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Background and Objectives: Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed., Methods: The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI-Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S-desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk-to-plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation., Results: The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight-adjusted maternal SCIT dose on average., Conclusion: The moderate between-subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants., (© 2020 The British Pharmacological Society.)

Background: Writing, sharing, answering, discussing and rating examination questions are a way to involve students in creating content and applying their knowledge. The PeerWise online question-setting platform facilitates student communities in this activity. This mixed-methods study asks the question: Does students' writing and answering examination questions enhance their engagement and learning of Neurology as a Life Science topic?, Methods: Over a 2-year period, self-assembled groups of 3-4 students submitted 1-2 multiple-choice questions (MCQs) every 2 weeks into the PeerWise portal for review by their peers. Summative examination results were compared with previous year's control group. Data were also collected regarding student engagement (number of MCQs answered or submitted comments) are compared to summative assessment results at the end of semester. Post-intervention student satisfaction surveys were analysed qualitatively and quantitatively to assess the effectiveness of the exercise., Results: With 174 and 80 student participants in intervention and control groups, respectively, no statistical difference was found in the average marks between the cohorts. However, within intervention group, positive correlation (Spearman's r = .272-.333) was found between higher level of student engagement with PeerWise and higher examination result. Positive correlation remained persistent after completion of the PeerWise exercise. Student survey revealed greater engagement with subject content, and qualitative thematic analysis was mapped to define various ways students engaged with the PeerWise activity., Conclusion: Tasking students to regularly generate and review MCQs enhances engagement with the topic, and higher engagement with PeerWise correlating to higher examination scores., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: We aimed to determine whether insurance expansions implemented through the Affordable Care Act (ACA) were associated with changes in coverage status, disease stage, and treatment of younger adults with testicular germ cell tumors (GCT)., Materials and Methods: We identified men aged 18-64 diagnosed with testicular GCTs between 2010 and 2015 in the National Cancer Data Base. We defined time periods as: pre-ACA (2010-2013) and post-ACA (2014-2015) and used difference-in-differences (DID) modeling to examine associations between state Medicaid expansion status and changes in insurance, stage at diagnosis, and treatment., Results: Following the ACA, the proportion of patients with any health insurance increased 3.7% (95% CI 3-4.5) in Medicaid expansion states and 3.0% (95% CI 1.5-4.5) in non-expansion states, mainly by gaining Medicaid and private insurance, respectively. The largest increases occurred in low-income patients, where Medicaid expansion was associated with an adjusted increase of 14.5 percentage points (95% CI 7.2-21.8) in Medicaid coverage following the ACA. We did not observe reductions in late-stage diagnoses during the observation period. Changes in the proportion of patients receiving chemotherapy or radiation for advanced-stage cancers were ongoing prior to the ACA and differed between expansion and non-expansion states, limiting assessment of ACA-related effects on individual treatments., Conclusions: Post-ACA, the proportion of newly diagnosed testicular cancer patients with health insurance increased, with the largest effects seen among lowest income individuals. Our findings that changes in practice preceded the ACA and differed by expansion status highlight the need for caution in assessing the legislation's impact.

DNA double-strand break repair by homologous recombination begins with nucleolytic resection of the 5' DNA strand at the break ends. Long-range resection is catalyzed by EXO1 and BLM-DNA2, which likely have to navigate through ribonucleotides and damaged bases. Here, we show that a short stretch of ribonucleotides at the 5' terminus stimulates resection by EXO1. Ribonucleotides within a 5' flap are resistant to cleavage by DNA2, and extended RNA:DNA hybrids inhibit both strand separation by BLM and resection by EXO1. Moreover, 8-oxo-guanine impedes EXO1 but enhances resection by BLM-DNA2, and an apurinic/apyrimidinic site stimulates resection by BLM-DNA2 and DNA strand unwinding by BLM. Accordingly, depletion of OGG1 or APE1 leads to greater dependence of DNA resection on DNA2. Importantly, RNase H2A deficiency impairs resection overall, which we attribute to the accumulation of long RNA:DNA hybrids at DNA ends. Our results help explain why eukaryotic cells possess multiple resection nucleases.

Background: Brain metastases (BM) are frequently observed in advanced renal-cell carcinoma (RCC). Historically these individuals have been excluded from clinical trials, but recently, with better local control, many can receive aggressive therapy after treatment. We evaluate our single-institution experience over various treatment eras., Patients and Methods: Patients undergoing evaluation for RCC BM from 2001 to 2018 were identified from our institutional database. Clinical notes, demographics, comorbidities, histology, central nervous system (CNS) treatments, systemic therapy, and outcomes were reviewed. Overall survival (OS) and CNS recurrence-free survival (RFS) were evaluated by the Kaplan-Meier method. Cumulative incidence was evaluated using a competing risk model., Results: We identified 158 patients with RCC BM, of whom 94.4% had clear-cell RCC, and 90.6% had extracranial metastases at diagnosis. Of these patients, 94 (60%) developed RCC BM over time, while 46 (29.1%) had RCC BM at initial presentation. Clinical symptoms were noted in 81.9% of patients. The median OS after diagnosis of RCC BM was 8.4 months, with a 3-year OS of 28.2%. The median CNS RFS was 8.5 months overall; however, those with one and more than one lesion had median CNS RFS of 12.4 and 6 months, respectively (P < .001)., Conclusion: The majority of RCC patients with BM are symptomatic and had prior metastatic disease that progressed to the brain. Those with a solitary RCC BM are less likely to develop CNS recurrence after local therapy and are ideal candidates for enrollment onto clinical trials., (Copyright © 2019. Published by Elsevier Inc.)

