Diagnostic accuracy of procalcitonin in adult non-neutropenic cancer patients with suspected infection: a systematic review and meta-analysis.

BACKGROUND: Procalcitonin (PCT) has garnered attention as a potential diagnostic biomarker for infection in cancer patients. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of procalcitonin (PCT) and to compare it with C-reactive protein (CRP) in adult non-neutropenic cancer patients with suspected infection. METHODS: A systematic literature search was performed in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify all relevant diagnostic accuracy studies. Original articles reporting the diagnostic accuracy of PCT for infection detection in adult patients with solid or hematological malignancies were included. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the hierarchical summary receiver operator characteristic (HSROC) curve, and corresponding 95% confidence interval (CI) were calculated. RESULTS: Seven studies were included in the meta-analysis. The pooled sensitivity and specificity of PCT were 60% (95% CI [45-74%]) and 78% (95% CI [69-86%]). The diagnostic odds ratio was estimated at 5.47 (95% CI [2.86-10.46]). Three studies compared the diagnostic accuracies of PCT and CRP. The pooled sensitivity and specificity values for PCT were 57% (95% CI [26-83%]) and 75% (95% CI [68-82%]), and those for CRP were 67% (95% CI [35-88%]) and 73% (95% CI [69-77%]). The pooled sensitivity and specificity of PCT and CRP did not differ significantly (p = 0.61 and p = 0.63). The diagnostic accuracy of PCT was similar to that of CRP as measured by the area under the HSROC curve (0.73, CI = 0.61-0.91 vs. 0.74, CI = 0.61-0.95, p = 0.93). CONCLUSION: While elevated PCT levels can be indicative of potential infection, they should not be solely relied upon to exclude infection. We recommend not using the PCT test in isolation; Instead, it should be carefully interpreted in the context of clinical findings.

Who needs to be screened for primary aldosteronism?

The prevalence of patients with primary aldosteronism (PA) is about 5%-15% in hypertensive patients, and it is common cause of secondary hypertension in clinical practice. Two major causes of PA are noted, namely bilateral adrenal hyperplasia and aldosterone-producing adenoma, and the general diagnosis is based on three steps: (1) screening, (2) confirmatory testing, and (3) subtype differentiation (Figure 1). The recommendation for screening patients is at an increased risk of PA, here we focus on which patients should be screened for PA, not only according to well-established guidelines but for potential patients with PA. We recommend screening for 1) patients with resistant or persistent hypertension, 2) hypertensive patients with hypokalemia (spontaneous or drug-induced), 3) young hypertensive patients (age <40 years), and 4) all hypertensive patients with a history of PA in first-degree relatives. Moreover, we suggest screening for 1) hypertensive patients themselves or first-degree relatives with early target organ damage, such as stroke and other diseases, 2) all hypertensive patients with a concurrent adrenal incidentaloma, 3) hypertensive patients with obstructive sleep apnea, 4) hypertensive patients with atrial fibrillation unexplained by structural heart defects and/or other conditions resulting in the arrhythmia, 5) hypertensive patients with anxiety and other psychosomatic symptoms, and 6) hypertensive patients without other comorbidities to maintain cost-effectiveness.

Proximal tubule-derived exosomes contribute to mesangial cell injury in diabetic nephropathy via miR-92a-1-5p transfer.

