Genetic variation in the estrogen metabolic pathway and mammographic density as an intermediate phenotype of breast cancer

Introduction: Several studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. In this study, we evaluate the association between mammographic density and genetic variants of the estrogen metabolic pathway. Methods: A total of 239 SNPs in 34 estrogen metabolic genes were studied in 1,731 Swedish women who participated in a breast cancer case-control study, of which 891 were cases and 840 were controls. Film mammograms of the medio-lateral oblique view were digitalized and the software Cumulus was used for computer-assisted semi-automated thresholding of mammographic density. Generalized linear models controlling for possible confounders were used to evaluate the effects of SNPs on mammographic density. Results found to be nominally significant were examined in two independent populations. The admixture maximum likelihood-based global test was performed to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three subpathways for androgen synthesis, androgen-to-estrogen conversion and estrogen removal. Results: Genetic variants of genes involved in estrogen metabolism exhibited no appreciable effect on mammographic density. None of the nominally significant findings were validated. In addition, global analyses on the overall estrogen metabolic pathway and its subpathways did not yield statistically significant results. Conclusions: Overall, there is no conclusive evidence that genetic variants in genes involved in the estrogen metabolic pathway are associated with mammographic density in postmenopausal women

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

The two sides of cytokine signaling and glaucomatous optic neuropathy

The mechanistic study of glaucoma pathogenesis has shifted to seeking to understand the effects of immune responses on retinal ganglion cell damage and protection. Cytokines are the hormonal factors that mediate most of the biological effects in both the immune and nonimmune systems. CD4-expressing T helper cells are a major source of cytokine production and regulation. Type 1 helper T (Th1) cells are characterized by the production of proinflammatory cytokines such as interferon-gamma, interleukin (IL)-2, IL-12, IL-23, and tumor necrosis factor-alpha while type 2 helper T (Th2) cells are characterized by the production of IL-4, IL-5, IL-6, and IL-10. The balance of Th1/Th2 cytokine production influences many pathological processes and plays both causative and protective roles in neuron damages. Growing evidence indicates that imbalances of Th1/Th2 cytokine production are involved in neural damage or protection in many neurological diseases. In this review, we discuss the possible roles of Th1/Th2 cytokine production and imbalance of Th1/Th2 cytokines in retina, especially glaucomatous optic neuropathy

A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone

<p>Abstract</p> <p>Background</p> <p>Breast cancer is a collection of diseases in which molecular phenotypes can act as both indicators and mediators of therapeutic strategy. Therefore, candidate therapeutics must be assessed in the context of multiple cell lines with known molecular phenotypes. Docosahexaenoic acid (DHA) and curcumin (CCM) are dietary compounds known to antagonize breast cancer cell proliferation. We report that these compounds in combination exert a variable antiproliferative effect across multiple breast cell lines, which is synergistic in SK-BR-3 cells and triggers cell signaling events not predicted by the activity of either compound alone.</p> <p>Methods</p> <p>Dose response curves for CCM and DHA were generated for five breast cell lines. Effects of the DHA+ CCM combination on cell proliferation were evaluated using varying concentrations, at a fixed ratio, of CCM and DHA based on their individual ED₅₀. Detection of synergy was performed using nonlinear regression of a sigmoid dose response model and Combination Index approaches. Cell molecular network responses were investigated through whole genome microarray analysis of transcript level changes. Gene expression results were validated by RT-PCR, and western blot analysis was performed for potential signaling mediators. Cellular curcumin uptake, with and without DHA, was analyzed via flow cytometry and HPLC.</p> <p>Results</p> <p>CCM+DHA had an antiproliferative effect in SK-BR-3, MDA-MB-231, MDA-MB-361, MCF7 and MCF10AT cells. The effect was synergistic for SK-BR-3 (ER^-PR^-Her2⁺) relative to the two compounds individually. A whole genome microarray approach was used to investigate changes in gene expression for the synergistic effects of CCM+DHA in SK-BR-3 cells lines. CCM+DHA triggered transcript-level responses, in disease-relevant functional categories, that were largely non-overlapping with changes caused by CCM or DHA individually. Genes involved in cell cycle arrest, apoptosis, inhibition of metastasis, and cell adhesion were upregulated, whereas genes involved in cancer development and progression, metastasis, and cell cycle progression were downregulated. Cellular pools of PPARγ and phospho-p53 were increased by CCM+DHA relative to either compound alone. DHA enhanced cellular uptake of CCM in SK-BR-3 cells without significantly enhancing CCM uptake in other cell lines.</p> <p>Conclusions</p> <p>The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon molecular phenotype. DHA enhancement of cellular curcumin uptake is one potential mechanism for observed synergy in SK-BR-3 cells; however, transcriptomic data show that the antiproliferation synergy accompanies many signaling events unique to the combined presence of the two compounds.</p

