About 50% of sarcomas have specific pathology-defining molecular alterations including mutations, fusion genes, and gene amplifications. Some of these alterations appear to be oncogenic drivers, and a subset can be utilized as targets for standard or experimental molecularly targeted agents in the clinic. In addition, immunotherapies may have a growing role in the treatment of sarcomas in the future.
Chlordecone is an organochlorine insecticide that was intensively used in the French West Indies to control the black weevil Cosmopolites sordidus in bananas. Its usage, however, resulted in the widespread pollution of the environment with heavy sanitary and social consequences, leading to population exposure mainly through food. Time-consuming and costly programs have been used to tackle this problem, and this study proposes to use the emerging sewage epidemiology approach to evaluate the current situation and the effect of such programs. The results determine the maximal value of chlordecone consumption, and considering the detection limit of the analytical protocol, the wastewater was found to have undetectable amounts of chlordecone. This value confirms the efficiency of the population protection strategy provided by French sanitary and environmental authorities. It also bolsters the usage of sewage epidemiology in pesticide assessment and relativizes the chlordecone risk compared to other chemicals of lesser concern.
The relationships between impervious surface area (ISA) patterns and characteristics have long been studied to examine the impacts of hydrological cycles, water management, surface energy balances, and biodiversity. This study assessed the Dianchi Lake watershed as a case study area to illustrate ISA change characteristics and their impacts on Dianchi Lake water quality. More than 200 Landsat images (from 1988 to 2017) were first downloaded through the US Geological Survey (USGS) online portal. Then, a series of ISA maps of the Dianchi Lake watershed at an annual resolution were built using a robust method we proposed. Then, the change characteristics of main water quality parameters were analyzed from spatial-temporal viewpoints. Finally, correlations between ISA and Lake water quality were made. The research results indicated that the ISA proportion of the Dianchi Lake watershed rapidly increased (from 1.84% in 1988 to 34.32% in 2017), the annual ISA total growth rate exceeded 21 km2/year, and the urban area encircled Dianchi Lake. The Dianchi Lake watershed has begun to adopt the "Rashly Advancing" and "Great Leap Forward" strategies of urbanization. Chlorophyll a (Chla), dissolved oxygen (DO), and transparency (Trans) showed significantly changing tendencies, whereas the values of pH, total nitrogen, and total phosphorus stayed relatively constant. The polynomial regression models and corresponding R2 values indicated strong correlations between ISA and three water quality parameters (Chla, DO, and Trans). The development of better strategies for the control and reduction of water pollution without optimizing ISA spatial distribution is essential for Kunming's continued urbanization.
Helicobacter, EarlyView.
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Rejuvenation Research, Ahead of Print.
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Rejuvenation Research, Ahead of Print.
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Rejuvenation Research, Ahead of Print.
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Rejuvenation Research, Ahead of Print.
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AbstractThe treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy often includes the combination of gemcitabine and docetaxel with or without doxorubicin in first‐line systemic therapy, but these cytotoxic agents only provide patients with advanced disease a 5‐year survival <30%. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uLMS. Critical ongoing studies investigating novel approaches including immunotherapeutics and genetic alterations also will be discussed.Implications for Practice.Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these compounds. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uterine leoimyosarcoma.