Polypores are diverse macrofungi that have been extensively studied for their lignocellulolytic enzyme production capabilities. Currently, these enzymes are being used for many industrial purposes. However, the high cost associated with their production is the main barrier to their broader application. This work aimed to study the optimal medium and conditions for endoglucanase production using solid state fermentation. Seven polypore strains were used for endoglucanase activity screening. The fermentation experiments were carried out in 250 ml Erlenmeyer flasks with green tea waste as a substrate. Notably, Microporus xanthopus strain KA038 showed the best level of activity (38.62 IU/gds). Various parameters such as moisture content, nitrogen source, initial pH value, inoculum size and incubation time were considered to determine the optimal conditions for endoglucanase production. The optimal medium consisted of green tea leaves as a carbon source, beef extract as an organic nitrogen source, NH 4 H 2 PO 4 as an inorganic nitrogen source, pH 7.0 and an incubation temperature at 30°C for 4 days resulted in a high enzyme yield with M. xanthopus strain KA038 (81.8 IU/gds).This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Porphyromonas gingivalis uses a type IX secretion system (T9SS) to deliver more than 30 proteins to the bacterial surface using a conserved C-terminal domain (CTD) as an outer membrane translocation signal. On the surface, the CTD is cleaved and an anionic lipopolysaccharide (A-PLS) is attached by PorU sortase. Among T9SS cargo proteins are cysteine proteases, gingipains, which are secreted as inactive zymogens requiring removal of an inhibiting N-terminal prodomain (PD) for activation. Here, we have shown that the gingipain proRgpB isolated from the periplasm of a T9SS-deficient P. gingivalis strain was stable and did not undergo autocatalytic activation. Addition of purified, active RgpA or RgpB, but not Lys-specific Kgp, efficiently cleaved the PD of proRgpB but catalytic activity remained inhibited because of inhibition of the catalytic domain in trans by the PD. In contrast, active RgpB was generated from the zymogen, although at a slow rate, by gingipain-null P. gingivalis lysate or intact bacterial cell suspension. This activation was dependent on the presence of the PorU sortase. Interestingly, maturation of proRgpB with the catalytic cysteine residues mutated to Ala expressed in the ΔRgpA mutant strain was indistinguishable from that in the parental strain. Cumulatively, this suggests that PorU not only has sortase activity but is also engaged in activation of gingipain zymogens on the bacterial cell surface., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Next Generation sequencing has greatly progressed the exploration of the oral microbiome's role in dental diseases, however, there has been little focus on the effect of sample storage conditions and their interaction with DNA extraction method. Dental plaque samples collected from 20 healthy participants were pooled and stored in either 75% ethanol or Bead solution for up to 6-months at -80 °C, prior to DNA extraction with either QIAamp (non-bead beating) or PowerSoil (bead-beating) kit, followed by Illumina sequencing of 16S rRNA gene. We found that storage media and not extraction method had the biggest influence on the diversity and abundance of the oral microbiota recovered. Samples stored in Bead solution, independent of the extraction kit, retrieved higher diversity (PowerSoil p = 1.64E-07, QIAamp p = 0.0085) and had dissimilar overall ecologies as indicated by lower level of shared diversity (PowerSoil p = 0.0000237, QIAamp p = 0.0088). Comparatively, samples stored in Bead solution and extracted with PowerSoil recovered a higher abundance of Streptococcus species. These data indicate that Bead solution can preserve the oral microbiome in dental plaque reliably, for periods of up to 6-months at -80 °C, and is compatible, with either a bead-beating or non-bead beating DNA extraction method.

Background: A pharmacogenomic clinical decision support tool (PGx-CDS) for thiopurine medications can help physicians incorporate pharmacogenomic results into prescribing decisions by providing up-to-date, real-time decision support. However, the PGx-CDS user interface may introduce errors and promote alert fatigue. The objective of this study was to develop and evaluate a prototype of a PGx-CDS user interface for thiopurine medications with user-centered design methods., Methods: This study had two phases: In phase I, we conducted qualitative interviews to assess providers' information needs. Interview transcripts were analyzed through a combination of inductive and deductive qualitative analysis to develop design requirements for a PGx-CDS user interface. Using these requirements, we developed a user interface prototype and evaluated its usability (phase II)., Results: In total, 14 providers participated: 10 were interviewed in phase I, and seven providers completed usability testing in phase II (3 providers participated in both phases). Most (90%) participants were interested in PGx-CDS systems to help improve medication efficacy and patient safety. Interviews yielded 11 themes sorted into two main categories: 1) health care providers' views on PGx-CDS and 2) important design features for PGx-CDS. We organized these findings into guidance for PGx-CDS content and display. Usability testing of the PGx-CDS prototype showed high provider satisfaction., Conclusion: This is one of the first studies to utilize a user-centered design approach to develop and assess a PGx-CDS interface prototype for Thiopurine Methyltransferase (TPMT). This study provides guidance for the development of a PGx-CDS, and particularly for biomarkers such as TPMT.

Passengers travelling on the London underground tubes currently have no means of knowing their whereabouts between stations. The challenge for providing such service is that the London underground tunnels have no GPS, Wi-Fi, Bluetooth, or any kind of terrestrial signals to leverage. This paper presents a novel yet practical idea to track passengers in realtime using the smartphone accelerometer and a training database of the entire London underground network. Our rationales are that London tubes are self-driving transports with predictable accelerations, decelerations, and travelling time and that they always travel on the same fixed rail lines between stations with distinctive bumps and vibrations, which permit us to generate an accelerometer map of the tubes' movements on each line. Given the passenger's accelerometer data, we identify in realtime what line they are travelling on and what station they depart from, using a pattern-matching algorithm, with an accuracy of up to about 90% when the sampling length is equivalent to at least 3 station stops. We incorporate Principal Component Analysis to perform inertial tracking of passengers' positions along the line when trains break away from scheduled movements during rush hours. Our proposal was painstakingly assessed on the entire London underground, covering approximately 940 km of travelling distance, spanning across 381 stations on 11 different lines.

A common theme in the persistence of microbial infections involves intracellular survival of microbial pathogens within host cells where they stay sheltered from attack by antimicrobial agents. In order to improve antimicrobial access inside host cells, we developed nanoparticles intracellular delivery of antibiotics. Using an intracellular infection model with the periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), we demonstrated significantly enhanced intracellular microbicidal activity with the standard antibiotic metronidazole (MET) through its conjugation onto 1-5 nm biocompatible nano-carrier, carbon quantum dot, which was derived from chlorophyll (cCQD). The conjugated cCQD-MET were rapidly internalized into the cultured cells, reaching almost 90% uptake within 3 h of the challenge. Our results consistently showed enhanced antimicrobial activity of the conjugate compared to MET alone. Even at concentrations as low as 0.26 µM, the conjugate showed 72% enhancement compared to the drug alone, resulting in significantly increased inhibition of intracellular P. gingivalis at lower antibiotic dosages. We achieved a high drug payload (80% w/w) on cCQD without affecting the potency of metronidazole as determined by cytotoxicity assays, cellular uptake of metronidazole, P. gingivalis invasion and elimination assays. The synthesized cCQD also displayed high fluorescence with 56% quantum yield at an absorbance peak of 380 nm and an emission peak of 480 nm, thus, allowing for fluorescence tracking and quantification of the drug intracellularly. A similar strategy may be used to repurpose other antibiotics for the treatment of intracellular bacterial infections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Typhoons have devastating impacts across many Asian countries. Vietnam is presently one of the most disaster-prone nations. Typhoons regularly disrupt human lives and livelihoods in various ways and cause significant damage. Making efficient policy decisions to minimize the vulnerability of affected communities is crucial. This requires a deep understanding of the factors that make a society vulnerable to extreme events and natural disasters. An appropriate approach is integrating the three dimensions of hazard, exposure and sensitivity, and community adaptive capacity. However, the vulnerability and adaptive capacity response to typhoons within Vietnam is poorly investigated. Here, we develop a conceptual framework that incorporates 21 indicators to identify vulnerability and adaptive capacity (VAC) using geospatial techniques at regional scales, applied over Vietnam. We find large spatial differences in VAC and are able to identify the top-priority regions that need to enhance their adaptation to typhoons. The Southern Coastal area, South East and Red River Delta demonstrate high and very high vulnerability because of their physical features and the intensity of typhoons that frequently cross these parts of Vietnam. The lower Mekong Delta and Northern Coastal areas are vulnerable to typhoon-driven flood threats, in particular where compounded by sea-level rise. Our framework successfully identified the spatial distribution and different levels of VAC within acceptable limits of uncertainty. It can therefore serve as a template to tackle national issues in disaster risk reduction in Vietnam and assist in the development of suitable mitigation strategies to achieve sustainable outcomes., (Copyright © 2019. Published by Elsevier B.V.)

