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Objective To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor. Methods We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors. Results Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% [95% CI: 78.9%, 83.4%] for the derivation and 82.3% [95% CI: 779.3%, 85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs. Conclusion The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.

Deep-level underground mining costs in South Africa are continuously rising due to the increased depth at which gold is being mined, resulting in a rise in virgin rock temperature and an increase in cooling requirements. Therefore, mines must evaluate various ventilation and cooling optimisation projects required to be implemented throughout their life of mine (LOM). This study develops a method to identify and prioritise large capital expenditure (CAPEX) underground environmental improvement projects, to improve thermal comfort underground. The solution presents a ‘multi-criteria decision-making’ (MCDM) process, incorporating the ‘analytic hierarchy process’ (AHP) and the ‘technique for order performance by similarity to ideal solution’ (TOPSIS) into the method to provide for scientific decision-making. These projects are evaluated based on four criteria, namely project risk, the impact on the underground thermal comfort, cost, and implementation time. This study’s solution uses ventilation simulations to determine the impact of the projects on the underground environment. The identification and evaluation of an environmental improvement project to best suit the current economic climate, while improving underground conditions and decreasing the safety risk is an essential aspect of the solution developed in this study. The method was implemented on a mechanised deep-level underground mine and showed that surface refrigeration is the most suitable alternative, which was implemented at the case study mine as validation of the developed solution. The study proves that the MCDM method is an adequate solution to incorporate subjective criteria into the decision-making process, resulting in a scientific and structured approach to making significant and complex decisions.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ~80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)–risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Objective During the surgical procedure of deep brain stimulation (DBS), insertion of an electrode in the subthalamic nucleus (STN) frequently causes a temporary improvement of motor symptoms, known as the microlesion effect (MLE). The objective of this study was to determine the correlation between the intraoperative MLE and the clinical effect of DBS. Materials and Methods Thirty Parkinson's disease (PD) patients with Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) part III (MDS-UPDRS III) scores during bilateral STN-DBS implantation were included in this retrospective study. MDS-UPDRS III subscores (resting tremor, rigidity, and bradykinesia) of the contralateral upper extremity were used. During surgery, these subscores were assessed directly before and after insertion of the electrode. Also, these subscores were determined in the outpatient clinic after 11 weeks on average (on-stimulation). All assessments were performed in off-medication state (at least 12 hours medication washout). Results Postinsertion MDS-UPDRS motor scores decreased significantly compared to preinsertion scores (p < 0.001 for both hemispheres). The MLE showed a positive correlation with the clinical effect of DBS in both hemispheres (rho = 0.68 for the primarily treated hemisphere, p < 0.001 and rho = 0.59 for the secondarily treated hemisphere, p < 0.01). Conclusion The MLE has a clinically relevant correlation with the effect of DBS in PD patients. These results suggest that the MLE can be relied upon as evidence of a clinically effective DBS electrode placement.

Contains fulltext : 287686.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity. MATERIAL AND METHODS: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester. RESULTS: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively. CONCLUSION: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

At present there is a significant unmet need for clinically available treatments for Parkinson’s disease (PD) patients to stably restore balance to dopamine network function, leaving patients with inadequate management of symptoms as the disease progresses. Gene therapy is an attractive approach to impart a durable effect on neuronal function through introduction of genetic material to reestablish dopamine levels and/or functionally recover dopaminergic signaling by improving neuronal health. Ongoing clinical gene therapy trials in PD are focused on enzymatic enhancement of dopamine production and/or the restoration of the nigrostriatal pathway to improve dopaminergic network function. In this review, we discuss data from current gene therapy trials for PD and recent advances in study design and surgical approaches.

