Integrative taxonomy of Peniculus,Metapeniculus, and Trifur (Siphonostomatoida: Pennellidae), copepod parasites of marine fishes from Chile: species delimitation analyses using DNA barcoding and morphological evidence

Pennellidae is a family of copepod parasites of widely distributed marine fishes. The pennellid species are usually morphologically differentiated by cephalothorax, neck, trunk, and abdomen shape. These characters, however, show high polymorphism and therefore using only this type of data, delimitation at species level of this genus is difficult. In this study, we explored the genetic distances calculated from sequences of a DNA barcoding marker (COI mt) (678 base pairs). We also explored the genetic distances of 25 Peniculus specimens associated within nine marine fish species, four Metapeniculus specimens associated within one marine fish species, and four Trifur specimens associated within one marine fish species. All specimens were collected in Antofagasta Bay, Chile and were calculated from sequences of a DNA barcoding marker (COI mt) (678 base pairs). The genetic distance among the Peniculus specimens was 0.95% from the different host species, the Metapeniculus specimens distance was 0.44% and the Trifur specimens was 2.25%. Genetic difference between Peniculus and Metapeniculus was 17.86% and Peniculus differ from T. tortuosus by 18.16%. We analysed the barcoding gene fragment using Bayesian Inference (BI) for phylogenetic reconstruction using three outgroups. Based on the phylogenetic analysis an ultrametric tree was built and a general mixed Yule-coalescent (bGMYC) model was conducted for species delimitation. Morphometrics analyses were made with Bayesian statistics. Mean and credibility limit (95%) for each parameter was calculated. Results show that based on morphology the individuals collected can be assigned to P. cf. fistula von Nordmann, 1832, Metapeniculus antofagastensis Castro-Romero & Baeza-Kuroki, 1985, and Trifur cf. tortuosus Wilson, 1917. High morphological polymorphism was observed for the lineage of Peniculus associated to several host species of marine fishes. Similar results were obtained for Trifur cf. tortuosus parasites on Chilean marine fishes.     

Cost-Effectiveness Analysis of Breast Cancer Control Interventions in Peru

Objectives

In Peru, a country with constrained health resources, breast cancer control is characterized by late stage treatment and poor survival. To support breast cancer control in Peru, this study aims to determine the cost-effectiveness of different breast cancer control interventions relevant for the Peruvian context.

Methods

We performed a cost-effectiveness analysis (CEA) according to WHO-CHOICE guidelines, from a healthcare perspective. Different screening, early detection, palliative, and treatment interventions were evaluated using mathematical modeling. Effectiveness estimates were based on observational studies, modeling, and on information from Instituto Nacional de Enfermedades Neoplásicas (INEN). Resource utilizations and unit costs were based on estimates from INEN and observational studies. Cost-effectiveness estimates are in 2012 United States dollars (US$) per disability adjusted life year (DALY) averted.

Results

The current breast cancer program in Peru ($8,426 per DALY averted) could be improved through implementing triennial or biennial screening strategies. These strategies seem the most cost-effective in Peru, particularly when mobile mammography is applied (from $4,125 per DALY averted), or when both CBE screening and mammography screening are combined (from $4,239 per DALY averted). Triennially, these interventions costs between $63 million and $72 million per year. Late stage treatment, trastuzumab therapy and annual screening strategies are the least cost-effective.

Conclusions

Our analysis suggests that breast cancer control in Peru should be oriented towards early detection through combining fixed and mobile mammography screening (age 45-69) triennially. However, a phased introduction of triennial CBE screening (age 40-69) with upfront FNA in non-urban settings, and both CBE (age 40-49) and fixed mammography screening (age 50-69) in urban settings, seems a more feasible option and is also cost-effective. The implementation of this intervention is only meaningful if awareness raising, diagnostic, referral, treatment and basic palliative services are simultaneously improved, and if financial and organizational barriers to these services are reduced.     

Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3

The aim of this study was to delineate the temporal and spatial sequence of STAT1 and STAT3 activation during development of GVHD following fully Major Histocompatibility Complex (MHC)-mismatched allogeneic Bone Marrow Transplantation (BMT). Activation of inflammatory signaling pathways in GVHD target organs was assessed by western blotting, phospho-flow cytometry and electromobility shift assays (EMSA). Development of GVHD was associated with significant expansion of phospho[p]-STAT1 and p-STAT3 expressing CD4⁺ T cells and CD8⁺ T cells. GVHD-specific STAT3/STAT1 activation preceded activation of Nuclear Factor-κB (NF-κB) and Mitogen Activated Protein Kinase (MAPK) and was associated with subsequent induction of STAT1 or STAT3-dependent inflammatory gene-expression programs (e.g. expression of IRF-1, SOCS1, IL-17). Our studies may help to establish a functional hierarchy of the signaling events leading to the development of GVHD and could be helpful in designing new molecularly targeted treatment approaches for GVHD.     

Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents

A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.     

Cognitive and physiological responses in humans exposed to a TETRA base station signal in relation to perceived electromagnetic hypersensitivity

Terrestrial Trunked Radio (TETRA) technology (“Airwave”) has led to public concern because of its potential interference with electrical activity in the brain. The present study is the first to examine whether acute exposure to a TETRA base station signal has an impact on cognitive functioning and physiological responses. Participants were exposed to a 420 MHz TETRA signal at a power flux density of 10 mW/m² as well as sham (no signal) under double‐blind conditions. Fifty‐one people who reported a perceived sensitivity to electromagnetic fields as well as 132 controls participated in a double‐blind provocation study. Forty‐eight sensitive and 132 control participants completed all three sessions. Measures of short‐term memory, working memory, and attention were administered while physiological responses (blood volume pulse, heart rate, skin conductance) were monitored. After applying exclusion criteria based on task performance for each aforementioned cognitive measure, data were analyzed for 36, 43, and 48 sensitive participants for these respective tasks and, likewise, 107,125, and 129 controls. We observed no differences in cognitive performance between sham and TETRA exposure in either group; physiological response also did not differ between the exposure conditions. These findings are similar to previous double‐blind studies with other mobile phone signals (900–2100 MHz), which could not establish any clear evidence that mobile phone signals affect health or cognitive function. Bioelectromagnetics 33:23–39, 2012. © 2011 Wiley Periodicals, Inc.     

Asparagine Endopeptidase Controls Anti-Influenza Virus Immune Responses through TLR7 Activation

Intracellular Toll-like receptors (TLRs) expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV), a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP) deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8⁺ T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.     

Conventional dendritic cells require IRAP-Rab14 endosomes for efficient cross-presentation

Dendritic cells (DCs) use cellular pathways collectively referred to as cross-presentation to stimulate CD8(+) T cells with peptide Ags derived from internalized, exogenous Ags. We have recently reported that DCs rely on aminoterminal trimming of cross-presented peptides by insulin-responsive aminopeptidase (IRAP), an enzyme localized in a regulated endosomal storage compartment. Considering a report contending that this role is limited to inflammatory DCs (Segura et al. 2009. Proc. Natl. Acad. Sci. USA 106: 20377-20381), in this study, we examined the role of IRAP in steady-state DC subpopulations. Steady-state conventional DCs (cDCs) and plasmacytoid DCs expressed similar amounts of IRAP. IRAP colocalized with the endosomal markers Rab14 and syntaxin 6, both known to be associated with regulated endosomal storage compartments, in CD8(+) and CD8(-) cDCs-however, to a greater extent in the former population. Likewise, IRAP recruitment to phagosomes was significantly stronger in CD8(+) DCs. IRAP deficiency compromised cross-presentation of soluble and particulate Ag by both CD8(+) and CD8(-) cDCs, again with a stronger effect in the former population. Thus, the requirement of IRAP in cross-presentation extends to steady-state cDCs. Moreover, these data suggest that increased recruitment of an IRAP(+)/Rab14(+) compartment to Ag-containing vesicles contributes to the superior cross-presentation efficacy of CD8(+) cDCs.