BACKGROUND: Diabetic nephropathy (DN) is an increasing threat to human health and regarded to be the leading cause of end-stage renal disease worldwide. Exosomes delivery may play a key role in cross-talk among kidney cells and the progression of DN. However, the mechanisms underlying exosomes in DN remain unclear. METHODS: The cross-disciplinary study, including in vivo, in vitro, and human studies was conducted to explore the cross-talk between proximal tubular epithelial cells (PTECs) and mesangial cells (MCs) in DN. We purified exosome from PTECs treated with high glucose and db/db mice and assessed their influences in the pathologic change of MCs and downstream signal pathway. Healthy individuals and type 2 diabetic patients were enrolled to examine the role of exosomes in clinical applications. RESULTS: High glucose stimulated PTECs to secrete exosomal miR-92a-1-5p, which was taken-up by glomerular MCs, inducing myofibroblast transdifferentiation (MFT) in vitro and in vivo. PTEC-released exosomal 92a-1-5p decreased reticulocalbin-3 expression, leading to endoplasmic reticulum (ER) stress by downregulating genes essential for ER homeostasis including calreticulin and mesencephalic astrocyte-derived neurotrophic factor. Treatment with miR-92a-1-5p inhibitor ameliorated kidney damage in db/db mice with DN. Urinary miR-92a-1-5p could predict kidney injury in type 2 diabetic patients. CONCLUSIONS: PTEC-derived exosomal miR-92a-1-5p modulated the kidney microenvironment in vivo and in vitro models, which altered ER stress and MFT in MCs resulting in DN progression. Further blocking miR-92a-1-5p epigenetic regulatory network could be a potential therapeutic strategy to prevent the progression of DN. Video Abstract.

Diabetic nephropathy (DN) has been the leading cause of end-stage renal disease worldwide. Exosomes play a principle role in cross-talk of kidney cells and further affect the onset or progression of DN. This study firstly demonstrated the communication between proximal tubular epithelial cells (PTECs) and mesangial cells (MCs) through exosome transmission. PTEC-released exosomal 92a-1-5p induced endoplasmic reticulum stress and epithelial-mesenchymal transition in MCs through reticulocalbin-3 modulation. Kidney damage was rescued in DN mice after treatment with miR-92a-1-5p inhibitor. Moreover, urinary exosomal miR-92a-1-5p could predict DN progression in type 2 diabetic patients. These findings prove the impact of exosomal miR-92a-1-5p on pathophysiologic mechanisms and its potential use in clinical care and prediction of DN.

Sex-specific interactive effect of melamine and DEHP on a marker of early kidney damage in Taiwanese adults: A national population-based study from the Taiwan Biobank.

Taiwan had the high incidence of chronic kidney disease (CKD) worldwide. Our objective was to examine associations between daily exposure of phthalates and melamine, two common nephrotoxins, and kidney damage risk in a well-established nationwide cohort. Study subjects were from Taiwan Biobank (TWB) with existing data of questionnaire and biochemical examinations. Average daily intake (ADI) levels of melamine and seven parental phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), DEP (Diethyl phthalate), and DMP (Dimethyl phthalate) were estimated using a creatinine excretion-based model from urine melamine and 10 phthalate metabolites. Urine microalbumin to creatinine ratio (ACR) was used to represent for the outcome of kidney damage. Two statistical strategies were used: First, a weighted quantile sum (WQS) regression model to select the most important exposure variables of ADI levels of phthalates and melamine associated with ACR; Second, to examine effects of those most important exposure variables on ACR in multivariable linear regression models. In total, 1153 eligible adults were left for analyses. Of them, 591 (51.3%) and 562 (48.7%) were men and women, respectively, with a median age of 49 years old. By WQS, a significant and positive association was found between ADI of melamine and phthalates and ACR (ß = 0.14, p = 0.002). ADI levels of melamine had the highest weight (0.57), followed by DEHP (0.13). Next, examining the two most important exposures in association with ACR, we found that the higher the melamine and DEHP intakes, the higher the ACR levels were found. An interaction effect was also found between melamine and DEHP intakes on urine ACR (p = 0.015). This result was more prominent in men (p = 0.008) than in women (p = 0.651). Environmental co-exposure of melamine and DEHP can potentially affect ACR in the community-dwelling Taiwanese adult population.

Effect of extended field-of-view approaches on the accuracy of stopping power ratio estimation for single-energy computed tomography simulators.