Gut microbiota alterations in Parkinson’s disease (PD) have been found in several studies and are suggested to contribute to the pathogenesis of PD. However, previous results could not be adequately adjusted for a potential confounding effect of PD medication and disease duration, as almost all PD participants were already using dopaminergic medication and were included several years after diagnosis. Here, the gut microbiome composition of treatment-naive de novo PD subjects was assessed compared to healthy controls (HC) in two large independent case-control cohorts (n = 136 and 56 PD, n = 85 and 87 HC), using 16S-sequencing of fecal samples. Relevant variables such as technical batches, diet and constipation were assessed for their potential effects. Overall gut microbiome composition differed between PD and HC in both cohorts, suggesting gut microbiome alterations are already present in de novo PD subjects at the time of diagnosis, without the possible confounding effect of dopaminergic medication. Although no differentially abundant taxon could be replicated in both cohorts, multiple short chain fatty acids (SCFA) producing taxa were decreased in PD in both cohorts. In particular, several taxa belonging to the family Lachnospiraceae were decreased in abundance. Fewer taxonomic differences were found compared to previous studies, indicating smaller effect sizes in de novo PD.

The low-stakes character of international large-scale educational assessments implies that a participating student might at times provide unrelated answers as if s/he was not even reading the items and choosing a response option randomly throughout. Depending on the severity of this invalid response behavior, interpretations of the assessment results are at risk of being invalidated. Not much is known about the prevalence nor impact of such random responders in the context of international large-scale educational assessments. Following a mixture item response theory (IRT) approach, an initial investigation of both issues is conducted for the Confidence in and Value of Mathematics/Science (VoM/VoS) scales in the Trends in International Mathematics and Science Study (TIMSS) 2015 student questionnaire. We end with a call to facilitate further mapping of invalid response behavior in this context by the inclusion of instructed response items and survey completion speed indicators in the assessments and a habit of sensitivity checks in all secondary data studies.

This note serves as a reminder that incremental fit indices are a form of standardized effect sizes and hence, all reservations with respect to interpretations of standardized effect sizes also transfer to their interpretation. Such a realization has major implications for the interpretation and use of incremental fit indices, for the theoretical (im)possibility of default universal rules of thumb in their application, and for simulation studies mapping incremental fit indices as if their value is comparable in an absolute sense across any and all conditions. A small but illustrative working example centered around the alleged impact of model type will drive these points home.

Humans live in unusually large groups, where relationships are thought to be maintained through complex socio-communicative abilities. The size and quality of social networks are associated with health and well-being outcomes throughout life. However, how some individuals manage to form larger social networks is not well understood. If socio-communicative traits evolved to form and maintain relationships, personality traits should be associated with variation in network size. Here, using the English Longitudinal Study of Ageing (ELSA), we investigate the impact of extraversion, agreeableness, and verbal communication on network size ( N = 5,202) and network size change over time ( N = 1,511) in later life for kin and friend networks. Higher levels of extraversion and agreeableness were associated with greater social network sizes but did not predict network size change over 14 years. The findings are discussed considering the evolutionary hypothesis that communicative and affiliative traits may have evolved to support the maintenance of social networks.

Objectives The use of systemic glucocorticoids (SGCs) is traditionally discouraged in the treatment of PsA and psoriasis due to the risk of psoriatic flares. However, despite this recommendation, SGCs are frequently prescribed for these patients. In this study we reappraise the old paradigm that SGCs are contra-indicated in the treatment of PsA and psoriasis. Methods A systematic search of MEDLINE, EMBASE and the Cochrane Library databases was performed in November 2019 to identify articles on any SGC use compared with no use in the PsA and psoriasis population. Topical glucocorticoid treatment was excluded. Our two primary outcomes focused on the prescribing characteristics and the occurrence of any type of flare. Results Our search yielded 4922 articles, and of these 21 full-text articles were eligible for inclusion. There were 11 retro- and prospective cohorts involving a total of 4,171,307 patients. Of these, 6727 (37.82%) of the patients with PsA and 1 460 793 (35.17%) of the patients with psoriasis were treated with any type of SGC. Ten observational/interventional studies did not report an increased risk or occurrence of psoriatic flares related to SGC use. Conclusion Our results indicate that SGCs are frequently prescribed for PsA and psoriasis patients. The occurrence of psoriatic flares appears to be low upon SGC exposure. In patients with a clear indication for SGCs, e.g. in need of rapid anti-inflammatory therapy or bridging of therapies, the use of SGCs should be considered in view of the low risk of skin flaring. It remains of importance to weigh risks for short- and long-term SGC-related side effects in clinical decision making.