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AbstractBackground.Older patients (≥60 years) with acute myeloid leukemia (AML) face difficult decisions regarding treatment with "intensive" chemotherapy that carries significant toxicity for a small chance of a cure versus "nonintensive" chemotherapy to control the disease, but with fewer side effects. However, studies of how these patients understand the risks and benefits of such treatments are lacking.Methods.We conducted a longitudinal study of older patients newly diagnosed with AML assessing patients' (n = 100) and oncologists' (n = 11) perceptions of treatment‐related mortality at enrollment and prognosis at 1 month. We examined concordance between patients' and oncologists' perceptions using Cohen's kappa (κ < 0.10 indicates little/no concordance).Results.We enrolled patients within 72 hours of initiating intensive (n = 50) or nonintensive (n = 50) chemotherapy. Whereas 91% of patients reported that they were "somewhat" to "extremely likely" to die from treatment, oncologists estimated that only 12% were at high risk of dying because of treatment (κ = −0.09). Ninety percent of patients reported that they were "somewhat" or "very likely" to be cured of their AML, whereas oncologists estimated this chance of cure for only 31% of patients (κ = 0.05). Among patients receiving intensive chemotherapy, 98% reported that they were "somewhat" or "very likely" to be cured, whereas their oncologists estimated this likelihood of cure for only 49% (κ = 0.04); among those receiving nonintensive chemotherapy and their clinicians, these proportions were 82% and 13%, respectively (κ = 0.03). Patients who indicated a lower likelihood of cure reported significantly higher depression symptoms (p = .03).Conclusion.Older patients with AML overestimate the risks and benefits of treatment. Interventions to facilitate communication and enhance patients' understanding of the goals of therapy and treatment risk are needed.Implications for Practice.Older patients with acute myeloid leukemia (AML) are confronted with challenging decisions regarding treatment with "intensive" chemotherapy that carries significant toxicity for a small chance of a cure versus "nonintensive" chemotherapy to control the disease, but with fewer side effects. A clear understanding of the likely outcome and risks of the various treatment strategies is essential for these patients to make informed decisions about their care. This article reports that older patients with AML overestimate both the risks and benefits of treatment and have substantial misperceptions about their prognosis. Interventions to enhance patients' understanding of their prognosis and treatment risk are needed.
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AbstractBackground.Triple‐negative breast cancer (TNBC) is a heterogeneous disease with subtypes having different "targetable" molecular aberrations. Metaplastic breast cancers (MpBCs) are typically TNBCs and commonly have alterations in the PI3K/Akt/mTOR pathway. We previously reported efficacy for an mTOR‐based chemotherapy regimen in MpBC. To determine if tumor subtype influences prognosis, we compared treatment outcomes of patients with MpBC with those of patients with nonmetaplastic TNBC receiving an mTOR‐based systemic therapy regimen.Patients and Methods.Patients with advanced MpBC and nonmetaplastic TNBC were treated at our institution from April 16, 2009, through November 4, 2014, using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab (DAT/DAE). Median progression‐free survival (PFS) and overall survival (OS) were estimated by the Kaplan‐Meier method. Cox regression analyses were used to evaluate associations between tumor histology and outcomes. Multivariable models were adjusted for all covariates.Results.Fourteen patients with nonmetaplastic TNBC and 59 patients with advanced MpBC were treated with DAT/DAE. MpBC patients were older (p = .002) and less likely to have a history of bevacizumab use (p = .023). Median PFS for the nonmetaplastic TNBC and MpBC patients was 2.5 months and 4.8 months, respectively. This difference in PFS was statistically significant on univariable (p = .006) but not multivariable analysis (p = .087). Median OS for the nonmetaplastic TNBC and MpBC patients was 3.7 months and 10.0 months, respectively (p = .0003). MpBC remained significantly associated with improved OS on multivariable analysis (p < .0001).Conclusion.In our study, DAT/DAE appeared to be more effective in MpBC compared with nonmetaplastic TNBC. These data support patient selection for targeted therapy in TNBC.Implications for Practice.Metaplastic breast cancers (MpBCs) represent <1% of all breast cancers, demonstrate mesenchymal differentiation, and are typically resistant to chemotherapy. Patients with advanced MpBC treated with an mTOR‐based systemic therapy regimen had better long‐term outcomes compared with patients with nonmetaplastic triple‐negative breast cancer treated with the same regimen, suggesting that metaplastic histology may predict benefit from agents targeting the PI3K/Akt/mTOR pathway.