BACKGROUND: Extended field-of-view (eFOV) methods have been proposed to generate larger demonstration FOVs for computed tomography (CT) simulators with a limited scanning FOV (sFOV) size in order to ensure accurate dose calculation and patient collision avoidance. Although the efficacy of these strategies has been evaluated for photon applications, the effect of stopping power ratio (SPR) estimation on proton therapy has not been studied. This study investigated the effect of an eFOV approach on the accuracy of SPR to water estimation in homogeneous and heterogeneous phantoms. MATERIALS AND METHODS: To simulate patient geometries, tissue-equivalent material (TEM) and customized extension phantoms were used. The TEM phantom supported various rod arrangements through predefined holes. Images were reconstructed to three FOV sizes using a commercial eFOV technique. A single-energy CT stoichiometric method was used to generate Hounsfield unit (HU) to SPR (HU-to-SPR) conversion curves for each FOV. To investigate the effect of rod location in the sFOV and eFOV regions, eight TEM rods were placed at off-center distances in the homogeneous phantom and scanned individually. Similarly, 16 TEM rods were placed in the heterogeneous TEM phantom and scanned simultaneously. RESULTS: The conversion curves derived from the sFOV and eFOV data were identical. The average SPR differences of soft-tissue, bone, and lung materials for rods placed at various off-center locations were 3.3%, 4.8%, and 39.6%, respectively. In the heterogeneous phantom, the difference was within 1.0% in the absence of extension. However, in the presence of extension, the difference increased to 2.8% for all rods, except for lung materials, whose difference was 4.8%. CONCLUSIONS: When an eFOV method is used, the SPR variation in phantoms considerably increases for all TEM rods, especially for lung TEM rods. This phenomenon may substantially increase the uncertainty of HU-to-SPR conversion. Therefore, image reconstruction with a standard FOV size is recommended.

Critical role of rhythms in prefrontal transcranial magnetic stimulation for depression: A randomized sham-controlled study.

Repetitive transcranial magnetic stimulation (rTMS) is an alternative treatment for depression, but the neural correlates of the treatment are currently inconclusive, which might be a limit of conventional analytical methods. The present study aimed to investigate the neurophysiological evidence and potential biomarkers for rTMS and intermittent theta burst stimulation (iTBS) treatment. A total of 61 treatment-resistant depression patients were randomly assigned to receive prolonged iTBS (piTBS; N = 19), 10 Hz rTMS (N = 20), or sham stimulation (N = 22). Each participant went through a treatment phase with resting state electroencephalography (EEG) recordings before and after the treatment phase. The aftereffects of stimulation showed that theta-alpha amplitude modulation frequency (fam ) was associated with piTBS_Responder, which involves repetitive bursts delivered in the theta frequency range, whereas alpha carrier frequency (fc ) was related to 10 Hz rTMS, which uses alpha rhythmic stimulation. In addition, theta-alpha amplitude modulation frequency was positively correlated with piTBS antidepressant efficacy, whereas the alpha frequency was not associated with the 10 Hz rTMS clinical outcome. The present study showed that TMS stimulation effects might be lasting, with changes of brain oscillations associated with the delivered frequency. Additionally, theta-alpha amplitude modulation frequency may be as a function of the degree of recovery in TRD with piTBS treatment and also a potential EEG-based predictor of antidepressant efficacy of piTBS in the early treatment stage, that is, first 2 weeks.

Benchmark dose in the presence of coexposure to melamine and diethylhexyl phthalate and urinary renal injury markers in pregnant women.