In view of the global pandemic of obesity and related metabolic diseases, there is an increased interest in alternative carbohydrates with promising physiochemical and health-related properties as a potential replacement for traditional sugars. However, our current knowledge is limited to only a small selection of carbohydrates, whereas the majority of alternative rare carbohydrates and especially their properties remain to be investigated. Unraveling their potential properties, like digestibility and glycemic content, could unlock their use in industrial applications. Here, we describe the enzymatic production and

Management of RA patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic DMARDs. Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available biological and/or targeted synthetic DMARDs may be truly ineffective (‘true’ refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that D2T RA is a syndrome involving different pathogenic mechanisms.

Chromatin replication involves the assembly and activity of the replisome within the nucleosomal landscape. At the core of the replisome is the Mcm2-7 complex (MCM), which is loaded onto DNA after binding to the Origin Recognition Complex (ORC). In yeast, ORC is a dynamic protein that diffuses rapidly along DNA, unless halted by origin recognition sequences. However, less is known about the dynamics of ORC proteins in the presence of nucleosomes and attendant consequences for MCM loading. To address this, we harnessed anin vitrosingle-molecule approach to interrogate a chromatinized origin of replication. We find that ORC binds the origin of replication with similar efficiency independently of whether the origin is chromatinized, despite ORC mobility being reduced by the presence of nucleosomes. Recruitment of MCM also proceeds efficiently on a chromatinized origin, but subsequent movement of MCM away from the origin is severely constrained. These findings suggest that chromatinized origins in yeast are essential for the local retention of MCM, which may enhance the ease of replisome assembly.

Objectives To evaluate whether addition of low-moderate dose prednisone to methotrexate (MTX) treatment can alleviate common MTX side-effects in rheumatoid arthritis (RA) patients. Methods We performed a post-hoc analysis of the CAMERA-II trial which randomized (1:1) 236 early DMARD and prednisone naive RA patients to treatment with MTX + prednisone 10 mg daily, or MTX monotherapy during two years. MTX dose was increased using a treat-to-target approach. We used Generalized Estimating Equations to model the occurrence of common MTX side-effects and of any adverse event over time, controlling for disease activity and MTX dose over time and other possible predictors of adverse events. To assess whether a possible effect was prednisone-specific, we performed the same analysis in the U-ACT-EARLY trial, in which the addition of tocilizumab (TCZ) to MTX was compared to MTX monotherapy in a comparable setting. Results MTX side-effects were reported at 5.9% of visits in the prednisone-MTX group, compared to 11.2% in the MTX monotherapy group. After controlling for MTX dose and disease activity over time, treatment duration, age, sex, and baseline transaminase levels, addition of prednisone significantly decreased the occurrence of MTX side-effects (OR: 0.54, CI: 0.38–0.77, p = 0.001). Specifically, the occurrence of nausea (OR 0.46, CI: 0.26–0.83, p = 0.009)) and elevated ALT/AST (OR 0.29, CI: 0.17–0.49, p p = 0.30). No difference in MTX side-effects was found between TCZ-MTX and MTX monotherapy in U-ACT-EARLY (OR 1.05, CI: 0.61–1.80, p = 0.87). Conclusion Addition of 10 mg prednisone daily to MTX treatment in RA patients may ameliorate MTX side-effects, specifically nausea and elevated ALT/AST.

