Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2.

Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation-specific homologous factor (EHF), a member of the E26 transformation-specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma-associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor-associated macrophages (TAMs) through the C-C motif chemokine 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co-expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development.

Myeloid-derived suppressor cells in cancer: therapeutic targets to overcome tumor immune evasion.

Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.

Are there more acute cardiac hospitalizations in winter in patients with systemic sclerosis? An analysis from the National Inpatient Sample.

Objective: Cold-induced transient myocardial ischemia has been described in patients with systemic sclerosis. The clinical impact of cold exposure in systemic sclerosis patients with acute cardiac conditions is unknown. We compared the seasonal variation of acute cardiac hospitalizations in patients with and without systemic sclerosis. Methods: We performed a retrospective cross-sectional study using the National Inpatient Sample from 2016 to 2019. The primary outcome was acute cardiac hospitalization primarily due to heart failure, acute myocardial infarction, or cardiac arrhythmias. We compared the proportion of acute cardiac hospitalizations in each season in patients with and without systemic sclerosis. We also performed a subgroup analysis by US geographic region (Northeast, Midwest, South, West). Results: There were a total of 10,118,002 acute cardiac hospitalizations over the 4-year study period. Compared to those without systemic sclerosis, patients with systemic sclerosis who were hospitalized for acute cardiac care were younger (mean age 67 ± 13 vs 70 ± 14 years, p < 0.01), a greater proportion were female (82% vs 45%, p < 0.01), and a smaller proportion were Caucasian (68% vs 71%, p < 0.01). There was a lesser proportion of traditional cardiovascular risk factors in systemic sclerosis compared to non-systemic sclerosis patients. There was no significant difference in the proportion of winter admissions between systemic sclerosis and non-systemic sclerosis patients for total acute cardiac hospitalizations (26.4% vs 25.9%, p = 0.51), heart failure (27.0% vs 26.5%, p = 0.64), acute myocardial infarction (26.9% vs 25.5%, p = 0.50), or arrhythmias (24.3% vs 25.0%, p = 0.68). The results were consistent across all four US geographic regions. Conclusion: Our study did not support that patients with systemic sclerosis had a disproportionally higher risk of acute cardiac hospitalization in winter compared to the general population. We found that systemic sclerosis patients hospitalized for acute cardiac care had a lower burden of traditional cardiovascular risk factors than their non-systemic sclerosis counterparts.

Feedstock and pyrolysis temperature influence biochar properties and its interactions with soil substances: Insights from a DFT calculation.

The use of biochar for soil improvement and emission reduction has been widely recognized for its excellent performance. However, the choice of feedstock and pyrolysis temperature for biochar production significantly affects its surface parameters and interactions with soil substances. In this study, we retrieved 465 peer-reviewed papers on the application of biochar in reducing greenhouse gas emissions and nutrient losses in soil and analyzed the changes in biochar physicochemical parameters from different feedstock and pyrolytic temperatures. Molecular simulation computing technology was also used to explore the impacts of these changes on the interaction between biochar and soil substances. The statistical results from the peer-reviewed papers indicated that biochar derived from wood-based feedstock exhibits superior physical characteristics, such as increased porosity and specific surface area. Conversely, biochar derived from straw-based feedstock was found to contain excellent element content, such as O, N, and H, and biochar derived from straw and produced at low pyrolysis temperatures contains a significant number of functional groups that enhance the charge transfer potential and adsorption stability by increasing surface charge density, charge distribution and bonding orbitals. However, it should be noted that this enhancement may also activate certain recalcitrant C compounds and promote biochar decomposition. Taken together, these results have significant implications for biochar practitioners when selecting suitable feedstock and pyrolysis temperatures based on agricultural needs and increasing their understanding of the interaction mechanism between biochar and soil substances.

Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies.

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide-drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide-drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions.

Neurological intervention transition model for dynamic prediction of good outcome in spontaneous subarachnoid haemorrhage.