Environmental exposures to mixtures of toxic chemicals have potential interaction effects that may lead to hazard index values exceeding one. However, current regulation levels, such as tolerable daily intake (TDI), are mostly based on experimental studies conducted with a single chemical compound. In this study, we assessed the relationships between melamine and di-(2-ethylhexyl) phthalate (DEHP) exposure and their coexposure with the early renal injury markers N-acetyl -D-glucosaminidase (NAG), albumin/creatinine ratio (ACR), and microalbuminuria in 1236 pregnant women. Various generalized linear models with interaction terms and Bayesian kernel machine regression models were used for the (co-)exposure response associations. We derived the benchmark dose (BMD) and the corresponding one-sided 95% confidence bound BMDL based on the estimated (covariate-adjusted) average daily intake of melamine and DEHP metabolites measured in spot urine of the women collected during the third trimester. Given a benchmark response of 0.1, the BMDL level of melamine (DEHP) exposure on NAG (ACR, microalbuminuria) was 2.67 (11.20, 4.45) µg/kg_bw/day, and it decreased to as low as 1.46 (3.83, 2.73) µg/kg_bw/day when considering coexposure to DEHP (melamine) up to the 90th percentile. Both the exposure threshold levels of melamine and DEHP for early renal injuries in pregnant women were several-fold to one order lower than the current recommended TDIs by the WHO and the US FDA and EPA and were even lower considering coexposure. Because of concurrent exposures in real-world environments, more stringent regulation levels are recommended in susceptible populations, such as pregnant women, due to potential synergistic mixture effects.

Efficient method for whole-breast irradiation therapy using Halcyon linear accelerators.

BACKGROUND: The Halcyon is a linear accelerator-based treatment machine designed for a high-throughput simplified workflow. The machine features a compact jawless design, dual-layer multileaf collimators, and a single 6-MV flattening filter-free (FFF) beam. However, the machine's 6-MV FFF beam may restrict its applicability to conventional techniques, such as field-in-field (FiF) radiotherapy, for breast cancer treatment. This study developed a practical and efficient hybrid method for imaging, planning, and irradiation procedures for whole-breast irradiation using Halcyon linear accelerators. MATERIALS AND METHODS: The proposed method involves five major steps: (1) field arrangement, (2) planning target volume (PTV) generation and evaluation, (3) basal plan generation, (4) inverse planning intensity-modulated radiation therapy plan generation, and (5) plan evaluation and irradiation. The PTV is generated using isodose curves plotted on the basis of tangential fields, which are applied to create a basal plan. Subsequently, a basal-dose-compensation approach is applied to further optimize the treatment plan. This efficient workflow necessitates executing only one onboard cone-beam computed tomography procedure. This study included 10 patients with early-stage breast cancer who were treated at our center. The performance of the proposed method was evaluated by comparing its corresponding irradiation time and dose statistics with those derived for a dynamically flattened beam-based FiF (DFB-FiF) method. RESULTS: All plans were normalized to ensure that 98% of the prescribed dose covered 95% of the PTV. On average, the global maximum doses in the proposed and DFB-FiF methods were lower than 106%. The homogeneity index for right-sided (left-sided) breast cancer was 0.053 (0.056) in the proposed method and 0.073 (0.076) in the DFB-FiF method. The dose statistics of normal tissues, including the contralateral breast, heart, and lungs, were comparable between the methods. However, the irradiation time per monitor unit in the proposed method was approximately five times faster than that in the DFB-FiF method, but the planning time and complexity were similar between the methods. CONCLUSIONS: This study developed and evaluated an efficient and practical hybrid method for whole-breast irradiation using the Halcyon. This method can significantly reduce the irradiation time, while providing comparable dose statistics to the DFB-FiF method.

KITLG Promotes Glomerular Endothelial Cell Injury in Diabetic Nephropathy by an Autocrine Effect.

Diabetic nephropathy (DN) is an increasing threat to human health. The impact of hyperglycemia or its metabolites, advanced glycation end-products (AGEs), on glomerular endothelial cells (GECs) and their pathophysiologic mechanisms are not well explored. Our results reveal that AGEs increased the expression and secretion of the KIT ligand (KITLG) in GECs. Both AGEs and KITLG promoted endothelial-to-mesenchymal transition (EndoMT) in GECs and further increased the permeability of GECs through the AKT/extracellular-signal-regulated kinase pathway. Inhibition of KITLG's effects by imatinib prevented AGE-medicated EndoMT in GECs, supporting the belief that KITLG is a critical factor for GEC injury. We found higher KITLG levels in the GECs and urine of db/db mice compared with db/m mice, and urinary KITLG levels were positively correlated with the urinary albumin-to-creatinine ratio (ACR). Furthermore, type 2 diabetic patients had higher urinary KITLG levels than normal individuals, as well as urinary KITLG levels that were positively correlated with urinary ACR and negatively correlated with the estimated glomerular filtration rate. KITLG plays a pathogenic role in GEC injury in DN and might act as a biomarker of DN progression.