INTRODUCTION: Fetal electrocardiography (NI-fECG) and electrohysterography (EHG) have been proven more accurate and reliable than conventional non-invasive methods (doppler ultrasound and tocodynamometry) and are less affected by maternal obesity. It is still unknown whether NI-fECG and EHG will eliminate the need for invasive methods, such as the intrauterine pressure catheter and fetal scalp electrode. We studied whether NI-fECG and EHG can be successfully used during labor.MATERIAL AND METHODS: A prospective clinical pilot study was performed in a tertiary care teaching hospital. A total of 50 women were included with a singleton pregnancy with a gestational age between 36 +0 and 42 +0 weeks and had an indication for continuous intrapartum monitoring. The primary study outcome was the percentage of women with NI-fECG and EHG monitoring throughout the whole delivery. Secondary study outcomes were reason and timing of a switch to conventional monitoring methods (i.e., tocodynamometry and fetal scalp electrode or doppler ultrasound), repositioning of the abdominal electrode patch, success rates (i.e., the percentage of time with signal output), and obstetric and neonatal outcomes. CLINICAL TRIAL REGISTRATION: Dutch trial register (NL8024).RESULTS: In 45 women (90%), NI-fECG and EHG monitoring was used throughout the whole delivery. In the other five women (10%), there was a switch to conventional methods: in two women because of insufficient registration quality of uterine contractions and in three women because of insufficient registration quality of the fetal heart rate. In three out of five cases, the switch was after full dilation was reached. Repositioning of the abdominal electrode patch occurred in two women. The overall success rate was 94.5%. In 16% (n = 8) of women, a cesarean delivery was performed due to non-progressing dilation (n = 7) and due to suspicion of fetal distress (n = 1). Neonatal metabolic acidosis did not occur. Two neonates (4%) were admitted to the neonatal intensive care unit for complications not related to intrapartum monitoring.CONCLUSIONS: NI-fECG and EHG can be successfully used during labor in 90% of women. Future research is needed to conclude whether implementation of electrophysiological monitoring can improve obstetric and neonatal outcomes.

Importance Non-invasive molecular biomarkers are needed to improve the early, accurate and precise diagnosis of invasive cutaneous melanoma. Objective To independently validate a previously-identified circulating microRNA signature of melanoma (MEL38). Secondly, to develop of a complementary microRNA signature, optimized for prognostication. Design, Setting & Participants MicroRNA expression profiling was performed on plasma samples from a multi-centre observational case-control study, involving patients with primary or metastatic melanoma, melanoma in-situ, non-melanoma skin cancer, or benign nevi. MicroRNA profiles from patients with length of survival, treatment and sentinel node biopsy data were used to develop the prognostic signature. Main Outcomes and Measures The primary outcome of interest for MEL38 was its association with melanoma status, including area under the curve, binary diagnostic sensitivity and specificity, and incidence-adjusted positive and negative predictive values. The prognostic signature was assessed using rates of survival per risk group and relationship to conventional predictors of outcome. Results Circulating microRNA profiles of 372 invasive melanoma patients and 210 control individuals were generated. The average age of all participants was 59, 49% were male. A MEL38 score >5.5 indicated the presence of invasive melanoma. Overall 551/582 (95%) of patients were correctly diagnosed, with 93% sensitivity and 98% specificity. MEL38 score range from 0 to 10 with an area under the curve of 0.98 (95% CI 0.97 to 1.0, P A novel prognostic 12-microRNA signature (MEL12) developed from 232 patients identified low, standard, or high-risk groups, with 94%, 78% and 58% rates of 10-year survival respectively (Log rank P Conclusion and Relevance The circulating MEL38 signature may assist in diagnosing patients with invasive melanoma versus other conditions associated with a lower – or negligible - risk of mortality. A complementary and prognostic MEL12 signature is predictive of SLNB status, clinical stage, and probability of survival. Plasma microRNA profiling may help optimise existing diagnostic pathways as well as enable personalised, risk-informed melanoma treatment decisions.

SummaryThe eukaryotic replicative helicase CMG centrally orchestrates the replisome and leads the way at the front of replication forks1. Understanding the motion of CMG on the DNA is therefore key to our understanding of DNA replication.In vivo, CMG is assembled and activated through a cell-cycle-regulated mechanism involving 36 polypeptides that has been reconstituted from purified proteins in ensemble biochemical studies2,3. Conversely, single-molecule studies of CMG motion have thus far4–6relied on pre-formed CMG assembled through an unknown mechanism upon overexpression of individual constituents7,8. Here, we report the first activation at the single-molecule level of CMG fully reconstituted from purified yeast proteins and the quantification of its motion. We observe that CMG can move on DNA in two ways: by unidirectional translocation and by diffusion. We demonstrate that CMG preferentially exhibits unidirectional translocation in the presence of ATP, whereas it preferentially exhibits diffusive motion in the absence of ATP. We also demonstrate that nucleotide binding halts diffusive CMG. Taken together, our findings support a mechanism by which nucleotide binding allows newly assembled CMG to engage with the DNA within its central channel without melting it, halting its diffusion and facilitating the initial DNA melting required to initiate DNA replication.