Deterioration of neurovascular conditions can be rapid in patients with spontaneous subarachnoid haemorrhage (SAH) and often lead to poor clinical outcomes. Therefore, it is crucial to promptly assess and continually track the progression of the disease. This study incorporated baseline clinical conditions, repeatedly measured neurological grades and haematological biomarkers for dynamic outcome prediction in patients with spontaneous SAH. Neurological intervention, mainly aneurysm clipping and endovascular embolisation, was also incorporated as an intermediate event in developing a neurological intervention transition (NIT) joint model. A retrospective cohort study was performed on 701 patients in spontaneous SAH with a study period of 14 days from the MIMIC-IV dataset. A dynamic prognostic model predicting outcome of patients was developed based on combination of Cox model and piecewise linear mixed-effect models to incorporate different types of prognostic information. Clinical baseline covariates, including cerebral oedema, cerebral infarction, respiratory failure, hydrocephalus and vasospasm, as well as repeated measured Glasgow Coma Scale (GCS), glucose and white blood cell (WBC) levels were covariates contributing to the optimal model. Incorporation of neurological intervention as an intermediate event increases the prediction performance compared with baseline joint modelling approach. The average AUC of the optimal model proposed in this study is 0.7783 across different starting points of prediction and prediction intervals. The model proposed in this study can provide dynamic prognosis for spontaneous SAH patients and significant potential benefits in critical care management.

Discovery of a dual-acting inhibitor of interleukin-1ß and STATs for the treatment of inflammatory bowel disease.

Currently, a significant proportion of inflammatory bowel disease (IBD) patients fail to respond to conventional drug therapy such as immunosuppressants and biologic agents. Interference with the JAK/STAT pathway and blocking of IL-1 signaling are two promising therapeutic strategies for these unresponsive IBD patients. This work describes the discovery of an inhibitor 10v that not only blocks NLRP3 and AIM-2 inflammasome-mediated IL-1ß signaling, but also reduces the expression of STAT1 and STAT5 in the JAK/STAT pathway. Importantly, 10v exhibits a significant anti-IL-1ß effect and decreases the levels of STAT1 and STAT5 in a mouse model of colitis. As a result, a novel small molecule is identified with a dual inhibitory capacity towards both inflammasomes/IL-1ß and STAT pathways, which supports further exploration of the therapeutic potential for IBD patients that do not respond to current drug therapy.

Pan-cancer analysis of ABCC1 as a potential prognostic and immunological biomarker.

ABCC1 belongs to the ATP-binding cassette (ABC) superfamily, which encompasses a total of 48 constituent members. ABCC1 has been shown to be associated with the growth, progression, and drug resistance of various types of cancer. However, the impact of ABCC1 on cancer immune infiltration and pan-cancer prognosis has been rarely studied. Our comprehensive pan-cancer analysis unveiled elevated ABCC1 expression across various cancers. ABCC1 overexpression consistently predicted unfavorable outcomes based on TCGA data. Moreover, ABCC1 expression exhibited intricate associations with diverse immune-related genes and demonstrated a close correlation with immune scores across multiple tumor types. Analysis of scRNA-seq data from the GEO database revealed that the expression of ABCC1 in hepatocellular carcinoma (HCC) cells is significant positively correlated with macrophage infiltration. Furthermore, various in vitro and in vivo experiments substantiated the role of ABCC1 in promoting the progression of HCC, along with increased macrophage recruitment. Based on the results, we propose ABCC1 as a potentially valuable prognostic indicator and a prospective target for immune-based cancer therapies.

Enhancing the transformation of carbon and nitrogen organics to humus in composting: Biotic and abiotic synergy mediated by mineral material.