High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery.

Diabetic nephropathy (DN) is an increasing threat to human health and is regarded as an important public issue. The pathophysiologic mechanisms of DN are complicated. The initiating molecular events triggering the loss function in mesangial cells (MCs) in DN are not well known. In this cross-disciplinary study, transcriptome analysis of high glucose (HG)-treated mouse MCs (MMCs) using next-generation sequencing and systematic bioinformatics analyses indicated that miR-15b-5p and its downstream target B cell lymphoma 2 (BCL-2) contribute to HG-induced apoptosis in MMCs. HG elevated miR-15b-5p expression, which in turn decreased the translation of BCL-2, leading to MMC apoptosis under HG. Apoptosis of MCs was enhanced in the presence of extracellular vesicles isolated from the urine of type 2 diabetic patients with high levels of miR-15b-5p. Furthermore, increased levels of urinary miR-15b-5p were found in db/db mice and type 2 diabetic patients, and such levels correlated with low baseline kidney function and rapid decline in kidney function during a mean of follow-up period of 2.4 ± 0.1 years. Therefore, miR-15b-5p induced mesangial cells apoptosis by targeting BCL-2 under HG. miR-15b-5p has the potential to predict kidney injury in DN. Blocking the miR-15b-5p epigenetic regulatory network could be a potential therapeutic strategy to prevent mesangial apoptosis in DN.

The Association of Targeted Gut Microbiota with Body Composition in Type 2 Diabetes Mellitus.

The association between body composition and gut microbiota in type 2 diabetes mellitus (DM) remains unknown. To elucidate the correlation of body composition and gut microbiota, we conducted a clinical study to enroll 179 patients with type 2 DM. Body composition of lean tissue index (LTI) and fat tissue index was measured by Body Composition Monitor. Eight pairs of 16S rRNA gene primers specific to Firmicutes, Bacteroidetes, the Clostridium leptum group, Bacteroides, Bifidobacterium, Akkermansia muciniphila, Escherichia coli, and Faecalibacterium prausnitzii were used to measure their abundance by quantitative polymerase chain reaction. The results showed that type 2 DM with higher abundance of phylum Firmicutes and a higher ratio of phyla Firmicutes to Bacteroidetes (phyla F/B ratio) had higher LTI. This significant correlation between phyla F/B ratio and LTI was especially evident in type 2 DM with high body mass index, and independent of glycemic control or dipeptidyl peptidase-4 inhibitor usage. In conclusion, our study demonstrated the positive association of LTI with the abundance of phylum Firmicutes and the phyla F/B ratio in type 2 DM.

Melamine and oxalate coexposure induces early kidney tubular injury through mitochondrial aberrations and oxidative stress.

Exposure to melamine, which is ubiquitous in daily life, is linked to adverse kidney outcomes. The melamine tolerable daily intake in humans is based on the no-observed-effect-level (NOEL) established in a single-toxicant murine model. However, humans are often simultaneously exposed to multiple environmental nephrotoxicants. The NOEL of melamine during coexposure with other toxicants needs to be evaluated. Oxalate is a potentially nephrotoxic terminal metabolite, and hyperoxaluria is reportedly associated with chronic kidney disease. We explored whether these two potential nephrotoxicants can interact and enhance kidney injury. We established a Sprague-Dawley rat model of coexposure to the melamine NOEL (63 mg/kg/day) and 2% hydroxy-L-proline (HLP, an oxalate precursor) in drinking water to simulate human environmental melamine exposure. Melamine/oxalate coexposure increased proximal tubular cell mitochondrial reactive oxygen species levels, lipid peroxidation and oxidative DNA damage. The degrees of mitochondrial damage, tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated in coexposed rat kidneys. The evidence indicated that exposure to the melamine NOEL can cause renal tubular injury via oxidative stress and that this effect may be enhanced via interaction of melamine with other environmental factors, such as oxalate. Thus, melamine risk assessment and toxicity prevention should be conducted carefully in different susceptible populations.

