Human malignant mesothelioma: molecular mechanisms of pathogenesis and progression

The continuing identification and elucidation of the molecular defects involved in mesothelioma pathogenesis and progression should lead to better disease control and greater therapeutic options in the near future. Goal of this review article is to summarize the most recent advances in molecular pathogenesis of mesothelioma and discuss possible therapeutic implications of these findings.     

Preservation of in vitro cultures of the mite pathogenic fungus Neozygites tanajoae

Neozygites tanajoae has recently been described as a new fungal pathogen distinct from Neozygites floridana. This pathogen is currently being used as a classical biological control agent against the cassava green mite, Mononychellus tanajoa (Bondar), in Africa. Neozygites tanajoae is a particularly fastidious species, and in vitro cultures of isolates from Brazil and Africa have only recently been established. In this study, the efficacy of several cryoprotectants at different exposure times, cooling rates, and warming rates for protecting hyphal bodies of N. tanajoae during cryopreservation was investigated. A protocol for preservation of cultures of N. tanajoae at ultra-low temperatures of -80 degrees C or -196 degrees C, using 1% trehalose + 2% dimethyl sulfoxide as cryoprotective agents, is described in detail. In this study, we demonstrate that N. tanajoae differs remarkably from N. floridana (isolates ARSEF 662 and ARSEF 5376) in the ability to withstand the stress of cold temperature (4 degrees C) and cryopreservation. In vitro cultures of the 2 N. floridana isolates remained viable at 4 degrees C for up to 47 d; however, cultures of N. tanajoae did not survive this temperature for 4 d. Cryopreservation methods successful for N. tanajoae isolates are not suitable for N. floridana and are unusual in comparison to those for many fungi.     

Gangliosides activate Trk receptors by inducing the release of neurotrophins

We used NIH-3T3 fibroblasts expressing the different Trk receptors to examine whether GM1 ganglioside and its semisynthetic derivative LIGA20 activate various neurotrophin receptors. GM1 induced autophosphorylation of TrkC more potently than TrkA or TrkB receptors. In contrast, LIGA20 activated TrkB tyrosine phosphorylation only. Therefore, Scatchard analysis was performed to determine whether GM1 binds to TrkC. GM1 failed to displace neurotrophin-3 binding, suggesting that this ganglioside does not act as a ligand for Trk receptors. In addition, GM1 failed to induce autophosphorylation of a chimeric receptor consisting of the extracellular domain of the tumor necrosis factor receptor and the intracellular domain of TrkA, suggesting that GM1 does not affect the tyrosine kinase domain. We next determined whether GM1 induces the release of neurotrophins from fibroblast cells. GM1 induced a rapid and significant increase in the amount of neurotrophin-3, but not other neurotrophins. This effect was independent of the presence of Trk because K252a did not prevent GM1-mediated release of neurotrophin-3. Moreover, GM1-mediated TrkC autophosphorylation was blocked by TrkC-IgG (but not TrkB-IgG) receptor bodies, further suggesting that GM1 activates TrkC by inducing the release of neurotrophin-3. This hypothesis was also tested in cultured cerebellar granule cells. GM1 induced neurotrophin-3 (but not brain-derived neurotrophic factor or nerve growth factor) release. In contrast, LIGA20 increased the secretion of brain-derived neurotrophic factor. Our data show that gangliosides may activate different Trk receptors by differentially affecting the release of neurotrophins.     

The importance of environmental heterogeneity and spatial distance in generating phylogeographic structure in edaphic specialist and generalist tree species of Protium (Burseraceae) across the Amazon Basin