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AbstractLessons Learned. The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1–3 every 7 days and irinotecan 125 mg/m2 days 1 and 8 of a 21‐day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin‐like growth factor‐1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology.Background.This phase I dose‐escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin‐like growth factor‐1 receptor (IGF‐1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy.Methods.Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m2, (b) linsitinib 450 mg and irinotecan 100 mg/m2, and (c) linsitinib 450 mg and irinotecan 125 mg/m2. Linisitinib was administered once daily on days 1–3, 8–10, and 15–17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer.Results.A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose‐limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m2 was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment‐related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% (n = 8) had stable disease with median duration of 5.25 months.Conclusion.Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.
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AbstractAim.This study systematically reviews the recent literature on the role of definitive radiotherapy (RT) in the management of vaginal cancer (VC) and presents comprehensive data on clinical outcomes and toxicity.Methods.The authors performed a literature search using PubMed (2007–2016) to identify all prospective and retrospective studies that have been published on RT in invasive VC.Results.Of the 199 identified studies, 13 met the inclusion criteria. All studies had a retrospective design. Overall, 793 patients (median, 45; range, 26–138) were included. A high heterogeneity was found across studies in terms of RT techniques, assessment criteria, and reported outcomes. The majority of the patients were treated with a combination of external beam RT and brachytherapy (74.2%). Acute and late grade ≥3 toxicity rates ranged from 0.0% to 24.4% (median, 8.7%) and from 0.0% to 22.5% (median, 12.8%), respectively. The 5‐year local control rates ranged between 39% and 79%. The 5‐year overall survival ranged between 34% and 71.0% (median, 63.5%). Early stage of the disease (International Federation of Gynecology and Obstetrics stages I–II vs. III–IV), small tumor size (<4 cm), previous hysterectomy, high pretreatment/treatment hemoglobin levels (≥12/12.5 mg/dL), and patients' age <70 or <64 years were correlated with better clinical outcomes.Conclusion.Only retrospective studies, in a limited number, have been published on RT in VC in the past decade, with significant heterogeneity in terms of treatment characteristic and evaluation criteria. Clinical results were strongly influenced by tumor stage. Prospective randomized studies are needed to improve patients' outcomes, especially in advanced‐stage disease.;23:1–10Implications for Practice.This study systematically reviews the recent literature on the role of definitive radiotherapy in the management of vaginal cancer and presents comprehensive data on clinical outcome and toxicity. The prognosis of patients is dismal, with a 5‐year overall survival of approximately 50%. Early stage of the disease, small tumor size, previous hysterectomy, high pretreatment/treatment hemoglobin levels, and patients' age were correlated with a better clinical outcome. A brachytherapy boost should be delivered, especially in patients with higher‐stage disease. The addition of concurrent weekly cisplatin should be considered in most patients, and transfusion should be used to maintain high hemoglobin levels.
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AbstractBackground.An increasing proportion of human epidermal growth receptor 2 (HER2) positive (HER2+) metastatic breast cancer (MBC) is diagnosed as de novo stage IV disease. We hypothesize that a subset of these patients who achieve no evidence of disease (NED) status after multimodality HER2‐targeted treatments may have prolonged progression‐free survival (PFS) and overall survival (OS).Materials and Methods.Patients with de novo stage IV, HER2+ MBC (n = 483) diagnosed between 1998 and 2015 were identified at two institutions (Yale and MD Anderson Cancer Centers). Clinical variables, treatment details, and survival outcomes were compared between those who achieved NED and those who did not.Results.All patients received trastuzumab, and 20% also received pertuzumab as first‐line therapy. The median OS was 5.5 years (95% confidence interval [Cl]: 4.8–6.2). Sixty‐three patients (13.0%) achieved NED; their PFS and OS rates were 100% and 98% (95% CI: 94.6%–100%), respectively, at 5 years and remained the same at 10 years. For patients with no NED (n = 420), the PFS and OS rates were 12% (95% CI: 4.5%–30.4%) and 45% (95% CI: 38.4%–52.0%) at 5 years and 0% and 4% (95% CI, 1.3%–13.2%) at 10 years, respectively. NED patients more frequently had solitary metastasis (79% vs. 51%, p = .005) and surgery to resect cancer (59% vs. 22%, p ≤ .001). In multivariate analysis, NED status (hazard ratio [HR]: 0.014, p = .0002) and estrogen receptor positive status (HR: 0.72; p = .04) were associated with prolonged OS.Conclusion.Among patients with de novo stage IV, HER2+ MBC, those who achieve NED status have a very high PFS and OS. Further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long‐term outcomes.Implications for Practice.In this retrospective review at two institutions, it was demonstrated that 13% of patients with de novo stage IV, human epidermal growth receptor 2 positive metastatic breast cancer achieved no evidence of disease (NED) status with trastuzumab‐based therapy plus/minus local therapies, and these patients had a very high progression‐free survival (100%) and overall survival (98%) at both the 5‐ and 10‐year time points. Achieving NED status may be an important therapeutic goal. However, further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long‐term outcomes.