To investigate the conversion of carbon and nitrogen organic matter to humus mediated by mineral material additives through biotic and abiotic pathways, three chicken manure composting experiments were conducted using calcium superphosphate (CS) and fly ash (FA). Results showed that CS and FA promoted carbon and nitrogen organic degradation and improved compost maturity. The ratio of humic acid-like to fulvic acid-like substances for FA (30) was significantly higher than for control (18) and CS (13). Excitation-emission-matrix spectra and parallel factor analysis identified a higher transformation of protein-like components into humic-like components in FA. Network analysis showed that CS improved compost maturity by promoting the rapid conversion of humus precursors to humus, while FA increased the richness and diversity of the microbial community, such as Chloroflexi, the unique phylum in FA. Overall, CS and FA facilitated the humification process through abiotic and biotic pathways, and FA had better humification performance.

When is the best time and grade to start ruxolitinib in corticosteroid-refractory acute graft-versus-host-disease: A multi-center research.

OBJECTIVE: Ruxolitinib was recently approved to treat corticosteroid-resistant acute graft-versus-host disease (GvHD). However, it is unknown as to whether starting ruxolitinib at a lower versus higher acute GvHD grade or earlier versus later affected outcomes. This study identified the impact of starting acute GvHD grade and start time after declaring corticosteroid resistance and the effect on complete and overall response rates to ruxolitinib therapy. METHODS: Retrospective, observational multi-center study. We divided cohorts into starting ruxolitinib ≤ 7 days (N = 45) versus at > 7 days after declaring corticosteroid resistance (N = 24). RESULTS: In ≤ 7 days cohort complete response (CR) rates at day 28 were 69% (54, 81%) versus 25% (11, 47%; p = .001) in > 7 days cohort, and overall response (OR) rates were 91% (78, 96%) versus 80% (48, 92%; p = .25). CONCLUSIONS: Our data suggest that starting ruxolitinib in ≤ 7 days of declaring corticosteroid failure regardless of G vHD grade improves complete response rate but not OR rates. Starting ruxolitinib at grade I and within 7 days may get a more significant response.

Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study.

OBJECTIVE: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP. METHODS: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA. RESULTS: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10-7). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by eigenvector centrality. CONCLUSIONS: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

Expression of interferon regulatory factor family and its prognostic value in acute myeloid leukemia.

Aim: To elucidate the clinicopathological and prognostic values of interferon regulatory factor (IRF) family genes in acute myeloid leukemia (AML). Patients & methods: Differential expression analysis and survival analysis from several reliable databases were conducted and further validated using patients with AML. Results: The expression level of IRF1/2/4/5/7/8/9 in patients with AML was upregulated, while IRF3/6 expression was downregulated. High IRF1/7/9 expression indicated a worse overall survival rate. Conclusion: Overexpression of IRF1/7/9 may be associated with poor survival in patients with AML, suggesting that the IRF family may be a promising therapeutic target.

Total Lipid Extracts of Honeybee Drone Larvae Are Modulated by Extraction Temperature and Display Consistent Anti-Inflammatory Potential.

Honeybee drone larvae are male bees that develop from unfertilized eggs and play a role in colony reproduction. The nutritional value of honeybee drone larvae is due to their high protein, lipid, and other nutrient contents, making them a profitable food source for humans in some cultures. Drone larvae lipids (DLLs) contribute to drone development; however, few studies have explored their substantial compositions and bioactive functions. In this study, we carried out DLL lipidomics analysis using UPLC-Q-Exactive-Orbitrap-MS prior to in vitro anti-inflammatory activity analysis. The results highlighted the importance of the extraction temperature on the DLL composition. A total of 21 lipids were found in the DLL extract, mostly categorized into five groups: nine phospholipids, three sphingolipids, two neutral lipids, one plant glycoglycerolipid, four lipid acyl, and others. Drying extraction at -20 °C produced more sphingolipids, phospholipids, and unsaturated fatty acids. Of 37 fatty acids, 18 were displayed at -20 °C degrees, as shown by GC-MS quantitative analysis. Myristic (246.99 ± 13.19 µg/g), palmitic (1707.87 ± 60.53 µg/g), stearic (852.32 ± 24.17 µg/g), and oleic (2463.03 ± 149.61 µg/g) acids were the predominant fatty acids. Furthermore, we examined the significant in vitro anti-inflammatory effects of DLL (-20 °C) using lipopolysaccharide (LPS)-challenged RAW264.7 cells. Nitric oxide (NO) and reactive oxygen (ROS) production and mRNA expression of IL-6, IL-10, COX-2, and iNOS were significantly decreased, demonstrating the anti-inflammatory function of DLL. Overall, this study provided insight into the lipid composition of DLL, revealed the influence of temperature, and explored the functionality of DLL (-20 °C), allowing for further application of DLLs as functional foods.