Assays that do not distinguish metastatic phenotype

Primer sequences used in realtime quantitative PCR

Genes altered between highly and weakly metastatic tumors

Questionnaires in educational research assessing students' attitudes and beliefs are low-stakes for the students. As a consequence, students might not always consistently respond to a questionnaire scale, but instead provide more random response patterns with no clear link to items' contents. We study inter-individual differences in students' intra-individual random responding profile across 19 questionnaire scales in the TIMSS 2015 eighth-grade student questionnaire in seven countries. A mixture IRT approach was used to assess students' random responder status on a questionnaire scale. A follow-up latent class analysis across the questionnaire revealed four random responding profiles that generalized across countries: A majority of consistent non-random responders, intermittent moderate random responders, frequent random responders, and students that were exclusively triggered to respond randomly on the confidence scales in the questionnaire. We discuss implications of our findings in light of general data-quality concerns and the potential ineffectiveness of early-warning monitoring systems in computer-based surveys.

A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.

PDF file - 732K, A. CLL cells were stimulated with CD40L for 72 hrs. After detachment, cells were incubated with 0.1 �M of ABT-737. Protein lysates were probed for Mcl-1, Bfl-1, Noxa and �-actin. B. Densitometric analysis of Mcl-1/ �-actin levels of fourteen CLL samples is shown. Bars represent the mean � SEM, *** P < .001.

Purpose: Chronic lymphocytic leukemia (CLL) cells in lymph nodes (LN), from which relapses are postulated to originate, display an antiapoptotic profile in contrast to CLL cells from peripheral blood (PB). The BH3 mimetic ABT-737 antagonizes the antiapoptotic proteins Bcl-XL and Bcl-2 but not Mcl-1 or Bfl-1. Previously, it was shown that CD40-stimulated CLL cells were resistant to ABT-737. We aimed to define which antiapoptotic proteins determine resistance to ABT-737 in CLL and whether combination of known antileukemia drugs and ABT-737 was able to induce apoptosis of CD40-stimulated CLL cells.Experimental Design: To mimic the LN microenvironment, PB lymphocytes of CLL patients were cultured on feeder cells expressing CD40L and treated with ABT-737 with or without various drugs. In addition, we carried out overexpression or knockdown of pro- and antiapoptotic proteins in immortalized primary B cells.Results: Upon CD40 stimulation patient-specific variations in ABT-737 sensitivity correlated with differences in levels of Mcl-1 and its antagonist Noxa. Knockdown of Noxa, as well as Mcl-1 overexpression, corroborated the importance of the Noxa/Mcl-1 ratio in determining the response to ABT-737. Inhibition of NF-κB resulted in increased Noxa levels and enhanced sensitivity to ABT-737. Interestingly, increasing the Noxa/Mcl-1 ratio, by decreasing Mcl-1 (dasatinib and roscovitine) or increasing Noxa levels (fludarabine and bortezomib), resulted in synergy with ABT-737.Conclusions: Thus, the Noxa/Mcl-1 balance determines sensitivity to ABT-737 in CD40-stimulated CLL cells. These data provide a rationale to investigate the combination of drugs which enhance the Noxa/Mcl-1 balance with ABT-737 to eradicate CLL in chemoresistant niches. Clin Cancer Res; 18(2); 487–98. ©2011 AACR.

PDF file - 866K, CLL cells were stimulated with CD40L for 48 hrs. After detachment, cells were incubated with 10 �M or 100 �M fludarabine � Q-VD (12,5 �M), � NAC (5mM). Protein lysates were probed for Noxa, Mcl-1 and �-actin.

PDF file - 986K, A. ABT-737 resistant CLL cells were stimulated with CD40L for 72 hours (n=4). The black line shows apoptosis levels from CLL cells detached from the feeder layer and subsequently treated with different concentrations of ABT-737 (0.001-10 �M). CLL cells treated with ABT-737 in the presence of CD40-expressing feeder cells are depicted in gray. B. ABT-737 sensitive CD40-stimulated CLL cells treated with ABT-737 after detachment from feeder cells (black line) and while continuously in contact with CD40-expressing feeder cells (gray line) (n=5).