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AbstractBackground.The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non‐small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC.Methods.Pretreatment plasma samples were available for 996 patients and were analyzed by matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry to generate VeriStrat labels (good, VS‐G, or poor, VS‐P).Results.Overall, no significant benefit in overall survival (OS) and progression‐free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS‐G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS‐P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468–0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546–0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264–0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353–0.576; p < .0001 for P+E). The VS‐G population had higher OS than the VS‐P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS‐G patients on the T+E arm had longer PFS, but not OS, than VS‐G patients on the P+E arm (p = .0108). Among EGFR mutation‐positive patients, those with VS‐G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS‐P patients had similar survival rates as VS‐G, EGFR‐wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E).Conclusion.In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation‐positive patients who will have a poor response to EGFR tyrosine kinase inhibitors.Implications for Practice.This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation‐positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation‐positive patients as an additional prognostic tool, and these results suggest that EGFR mutation‐positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.
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Laser Doppler flow meter is a safe, useful, and noninvasive tool to monitor microvascular blood flow. It measures the changes in flow either over time or differences in flow over an area of skin or other exposed tissue. The primary function of LDF is to produce blood perfusion output signal that is proportional to the red blood cell perfusion (or flux). A simple analog-based laser Doppler flow meter is used to record the biosignals arising from the microvascular network of a surface lesion in the face of a human being. An innovative technique is developed to overcome one of the major technical limitations that involved removing the continuous artifacts or noise generated by the movement of the cable, the probe as well as the operator or the patient. A color heat map in MATLAB is created to facilitate its easy analysis, interpretation, and understanding of the blood flow changes over a period of time across a cross-sectional area in an image format processed after acquiring the biosignals (flux) using LDF by the clinicians or by the technician who is performing the vascular assessment of the lesion.
Modern bioenergy is being recognized as an increasingly important low-carbon resource by policy-makers around the world to meet climate policy targets. In India also, there is a clear recognition of the significant role of bioenergy in electricity generation as well as in other applications. In this study, a preliminary attempt has been made to assess the techno-economic feasibility of biomass pellets-based power (BPBP) generation in India. Surplus availability of biomass feedstock from agriculture and forestry/wasteland sector is estimated at 242 million tonnes (Mt) for 2010–11 and is expected to rise to 281 Mt in 2030–31 due to increased crop production and associated waste/residue availability. In terms of related capacity, the potential of BPBP projects is estimated at 35 GW for 2030–31. The associated carbon dioxide mitigation potential resulting from the substitution of coal is estimated at 205 Mt in 2030–31 if the entire biomass surplus is to be diverted for power generation. The levelized cost of electricity is estimated at €0.12 per kWh for BPBP projects as compared to €0.10 per kWh for imported coal based power plants. For states with the lower tariff for biomass power, the break-even price of carbon for BPBP projects is estimated at €18 per tonne. Additionally, BPBP projects will generate employment of more than 5 million person-months in the construction of biomass power plants and over 200,000 full-time employments in the operation of BPBP plants and in the production of biomass pellets.