Dexmedetomidine alleviates renal tubular ferroptosis in sepsis-associated AKI by KEAP1 regulating the degradation of GPX4.

Sepsis-associated acute kidney injury (SA-AKI) has a high mortality rate and lacks effective targeted treatment. We applied lipopolysaccharides-induced injury models in human and mouse renal tubular epithelial cells, and at the same time, we selected a commonly used sedative drug, dexmedetomidine, to investigate its potential for renal protection. We found a significant increase in the expression level of HSP90, and the interaction with glutathione peroxidase 4 (GPX4) led to autophagic degradation of GPX4, triggering ferroptosis. Dexmedetomidine reduced the degradation of GPX4 by increasing the binding of KEAP1 and HSP90 in the cytoplasm. Therefore, lipid peroxidation and ferroptosis were reduced. Similarly, dexmedetomidine showed renal protective effects in C57BL/6J male mice with SA-AKI induced by cecal ligation. Our study reveals a new mechanism of renal tubular epithelial cell ferroptosis in SA-AKI treated with dexmedetomidine.

LINC01980 induced by TGF-beta promotes hepatocellular carcinoma metastasis via miR-376b-5p/E2F5 axis.

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies worldwide. However, the molecular mechanism of HCC metastasis is largely unknown. Long non-coding RNA (lncRNA) plays a key role in gene regulation, and dysregulation of lncRNA is critical to cancer metastasis. LINC01980 has been reported in ESCC recently, but the mechanism underlying its function in HCC is still unknown. In this study, we found that LINC01980 was upregulated and associated with notably poor overall survival in HCC patients. Functionally, LINC01980 played a carcinogenic role and promoted HCC metastasis. Mechanically, LINC01980 enhanced the E2F5 expression via competitively binding miR-376b-5p, thereby inducing epithelial-mesenchymal transition and promoting HCC cells migration and invasion. In addition, LINC01980-mediated HCC cells metastasis was dependent on E2F5. What's more, TGF-ß activated LINC01980 transcription through the canonical TGF-ß/SMAD signaling pathway in HCC. In conclusion, LINC01980, activated by the canonical TGF-ß/SMAD pathway, promoted HCC metastasis via miR-376b-5p/E2F5 axis. Therefore, LINC01980 might be a potential prognostic biomarker and therapeutic target of HCC.

SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells.

BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML. METHODS: The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used. RESULTS: Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein. CONCLUSIONS: Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

[Human Umbilical Cord-Derived Mesenchymal Stem Cells Prevent Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation Via Exosome-Mediated MicroRNA and Its Mechanism].

OBJECTIVE: To explore molecular mechanisms by which umbilical cord-derived mesenchymal stem cells suppress the development of GVHD after bone marrow hematopoietic stem cell transplantation. METHODS: A mouse model of aGVHD was constructed after bone marrow hematopoietic stem cell transplantation, and the umbilical cord-derived mesenchymal stem cells were cultured, and then injected into the aGVHD mouse model, so as to investigate its prophylactic efficacy. Prophylactic effect of the exosomes isolated from umbilical cord-derived mesenchymal stem cells on aGVHD mice was assessed. Sequencing analysis of miRNA from exosomes was performed. RESULTS: aGVHD model was successfully constructed after hematopoietic stem cell transplantation. By injecting umbilical cord-derived mesenchymal stem cells into the GVHD mouse model, it was found that the treatment significantly prolonged survival time of mice compared to the untreated group. Injection exosomes derived from umbilical cord-derived mesenchymal stem cells into the GVHD mouse model significantly prolonged the survival time of mice compared to the untreated group. High-throughput sequencing data showed that microRNA such as miR-21 in exosomes isolated from umbilical cord-derived mesenchymal stem cells, which mainly affected the signaling pathways such as cell adhesion, RNA degradation. CONCLUSION: The umbilical cord-derived mesenchymal stem cells can prevent the occurrence of aGVHD after HSCT, which is mediate by MicroRNA in the exosomes derived from umbilical cord-derived mesenchymal stem cells.