Taiwan mini-frontier of primary aldosteronism: Updating treatment and comorbidities detection.

The aim of this study was to update the information on internationally acceptable standards and clinical practice recommendations for the management of patients with primary aldosteronism (PA). The Taiwan Society of Aldosteronism (TSA) Task Force acknowledged the novel issues of PA and reached a group consensus on PA in Taiwan by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. Unilateral adrenalectomy is the preferred treatment for patients with aldosterone-producing adenoma (APA). For medical treatment with mineralocorticoid receptor antagonists (MRAs), spironolactone is the first-line treatment, and eplerenone is a reasonable alternative in PA patients intolerant or contraindicated to spironolactone. The dose of MRAs can be titrated according to plasma renin activity (PRA). For screening PA-related comorbidities, we suggest albuminuria to predict a post-treatment decline in renal function, echocardiography as cardiac evaluation, bone mineral density scan for osteoporosis, and obstructive sleep apnea. In tissue and genetic surveys, we suggest immunohistochemical staining and somatic mutation screening for post-operative adrenal specimens in APA patients. With this consensus, we hope to update the information on PA for clinical physicians to facilitate better identification, management and treatment of patients with PA.

ß-blocker dialyzability and the risk of mortality and cardiovascular events in patients undergoing hemodialysis.

BACKGROUND: ß-blocker (BB) dialyzability has been proposed to limit their efficacy among hemodialysis (HD) patients. We attempted to confirm this hypothesis by comparing health outcomes associated with the initiation of dialyzable or nondialyzable BBs in a nationwide cohort of HD patients. METHODS: We created a prospective cohort study of 15 699 HD patients who initiated dialyzable BBs (atenolol, acebutolol, metoprolol and bisoprolol) and 20 904 hemodialysis patients who initiated nondialyzable BBs (betaxolol, carvedilol and propranolol) between 2004 and 2011 in Taiwan healthcare. We compared the risk of all-cause mortality and major adverse cardiovascular events (MACEs, a composite of the acute coronary syndrome, ischemic stroke and heart failure) between users of dialyzable versus nondialyzable BBs during a 2-year follow-up. RESULTS: New users of dialyzable BBs were younger, more often men, with diabetes mellitus, hypertension and hyperlipidemia compared with users of nondialyzable BBs. Compared with nondialyzable BBs, initiation of dialyzable BBs was associated with lower all-cause mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.75-0.88]} and lower risk of MACEs [HR 0.89 (95% CI 0.84-0.93)]. Results were confirmed in subgroup analyses, censoring at BB discontinuation or switch, after 1:1 propensity score matching, reclassifying bisoprolol or excluding bisoprolol/carvedilol users. CONCLUSIONS: This study does not offer support for the hypothesis that the dialyzability of BBs reduces their efficacy in HD patients.

A probabilistic approach for benchmark dose of melamine exposure for a marker of early renal dysfunction in patients with calcium urolithiasis.