Road-based transport emissions are a major source of atmospheric metal pollution. However, there have been few studies on emissions from road traffic in mountainous areas. In this study, epiphytic mosses from trees at different elevations of a highway, a typical road with extraordinary elevation change in a mountainous area of karst in Guizhou, China, were analyzed for metal content as well as the spatial distribution pattern of metals. Mosses were sampled from three sections of highway at different elevations, from 1292–1357, 1394–1441, to 1481–1548 m. Principal component analysis and heat-map clustering were used to identify the principal factors affecting metal deposition. The results show that the metals of mosses from different elevations were divided into four factors. Group 1 which included Ni, Fe, Mg, Ba, and Al was attributed to a dominantly geogenic source. Group 2 included Zn, Cu, Mn, and Cr, from vehicle-related materials including tires and brakes. Group 3, Cd, can be attributed to high Cd background levels from local origins and traffic emissions, particularly tire wear. Group 4, Pb, is associated with brake wear and historical deposition. The epiphytic moss widely distributed in the study area, Ectropothecium aneitense Broth. & Watts, was used to analyze the spatial distribution pattern of the metals. Metal content gradually decreased with increase in elevation. Levels of Ni, Fe, Mn, Ba, and Cd were all significantly correlated with elevation (p < 0.05), simultaneously affected by terrain and vertically stratified. We highlighted the vertical distribution characteristics of metal in epiphytic mosses in this study, which could improve moss application for ecological monitoring due to road-based transport emissions with elevation changes.
This paper explores the direct impact of new technology on the energy intensity in China. The autoregressive distributed lag (ARDL) bounds test approach to cointegration is utilised over the extended period of 1985–2013. The variables found cointegrated and confirm the long-run association among all the underlying vectors. Furthermore, the results of long- and short-run analysis reveal that new technology spurs energy intensity in China. A 1% increase in technological innovation boosts energy intensity by 0.4% and 0.03% in the long and short run, respectively. The findings suggest that the establishment of smart grids and solar energy parks followed by the reforms in energy sector is yet to achieve plausible efficiency in China. The existing investment and innovation policy reforms are insufficient to assist the energy sector to cope up with the country's exceptional economic growth trend. Unlike other studies, this paper accommodates structural break in the series. During sensitivity analysis, the model is found stable. Hence, the findings possess important policy implications for China and open up new discussion in the field.
Synovial chondromatosis is a benign nodular cartilaginous proliferation that mainly occurs in large joints. The temporomandibular joint is considered to be rarely affected. Several cases of synovial chondromatosis of the temporomandibular joint have been reported with clinical and histological features. People with this disease may present with swelling, pain, intracapsular sounds, and limitation of mandibular movement. Radiographs are an important component in the diagnostic process for synovial chondromatosis. In this article, we report three cases of synovial chondromatosis occurring in the temporomandibular joint with a focus on the radiological features, including those on plain films, cone-beam computed tomography (CT) images, and conventional CT images. The three cases had totally different radiological features. The imaging differences were analyzed and compared to create combined diagnostic methods based on clinical features and examination techniques. The role of cone-beam CT examination in the diagnosis of the disease is discussed.
The aim of this study was to evaluate an automatic multi-atlas-based segmentation method for generating prostate, peripheral (PZ), and transition zone (TZ) contours on MRIs with and without fat saturation (±FS), and compare MRIs from different vendor MRI systems.
T2-weighted (T2) and fat-saturated (T2FS) MRIs were acquired on 3T GE (GE, Waukesha, WI, USA) and Siemens (Erlangen, Germany) systems. Manual prostate and PZ contours were used to create atlas libraries. As a test MRI is entered, the procedure for atlas segmentation automatically identifies the atlas subjects that best match the test subject, followed by a normalized intensity-based free-form deformable registration. The contours are transformed to the test subject, and Dice similarity coefficients (DSC) and Hausdorff distances between atlas-generated and manual contours were used to assess performance.