Background: It remains controversial if Mohs surgery is superior to surgical excision in treating localized sebaceous carcinoma., Objective: To compare Mohs surgery and surgical excision for treating patients with localized sebaceous carcinoma., Materials and Methods: The US National Cancer Database was used to identify patients with histologically confirmed Stage 0 to 2 sebaceous carcinoma from 2004 to 2014. Clinicopathologic and socioeconomic factors were compared between treatment groups using the chi-square test. Overall survival (OS) was evaluated by log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses compared with age- and sex-matched US population were performed., Results: Of 1,265 patients, 234 received Mohs surgery and 1,031 received surgical excision. Mohs surgery had a higher rate of negative margin (p = .004). On multivariate Cox regression analysis, Mohs surgery was associated with longer OS than surgical excision (HR: 0.703, 95% CI: 0.496-0.995, p = .047). The survival benefit of Mohs surgery persisted on relative survival analysis and propensity score-matched analysis (p = .0385), after matching the 2 groups on patient and disease characteristics., Conclusion: Patients who received Mohs surgery had significantly longer OS when compared with those who received surgical excision. Prospective clinical trials comparing these treatment paradigms are warranted.

Although the photoluminescence of gold clusters has been extensively studied so far, there are still questions on the origin of the emission in these materials. In this work, we report time-dependent density functional theory calculations on the absorption and emission spectra of the well-studied Au 25 (SR) 18 - cluster, the lowest energy isomer of the Au 38 (SR) 24 cluster, and five isomers of the Au 22 (SR) 18 cluster. Good agreement between the calculated and measured absorption spectra, as well as with the lowest-energy emission values for these clusters, was demonstrated, verifying the accuracy of the theoretical methods employed. Our results for Au 25 (SR) 18 - explain a newly observed feature in the absorption peak, also rationalizing the optical response in terms of the superatom model. The analysis of the absorption and emission characteristics of the Au 25 (SR) 18 - and Au 38 (SR) 24 clusters provides an estimate of the spectral regions, where fluorescence or phosphorescence is predicted to occur. Interestingly, we find that for Au 22 (SR) 18 , one of the five proposed structures could be present at a significant concentration in the sample, even though it is not the lowest in energy structure, which can be explained, in part, by solvent effects.

Purpose: We described the medication use during pregnancy in the French population using the French Pregnancy Cohort (FPC)., Methods: The FPC was built with the sampling of all pregnant women included in the French Echantillon généraliste des bénéficiaires (EGB), which is a 1/97th representative sample of the population covered by the French health insurance. The EGB includes anonymized information on the socio-demographic and medical characteristics of beneficiaries, and the health care services they have received such as diagnoses and procedure codes as well as data on filled reimbursed medication; EGB also includes data on hospital stays in all public and private French health facilities. Each filled prescription record contains information on drug brand and generic names, date of prescription and date of dispensing, quantity dispensed, mode of administration, duration of prescription, dosage, and prescribing physician specialty. FPC includes data on all pregnancies of women in the EGB (2010-2013). Date of entry in the FPC is the first day of pregnancy regardless of pregnancy outcome (spontaneous abortions or planned abortions (with or without medical reasons), deliveries), and data on women are collected retrospectively for a period of one year before pregnancy, and prospectively during pregnancy, and up to one year after delivery. The prevalence of prescribed medications before, during and after pregnancy was compared; comparison was also done between trimesters. Pregnancy outcomes are described and include spontaneous and planned abortions, livebirths, and stillbirths., Results: FPC includes data on 36,065 pregnancies. Among them, 27,253 (75.6%) resulted in a delivery including 201 stillbirths (0.7%). The total number of spontaneous abortions was 6,718 (18.6%), and planned abortions 2,094 (5.8%). The prevalence of filled medication use was 91.1%, 89.9%, and 95.6% before, during and after pregnancy, respectively. Although there was a statistically significant decrease in the proportion of use once the pregnancy was diagnosed (first trimester exposure, 76.4% vs. exposure in the year prior to pregnancy, 91.1% (p < .01)), post-pregnancy medication use was above the pre-pregnancy level (95.6%). Maternal depression was the most prevalent comorbidity during pregnancy (20%), and post-partum depression was higher in those who delivered a stillborn infant (38.8%) as well as in those with a spontaneous (19.5%) or planned abortion (22.4%) compared to those with a liveborn (12.0%)., Conclusion: FPC is an excellent tool for the study of the risk and benefit of drug use during the perinatal period. FPC has the advantage of including a representative sample of French pregnant women, and study medications only available in France in addition to others available worldwide., Competing Interests: The authors have declared that no competing interests exist.

Oral cancers, primarily squamous cell carcinomas (SCCs), progress either slowly or aggressively. Here we assessed the role of macrophages in SCC behavior. We used mouse SCC cells derived from tumors harboring a Kras G12D activation mutation and Smad4 deletion in keratin 15-positive stem cells and a human oral SCC cell line, FaDu, which has NRAS amplification and SMAD4 deletion. SCC cells were transplanted into immune-compromised or immune-competent (syngeneic) recipients. After tumors were established, we used clodronate liposomes to ablate macrophages. We found that the number of tumor-associated macrophages (TAMs) was not affected by the presence of T cells but differed considerably among tumors derived from different SCC lines. Clodronate significantly reduced TAMs and splenic macrophages, resulting in reduced SCC volumes. Tumors with clodronate treatment did not show decreased proliferation but did exhibit increased apoptosis and reduced vascular density. FLIP (Fas-associated via death domain-like interleukin 1β-converting enzyme inhibitory protein), an apoptosis inhibitor abundantly produced in tumor cells and TAMs, was reduced in tumor cells of clodronate-treated mice. Reduced FLIP levels correlated with reductions in phosphorylated nuclear NFκB p65 and NFκB inhibitor attenuated FLIP protein levels in SCC cells. Furthermore, TGFβ1 serum levels and pSmad3 were reduced in clodronate-treated mice, but their reductions were insufficient to reverse epithelial-mesenchymal transition or TGFβ-mediated angiogenesis in endothelial cells. Consequently, metastasis was not significantly reduced by macrophage reduction. However, reduced pSmad3 correlated with reduction of its transcriptional target, vascular endothelial growth factor A, in clodronate-treated tumor cells, which correlated with reduced vascular density in clodronate-treated tumors. Taken together, our study revealed that macrophages contribute to SCC expansion through interactions with tumor cells but are dispensable for SCC metastasis. Our study provides novel insights into understanding the contributions and limitations of TAMs in SCC progression.

