Syk activation in circulating and tissue innate immune cells in antineutrophil cytoplasmic antibody-associated vasculitis

OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option

Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer

BACKGROUND. Monocarboxylate transporters (MCTs) are transmembrane proteins involved in the transport of monocarboxylates across the plasma membrane, which appear to play an important role in solid tumours, however the role of MCTs in prostate cancer is largely unknown.The aim of the present work was to evaluate the clinico-pathological value of monocarboxylate transporters (MCTs) expression, namely MCT1, MCT2 and MCT4, together with CD147 and gp70 as MCT1/4 and MCT2 chaperones, respectively, in prostate carcinoma. METHODS. Prostate tissues were obtained from 171 patients, who performed radical prostatectomy and 14 patients who performed cystoprostatectomy. Samples and clinico-pathological data were retrieved and organized into tissue microarray (TMAs) blocks. Protein expression was evaluated by immunohistochemistry in neoplastic (n= 171), adjacent non-neoplastic tissues (n= 135), PIN lesions (n=40) and normal prostatic tissue (n=14). Protein expression was correlated with patients' clinicopathologic characteristics. RESULTS. In the present study, a significant increase of MCT2 and MCT4 expression in the cytoplasm of tumour cells and a significant decrease in both MCT1 and CD147 expression in prostate tumour cells was observed when compared to normal tissue. All MCT isoforms and CD147 were expressed in PIN lesions. Importantly, for MCT2 and MCT4 the expression levels in PIN lesions were between normal and tumour tissue, which might indicate a role for these MCTs in the malignant transformation. Associations were found between MCT1, MCT4 and CD147 expressions and poor prognosis markers; importantly MCT4 and CD147 overexpression correlated with higher PSA levels, Gleason score and pT stage, as well as with perineural invasion and biochemical recurrence. CONCLUSIONS. Our data provides novel evidence for the involvement of MCTs in prostate cancer. According to our results, we consider that MCT2 should be further explored as tumour marker and both MCT4 and CD147 as markers of poor prognosis in prostate cancer.NPG, CP and VMG received fellowships from the Portuguese Foundation for Science and Technology (FCT), refs. SFRH/BD/61027/2009, SFRH/BPD/69479/ 2010 and SFRH/BI/33503/2008, respectively. This work was supported by the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of Programa Operacional Temático Factores de Competitividade” (COMPETE) of Quadro Comunitário de Apoio III and co-financed by Fundo Comunitário Europeu FEDER

The cdh1 c.1901c>t variant: A founder variant in the portuguese population with severe impact in mrna splicing

Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.This research and its authors were funded by FEDER—Fundo Europeu de Desenvolvi-mento Regional funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274) and LEGOH (PTDC/BTM-TEC/6706/2020). This work was also financed by the projects NORTE-01-0145-FEDER-000003 (DOCnet)—supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)—project POCI-01-0145-FEDER-016390 (CancelStem) and PTDC/BTM-TEC/30164/2017 (3DChroMe), funded by ERDF, POCI, and FCT

Macro-Climatic Distribution Limits Show Both Niche Expansion and Niche Specialization among C4 Panicoids

Grasses are ancestrally tropical understory species whose current dominance in warm open habitats is linked to the evolution of C4 photosynthesis. C4 grasses maintain high rates of photosynthesis in warm and water stressed environments, and the syndrome is considered to induce niche shifts into these habitats while adaptation to cold ones may be compromised. Global biogeographic analyses of C4 grasses have, however, concentrated on diversity patterns, while paying little attention to distributional limits. Using phylogenetic contrast analyses, we compared macro-climatic distribution limits among ~1300 grasses from the subfamily Panicoideae, which includes 4/5 of the known photosynthetic transitions in grasses. We explored whether evolution of C4 photosynthesis correlates with niche expansions, niche changes, or stasis at subfamily level and within the two tribes Paniceae and Paspaleae. We compared the climatic extremes of growing season temperatures, aridity, and mean temperatures of the coldest months. We found support for all the known biogeographic distribution patterns of C4 species, these patterns were, however, formed both by niche expansion and niche changes. The only ubiquitous response to a change in the photosynthetic pathway within Panicoideae was a niche expansion of the C4 species into regions with higher growing season temperatures, but without a withdrawal from the inherited climate niche. Other patterns varied among the tribes, as macro-climatic niche evolution in the American tribe Paspaleae differed from the pattern supported in the globally distributed tribe Paniceae and at family level.Fil: Aagesen, Lone. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Biganzoli, Fernando. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Métodos Cuantitativos y Sistemas de Información; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bena, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Godoy Bürki, Ana Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Reinheimer, Renata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Zuloaga, Fernando Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; Argentin

If You Could Only Choose Five Psychotropic Medicines: Updating the Interagency Emergency Health Kit

Mark van Ommeren and colleagues describe how they chose five psychotropic medicines to add to the Interagency Emergency Health Kit, which is a box with medicines and medical supplies designed to help people in major humanitarian emergencies

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-

A cross-sectional study of different patterns of oral contraceptive use among premenopausal women and circulating IGF-1: implications for disease risk

<p>Abstract</p> <p>Background</p> <p>Insulin-like growth factor-1 (IGF-1) is important in normal growth, development, and homeostasis. Current use of oral contraceptives (OC) decreases IGF-1 concentrations; however, the effect of past use, age/timing of use, and type of OC used on IGF-1 levels is unknown. OC are the most commonly used form of birth control worldwide. Both IGF-1 and OC use have been linked to premenopausal breast and colorectal cancers, osteoporosis and cardiovascular disease (CVD). Understanding the effects of different patterns of OC use on IGF-1 levels may offer insight into its influence on disease risk in young women.</p> <p>Methods</p> <p>In a cross-sectional study of 328 premenopausal women ages 18 to 21 and 31 to 40 we examined the relationship between different patterns of OC use and circulating IGF-1 using adjusted linear regression analysis. Information on OC use was obtained through an interviewer administered questionnaire. Plasma IGF-1 was assessed with enzyme linked immunosorbent assay (ELISA).</p> <p>Results</p> <p>Among women aged 18 to 21, ever OC use was significantly associated with decreased IGF-1 levels compared to never use (β = -57.2 ng/ml, 95% confidence interval (CI): -88.7, -25.8). Among women aged 31 to 40, past users who first used OC at 25 years of age or older (β = 43.8 ng/ml, 95% CI: 8.8, 78.8), in the last 15 years (β = 35.1 ng/ml, 95% CI: 9.3, 61.0) or after 1995 (β = 46.6 ng/ml, 95% CI: 13.4, 79.8) had significantly higher IGF-1 levels compared to never users.</p> <p>Conclusion</p> <p>This is the first study to highlight the long term effects of OC use after cessation on IGF-1 levels among premenopausal women, which previously were thought to be transitory. Future studies of past use and IGF-1 levels are required and must consider age/timing of use and type/generation of OC used. Additional studies are needed to confirm the potential mediation of IGF-1 levels in the links between OC use and health outcomes.</p

Sleep duration and the risk of breast cancer: the Ohsaki Cohort Study

In a prospective study of 23 995 Japanese women, short sleep duration was associated with higher risk of breast cancer (143 cases), compared with women who slept 7 h per day, the multivariate hazard ratio of those who slept ⩽6 h per day was 1.62 (95% confidence interval: 1.05–2.50; P for trend=0.03)