A nongenomic mechanism for progesterone-mediated immunosuppression: Inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes

The mechanism by which progesterone causes localized suppression of the immune response during pregnancy has remained elusive. Using human T lymphocytes and T cell lines, we show that progesterone, at concentrations found in the placenta, rapidly and reversibly blocks voltage-gated and calcium-activated K+ channels (KV and KCa, respectively), resulting in depolarization of the membrane potential. As a result, Ca2+ signaling and nuclear factor of activated T cells (NF-AT)-driven gene expression are inhibited. Progesterone acts distally to the initial steps of T cell receptor (TCR)-mediated signal transduction, since it blocks sustained Ca2+ signals after thapsigargin stimulation, as well as oscillatory Ca2+ signals, but not the Ca2+ transient after TCR stimulation. K+ channel blockade by progesterone is specific; other steroid hormones had little or no effect, although the progesterone antagonist RU 486 also blocked KV and KCa channels. Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3 and charybdotoxin-resistant components of KV current and KCa current in T cells, as well as blocking several cloned KV channels expressed in cell lines. Progesterone had little or no effect on a cloned voltage-gated Na+ channel, an inward rectifier K+ channel, or on lymphocyte Ca2+ and Cl- channels. We propose that direct inhibition of K+ channels in T cells by progesterone contributes to progesterone-induced immunosuppression

Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer : randomized clinical trial

BACKGROUND: The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm. METHODS: One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non-erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided. RESULTS: Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs -2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse. CONCLUSIONS: Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis

Challenges to the development of antigen-specific breast cancer vaccines

Continued progress in the development of antigen-specific breast cancer vaccines depends on the identification of appropriate target antigens, the establishment of effective immunization strategies, and the ability to circumvent immune escape mechanisms. Methods such as T cell epitope cloning and serological expression cloning (SEREX) have led to the identification of a number target antigens expressed in breast cancer. Improved immunization strategies, such as using dendritic cells to present tumor-associated antigens to T lymphocytes, have been shown to induce antigen-specific T cell responses in vivo and, in some cases, objective clinical responses. An outcome of successful tumor immunity is the evolution of antigen-loss tumor variants. The development of a polyvalent breast cancer vaccine, directed against a panel of tumor-associated antigens, may counteract this form of immune escape

Role of Delamination in Zeolite-Catalyzed Aromatic Alkylation: UCB‑3 versus 3‑D Al-SSZ-70

Delaminated zeolite UCB-3 exhibits 2.4-fold greater catalytic activity relative to its three-dimensional (3D) zeolite counterpart, Al-SSZ-70, and 2.0-fold greater activity (per catalyst mass) when compared with industrial catalyst MCM-22, for the alkylation of toluene with propylene at 523 K. The former increase is nearly equal to the observed relative increase in external surface area and acid sites upon delamination. However, at 423 K for the same reaction, UCB-3 exhibits a 3.5-fold greater catalytic activity relative to 3D Al-SSZ-70. The higher relative rate enhancement for the delaminated material at lower temperature can be elucidated on the basis of increased contributions from internal acid sites. Evidence of possible contributions from such acid sites is obtained by performing catalysis after silanation treatment, which demonstrates that although virtually all catalysis in MCM-22 occurs on the external surface, catalysis also occurs on internal sites for 3D Al-SSZ-70. The additional observed enhancement at low temperatures can therefore be rationalized by greater access to internal active sites as a result of sheet breakage during delamination. Such breakage leads to shorter characteristic internal diffusion paths and was visualized using TEM comparisons of UCB-3 and 3D Al-SSZ-70

Improving Management and Conservation of Cusk (Brosme brosme): Habitat Distribution, Bycatch Interactions, and Conservation Practices

Cusk (Brosme brosme) are a National Oceanic and Atmospheric Administration species of concern, currently under internal status review for the Endangered Species Act, but are considered data limited. Current concerns for cusk include: decline in abundance, increase in fishing mortality relative to survey biomass, increased patchiness in habitat, and lack of management (72 FR 10710). Future management will require an improved understanding of cusk distribution, habitat use, spatial distribution of bycatch interactions, and the impact of bycatch on the population. This study set out to evaluate changes in cusk distribution and habitat, locations and levels of bycatch, and the feasibility of implementing conservation measures to reduce discard mortality of cusk bycatch. Data limited approaches were developed to map cusk habitat and potential areas of bycatch. A spatio-temporal delta-Generalized Linear Mixed Model (GLMM) was used to combine observations from the Northeast Fisheries Science Center (NEFSC) spring and fall research bottom trawl survey with the NEFSC western Gulf of Maine (GOM) co-operative research longline survey. The resulting density estimates were then used to develop model-based habitat suitability index (HSI) maps for cusk with increased data resolution. The American lobster (Homarus americanus) fishery is thought to be a significant source of mortality for cusk, as such bycatch of cusk within this fishery was evaluated. Bycatch ‘hotspots’ were predicted based on the overlap of cusk and American lobster high quality habitat. Field studies were conducted in collaboration with Maine lobster fishermen to evaluate the ability of cusk to survive incidental catches within the lobster fishery. These studies resulted in an estimated 75% survival rate in the medium-term (4 – 14 days) if recompressed. To evaluate the impact of implementing the recompression of cusk as a conservation measure throughout the Maine lobster fleet stock assessment simulations were conducted. Cusk bycatch was first estimated for the Maine lobster fishery to develop the simulation scenarios. These estimates indicate 2 – 9 cusk are caught per 10,000 trap hauls, depending on location. Life history parameters were also estimated for cusk for the simulations. The stock assessment simulations indicated that a decrease in fishing mortality would be beneficial to the population, but only decreasing mortality from the Maine lobster fishery would not be enough to significantly improve the population status

Sensory profile of portuguese white wines using long-term memory: a novel nationwide approach

White wine sensory profiling of all 12 Protected Geographical Indications (PGIs) of mainland Portugal was achieved through completion of extended sensory questionnaires by 20 professional wine experts. No samples were assessed; the experiment was based on memory alone. Three macro-zonings were found and typicality differences were statistically validated and sensory described. PGI MINHO was found the most typical of all PGIs, with several extreme rates on Color, Aroma and Taste. SOUTHERN cluster of the four meridional PGIs presented several extreme, therefore typical, sensory assessments, mostly opposite to the profile of PGI Minho. Color tonality, alcohol and acidity were mutually related and respective variations were correlated with published findings and expressed as key factors for regional macro-zoning differentiation. Moreover, with the proposed methodology it was possible to achieve a novel nationwide sensory characterization of PGIs, overcoming ongoing macroscaling and sample representativeness limitations and envisaging new nation-sized sensory studiesinfo:eu-repo/semantics/publishedVersio