Three atlases were generated based on GE_T2 (n = 30), GE_T2FS (n = 30), and Siem_T2FS (n = 31). When test images matched the contrast and vendor of the atlas, DSCs of 0.81 and 0.83 for T2 ± FS were obtained (baseline performance). Atlases performed with higher accuracy when segmenting (i) T2FS vs. T2 images, likely due to a superior contrast between prostate vs. surrounding tissue; (ii) prostate vs. zonal anatomy; (iii) in the mid-gland vs. base and apex. Atlases performance declined when tested with images with differing contrast and MRI vendor. Conversely, combined atlases showed similar performance to baseline.
The MRI atlas-based segmentation method achieved good results for prostate, PZ, and TZ compared to expert contoured volumes. Combined atlases performed similarly to matching atlas and scan type. The technique is fast, fully automatic, and implemented on commercially available clinical platform.
Publication date: Available online 22 August 2018
Source: Journal of Autoimmunity
Author(s): Inken Wohlers, Lars Bertram, Christina M. Lill
Genome-wide association studies (GWAS) have identified a large number of genetic risk loci for autoimmune diseases. However, the functional variants underlying these disease associations remain largely unknown. There is evidence that microRNA-mediated regulation may play an important role in this context. Therefore, we assessed whether autoimmune disease loci unfold their effects via altering microRNA expression in relevant immune cells.
To this end, we performed comprehensive data integration of many large and publicly available datasets to combine information on autoimmune disease risk loci with RNA-Seq-based microRNA expression data. Specifically, we carried out microRNA expression quantitative trait loci (eQTL) analyses across 115 GWAS regions associated with 12 autoimmune diseases using next-generation sequencing data of 345 lymphoblastoid cell lines. Statistical analyses included the application and extension of a recently proposed framework (joint likelihood mapping) to microRNA expression data and microRNA target gene enrichment analyses of relevant GWAS data.
Overall, only a minority of autoimmune disease risk loci may exert their pathophysiologic effects by altering microRNA expression based on JLIM. However, detailed functional fine-mapping revealed two independent GWAS regions harboring autoimmune disease risk SNPs with significant effects on microRNA expression. These relate to SNPs associated with Crohn's disease (CD; rs102275) and rheumatoid arthritis (RA; rs968567), which affect the expression of miR-1908-5p (prs102275 = 1.44e-20, prs968567 = 2.54e-14). In addition, an independent CD risk SNP, rs3853824, was found to alter the expression of miR-3614-5p (p = 5.70e-7). To support these findings, we demonstrate that GWAS signals for RA and CD were enriched in genes predicted to be targeted by both microRNAs (all with p < 0.05).
In summary, our study points towards a potential pathophysiological role of miR-1908-5p and miR-3614-5p in autoimmunity.
Publication date: Available online 22 August 2018
Source: Trends in Endocrinology & Metabolism
Author(s): Jun Ren, James R. Sowers, Yingmei Zhang
Recent advances in health care have improved the management of cardiometabolic disorders, and prolonged lifespan. However, the ever-rising prevalence of metabolic stress related to obesity (insulin resistance, diabetes, hypertension, and dyslipidemia) has greatly challenged geriatric care. The ubiquitin–proteasome system and autophagy–lysosomal pathways represent two major, yet distinct cellular machineries, for degradation and removal of damaged or long-lived proteins and organelles; the function of which declines with aging. To seek new strategies for cardiovascular aging under various metabolic diseases, it is imperative to understand the precise role for metabolic stress and protein quality control, in particular autophagy, in premature cardiovascular aging. Targeting metabolic stress and autophagy may offer exciting new avenues for the management of cardiovascular aging.
