1,695 research outputs found

    Prognostic Implications of Lateral Lymph Nodes in Rectal Cancer:A Population-Based Cross-sectional Study with Standardized Radiological Evaluation after Dedicated Training

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    BACKGROUND: There is an ongoing discussion regarding the prognostic implications of the presence, short-axis diameter, and location of lateral lymph nodes. OBJECTIVE: To analyze lateral lymph node characteristics, the role of downsizing on restaging MRI, and associated local recurrence rates for patients with cT3-4 rectal cancer after MRI re-review and training. DESIGN: Retrospective population-based cross-sectional study. SETTINGS: This collaborative project was led by local investigators from surgery and radiology departments in 60 Dutch hospitals. PATIENTS: A total of 3057 patients underwent rectal cancer surgery in 2016: 1109 had a cT3-4 tumor located ≤8 cm from the anorectal junction, of whom 891 received neoadjuvant therapy. MAIN OUTCOME MEASURES: Local recurrence and (ipsi) lateral local recurrence rates. RESULTS: Re-review identified 314 patients (35%) with visible lateral lymph nodes. Of these, 30 patients had either only long-stretched obturator (n = 13) or external iliac (n = 17) nodes, and both did not lead to any lateral local recurrences. The presence of internal iliac/obturator lateral lymph nodes (n = 284) resulted in 4-year local recurrence and lateral local recurrence rates of 16.4% and 8.8%, respectively. Enlarged (≥7 mm) lateral lymph nodes (n = 122) resulted in higher 4-year local recurrence (20.8%, 13.1%, 0%; p &lt;.001) and lateral local recurrence (14.7%, 4.4%, 0%; p &lt; 0.001) rates compared to smaller and no lateral lymph nodes, respectively. Visible lateral lymph nodes (HR 1.8 [1.1-2.8]) and enlarged lateral lymph nodes (HR 1.9 [1.1-3.5]) were independently associated with local recurrence in multivariable analysis. Enlarged lateral lymph nodes with malignant features had higher 4-year lateral local recurrence rates of 17.0%. Downsizing had no impact on lateral local recurrence rates. Enlarged lateral lymph nodes were found to be associated with higher univariate 4-year distant metastasis rates (36.4% vs 24.4%; p = 0.021), but this was not significant in multivariable analyses (HR 1.3 [0.9-1.]) and did not worsen overall survival. LIMITATIONS: This study was limited by the retrospective design and total number of patients with lateral lymph nodes. CONCLUSIONS: The risk of lateral local recurrence due to (enlarged) lateral lymph nodes was confirmed, but without the prognostic impact of downsizing after neoadjuvant therapy. These results point toward the incorporation of primary lateral lymph node size into treatment planning. See Video Abstract.</p

    The role of O-GlcNAcylation in development

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    A smartphone- and wearable-based biomarker for the estimation of unipolar depression severity

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    Abstract Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely monitored self-reported assessments and objectively measured activities with depression severity assessments often applied in clinical trials. 30 unipolar depressed patients and 29 age- and gender-matched healthy controls were enrolled in this study. Each participant’s daily physiological, physical, and social activity were monitored using a smartphone-based application (CHDR MORE™) for 3 weeks continuously. Self-reported depression anxiety stress scale-21 (DASS-21) and positive and negative affect schedule (PANAS) were administered via smartphone weekly and daily respectively. The structured interview guide for the Hamilton depression scale and inventory of depressive symptomatology–clinical rated (SIGHD-IDSC) was administered in-clinic weekly. Nested cross-validated linear mixed-effects models were used to identify the correlation between the CHDR MORE™ features with the weekly in-clinic SIGHD-IDSC scores. The SIGHD-IDSC regression model demonstrated an explained variance (R2) of 0.80, and a Root Mean Square Error (RMSE) of ± 15 points. The SIGHD-IDSC total scores were positively correlated with the DASS and mean steps-per-minute, and negatively correlated with the travel duration. Unobtrusive, remotely monitored behavior and self-reported outcomes are correlated with depression severity. While these features cannot replace the SIGHD-IDSC for estimating depression severity, it can serve as a complementary approach for assessing depression and drug effects outside the clinic

    Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting

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    Background: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. Methods: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either ‘node-picking’ (the removal of an individual LLN) or ‘partial regional node dissection’ (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those undergoing only rectal resection. Results: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7–3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2–2.5, p = 0.874). Conclusion: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.</p

    Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression

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    Objectives: Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice.Methods: We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/−) and intestinal Slc2a2 KO, to assess the impact of metformin treatment.Results: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/−) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/− animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells.Conclusions: Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.</p

    Exploiting O-GlcNAc transferase promiscuity to dissect site-specific O-GlcNAcylation

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    Protein O-GlcNAcylation is an evolutionary conserved post-translational modification catalysed by the nucleocytoplasmic O-GlcNAc transferase (OGT) and reversed by OGlcNAcase (OGA). How site-specific O-GlcNAcylation modulates a diverse range of cellular processes is largely unknown. A limiting factor in studying this is the lack of accessible techniques capable of producing homogeneously O-GlcNAcylated proteins, in high yield, for in vitro studies. Here, we exploit the tolerance of OGT for cysteine instead of serine, combined with a co-expressed OGA to achieve site-specific, highly homogeneous mono-glycosylation. Applying this to DDX3X, TAB1, and CK2α, we demonstrate that near-homogeneous mono-S-GlcNAcylation of these proteins promotes DDX3X and CK2α solubility and enables production of mono-S-GlcNAcylated TAB1 crystals, albeit with limited diffraction. Taken together, this work provides a new approach for functional dissection of protein O-GlcNAcylation

    Inhibition of GSK3 enhances NRF2 stability and nuclear localisation in pancreatic beta cells

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    Aim: Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause of beta cell dysfunction and apoptosis in diabetes. Nrf2 (Nuclear factor-erythroid 2 p45-related factor 2) is a master regulator of the adaptive response to oxidative stress. Its activity is tightly regulated by cytoplasmic Keap1 (Kelch-like ECH-associated protein-1). We, and others, have now demonstrated that Nrf2 is not only regulated by Keap1 but also by the insulin-regulated protein kinase Gsk3 (Glycogen synthase kinase-3). Phosphorylation of Nrf2 by Gsk3 enhances beta-TrCP binding and ubiquitylation by cullin-1, resulting in increased proteasomal degradation of Nrf2. Thus, we hypothesize that the increase in Gsk3 activity in beta cells suppresses Nrf2 levels and diminishes expression of Nrf2-target genes.Methods: INS1 cells (beta cell line) or isolated C57BL/6J mouse islets were exposed to selective Gsk3 inhibitors (CT) alone or in combination with the Keap1 inhibitor TBE31. Upon lysis, protein and mRNA levels were measured by Western blotting and qPCR, respectively.Results: Treating INS1 cells over 24 hours with TBE31 significantly enhanced Nrf2 protein levels. The presence of CT along with TBE31 resulted in prolonged Nrf2 stability and enhanced nuclear localization (p&lt; 0.05). The level of mRNA for the Nrf2-target gene NAD(P)H Quinone Dehydrogenase 1 (Nqo1) was significantly enhanced by the presence of CT (p&lt; 0.05) in both INS1 and isolated mouse islets.Summary: We have demonstrated that Gsk3 regulates the antioxidant response of pancreatic beta cells by modifying the availability and function of Nrf2. Inhibition of Gsk3 is, therefore, a strategy to investigate for protecting beta cells from antioxidant stress
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