The optimal method of magnetic resonance imaging (MRI)-ultrasound (US) fusion biopsy to adequately sample regions of interest (ROIs) remains unknown. We sought to determine the number and location of cores needed to adequately detect clinically significant prostate cancer (PCa). We identified patients undergoing MRI-US fusion prostate biopsy at our institution for known history or clinical suspicion of PCa. Multiparametric MRI studies were reviewed using Likert and Prostate Imaging Reporting and Data System (PI-RADS) v2 schema. Multiple targeted cores were taken from each ROI followed by 12-core systematic biopsy. In a distinct cohort of patients, lesions were targeted using a predetermined five-core template. We estimated cancers detected through sampling of five or fewer cores, assessed by core number and core location. We identified 744 patients with 581 lesions with PCa. Seventy-seven percent (279/361) of Gleason (G) ≥3+4 tumors and 72% (137/189) of G >3+4 tumors were detected on two-core sampling. Relative to all targeted cores, a two-core approach missed 16% of clinically significant cancers at first biopsy, 27% in prior negative, and 32% in active surveillance patients. Detection of G ≥3+4 cancers did not differ by core location. Sampling of two cores of ROIs misses nearly one-quarter of clinically significant PCa detected on additional sampling. PATIENT SUMMARY: We aimed to understand how the number of cores obtained from a suspicious area during prostate magnetic resonance imaging-ultrasound fusion biopsy affects cancer detection. We found that sampling of five cores missed substantially fewer cancers compared to two cores., (Published by Elsevier B.V.)

Introduction: Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats-suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA., Methods: Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS., Results: Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation-in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression., Conclusions: Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation-suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.

Hypercalcaemia is a rare but potentially life-threatening consequence of malignancies. Solid cancers, such as lymphomas, increase serum calcium primarily through parathyroid hormone-related protein or ectopic production of 1alpha-hydroxylase. We present a case of 56-year-old woman with Sjogren's syndrome and psoriasis in the setting of chronic methotrexate (MTX) use who developed worsening hypercalcaemia and symptoms suggestive of lymphoma. Pathology results diagnosed her with MTX-induced iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD). This case reminds clinicians that chronic MTX use is associated with LPDs and can ultimately lead to hypercalcaemia. The patient's MTX and other immunosuppressive medications were stopped, and her calcium corrected with fluids and calcitonin. At her 8-month follow-up postdischarge, the patient was asymptomatic with normal laboratory results and in partial clinical remission., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Global environments are threatened by intensively natural variation and continuously increased human-made disturbances. Assessment of the global eco-environment vulnerability (global EV or GEV) caused by both natural and human-induced disturbances plays a key role in providing valuable information about ecological and environmental background for designing suitable policy measures to improve and restore environment. We present the first global-scale map of quantified eco-environmental vulnerability by integrating remote sensing, GIS modelling, and global census datasets, employing 16 influential factors across five domains: socioeconomics, land resources, natural hazards, hydrometeorology, and topography. The GEV is classified into six levels, namely very low vulnerability, low vulnerability, medium vulnerability, medium high vulnerability, high vulnerability, and very high vulnerability. At global scale, a small fraction of the globe (10.1%) is strongly (high and very high vulnerability) affected by influential factors. Among continents, the largest fraction of very high vulnerability level is attributed to Asia (74.6%) followed by Africa (19.6%). National-scale analysis shows that China and India are the most vulnerable in Asia and in the world. Our study provides accumulative impacts of manmade and natural disturbances, which are vital for decision makers to set improvement targets on specific areas over local, regional, and global scales, and design and adopt new practices to lessen natural and manmade disturbances on environment, while keeping track of evolution of the other environmental aspects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A-So airbase, located in A-Luoi Valley - Central Vietnam, is a former military base occupied by US Special Forces between 1963 and 1966. The storage of Agent Orange in A-So airbase during the Vietnam War now poses a high potential for PCDD/F contamination in soils and sediments. In order to evaluate the occurrence and characteristics of PCDD/Fs in A-So former airbase, which has been reserved for a long time and suffered almost no significant anthropogenic impacts, soil and sediment samples were collected from 40 sites of two adjacent zones A and B in an area of 160,000 m 2 . Seventeen 2,3,7,8-substituted PCDD/Fs were analyzed using HRCG/HRMS (US EPA method 1613). Results indicate that concentrations of PCDD/Fs measured in zone A ranged from 95.0 to 4534 ng kg dw -1 (4.58 to 746 ng TEQ kg dw -1 ), while those in zone B were in the range of 80.8-4150 ng kg dw -1 (2.70-89.0 ng TEQ kg dw -1 ). The concentrations of PCDD/Fs observed in zone A are higher than those in zone B, suggesting that PCDD/Fs could be transported from zone A to zone B through surface soil erosion and runoff events. The main contributor to the total TEQ concentration was 2,3,7,8-TCDD, which was the indicator of Agent Orange contamination, accounting for 91 ± 9% and 72 ± 17% of the total TEQ concentrations measured in zones A and B, respectively. Comparison of PCDD/F concentrations in different soil layers reveals that the topsoil layer (at depth < 1 m) contributed 81-95% to the total PCDD/Fs in the study area, indicating that future remediation projects should focus on this topsoil layer. Since PCDD/F contamination in A-So airbase has not significantly improved for the last 20 years, remediation projects are urgently needed in order to mitigate the negative impacts of PCDD/F contamination on human health and wellbeing., (Copyright © 2019. Published by Elsevier B.V.)

Identifying vulnerable levels of eco-environment over a global scale is critical for environmental management and ecological conservation. We present the method to optimize the use of freely assessable datasets to derive 16 factors for a proposed assessment framework (Nguyen and Liou, 2019; Liou et al., 2017; Nguyen et al., 2016) [[1], [2], [3]]. Results show that the datasets are suitable for evaluating global eco-environmental vulnerability (GEV). PM 2.5 that is a hazardous substance in environment and an anthropogenic disturbance associated with nature and human-made influence is selected to validate the GEV map. The GEV map well correlates with PM 2.5 distribution patterns with correlation coefficient of approximately 0.82. All datasets and mapping procedures are processed in ArcGIS 10.3/QGIS 2.16.3 software. Advantages of our method include three aspects: •The analysis procedure is simple but powerful, while dealing with various complex environmental issues.•The framework is flexible to adjust influential indicators subject to the conditions of concerned regions and purposes of decision makers.•The framework can be easily applied for different concerned regions over various scales. Our findings include GEV mapping and eco-protection zoning that provide key hotspots of eco-environmental vulnerability levels over a global scale for the decision makers and people to take further actions to lessen disturbances and achieve environmental sustainability.

Introduction: Approximately 7% of patients with localized upper tract urothelial cancer (UTUC) are treated without definitive therapy. Understanding outcomes and alternative therapy would aid in counseling older patients with comorbidities., Materials and Methods: We utilized the National Cancer Database to identify patients with localized UTUC managed non-surgically between 2004 and 2013. Patient demographics, comorbidity, tumor grade, and chemotherapy and radiation utilization were recorded. Survival analyses were performed with the Kaplan-Meier method and a cox proportional hazard regression model., Results: We identified 3157 (10.9%) patients with localized UTUC who did not receive definitive surgery. Median age was 79 years, 55% were males, 79% had government health insurance, and 68% had a Charlson-Deyo Score (CDS) of 0. Tumor grade was low (grade 1 or 2) in 632 (36.4%) and high (grade 3 or 4) in 1104 (63.6%). Median overall survival (OS) for the cohort was 2.2 years, significantly shorter for patients with greater comorbidities. Chemotherapy or radiation was performed in 294 (9.3%) and 197 (6.3%) patients respectively. There were no OS differences for individuals receiving chemotherapy. Of patients who received radiation therapy, the median OS was 1.4 versus 2.0 years, (p < 0.001) favoring no radiation. Those with high grade tumors had worse survival (1.9 versus 3.8 years (p < 0.001). Significant predictors of shorter OS included older age, male gender, higher CDS, and government insurance., Conclusions: In this population-based cohort, 10.9% of patients with localized UTUC were managed non-surgically. There was no OS advantage noted in cohorts receiving chemotherapy and radiation therapy. Median OS was significantly shorter for those with higher grade disease, increasing comorbidity profile, male gender, and those with government insurance status.