This study aimed to estimate the probability of an unfavourable aesthetic outcome (AO) 2 years after breast-conserving therapy (BCT) and evaluate the possible influence of brachytherapy (BT) and external beam radiotherapy (EBRT) boost on patient-reported outcomes (PROs) and AO.
Patients treated with BCT starting April 2015 were prospectively included. Selection of the boost technique followed an in-house flowchart based on the depth of the tumour bed. An electron boost was performed for a superficial clinical target volume (maximum 28 mm under the epidermis), a BT boost was proposed in all other cases. Patients were followed-up for 2 years. AO was scored by the BCCT.core software and the patient. Further PROs were measured with the EORTC QLQ-C30, QOL-BR23 and the BIBCQ questionnaires.
The analysis included 175 patients, 80 received a BT boost and 95 an EBRT boost. BT patients were significantly older; had a higher breast cup and band size, body mass index and surgical specimen weight of the wide excision; more seroma at baseline and less positive surgical section margins than patients in the EBRT group, and more patients drank alcohol. Cancer- and breast cancer-specific quality of life (QOL) and body image did not differ between the boost techniques over time. Although mean scores for breast symptoms and sexual enjoyment did differ significantly over time (p = 0.05 and < 0.01, respectively), the effect was due to differences before boost administration. Measured with BCCT.core, AO was unfavourable in 28% of patients 2 years after treatment (31% scored by the patient) and results were similar in the BT and EBRT groups.
Using the presented flowchart (See Verhoeven et al. [16]), AO and PROs on QOL or body image up to 2 years after BCT are not influenced by the boost technique.
Publication date: Available online 22 August 2018
Source: Journal of Dermatological Science
Author(s):
| Related Articles |
Effect of Delaying Replacement of Parenteral Nutrition Intravenous Administration Sets: Preclinical Experiments and a Dynamic Laboratory Model of Microbial Colonization.
JPEN J Parenter Enteral Nutr. 2018 Aug;42(6):987-997
Authors: Gavin NC, McMillan D, Keogh S, Choudhury MA, Ray-Barruel G, Rickard CM
Abstract
BACKGROUND: Recommendations prescribe daily intravenous administration set (IVAS) replacement for parenteral nutrition (PN) comprising intravenous fat emulsions (IVFE) due to risk of micro-organism growth and resultant central-line associated bloodstream infections (CLABSIs), but system disconnection for this practice may allow contamination and CLABSIs.
MATERIALS AND METHODS: Laboratory experiments and model development were used to simulate PN administration after contamination from healthcare workers' hands. This study observed the growth of micro-organisms known to cause CLABSIs in a variety of PN and other IV fluids and developed a model to investigate the effect of delaying IVAS replacement on microbial growth for up to 7 days.
RESULTS: Micro-organisms grew at different rates and were affected by solution type. In static experiments, growth was supported in IVFE and all-in-one PN, but suppressed in 50% glucose. Growth patterns were consistent over time for Staphylococcus epidermidis, Staphylococcus aureus, and Candida albicans in IVFE, all-in-one PN, and 0.9% sodium chloride in both static and dynamic experiments. C. albicans grew exponentially to clinically significant numbers in all-in-one PN and IVFE IVAS after 30 hours, but negligible growth of S. epidermidis or S. aureus occurred for 7 days.
CONCLUSION: All-in-one PN and IVFE support the C. albicans growth after minimal initial contamination, with micro-organisms migrating from the fluid bag to the central venous access device. Improved aseptic nontouch technique during clinical practice is vital to prevent contamination. Daily IVAS replacement of for all-in-one PN and IVFE should continue until the safety of prolonging IVAS replacement is confirmed by randomized trials.