Environmental exposure to melamine has been associated with early renal injury in urolithiasis patients even when urinary concentrations of melamine are low. The aim of this study was to derive a benchmark dose (BMD) for melamine for urolithiasis patients. To do this, one-spot urine sample from 309 participants was obtained to measure urinary melamine and N-acetyl ß-D-glucosaminidase (NAG), an early renal damage biomarker. The participants were then classified into four exposure groups based on the outcomes of melamine tableware usage questionnaire. A beta distribution of urinary excretion fraction for each group was assumed to estimate their average daily intakes (AvDIs) of melamine. The BMD and the corresponding one-sided 95% lower bound (BMDL) was then derived based on Bayesian model averaging of alternative regression models between the participants' NAG levels and their estimated AvDIs, adjusting for age, gender, and other covariates. Bayesian Markov chain Monte Carlo simulations were used for all the estimates. With a benchmark response of 0.10, the simulated BMDL of 4.89 µg/kg-bw/day for melamine exposure threshold was much lower than the WHO's current recommended tolerable daily intake of 200 µg/kg_bw/day and the US FDA's 63 µg/kg_bw/day. The current regulation level of melamine might not safeguard urolithiasis patients from further deterioration of renal function.

Fragment-Based Covalent Ligand Screening Enables Rapid Discovery of Inhibitors for the RBR E3 Ubiquitin Ligase HOIP.

Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and alterations in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signaling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multiprotein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochemical ubiquitination assays, chemical synthesis, and protein crystallography to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics, we demonstrate that these compounds effectively penetrate mammalian cells to label and inhibit HOIP and NF-κB activation, making them suitable hits for the development of selective probes to study LUBAC biology. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compounds for challenging targets, which holds promise to be a general approach for the development of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.

Independent Association of Overhydration with All-Cause and Cardiovascular Mortality Adjusted for Global Left Ventricular Longitudinal Systolic Strain and E/E' Ratio in Maintenance Hemodialysis Patients.

BACKGROUND/AIMS: Fluid overload is common and associated with morbidity and mortality in patients with end-stage renal disease. The relationship between fluid overload and cardiac function is complex, and whether fluid overload is associated with adverse outcomes in patients undergoing hemodialysis (HD) independently of systolic and diastolic function of the left ventricle (LV) remains unclear. METHODS: The present study aimed to investigate the relationship between overhydration and all-cause and cardiovascular (CV) mortality after adjusting for LV function in 178 maintenance HD patients. The relative hydration status (overhydration/ extracellular water, ∆HS) was measured using a body composition monitor, and then used to assess the fluid status. A ∆HS ≥7% was defined as fluid overload. Global left ventricular longitudinal systolic strain (GLS), and the early filling and early diastolic mitral annular velocity (E/E') ratio were assessed using speckle-tracking and tissue Doppler echocardiography. RESULTS: During a mean follow-up period of 2.7 years, 24 patients died, including 11 CV deaths. An increased ∆HS was significantly associated with all-cause and CV mortality in the univariate analysis. This prognostic significance remains after multivariate adjusting for GLS and E/E' ratio for all-cause (HR, 1.123; 95% CI, 1.063-1.186; p-value < 0.001) and CV (HR, 1.088; 95% CI, 1.005-1.178; p-value =0.037) mortality. Moreover, ∆HS significantly improved the prognostic value beyond conventional clinical and echocardiographic parameters. CONCLUSION: A higher ∆HS was independently associated with increased all-cause and CV mortality after adjusting for systolic and diastolic function of the LV. This suggests that ∆HS may be a relevant target for improving outcomes in maintenance HD patients.

Angiopoietin-2, Renal Deterioration, Major Adverse Cardiovascular Events and All-Cause Mortality in Patients with Diabetic Nephropathy.