Objective: To describe pain assessment, the pattern of analgesic and sedative drug use, and adverse drug reactions in a neonatal intensive care unit (NICU) during the postsurgery phase., Method: Demographic characteristics, pain scores, and drug use were extracted and analyzed from electronic patient medical files for infants after surgery, admitted consecutively between January 2012 and June 2013., Result: One hundred and sixty-eight infants were included. Acute (DAN score) and prolonged (EDIN score) pain assessment scores were used in 79% and 64% of infants, respectively, on the 1st day. This percentage decreased over the 7 days following surgery. The weekly average scores postsurgery were 2/15 (±2.2) for the EDIN score and 1.6/10 (±2.0) for the DAN score. The rates of pain control were 88% for the EDIN and 72% for the DAN. The most prescribed opiate drug was fentanyl (98 patients; 58%) with an average dose of 1.8 (±0.6) μg/kg/h. Midazolam was used in 95 patients (56%), with an average dose of 35 (±14) μg/kg/h. A bolus was administered in 7% (±7.4) of the total dose for fentanyl and 8% (±9.3) for midazolam. Similar doses were used in term and preterm neonates. Of 118 patients receiving fentanyl and/or midazolam, 40% presented urinary retention, 28% a weaning syndrome. Paracetamol (155 patients; 92%) and nalbuphine (55 patients; 33%) were the other medications most often prescribed., Conclusion: The off-label use of fentanyl and midazolam was necessary to treat pain after surgery. Pain assessment should be conducted for all neonates in order to optimize their treatment. Research on analgesic and sedative medicine in vulnerable neonates seems necessary to standardize practices and reduce adverse drug reactions., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: Kidney masses suspicious for malignancy are frequently detected by cross-sectional imaging; however, little is known about the burden of surgical treatment for tumors found to be benign following excision., Material and Methods: We queried the National Inpatient Sample to identify records of individuals who received surgical treatment for renal neoplasms between 2004 and 2014. We characterized temporal treatment trends, patient demographics, treatment related complications, and charges., Results: We identified 7,099 (8.5%) and 76,892 (91.5%) patients who were treated for benign and malignant tumors, respectively. Benign masses accounted for 14.8% of partial and 5.5% of radical nephrectomies. The rates of surgery for benign tumors have remained steady (P = 0.058). The frequency of inpatient death was higher in those with malignant disease (0.63% vs. 0.18%, P < 0.0001). Median length of stay was longer for individuals with malignant renal tumors (4.86 vs. 4.12 days, P < 0.0001). The total discharge bill adjusting for inflation for benign or malignant renal surgery increased each year (R 2  = 0.428, R 2  = 0.719, P = 0.001, P = 0.0311, respectively). As of 2014, the estimated national inpatient cost of management for benign renal tumors was $153 million dollars ($55,573/individual)., Conclusions: 8.5% of inpatient renal surgical admissions are performed for benign masses. There has been a trend toward decreased operative management for benign renal tumors over time. Surgical management remains a significant economic burden. Efforts to prospectively evaluate modalities for pretreatment identification should be further pursued., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Obesity is associated with periodontitis, but the mechanisms underlying this association have yet to be unraveled. The present investigation was to evaluate a common rat model, in which obesity is induced by high-fat, high-sucrose diet (HFSD), for its applicability in periodontal research., Materials and Methods: Ten male Wistar rats were fed a 3-month HFSD along with a matching control group. Afterwards, the body weight, adipocyte morphology, leptin and adiponectin levels in adipose tissue, gingiva, and serum as well as the serum levels of triglyceride, cholesterol, and glucose were analyzed. For statistical analyses, parametric and non-parametric tests were applied (p < 0.05)., Results: Body weight was significantly higher in the HFSD group after dieting as compared to control. HFSD caused a significant increase in serum triglyceride, low-density lipoprotein cholesterol, and leptin levels and a significant decrease in high-density lipoprotein cholesterol. Furthermore, adipose tissue from HFSD rats exhibited significantly larger adipocytes, displayed a significant upregulation of leptin and, surprisingly, elevated adiponectin levels, which is in contrast to chronic obesity in humans. Although leptin and adiponectin were also observed in gingival biopsies, no obvious differences between the groups were found., Conclusions: Although this rat diet-induced obesity model is characterized by changes typical of obesity, it also has limitations, which have to be considered when data, especially with regard to adipokines, are extrapolated to humans., Clinical Relevance: The rodent diet-induced obesity model may be useful for unraveling pathomechanisms underlying the association between obesity and periodontal destruction but conclusions have to be drawn with caution.

Background: Glycated haemoglobin (HbA1c) test has been increasingly promoted as an alternative to fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT) to diagnose dysglycaemia but its performance in HIV-infected Africans has yet to be established. This study aimed to assess the diagnostic accuracy of HbA1c for dysglycaemia including FPG-defined and OGTT-defined dysglycaemia, and OGTT-defined diabetes in HIV-infected Africans, and the effect of HbA1c-predicted dysglycaemia on Joint Interim Statement (JIS)-based prevalent metabolic syndrome (MS)., Methods: A cross-sectional study included HIV-positive patients recruited across public healthcare facilities in the Western Cape. The recommended HbA1c cut-points were tested alongside the optimal cut-points obtained from receiver operating characteristic curve analyses, while the agreement between the MS criteria were assessed using kappa statistic., Results: 748 participants (157 men), median age 38 years, 93% on anti-retroviral drugs were included. The optimal HbA1c cut-points of 5.75% (39.3 mmol/mol) showed 54% sensitivity, 84% specificity for FPG-defined dysglycaemia, and 52% sensitivity, 85% specificity for OGTT-defined dysglycaemia. The HbA1c value of 5.85% (40.4 mmol/mol) (63% sensitivity, 99% specificity) was optimal for diabetes. The internationally advocated cut-point of 6.5% (48 mmol/mol) had 37% sensitivity and 99% specificity for diabetes, while HbA1c ≥5.7% (≥39 mmol/mol) yielded similar performance with the study-specific cut-point for any dysglycaemia. MS prevalence by the JIS criteria (28.2%) increased to 29.7% when using HbA1c ≥5.75% (≥39.3 mmol/mol) and to 32.9% with HbA1c ≥5.7% (≥39 mmol/mol); agreement between the original and modified criteria was generally good., Conclusions: This study agrees with the internationally recommended HbA1c cut-point for detecting dysglycaemia, but not for diabetes in HIV-infected Africans. In line with previous studies in general African populations, our findings suggest that similar factors interfere with HbA1c values regardless of HIV infection status. Replacing FPG-based with HbA1c-predicted dysglycaemia in the JIS criteria to diagnose MS is feasible in HIV-infected Africans., Competing Interests: EJM is employed by Global Evaluation Science. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials.