PMID: 30133843 [PubMed - in process]
Dissolved organic phosphorus (DOP) in rainwater runoff or other contaminated waters can cause or aggravate eutrophication of water bodies. Water treatment residual (WTR) containing spent coagulant has been shown to provide excellent adsorption capacity for inorganic phosphorus such as orthophosphate, but little information has been available on adsorption of DOPs by WTR. In this study, the adsorption characteristics of myo-inositol-1,2,3,4,5,6-hexakisphosphate (IHP), a prototype DOP in soil and stormwater, by WTR were investigated through batch adsorption equilibrium and kinetic experiments. The influences of pH and various size fractions of WTR on the adsorption capacity were tested and analyzed, and the adsorption mechanism was elucidated based on Fourier-transform infrared spectroscopy (FTIR) analysis. The experimental results showed that WTR can effectively adsorb IHP from simulated rainwater, and the IHP uptake was favored under neutral and acidic conditions. Moreover, the 1.0–2.0-mm fraction of the WTR particles was most suitable for practical application because of the well-balanced adsorption rate and capacity. The classical Langmuir isotherm model well described the equilibrium adsorption data and the pseudo-second-order kinetic model adequately interpreted the rate data. Thermodynamic analysis revealed that the adsorption is a spontaneous, endothermic, and entropy-driven reaction. The FTIR analysis indicated that adsorption of IHP on WTR is associated with the formation of ≡Al–PO3− groups and the release of –OH from WTR. A comparison of the adsorption capacities of orthophosphate and IHP on WTR suggested that binding one IHP may take two times more sites than for orthophosphate, indicating that two of the six phosphate groups in IHP were bound to WTR. This work shows that recycled WTR may be used as a low-cost adsorbent for effective removal of organic phosphate in gray water and wastewater.
The increasing use of Fe3O4 nanoparticles (NPs) had posed an emerging challenge to wastewater treatment processes, and their potential impact on anaerobic ammonium oxidation (anammox) process of unplanted subsurface-flow constructed wetlands (USFCWs) was investigated firstly under the long-term exposure of different Fe3O4 NP concentrations. It was found that Fe3O4 NP exposure could improve total nitrogen (TN) removal. The abundance of Candidatus Anammoxoglobus increased significantly at 10 mg/L Fe3O4 NPs, while decreased under 1 mg/L Fe3O4 NP exposure. Desulfosporosinus and Exiguobacterium increased to some extent at 1 mg/L Fe3O4 NPs, suggesting that Fe-anammox played an important role in TN removal. The ROS production increased with the increase of Fe3O4 NP concentration, and the integrity of cell membrane was good under Fe3O4 NP exposure. The functional genes that related to inorganic ion transport and metabolism and lipid transport and metabolism were upregulated, and cell motility decreased after long-term exposure of 1 mg/L Fe3O4 NPs.
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The molecular mechanisms that promote pathologic alterations in human physiology mediated by short-term exposure to traffic pollutants remains not well understood. This work was to develop mechanistic networks to determine which specific pathways are activated by real-world exposures of traffic-related air pollution (TRAP) during rest and moderate physical activity (PA). A controlled crossover study to compare whole blood gene expression pre and post short-term exposure to high and low of TRAP was performed together with systems biology analysis. Twenty-eight healthy volunteers aged between 21 and 53 years were recruited. These subjects were exposed during 2 h to different pollution levels (high and low TRAP levels), while either cycling or resting. Global transcriptome profile of each condition was performed from human whole blood samples. Microarrays analysis was performed to obtain differential expressed genes (DEG) to be used as initial input for GeneMANIA software to obtain protein-protein (PPI) networks. Two networks were found reflecting high or low TRAP levels, which shared only 5.6 and 15.5% of its nodes, suggesting specific cell signaling pathways being activated in each environmental condition. However, gene ontology analysis of each PPI network suggests that each level of TRAP regulate common members of NF-κB signaling pathway. Our work provides the first approach describing mechanistic networks to understand TRAP effects on a system level.
Dermatologic Therapy, EarlyView.
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British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
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Clinical and Experimental Dermatology, EarlyView.
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Clinical and Experimental Dermatology, EarlyView.
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