PDF file - 620K, CLL cells were stimulated with CD40L for the indicated time (24, 48 and 72 hrs). Western blots of Bfl-1 were quantified with Odyssey software in both ABT-737 sensitive (n=4) and ABT-737 resistant (n=4) CD40-stimulated CLL cells. Bars represent the mean � SEM.

PDF file - 793K, Nucleofection with Noxa siRNA or control siRNA was performed on CLL cells in the presence or absence of the proteasoom inhibitor GSI. Protein lysates were probed for Mcl-1, Noxa and �-actin. As a control, lysates of untransfected CLL cells in the presence or absence of GSI are shown.

52-page, 2.4 MB pdf

Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR–based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.

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Envisioning one's (non)smoking future may make (un)desired future identities more accessible, salient, and personally relevant and facilitate smoking cessation. The current study assessed whether a future-self intervention can weaken smoker self-identity and expected identity loss when quitting smoking, and strengthen quitter- and nonsmoker self-identity, while accounting for personal factors—socioeconomic position, nicotine dependence, consideration of future consequences, and clarity of the envisioned future-self. Additionally, it examined the association between smoking-related identity and quitting intention and behavior. ispartof: Social Science & Medicine vol:320 status: Published online

The creative industry is a sector where digitisation inevitably changes work practices and the skill requirements are high. The rapid digitisation makes it imperative for workers to acquire digital skills beyond mere technical use. The aim of this study is twofold: (1) to offer a deeper analysis of the nature and level of 21st-century digital skills and (2) to explore the roles of both individual workers and organisations in skill development. In total, 24 interviews were conducted with founders and managing directors of creative organisations based in the Netherlands. The results show that they believe that workers’ technical skill levels are naturally high; while in fact, digital skills might require attention when content-related aspects are considered. The first priority in this case should be to raise awareness within an organisation’s management. Thereafter, intentional and structural efforts on the part of individual workers and organisations are needed to improve skill development practices in the workplace.

Background: Early identification of patients at risk of psoriatic arthritis (PsA) is essential to facilitate early diagnosis and improve clinical outcomes. Severe cutaneous psoriasis has been proposed to be associated with PsA, but a recent assessment of the evidence is lacking. Therefore, in this systematic review, we address the association of psoriasis skin severity with the presence and development of PsA. Summary: We included articles from a review published in 2014 and supplemented these with recent literature by performing an additional systematic search to identify studies published between 1 January 2013 and 11 February 2021. A meta-analysis was performed when sufficient comparable evidence was available. Of 2,000 screened articles, we included 29 in the analysis, of which 16 were identified by our updated search. Nineteen studies reported psoriasis severity as psoriasis area and severity index (PASI), ten studies as body surface area (BSA), and two studies as “number of affected sites.” Most studies show that more extensive skin disease is associated with the presence of PsA. The quantitative pooled analyses demonstrate higher PASI (mean difference [Δ] 1.59; 95% confidence interval [CI] 0.29–2.89) and higher BSA (Δ 5.31; 95% CI 1.78–8.83) in patients with PsA as compared to psoriasis patients without PsA. Results from prospective studies – that assess the risk of future development of PsA in psoriasis patients – were inconclusive. Key Messages: In patients with psoriasis, more severe skin involvement is associated with the presence of PsA, underpinning the importance of optimal dermatology-rheumatology collaboration in clinical care. There are insufficient data to support the use of psoriasis skin severity to predict the future development of PsA in psoriasis patients.