Background: Patients treated for renal cell carcinoma (RCC) may be diagnosed with a metachronous, contralateral tumor. We evaluated the risks of contralateral tumor development using the Surveillance, Epidemiology, and End Results database., Methods: Among RCC patients, we identified those with a metachronous, contralateral RCC diagnosed ≥1 year after primary diagnosis. We performed a competing risks analysis to evaluate associations between clinicopathologic factors and metachronous, bilateral RCC. Cumulative incidence and standardized incidence ratios (SIRs) were calculated., Results: There were 80,403 cases of RCC identified, with a median follow-up of 8.3 years; of these, 1063 (1.3%) developed metachronous, contralateral RCC (median of 6 years after diagnosis). The cumulative incidence at 10, 20, and 30 years of follow-up was 1.5%, 3.1%, and 4.7%, respectively. An increased risk was observed among men (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.20-1.55), blacks (HR, 2.00; 95% CI, 1.71-2.33), and those with papillary histology (HR, 1.72; 95% CI, 1.41-2.10). Risk of metachronous disease decreased with increasing age at primary diagnosis (HR per 1-year increase, 0.97; 95% CI, 0.96-0.97). The SIRs were highest among those diagnosed at a younger age and remained elevated even after extended follow-up (>10 years)., Conclusions: Our findings suggest that the cumulative incidence of metachronous, contralateral RCC may be higher than previously reported. Younger age, black race, papillary histology, and male sex increase the risk of metachronous, contralateral RCC development. The high SIRs seen in all demographic groups may support a rationale for lifelong surveillance, especially in high-risk subgroups with early disease onset., (© 2018 American Cancer Society.)

Objective: To evaluate trends in the utilization of active surveillance (AS) in a nationally representative cancer database. AS has been increasingly recognized as an effective strategy for patients with small renal masses but little is known about national usage patterns., Methods: We identified patients with clinical T1a renal masses within the National Cancer Database in 2010 through 2014. Patients were classified according to initial management strategy received including AS, surgery, ablation, or other treatment. We characterized time trends in the use of AS vs definitive therapy and examined clinical and socio-demographic determinants of AS among patients with small renal masses using multivariable logistic regression models., Results: We identified 59,189 patients who satisfied the inclusion criteria. Of the total cohort, 1733 (2.9%) individuals received initial management with AS, while 57,456 (97.1%) received definitive treatment. Surveillance rates remained below 5% in all years. On multivariate analysis, patient age (OR: 1.08, 95% CI 1.08-1.09), smaller tumor size of <2 cm vs ≥2 cm (OR: 2.43, 95% CI: 2.20-2.7, P < .0001), management at an academic center vs community center (OR: 2.05, 95% CI: 1.83-2.29), and African American vs Caucasian race (OR: 1.56, 95% CI:1.35-1.80) were independently associated with use of AS as initial management., Conclusion: In a representative national cohort of patients with small renal masses, we observed clinical and facility-level differences in the utilization of active surveillance in patients with T1a renal masses. Further investigation is warranted to better understand the forces underlying initial management decisions for patients with small renal masses., (Copyright © 2019. Published by Elsevier Inc.)

Background: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking., Objective: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study., Study Design: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5., Results: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001)., Conclusions: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic resection of the DNA break ends. The current model, being based primarily on genetic analyses in Saccharomyces cerevisiae and companion biochemical reconstitution studies, posits that end resection proceeds in two distinct stages. Specifically, the initiation of resection is mediated by the nuclease activity of the Mre11-Rad50-Xrs2 (MRX) complex in conjunction with its cofactor Sae2, and long-range resection is carried out by exonuclease 1 (Exo1) or the Sgs1-Top3-Rmi1-Dna2 ensemble. Using fully reconstituted systems, we show here that DNA with ends occluded by the DNA end-joining factor Ku70-Ku80 becomes a suitable substrate for long-range 5'-3' resection when a nick is introduced at a locale proximal to one of the Ku-bound DNA ends. We also show that Sgs1 can unwind duplex DNA harboring a nick, in a manner dependent on a species-specific interaction with the ssDNA-binding factor replication protein A (RPA). These biochemical systems and results will be valuable for guiding future endeavors directed at delineating the mechanistic intricacy of DNA end resection in eukaryotes., (© 2018 Wang et al.)

Porphyromonas gingivalis is a keystone bacterial pathogen of chronic periodontitis. P. gingivalis is unable to synthesise the porphyrin macrocycle and relies on exogenous porphyrin, including haem or haem biosynthesis intermediates from host sources. We show that under the iron-limited conditions prevailing in tissue environments, P. gingivalis expresses a haemophore-like protein, HusA, to mediate the uptake of essential porphyrin and support pathogen survival within epithelial cells. The structure of HusA, together with titration studies, mutagenesis and in silico docking, show that haem binds in a hydrophobic groove on the α-helical structure without the typical iron coordination seen in other haemophores. This mode of interaction allows HusA to bind to a variety of abiotic and metal-free porphyrins with higher affinities than to haem. We exploit this unusual porphyrin-binding activity of HusA to target a prototypic deuteroporphyrin-metronidazole conjugate with restricted antimicrobial specificity in a Trojan horse strategy that effectively kills intracellular P. gingivalis.

Olive knot, caused by Pseudomonas savastanoi pv. savastanoi, is a limiting disease in the production of table and oil olives in California. The genetic variability among 152 strains from major production areas of California was determined using BOX, ERIC, and REP primers in repetitive element sequence-based polymerase chain reaction. Overall genetic variability was low, and strains shared at least 82% similarity. Phenetic analyses identified several genotypes but most strains belonged to one of two major groups. Three copper-resistant strains had two fingerprints that were distinct from any of the sensitive strains, indicating that they may have been introduced from other production areas or hosts. In inoculations, two copper-resistant strains were mostly equally as virulent as two copper-sensitive strains. Inoculum was exuded at high levels (>10 8 CFU/g of knot tissue) within 10 min from hydrated olive knots, and concentrations were 2- to 3-log higher than the minimum needed to induce knot formation. Arbequina olive was significantly more susceptible to infection and developed a higher incidence of knots on leaf scar and lateral wounds (59.7 to 80.6% incidence) than Manzanillo (47.4 to 68.2% incidence). In wound-healing studies, both types of wounds were less susceptible to infection ≥10 days after injury, indicating a critical period for infection and application of bactericides during favorable environments.

Purpose: To aid prescribers in assessing a patient's risk for statin-induced myopathy (SIM), we performed a comprehensive review of currently known risk factors and calculated aggregated odds ratios for each risk factor through a meta-analysis., Methods: This meta-analysis was done through four phases: (1) Identification of the relevant primary literature; (2) abstract screening using inclusion and exclusion criteria; (3) detailed review and data extraction; and (4) synthesis and statistical analysis., Results: Out of 44 papers analyzed from 836 papers searched from MEDLINE, 18 different potential risk factors were collected, divided into three categories: three demographics (11 papers), ten clinical factors (31 papers), and five pharmacogenetics/biomarkers (12 papers). Risk factors significant for myopathy and/or rhabdomyolysis included age, gender, diabetes, renal impairment, cardiovascular disease, certain interacting drugs, and mutations of the SLCO1B1 gene, which encodes a transporter protein in the liver. Several factors, such as gender, race, cardiovascular disease, and the GATM gene, which encodes a protein for creatine synthesis, appeared to be protective in terms of the outcomes of interest., Conclusions: This comprehensive assessment of risk factors can help support clinicians in reducing the incidence of SIM in their patient population on statins.

