylori when the bacterial load is high, allowing for persistent colonization of the gastric mucosa.     

Utilization of glycogen but not plasma glucose is reduced in individuals with NIDDM during mild-intensity exercise

Colberg, Sheri R., James M. Hagberg, Steve D. McCole, JosephM. Zmuda, Paul D. Thompson, and David E. Kelley. Utilization ofglycogen but not plasma glucose is reduced in individuals with NIDDMduring mild-intensity exercise. J. Appl.Physiol. 81(4): 2027-2033, 1996.To test thehypothesis that substrate utilization during mild-intensity exercisediffers in non-insulin-dependent diabetes mellitus (NIDDM) comparedwith nondiabetic subjects, seven lean healthy subjects (L), seven obesehealthy subjects (O), and seven individuals with NIDDM were studiedduring 40 min of mild-intensity cycling (40% of peakO₂ uptake). Systemic utilization of plasma glucose (Glc Rd) was determined by using isotope dilution methods. Gas exchange was measured to determine rates of carbohydrate (CHO) and lipid oxidation. During exercise, when CHOoxidation was greater than Glc Rd, the net oxidation of glycogen wascalculated as the difference: CHO oxidation  Glc Rd. Duringmild-intensity cycling, the respiratory exchange ratio was similaracross groups (0.87 ± 0.02, 0.85 ± 0.02, and 0.86 ± 0.01 inL, O, and NIDDM subjects, respectively), and CHO oxidation accountedfor one-half of total energy expenditure during exercise. Glc Rdincreased during exercise and was greatest in subjects with NIDDM (3.0 ± 0.2, 2.9 ± 0.2, and 4.5 ± 0.4 ml ^· kg^{1 ·} min¹in L, O, and NIDDM subjects, respectively,P < 0.05), yet Glc Rd wasless than CHO oxidation during exercise, indicating net oxidation ofglycogen. Glycogen oxidation was greater in L and O than in NIDDMsubjects (3.4 ± 1.0, 2.5 ± 0.9, and 1.7 ± 0.8 ml ^· kg^{1 ·} min¹;P < 0.05). In summary, duringmild-intensity exercise, NIDDM subjects have an increased Glc Rd and adecreased oxidation of muscle glycogen.

     

Impact of post-thymic cellular longevity on the development of age-associated CD4+ T cell defects

Elderly people are at higher risk for infections due to declining cellular and humoral immune responses. Central to this dysfunction is the reduced responsiveness of the naive CD4(+) T cell compartment. Previous data from our laboratory suggest that although defects in the aged naive CD4(+) T cell response are apparent in recent thymic emigrant populations, additional defects develop during extended post-thymic longevity in the periphery. To further investigate the factors that lead to aging defects, we took advantage of the OT-II TCR-transgenic (Tg) mouse model. We show that because of an apparent superantigen-mediated loss of naive Vbeta5(+) Tg CD4(+) T cells from the periphery of aging OT-II mice, this compartment becomes enriched for cells of reduced post-thymic longevity, resulting in a frequency of recent thymic emigrants in aged mice that is similar to that of young mice. Purification and functional analysis of aged OT-II cells with reduced post-thymic longevity reveal that they have an age-associated decrease in expansion and IL-2 production in response to Ag in vitro. However, the in vivo expansion, IL-2 production, and cognate B cell helper ability of these cells are similar to those of cells from young mice. In contrast, T cells from aged HNT Tg mice demonstrate extended post-thymic longevity and exhibit severe defects in the same in vitro and in vivo models. These data support a correlation between the requirement for increased post-thymic longevity and the development of the most severe naive CD4(+) T cell-aging defects.