Abundances of Iron-Binding Photosynthetic and Nitrogen-Fixing Proteins of Trichodesmium Both in Culture and In Situ from the North Atlantic

Marine cyanobacteria of the genus Trichodesmium occur throughout the oligotrophic tropical and subtropical oceans, where they can dominate the diazotrophic community in regions with high inputs of the trace metal iron (Fe). Iron is necessary for the functionality of enzymes involved in the processes of both photosynthesis and nitrogen fixation. We combined laboratory and field-based quantifications of the absolute concentrations of key enzymes involved in both photosynthesis and nitrogen fixation to determine how Trichodesmium allocates resources to these processes. We determined that protein level responses of Trichodesmium to iron-starvation involve down-regulation of the nitrogen fixation apparatus. In contrast, the photosynthetic apparatus is largely maintained, although re-arrangements do occur, including accumulation of the iron-stress-induced chlorophyll-binding protein IsiA. Data from natural populations of Trichodesmium spp. collected in the North Atlantic demonstrated a protein profile similar to iron-starved Trichodesmium in culture, suggestive of acclimation towards a minimal iron requirement even within an oceanic region receiving a high iron-flux. Estimates of cellular metabolic iron requirements are consistent with the availability of this trace metal playing a major role in restricting the biomass and activity of Trichodesmium throughout much of the subtropical ocean

The Forward Physics Facility at the High-Luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

The dominant Anopheles vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>This is the second in a series of three articles documenting the geographical distribution of 41 dominant vector species (DVS) of human malaria. The first paper addressed the DVS of the Americas and the third will consider those of the Asian Pacific Region. Here, the DVS of Africa, Europe and the Middle East are discussed. The continent of Africa experiences the bulk of the global malaria burden due in part to the presence of the <it>An. gambiae </it>complex. <it>Anopheles gambiae </it>is one of four DVS within the <it>An. gambiae </it>complex, the others being <it>An. arabiensis </it>and the coastal <it>An. merus </it>and <it>An. melas</it>. There are a further three, highly anthropophilic DVS in Africa, <it>An. funestus</it>, <it>An. moucheti </it>and <it>An. nili</it>. Conversely, across Europe and the Middle East, malaria transmission is low and frequently absent, despite the presence of six DVS. To help control malaria in Africa and the Middle East, or to identify the risk of its re-emergence in Europe, the contemporary distribution and bionomics of the relevant DVS are needed.</p> <p>Results</p> <p>A contemporary database of occurrence data, compiled from the formal literature and other relevant resources, resulted in the collation of information for seven DVS from 44 countries in Africa containing 4234 geo-referenced, independent sites. In Europe and the Middle East, six DVS were identified from 2784 geo-referenced sites across 49 countries. These occurrence data were combined with expert opinion ranges and a suite of environmental and climatic variables of relevance to anopheline ecology to produce predictive distribution maps using the Boosted Regression Tree (BRT) method.</p> <p>Conclusions</p> <p>The predicted geographic extent for the following DVS (or species/suspected species complex*) is provided for Africa: <it>Anopheles </it>(<it>Cellia</it>) <it>arabiensis</it>, <it>An. </it>(<it>Cel.</it>) <it>funestus*</it>, <it>An. </it>(<it>Cel.</it>) <it>gambiae</it>, <it>An. </it>(<it>Cel.</it>) <it>melas</it>, <it>An. </it>(<it>Cel.</it>) <it>merus</it>, <it>An. </it>(<it>Cel.</it>) <it>moucheti </it>and <it>An. </it>(<it>Cel.</it>) <it>nili*</it>, and in the European and Middle Eastern Region: <it>An. </it>(<it>Anopheles</it>) <it>atroparvus</it>, <it>An. </it>(<it>Ano.</it>) <it>labranchiae</it>, <it>An. </it>(<it>Ano.</it>) <it>messeae</it>, <it>An. </it>(<it>Ano.</it>) <it>sacharovi</it>, <it>An. </it>(<it>Cel.</it>) <it>sergentii </it>and <it>An. </it>(<it>Cel.</it>) <it>superpictus*</it>. These maps are presented alongside a bionomics summary for each species relevant to its control.</p

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P &lt; 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P &lt; 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk