1,243 research outputs found

    Bone matrix components activate the NLRP3 inflammasome and promote osteoclast differentiation

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    AbstractThe NLRP3 inflammasome senses a variety of signals referred to as danger associated molecular patterns (DAMPs), including those triggered by crystalline particulates or degradation products of extracellular matrix. Since some DAMPs confer tissue-specific activation of the inflammasomes, we tested the hypothesis that bone matrix components function as DAMPs for the NLRP3 inflammasome and regulate osteoclast differentiation. Indeed, bone particles cause exuberant osteoclastogenesis in the presence of RANKL, a response that correlates with NLRP3 abundance and the state of inflammasome activation. To determine the relevance of these findings to bone homeostasis, we studied the impact of Nlrp3 deficiency on bone using pre-clinical mouse models of high bone turnover, including estrogen deficiency and sustained exposure to parathyroid hormone or RANKL. Despite comparable baseline indices of bone mass, bone loss caused by hormonal or RANKL perturbations is significantly reduced in Nlrp3 deficient than in wild type mice. Consistent with the notion that osteolysis releases DAMPs from bone matrix, pharmacologic inhibition of bone resorption by zoledronate attenuates inflammasome activation in mice. Thus, signals originating from bone matrix activate the NLRP3 inflammasome in the osteoclast lineage, and may represent a bone-restricted positive feedback mechanism that amplifies bone resorption in pathologic conditions of accelerated bone turnover.</jats:p

    Appendiceal goblet cell carcinoma has marginal advantages from perioperative chemotherapy: a population-based study with an entropy balancing analysis

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    PurposeThe aim is to clarify the use of perioperative chemotherapy in resectable goblet cell carcinoma (GCC).MethodsA retrospective study was carried out based on the Surveillance, Epidemiology, and End Results study. The population was divided: into patients who received only radical surgery (group A) and those who received radical surgery plus chemotherapy (group B). An entropy balancing was carried out to correct the imbalance between the two groups. Two models were generated. Model 1 contained only high-risk patients: group B and a "virtual" group A with similar characteristics. Model 2 included only low-risk patients: group A and "virtual" group B with identical attributes. The efficacy of entropy balancing was evaluated with the d value. The overall survival was compared and reported with Hazard Ratio (HR) within a confidence interval of 95% (95 CI).ResultsThe groups A and B were imbalanced for tumor size (d = 0.392), T (d = 1.128), N (d = 1.340), M (d = 1.456), mean number of positive lymph nodes (d = 0.907), and LNR (d = 0.889). Before the balancing, the risk of death was higher in group B than in A (4.3; 2.5 to 7.4). After reweighting, all large differences were eliminated (d &lt; 0.200). In high-risk patients, the risk of death was higher in patients who underwent surgery alone than those who received perioperative chemotherapy (HR 0.5; 0.2 to 1.3) without statistical significance (p = 0.187). In low-risk patients, the risk of death was similar (HR 1.1; 0.3 to 3.3).ConclusionPerioperative chemotherapy could provide some marginal advantages to high-risk patients

    Identification of Phosphorylation Sites Altering Pollen Soluble Inorganic Pyrophosphatase Activity

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    Protein phosphorylation regulates numerous cellular processes. Identifying the substrates and protein kinases involved is vital to understand how these important posttranslational modifications modulate biological function in eukaryotic cells. Pyrophosphatases catalyze the hydrolysis of inorganic phosphate (PPi) to inorganic phosphate Pi, driving biosynthetic reactions; they are essential for low cytosolic inorganic phosphate. It was suggested recently that posttranslational regulation of Family I soluble inorganic pyrophosphatases (sPPases) may affect their activity. We previously demonstrated that two pollen-expressed sPPases, Pr-p26.1a and Pr-p26.1b, from the flowering plant Papaver rhoeas were inhibited by phosphorylation. Despite the potential significance, there is a paucity of data on sPPase phosphorylation and regulation. Here, we used liquid chromatographic tandem mass spectrometry to map phosphorylation sites to the otherwise divergent amino-terminal extensions on these pollen sPPases. Despite the absence of reports in the literature on mapping phosphorylation sites on sPPases, a database survey of various proteomes identified a number of examples, suggesting that phosphorylation may be a more widely used mechanism to regulate these enzymes. Phosphomimetic mutants of Pr-p26.1a/b significantly and differentially reduced PPase activities by up to 2.5-fold at pH 6.8 and 52% in the presence of Ca2+ and hydrogen peroxide over unmodified proteins. This indicates that phosphoregulation of key sites can inhibit the catalytic responsiveness of these proteins in concert with key intracellular events. As sPPases are essential for many metabolic pathways in eukaryotic cells, our findings identify the phosphorylation of sPPases as a potential master regulatory mechanism that could be used to attenuate metabolism

    Is the complement protein C1q a pro- or anti-tumorigenic factor? Bioinformatics analysis involving human carcinomas

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    C1q is the first subcomponent of the classical pathway of the complement system and belongs to the C1q/Tumor Necrosis Factor superfamily. C1q can perform a diverse range of immune and non-immune functions in a complement-dependent as well as -independent manner. Being a pattern recognition molecule of the innate immunity, C1q can recognize a number of self, non-self and altered-self ligands and bring about effector mechanisms designed to clear pathogens via opsonisation and inflammatory response. C1q is locally synthesized by macrophages and dendritic cells, and thus, can get involved in a range of biological processes, such as angiogenesis and tissue remodeling, immune modulation, and immunologic tolerance. The notion of C1q involvement in the pathogenesis of cancer is still evolving. C1q appears to have a dual role in cancer: tumor promoting as well as tumor-protective, depending on the context of the disease. In the current study, we performed a bioinformatics analysis to investigate whether C1q can serve as a potential prognostic marker for human carcinoma. We used the Oncomine database and the survival analysis platforms Kaplan-Meier plotter. Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer for disease-free survival, and in HER2-positive breast cancer for overall survival, while it showed a pro-tumorigenic role of C1q in lung adenocarcinoma, and in clear cell renal cell carcinoma. This in silico study, if validated via a retrospective study, can be a step forward in establishing C1q as a new tool as a prognostic biomarker for various carcinoma.Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Ital

    Assessment of spatio-temporal variability of faecal pollution along coastal waters during and after rainfall events

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    © The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Manini, E., Baldrighi, E., Ricci, F., Grilli, F., Giovannelli, D., Intoccia, M., Casabianca, S., Capellacci, S., Marinchel, N., Penna, P., Moro, F., Campanelli, A., Cordone, A., Correggia, M., Bastoni, D., Bolognini, L., Marini, M., & Penna, A. Assessment of spatio-temporal variability of faecal pollution along coastal waters during and after rainfall events. Water, 14(3), (2022): 502, https://doi.org/10.3390/w14030502.More than 80% of wastewaters are discharged into rivers or seas, with a negative impact on water quality along the coast due to the presence of potential pathogens of faecal origin. Escherichia coli and enterococci are important indicators to assess, monitor, and predict microbial water quality in natural ecosystems. During rainfall events, the amount of wastewater delivered to rivers and coastal systems is increased dramatically. This study implements measures capable of monitoring the pathways of wastewater discharge to rivers and the transport of faecal bacteria to the coastal area during and following extreme rainfall events. Spatio-temporal variability of faecal microorganisms and their relationship with environmental variables and sewage outflow in an area located in the western Adriatic coast (Fano, Italy) was monitored. The daily monitoring during the rainy events was carried out for two summer seasons, for a total of five sampling periods. These results highlight that faecal microbial contaminations were related to rainy events with a high flow of wastewater, with recovery times for the microbiological indicators varying between 24 and 72 h and influenced by a dynamic dispersion. The positive correlation between ammonium and faecal bacteria at the Arzilla River and the consequences in seawater can provide a theoretical basis for controlling ammonium levels in rivers as a proxy to monitor the potential risk of bathing waters pathogen pollution.This research was funded by WATERCARE project (Water management solutions for reducing microbial environment impact in coastal areas, project ID 10044130, https://www.italy-croatia.eu/web/watercare, accessed on 17 October 2021) funded by the European Union under the Interreg Italy–Croatia CBC Programme

    Evolving knowledge in surgical oncology of pancreatic cancer: from theory to clinical practice-a fifteen-year journey at a tertiary referral centre

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    Pancreatic ductal adenocarcinoma (PDAC) is an increasing disease having a poor prognosis. The aim of the present study was to evaluate the effect of different models of care for pancreatic cancer in a tertiary referral centre in the period 2006-2020. Retrospective study of patients with PDAC observed from January 2006 to December 2020. The demographic and clinical data, and data regarding the imaging techniques used, preoperative staging, management, survival and multidisciplinary tumour board (MDTB) evaluation were collected and compared in three different periods characterised by different organisation of pancreatic cancer services: period A (2006-2010); period B (2011-2015) and period C (2016-2020). One thousand four hundred seven patients were analysed: 441(31.3%) in period A; 413 (29.4%) in B and 553 (39.3%) in C. The proportion of patients increased significantly, from 31.3% to 39.3% (P = 0.032). Body mass index (P = 0.033), comorbidity rate (P = 0.002) and Karnofsky performance status (P &lt; 0.001) showed significant differences. Computed tomography scans (P &lt; 0.001), endoscopic ultrasound (P &lt; 0.001), fine needle aspiration, fine needle biopsy (P &lt; 0.001), and fluorodeoxyglucose-positron emission tomography/computed tomography (P &lt; 0.001) increased; contrast-enhanced ultrasound (P = 0.028) decreased. The cTNM was significantly different (P &lt; 0.001). The MDTB evaluation increased significantly (P &lt; 0.001). Up-front surgery and exploratory laparotomy decreased (P &lt; 0.001), neoadjuvant treatment increased (P &lt; 0.001). The present study showed the evolving knowledge in surgical oncology of pancreatic cancer at a tertiary referral centre over the time. The different models of care of pancreatic cancer, in particular the introduction of the MDTB and the institution of a pancreas unit to the decision-making process seemed to be influential

    Outbreak of Mycobacterium chelonae Infection Associated with Tattoo Ink

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    Background In January 2012, on the basis of an initial report from a dermatologist, we began to investigate an outbreak of tattoo-associated Mycobacterium chelonae skin and softtissue infections in Rochester, New York. The main goals were to identify the extent, cause, and form of transmission of the outbreak and to prevent further cases of infection. Methods We analyzed data from structured interviews with the patients, histopathological testing of skin-biopsy specimens, acid-fast bacilli smears, and microbial cultures and antimicrobial susceptibility testing. We also performed DNA sequencing, pulsed-field gel electrophoresis (PFGE), cultures of the ink and ingredients used in the preparation and packaging of the ink, assessment of source water and faucets at tattoo parlors, and investigation of the ink manufacturer. Results Between October and December 2011, a persistent, raised, erythematous rash in the tattoo area developed in 19 persons (13 men and 6 women) within 3 weeks after they received a tattoo from a single artist who used premixed gray ink; the highest occurrence of tattooing and rash onset was in November (accounting for 15 and 12 patients, respectively). The average age of the patients was 35 years (range, 18 to 48). Skin-biopsy specimens, obtained from 17 patients, showed abnormalities in all 17, with M. chelonae isolated from 14 and confirmed by means of DNA sequencing. PFGE analysis showed indistinguishable patterns in 11 clinical isolates and one of three unopened bottles of premixed ink. Eighteen of the 19 patients were treated with appropriate antibiotics, and their condition improved. Conclusions The premixed ink was the common source of infection in this outbreak. These findings led to a recall by the manufacturer

    Detrimental Effects of Environmental Tobacco Smoke in Relation to Asthma Severity

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    Background: Environmental tobacco smoke (ETS) has adverse effects on the health of asthmatics, however the harmful consequences of ETS in relation to asthma severity are unknown. Methods: In a multicenter study of severe asthma, we assessed the impact of ETS exposure on morbidity, health care utilization and lung functions; and activity of systemic superoxide dismutase (SOD), a potential oxidative target of ETS that is negatively associated with asthma severity. Findings: From 2002-2006, 654 asthmatics (non-severe 366, severe 288) were enrolled, among whom 109 non-severe and 67 severe asthmatics were routinely exposed to ETS as ascertained by history and validated by urine cotinine levels. ETS-exposure was associated with lower quality of life scores; greater rescue inhaler use; lower lung function; greater bronchodilator responsiveness; and greater risk for emergency room visits, hospitalization and intensive care unit admission. ETS-exposure was associated with lower levels of serum SOD activity, particularly in asthmatic women of African heritage. Interpretation: ETS-exposure of asthmatic individuals is associated with worse lung function, higher acuity of exacerbations, more health care utilization, and greater bronchial hyperreactivity. The association of diminished systemic SOD activity to ETS exposure provides for the first time a specific oxidant mechanism by which ETS may adversely affect patients with asthma. © 2011 Comhair et al

    Review: Time use as an explanation for the agri-nutrition disconnect? Evidence from rural areas in low and middle income countries

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    Time is a vital input into nutritional outcomes, as it is necessary for the production, procurement and preparation of food, child feeding and childcare. Thus, agricultural interventions may fail to improve nutritional outcomes if they do not take account of time constraints, particularly of rural women who spend a considerable portion of their time in agriculture. Given the potential trade-offs pertaining to time in productive vs. reproductive activities and its implications for maternal and child nutrition, the goal of this review is to systematically map and assess the available evidence, both qualitative and quantitative studies, agriculture-time use-nutrition pathway. Through an analysis of 89 studies, identified through a systematic search, on rural areas of low and middle-income countries, we observe three findings. First, women play a key role in agriculture, as reflected in their time commitments. Second, evidence from a very limited set of studies suggests that agricultural interventions tend to increase time commitments in agriculture of the household members for whom impact is measured. Third, while changing time use tends to change nutritional outcomes, it does so in a range of complex ways and there is no agreement on the impact. Nutritional impacts are varied because households and household members respond to increased time burden and workload in different ways
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