Aim Edaphic heterogeneity may be an important driver of population differentiation in the Amazon but remains to be investigated in trees. We compared the phylogeographic structure across the geographic distribution of two Protium (Burseraceae) species with different degrees of edaphic specialization: Protium alvarezianum, an edaphic specialist of white‐sand habitat islands; and Protium subserratum, an edaphic generalist found in white sand as well as in more widespread soil types. We predicted that in the edaphic specialist, geographic distance would structure populations more strongly than in the edaphic generalist, and that soil type would not structure populations in the edaphic generalist unless habitat acts as a barrier promoting population differentiation. Location Tropical rain forests of the Peruvian and Brazilian Amazon, Guyana and French Guiana. Methods We sequenced 1209–1211 bp of non‐coding nuclear ribosomal DNA (internal transcribed spacer and external transcribed spacer) and a neutral low‐copy nuclear gene (phytochrome C) from P. subserratum (n = 65, 10 populations) and P. alvarezianum (n = 19, three populations). We conducted a Bayesian phylogenetic analysis, constructed maximum parsimony haplotype networks and assessed population differentiation among groups (soil type or geographic locality) using analysis of molecular variance and spatial analysis of molecular variance. Results The edaphic specialist exhibited considerable genetic differentiation among geographically distant populations. The edaphic generalist showed significant genetic differentiation between the Guianan and Amazon Basin populations. Within Peru, soil type and not geographic distance explained most of the variation among populations. Non‐white‐sand populations in Peru exhibited lower haplotype/nucleotide diversity than white‐sand populations, were each other’s close relatives, and formed an unresolved clade derived from within the white‐sand populations. Main conclusions Geographic distance is a stronger driver of population differentiation in the edaphic specialist than in the generalist. However, this difference did not appear to be related to edaphic generalism per se as adjacent populations from both soil types in the edaphic generalist did not share many haplotypes. Populations of the edaphic generalist in white‐sand habitats exhibited high haplotype diversity and shared haplotypes with distant white‐sand habitat islands, indicating that they have either efficient long‐distance dispersal and/or larger ancestral effective population sizes and thus retain ancestral polymorphisms. These results highlight the importance of edaphic heterogeneity in promoting population differentiation in tropical trees.     

Cinnamoyl nitrogen mustard derivatives of pyrazole analogues of tallimustine modified at the amidino moiety: design, synthesis, molecular modeling and antitumor activity studies

The design, synthesis and in vitro activities of a series of cinnamoyl nitrogen mustard pyrazole analogues of tallimustine 8-13, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed. In spite of the relevance of these modifications on the amidino moiety, these derivatives showed significant growth inhibitory activity against mouse leukemia L1210 cells. A selected series of compounds have been evaluated for their sequence selective alkylating properties and cytotoxicity against human K562 leukemia cells. Therefore, the presence of the amidino moiety, and in general of a basic moiety, is not an absolute requirement for biological activity. Our preliminary results indicated that the compounds of this series have a pattern of alkylation similar to that of tallimustine, but they seem to be less reactive overall in alkylating naked DNA.     

Aspects of potato leafhopper (Homoptera: Cicadellidae) biology on Solanum berthaultii and other potato genotypes

Survival of nymphs and adult males and females of potato leafhopper, Empoasca fabae (Harris), on six potato (Solanum spp.) genotypes with varied levels of resistance was evaluated and related to type, density, and droplet/head size of foliar glandular trichomes. Survival was greater on Solanum tuberosum cultivars ('Allegany' and 'Elba') compared with accessions of the wild S. berthaultii (PI 473331 and PI 473334). The barrier provided by glandular trichomes may affect survival of E.fabae by restricting nymph and adult feeding. PI 473331 was the most pubescent host, bearing type A and type B trichomes and the most unsuitable host for E. fabae. Allegany possesses leaflets with low trichome densities and small gland diameter and was the most suitable host for adult E. fabae survival. Females generally had higher survival rates than males. Nymphal and adult leafhoppers differed greatly in their survival rates, particularly on S. tuberosum x S. berthaultii hybrids (Q174-2 and NY123). Interestingly, nymphs had longer (190 d) mean lethal time (LT50) than adults (31 d) when held on Q174-2, and a lower LT50 (19 d) when held on NY123 compared with adults (104 d). Starvation, dehydration, or both were likely associated with mortality of nymphs confined on PI 473331 and PI 473334. Nymphs on these accessions died at a comparable rate to those confined on a starvation treatment and more rapidly than those supplied with water only, sucrose solution or other potato genotypes. Darkened trichome exudates were observed on insects held on PI 473331 and PI 473334, consistent with previous reports that glandular trichomes of S. berthaultii contain phenolic oxidation chemistry. This study aids in the identification of the probable mechanisms of resistance to E. fabae used by S. berthaulti and its hybrids with S. tuberosum.     

Effect of pre-stroke use of ACE inhibitors on ischemic stroke severity

Background  

Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEI) are effective in prevention of ischemic stroke, as measured by reduced stroke incidence. We aimed to compare stroke severity between stroke patients who were taking ACEI before their stroke onset and those who were not, to examine the effects of pretreatment with ACEI on ischemic stroke severity.     

Cost-effectiveness and economic returns of group-based parenting interventions to promote early childhood development: Results from a randomized controlled trial in rural Kenya

BackgroundEarly childhood development (ECD) programs can help address disadvantages for the 43% of children under 5 in low- and middle-income countries (LMICs) experiencing compromised development. However, very few studies from LMIC settings include information on their program’s cost-effectiveness or potential returns to investment. We estimated the cost-effectiveness, benefit–cost ratios (BCRs), and returns on investment (ROIs) for 2 effective group-based delivery models of an ECD parenting intervention that utilized Kenya’s network of local community health volunteers (CHVs).Methods and findingsBetween October 1 and November 12, 2018, 1,152 mothers with children aged 6 to 24 months were surveyed from 60 villages in rural western Kenya. After baseline, villages were randomly assigned to one of 3 intervention arms: a group-only delivery model with 16 fortnightly sessions, a mixed-delivery model combining 12 group sessions with 4 home visits, and a control group. At endline (August 5 to October 31, 2019), 1,070 children were retained and assessed for primary outcomes including cognitive and receptive language development (with the Bayley Scales of Infant Development, Third Edition) and socioemotional development (with the Wolke scale). Children in the 2 intervention arms showed better developmental outcomes than children in the control arm, although the group-only delivery model generally had larger effects on children. Total program costs included provider’s implementation costs collected during the intervention period using financial reports from the local nongovernmental organization (NGO) implementer, as well as societal costs such as opportunity costs to mothers and delivery agents. We combined program impacts with these total costs to estimate incremental cost-effectiveness ratios (ICERs), as well as BCRs and the program’s ROI for the government based on predictions of future lifetime wages and societal costs. Total costs per child were US$140 in the group-only arm and US$145 in the mixed-delivery arm. Because of higher intention-to-treat (ITT) impacts at marginally lower costs, the group-only model was the most cost-effective across all child outcomes. Focusing on child cognition in this arm, we estimated an ICER of a 0.37 standard deviation (SD) improvement in cognition per US$100 invested, a BCR of 15.5, and an ROI of 127%. A limitation of our study is that our estimated BCR and ROI necessarily make assumptions about the discount rate, income tax rates, and predictions of intervention impacts on future wages and schooling. We examine the sensitivity of our results to these assumptions.ConclusionsTo the best of our knowledge, this study is the first economic evaluation of an effective ECD parenting intervention targeted to young children in sub-Saharan Africa (SSA) and the first to adopt a societal perspective in calculating cost-effectiveness that accounts for opportunity costs to delivery agents and program participants. Our cost-effectiveness and benefit–cost estimates are higher than most of the limited number of prior studies from LMIC settings providing information about costs. Our results represent a strong case for scaling similar interventions in impoverished rural settings, and, under reasonable assumptions about the future, demonstrate that the private and social returns of such investments are likely to largely outweigh their costs.Trial registrationThis trial is registered at ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03548558","term_id":"NCT03548558"}}NCT03548558, June 7, 2018. American Economic Association RCT Registry trial AEARCTR-0002913.

Italo Lopez Garcia and colleagues conduct an economic evaluation of an effective parenting intervention to promote cognitive, receptive language, and socioemotional development among children under 3 years in Kenya.     

Ricerche morfologiche ed istochimiche sui lipidi nel pancreas dei mammiferi

Con 10 figure nel testo.