BackgroundConnective tissue diseases-associated interstitial lung disease (CTD-ILD) is a heterogeneous condition that impairs quality of life and is associated with premature death. Progressive pulmonary fibrosis (PPF) has been identified as an important risk factor for poor prognosis. However, different criteria for PPF are used in clinical studies, which may complicate comparison between trials and translation of study findings into clinical practice.MethodsThis is a retrospective single center study in patients with CTD-ILD. The prognostic relevance of PPF definitions, including INBUILD, ATS/ERS/JRS/ALAT 2022, and simplified progressive fibrosing (simplified PF) criteria, were examined in this cohort and validated in the other reported Dutch CTD-ILD cohort.ResultsA total of 230 patients with CTD-ILD were included and the median follow-up period was six (3—9) years. Mortality risk was independently associated with age (adjusted HR 1.07, p p = 0.045), extent of fibrosis on high-resolution computed tomography (HRCT) at baseline (adjusted HR 1.05, p = 0.018) and baseline DLCO (adjusted HR 0.97, p = 0.013). Patients with regular pulmonary function tests in the first 2 years (adjusted HR 0.42, p = 0.002) had a better survival. The prognostic relevance for survival was similar between the three PPF criteria in the two cohorts.ConclusionHigher age, smoking, increased extent of fibrosis and low baseline DLCO were associated with poor prognosis, while regular pulmonary function evaluation was associated with better survival. The INBUILD, ATS/ERS/JRS/ALAT 2022, and simplified PF criteria revealed similar prognostication.

BACKGROUND Recent studies have shown positive, though small clinical effects of digital smoking cessation (SC) interventions for cancer survivors. However, research on associations between participant characteristics, intervention engagement, and outcomes is limited. OBJECTIVE The aim of this study was to explore predictors and moderators of engagement and outcome of ‘MyCourse Quit Smoking’(in Dutch: ‘MijnKoers Stoppen met Roken’), a digital minimally guided intervention for cancer survivors. METHODS A secondary analysis of data from the randomized controlled trial was performed. The number of cigarettes smoked in the past 7 days at 6-month follow-up was the primary outcome measure. We analyzed interactions between participant characteristics (eleven variables), intervention engagement (three variables), and outcome using Robust Linear (Mixed) Modelling. RESULTS In total, 165 participants were included in our study. Female participants accessed the intervention less often than men (B=-11.12, p=.004). A higher Alcohol Use Disorders Identification Test (AUDIT) score at baseline was associated with a significantly higher number of logins (B=1.10, p CONCLUSIONS Overall, a limited number of associations was found between participant characteristics, engagement and outcome, except for gender, problematic alcohol use, and nicotine dependence. Future studies are needed to shed light on how this knowledge can be used to improve the effects of digital SC programs for cancer survivors. CLINICALTRIAL The Netherlands Trial Register NTR6011; https://www.trialregister.nl/trial/5434

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IntroductionAvian preen oil, secreted by the uropygial gland, is an important source of volatile compounds that convey information about the sender’s identity and quality, making preen oil useful for the recognition and assessment of potential mates and rivals. Although intrinsic factors such as hormone levels, genetic background, and diet can affect preen oil volatile compound composition, many of these compounds are not the products of the animal’s own metabolic processes, but rather those of odor-producing symbiotic microbes. Social behavior affects the composition of uropygial microbial communities, as physical contact results in microbe sharing. We experimentally manipulated social interactions in captive dark-eyed juncos (Junco hyemalis) to assess the relative influence of social interactions, subspecies, and sex on uropygial gland microbial composition and the resulting preen oil odor profiles.MethodsWe captured 24 birds at Mountain Lake Biological Station in Virginia, USA, including birds from two seasonally sympatric subspecies – one resident, one migratory. We housed them in an outdoor aviary in three phases of social configurations: first in same-sex, same-subspecies flocks, then in male-female pairs, and finally in the original flocks. Using samples taken every four days of the experiment, we characterized their uropygial gland microbiome through 16S rRNA gene sequencing and their preen oil volatile compounds via GC-MS.ResultsWe predicted that if social environment was the primary driver of uropygial gland microbiome composition, and if microbiome composition in turn affected preen oil volatile profiles, then birds housed together would become more similar over time. Our results did not support this hypothesis, instead showing that sex and subspecies were stronger predictors of microbiome composition. We observed changes in volatile compounds after the birds had been housed in pairs, which disappeared after they were moved back into flocks, suggesting that hormonal changes related to breeding condition were the most important factor in these patterns.DiscussionAlthough early life social environment of nestlings and long-term social relationships have been shown to be important in shaping uropygial gland microbial communities, our study suggests that shorter-term changes in social environment do not have a strong effect on uropygial microbiomes and the resulting preen oil volatile compounds.

Additional file 1. Fig. S1. Flow diagram showing the study section process. Additional sections.