BACKGROUND/AIMS: Diabetic nephropathy is the leading cause of end-stage renal disease and accounts for 30∼40% of patients requiring maintenance dialysis, thereby increasing the burden on health insurance programs. Diabetic nephropathy is also the strongest predictor of cardiovascular morbidity and mortality. The aim of this study was to examine whether angiopoietin-2 (Angpt2), a modulator of endothelial function, affects the clinical outcomes of diabetic patients. METHODS: This study enrolled 236 patients with diabetes mellitus with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 from January 2006 to December 2011, who were followed until June 2017. Clinical outcomes included renal outcomes (commencing dialysis and rapid decline in renal function (eGFR decline > 3 ml/min per 1.73 m2/year)), major adverse cardiovascular events (MACEs), and all-cause mortality. RESULTS: Over a mean follow-up period of 3.9±2.7 years, 135 (57.2%) patients commenced dialysis, 106 (44.9%) had rapid decline in renal function, and 50 (21.2%) had MACEs or died from all-causes. Log-formed Angpt2 was significantly associated with increased risks of commencing dialysis (HR: 3.91, 95% CI: 1.56-9.76), rapid renal function decline (OR: 6.81, 95% CI: 1.06-43.88), and MACEs or all-cause mortality (HR: 6.34, 95% CI: 1.18-33.97) in the adjusted analysis. Patients in the highest quartile had hazard ratios of 2.90 and 3.11 for commencing dialysis and rapid renal function decline, respectively, compared to those in the lowest quartile after adjustments. Similar significant dose-response results were found in composite outcomes of either MACEs or all-cause mortality. CONCLUSION: Angpt2 is an independent predictor of adverse clinical outcomes in diabetic patients. Further studies are needed to identify the pathogenic role of Angpt2 in renal deterioration and cardiovascular complications of diabetes mellitus.

Association between albumin and C-reactive protein and ankle-brachial index in haemodialysis.

AIM: Peripheral artery occlusive disease (PAOD) is associated with increased rates of cardiovascular mortality, morbidity and hospitalization in patients undergoing dialysis. An ankle-brachial index (ABI) less than 0.9 has been used to diagnose PAOD. The aim of this study was to evaluate associations among inflammation, malnutrition and their interactions on the risk of PAOD. METHODS: Two hundred and twenty-two haemodialysis patients (mean age 61.0 ± 11.7 years, 56.8% men) were enrolled and stratified into four groups according to median values of albumin (3.87 g/dL) and logarithm of C-reactive protein (CRP) (0.48 mg/L). Associations between the study groups and an ABI less than 0.9 were assessed using multiple logistic regression analysis. Receiver operating characteristic curves were constructed to predict an ABI less than 0.9. RESULTS: A lower level of albumin and higher level of CRP were significantly associated with an ABI less than 0.9 in multivariate analysis (odds ratio, 5.688; 95% confidence interval, 1.369-23.626; P = 0.017) after adjusting for demographic, clinical, biochemical and medication data. The interaction between albumin and CRP in relation to an ABI less than 0.9 was significant in multivariate analysis (odds ratio, 1.797; 95% confidence interval, 1.258-2.568; P = 0.001). The areas under the curve for albumin, CRP and albumin + CRP for the prediction of ABI less than 0.9 were 0.311, 0.654 and 0.733, respectively. CONCLUSION: Patients undergoing haemodialysis with a lower albumin level and higher CRP level have an increased risk of PAOD. A combination of malnutrition and inflammation may be associated with PAOD in haemodialysis patients.

Electrophysiological and behavioral evidence reveals the effects of trait anxiety on contingent attentional capture.

Few studies have investigated the effects of anxiety on contingent attentional capture. The present study examined contingent attentional capture in trait anxiety by applying a rapid serial visual presentation (RSVP) paradigm during electroencephalographic recording. Overall, the behavioral and electrophysiological results showed a larger capture effect when a distractor was the same color as the target compared to when the distractor was not of the target color. Moreover, high-anxiety individuals showed a larger N2pc in the target colored distractor condition and nontarget colored distractor condition compared to the distractor-absent condition. In addition, the reaction time was slower when distractors were presented in the left visual field compared to when they were in the right visual field. This pattern was not seen in low-anxiety individuals. The findings may indicate that high-anxiety individuals allocate attention to the target less efficiently and have reduced suppression of distractors compared to low-anxiety individuals who could suppress attention to the distractors more efficiently. Future work could valuably investigate the consequences of such differences in terms of benefits and disruption associated with attentional capture differences in a range of anxious populations in different risk monitoring situations.