Primary cutaneous peripheral T-cell lymphoma, unspecified (PCPTL) accounts for <6% of cutaneous T-cell lymphoma cases. Due to its rarity, no large study exists in the literature on PCPTL. Among 4057 patients with PCPTL diagnosed from 2004 to 2014 in the National Cancer Database, 428, 913, 517, 754, and 1435 had lesions localized primarily to the upper extremity, head and neck, lower extremity, trunk, and overlapping lesion or unspecified site, respectively. PCPTL that primarily involved the head and neck had the longest overall survival (OS), followed by PCPTL that primarily involved the trunk, upper extremity, and lower extremity. Patients with lesions localized to the lower extremity had significantly shorter OS when compared to those with disease localized to other primary sites after adjusting for confounding factors. The difference in OS among disease sites was only significant in stage I disease, but not higher stages, and persisted in younger patients.

Aim: Resistance against antifungals used for Candida albicans (Ca) treatment is mediated by two multidrug transporters, Mdr1p and Cdr1p, which are of enormous interest to the development of modulators combined with antifungals., Experimental: A set of chalcones was synthesized by condensation reactions in laboratory and was then subject to biological assays to evaluate the effects on different yeast strains.  Results: The obtained chalcones were screened using the checkerboard liquid chemosensitization assays. Compounds 4, 10, 12 and 18, when combined with fluconazole, triggered strong sensitization on yeast strains overexpressing CaMdr1p and CaCdr1p, whereas displaying no cytotoxicity by themselves towards control strains and transporter-expressing yeast cells. In the Nile Red transport assay, the two most active compounds, 12 and 18 showed moderate-to-high accumulation of Nile Red with different behaviors towards the two transporters., Conclusion: Chalcones are promising drug candidates for further development to make azole antifungals active again.

Purpose: Tumor heterogeneity may represent a barrier to preoperative genomic characterization by needle biopsy in clear cell renal cell carcinoma (ccRCC). The extent of heterogeneity in small renal tumors remains unknown. Therefore, we set out to evaluate heterogeneity in resected large and small renal tumors. Experimental Design: We conducted a study from 2013 to 2016 that evaluated 47 consecutive ccRCC tumors resected during radical or partial nephrectomy. Cases were designated as small (<4 cm) and large (>7 cm) tumors. Each tumor had three regions sampled. Copy-number variation (CNV) was assessed and gene expression analysis was performed to characterize the clear-cell A and B (ccA/ccB) profile and the cell-cycle progression (CCP) score. Genomic heterogeneity between three regions was evaluated using CNV subclonal events, regional expression profiles, and correlation between gene expression. Results: Twenty-three small and 24 large tumors were analyzed. Total CNVs and subclonal CNVs events were less frequent in small tumors ( P < 0.001). Significant gene expression heterogeneity was observed for both CCP scores and ccA/ccB classifications. Larger tumors had more variance in CCP scores ( P = 0.026). The distribution of ccA/ccB differed between small and large tumors with mixed ccA/ccB tumors occurring more frequently in the larger tumors ( P = 0.024). Analysis of five mixed tumors (with both ccA/ccB regions) demonstrated the more aggressive ccB phenotype had greater CNV events ( P = 0.014). Conclusions: Small renal tumors have much less genomic complexity and fewer subclonal events. Pretreatment genomic characterization with single-needle biopsy in small tumors may be useful to assess biologic potential and may influence therapy. Clin Cancer Res; 24(17); 4137-44. ©2018 AACR ., (©2018 American Association for Cancer Research.)

In this work, we carried out a systematic investigation to assess the effects of ligands on the structure, stability, and absorption spectra of ultrasmall CdSe tetrahedral quantum dots, where the cores of small tetrahedral quantum dots have been postulated to be stabilized by amine and carboxylate ligands. We found that amine and carboxylate ligands form extensive hydrogen bonding networks, which provide thermodynamic stability to the clusters. On the basis of the optimized structures, good agreement between observed and computed spectra was obtained. The ligands were also found to have a large influence on the color and intensity of the electronic absorption spectra, particularly for the small clusters, which were previously monitored with in situ UV-visible absorbance spectroscopy. Our work provides an understanding of the effect of ligands that influence thermodynamic stability and electronic absorption of ultrasmall quantum dots, thus potentially motivating further experimental exploration.

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: As part of efforts to prevent childhood overweight and obesity, we need to understand the relationship between total fat intake and body fatness in generally healthy children., Objectives: To assess the effects and associations of total fat intake on measures of weight and body fatness in children and young people not aiming to lose weight., Search Methods: For this update we revised the previous search strategy and ran it over all years in the Cochrane Library, MEDLINE (Ovid), MEDLINE (PubMed), and Embase (Ovid) (current to 23 May 2017). No language and publication status limits were applied. We searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing and unpublished studies (5 June 2017)., Selection Criteria: We included randomised controlled trials (RCTs) in children aged 24 months to 18 years, with or without risk factors for cardiovascular disease, randomised to a lower fat (30% or less of total energy (TE)) versus usual or moderate-fat diet (greater than 30%TE), without the intention to reduce weight, and assessed a measure of weight or body fatness after at least six months. We included prospective cohort studies if they related baseline total fat intake to weight or body fatness at least 12 months later., Data Collection and Analysis: We extracted data on participants, interventions or exposures, controls and outcomes, and trial or cohort quality characteristics, as well as data on potential effect modifiers, and assessed risk of bias for all included studies. We extracted body weight and blood lipid levels outcomes at six months, six to 12 months, one to two years, two to five years and more than five years for RCTs; and for cohort studies, at baseline to one year, one to two years, two to five years, five to 10 years and more than 10 years. We planned to perform random-effects meta-analyses with relevant subgrouping, and sensitivity and funnel plot analyses where data allowed., Main Results: We included 24 studies comprising three parallel-group RCTs (n = 1054 randomised) and 21 prospective analytical cohort studies (about 25,059 children completed). Twenty-three studies were conducted in high-income countries. No meta-analyses were possible, since only one RCT reported the same outcome at each time point range for all outcomes, and cohort studies were too heterogeneous to combine.Effects of dietary counselling to reduce total fat intake from RCTsTwo studies recruited children aged between 4 and 11 years and a third recruited children aged 12 to 13 years. Interventions were combinations of individual and group counselling, and education sessions in clinics, schools and homes, delivered by dieticians, nutritionists, behaviourists or trained, supervised teachers. Concerns about imprecision and poor reporting limited our confidence in our findings. In addition, the inclusion of hypercholesteraemic children in two trials raised concerns about applicability.One study of dietary counselling to lower total fat intake found that the intervention may make little or no difference to weight compared with usual diet at 12 months (mean difference (MD) -0.50 kg, 95% confidence interval (CI) -1.78 to 0.78; n = 620; low-quality evidence) and at three years (MD -0.60 kg, 95% CI -2.39 to 1.19; n = 612; low-quality evidence). Education delivered as a classroom curriculum probably decreased BMI in children at 17 months (MD -1.5 kg/m 2 , 95% CI -2.45 to -0.55; 1 RCT; n = 191; moderate-quality evidence). The effects were smaller at longer term follow-up (five years: MD 0 kg/m 2 , 95% CI -0.63 to 0.63; n = 541; seven years; MD -0.10 kg/m 2 , 95% CI -0.75 to 0.55; n = 576; low-quality evidence).Dietary counselling probably slightly reduced total cholesterol at 12 months compared to controls (MD -0.15 mmol/L, 95% CI -0.24 to -0.06; 1 RCT; n = 618; moderate-quality evidence), but may make little or no difference over longer time periods. Dietary counselling probably slightly decreased low-density lipoprotein (LDL) cholesterol at 12 months (MD -0.12 mmol/L, 95% CI -0.20 to -0.04; 1 RCT; n = 618, moderate-quality evidence) and at five years (MD -0.09, 95% CI -0.17 to -0.01; 1 RCT; n = 623; moderate-quality evidence), compared to controls. Dietary counselling probably made little or no difference to HDL-C at 12 months (MD -0.03 mmol/L, 95% CI -0.08 to 0.02; 1 RCT; n = 618; moderate-quality evidence), and at five years (MD -0.01 mmol/L, 95% CI -0.06 to 0.04; 1 RCT; n = 522; moderate-quality evidence). Likewise, counselling probably made little or no difference to triglycerides in children at 12 months (MD -0.01 mmol/L, 95% CI -0.08 to 0.06; 1 RCT; n = 618; moderate-quality evidence). Lower versus usual or modified fat intake may make little or no difference to height at seven years (MD -0.60 cm, 95% CI -2.06 to 0.86; 1 RCT; n = 577; low-quality evidence).Associations between total fat intake, weight and body fatness from cohort studiesOver half the cohort analyses that reported on primary outcomes suggested that as total fat intake increases, body fatness measures may move in the same direction. However, heterogeneous methods and reporting across cohort studies, and predominantly very low-quality evidence, made it difficult to draw firm conclusions and true relationships may be substantially different., Authors' Conclusions: We were unable to reach firm conclusions. Limited evidence from three trials that randomised children to dietary counselling or education to lower total fat intake (30% or less TE) versus usual or modified fat intake, but with no intention to reduce weight, showed small reductions in body mass index, total- and LDL-cholesterol at some time points with lower fat intake compared to controls. There were no consistent effects on weight, high-density lipoprotein (HDL) cholesterol or height. Associations in cohort studies that related total fat intake to later measures of body fatness in children were inconsistent and the quality of this evidence was mostly very low. Most studies were conducted in high-income countries, and may not be applicable in low- and middle-income settings. High-quality, longer-term studies are needed, that include low- and middle-income settings to look at both possible benefits and harms.

Core-shell particles (superficially porous particles, SPPs) have been proven to provide high-throughput and effective separations of a variety of chiral molecules. However, due to their limited commercialization, many separations have not been reported with these stationary phases. In this study, four SPP chiral stationary phases (CSPs) were utilized for the enantiomeric separation of 150 chiral amines. These amines encompass a variety of structural and drug classes, which are particularly important to the pharmaceutical industry and in forensics. This comprehensive evaluation demonstrates the power of these CSPs and the ease of method development and optimization. The CSPs used in this study included the macrocyclic glycopeptide-based CSPs (VancoShell and NicoShell), the cyclodextrin-based CSP (CDShell-RSP), and the cyclofructan-based CSP (LarihcShell-P). These CSPs offered versatility for a variety of applications and worked in a complementary fashion to baseline separate all 150 amines. The LarihcShell-P was highly effective for separating primary amines. VancoShell, NicoShell, and CDShell-RSP were useful for separating all types of amines. These CSPs are multi-modal and can be utilized with mass spectrometry compatible solvents. Eighteen racemic controlled substances were simultaneously baseline separated in a single liquid chromatography-mass spectrometry (LC-MS) analysis. Details in high-performance liquid chromatography (HPLC) parameters will be discussed as well as the improved chromatographic performance afforded by the SPP CSPs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Primary cutaneous CD30 + T cell lymphoproliferative disorders (PCLPD), the second most common type of primary cutaneous T cell lymphomas, accounts for approximately 25-30% of cutaneous T-cell lymphoma cases. However, only small retrospective studies have been reported. We aimed to identify prognostic factors and evaluate the overall survival (OS) of patients with PCLPD stratified by ethnicity. We identified 1496 patients diagnosed with PCLPD between 2004 and 2014 in the US National Cancer Database. Chi-square test and anova were used to evaluate differences in demographic and disease characteristics, socioeconomic factors and treatments received. OS was evaluated with the log-rank test, Cox proportional hazard regression analysis, and propensity score matching. The study included 1267 Caucasians, 153 African Americans (AA), 43 Asians, and 33 of other/unknown ethnicity. Older age, higher Charlson-Deyo score, higher clinical stage and receipt of chemotherapy were predictors of shorter OS. Primary disease site on a lower extremity was associated with shorter OS, while a head and neck location was associated with longer OS. AA patients had shorter OS when compared to Caucasian patients on multivariate analysis. This ethnic disparity persisted on propensity-score matched analysis and after matching Caucasian and AA patients on demographic and disease characteristics, socioeconomic factors and treatments received, and age and gender-matched relative survival analyses., (© 2018 John Wiley & Sons Ltd.)

Aim: Cisplatin resistance in ovarian cancer remains a complex problem as tumors frequently develop resistance against drugs, a mechanism sometimes mediated by ATP-Binding Cassette transporters. Our goal was to find compounds restricting their inhibition capacity to the cisplatin efflux mediated by ABCC2 pump, among previously identified inhibitors, derived from the 2- indolylmethylenebenzofuranones. Methodology & results: An original method setup allows direct quantitation of platinum by employing cyTOF mass cytometry. Among tested derivatives, some led to a full platinum accumulation and efficiently resensitized cisplatin-resistant A2780 cells to cisplatin while preserving most of the calcein efflux activity., Conclusion: CyTOF is therefore a powerful and promising method to quantify cisplatin accumulation that may be used in the clinical setting to improve and personalize cancer treatment.

It remains controversial whether concurrent or subsequent chemoradiotherapy (CRT) provides additional survival benefits when compared to radiotherapy (RT) alone in localized extranodal natural killer/T-cell lymphoma (ENKTL), nasal type We identified 248 patients from the US National Cancer Data Base who were diagnosed with localized ENKTL from 2004-2014; 68.9% received CRT and 31.1% received RT alone. Over time, the use of CRT increased, while the use of RT alone decreased (p < .001). On multivariate analysis, CRT was associated with longer OS than RT alone (HR: 0.504; 95% CI: 0.338-0.751; p < .001), while uninsured status and African-American race were associated with shorter OS. The survival advantages of CRT over RT alone persisted on propensity score matching for the entire cohort (p = .0014) and in a subgroup analysis of elderly patients (p < .001). In conclusion, patients who received CRT had significantly longer OS than those who received RT alone. These results also apply to elderly patients.