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia.

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML progression in patient-derived xenograft (PDX) mouse models. Mechanistically, chiglitazar-mediated PPARα activation inhibited the transcriptional activity of the PIK3AP1 gene promoter and down-regulated the PI3K/Akt signaling pathway and anti-apoptotic Bcl-2 proteins, leading to cell proliferation inhibition and apoptosis induction, which was synergized with venetoclax. These findings suggest that combinatorial Bcl-2 inhibition and PPARα activation selectively eliminates AML cells in vivo and vitro, representing an effective therapy for patients with relapsed and refractory AML.

Fabricating process-electrochemical property correlation of laser-scribed graphene and smartphone-based electrochemical platform for portable and sensitive biosensing.

Laser-scribed graphene (LSG), a promising electrode material has attracted special research interest in recent years. Here, the fabricating process-electrochemical property correlation of laser-scribed graphene (LSG) devices was discussed emphatically and a pertinent optimization was performed to achieve better electroanalytical performance. Experiment results indicated that the laser scribing technique possessed great process latitude and reducing laser power and scribing speed facilitated fabricating high-quality graphene electrodes. Benefiting from its binder-free 3D porous network structure and high active/geometric area ratio, the optimized LSG electrode was superior to the screen-printed carbon electrode (SPCE) on electrochemical performance in the [Fe(CN)6]3-/4- redox system. Integrating the LSG electrode with a homemade hand-held detector, a portable electrochemical sensing platform with smartphone readout was developed. It realized a specific detection of H2O2 (linear range: 0.02-3.4 mM, sensitivity: 24.56 µA mM-1 cm-2), glucose (linear range: 0.04-4.0 mM, sensitivity: 16.35 µA mM-1 cm-2) by directly decorating biological enzymes without artificial redox mediator and featured a satisfactory comprehensive performance. The constructed immunosensor for tumor necrosis factor-α exhibited a wide linear range (2-500 pg mL-1) and a 4.3-fold enhancement in sensitivity compared with that of SPCE. With satisfactory selectivity, reproducibility, and sensitivity, the developed smartphone-based electrochemical sensing platform held great promise in accurate detection on the spot. This work also provided a significant reference for tailoring binder-free carbonaceous electrode materials toward the desired application.

Prognostic significance of pericardial effusion in systemic sclerosis-associated pulmonary hypertension: analysis from the PHAROS Registry.

OBJECTIVES: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to determine the prognostic significance of pericardial effusion in patients with SSc-PH. METHODS: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) is a prospective multicentre registry which enrolled patients with newly diagnosed SSc-PH from 2005 to 2016. The prognostic impact of pericardial effusion status, including those who ever or never had pericardial effusion, and those who had persistent or intermittent pericardial effusion, was analyzed. Kaplan-Meier survival analyses, log-rank test, and multivariable Cox proportional hazards regression were performed. RESULTS: Of the 335 patients with SSc-PH diagnosed by right heart catheterization and documentation of pericardial effusion presence or absence on echocardiogram, 166 (50%) ever had pericardial effusion. Ever having pericardial effusion was not predictive of survival (Log-rank test p= 0.49). Of the 245 SSc-PH patients who had at least two echocardiograms, 44% had a change in pericardial effusion status over an average of 4.3 years of follow up. Having a persistent pericardial effusion was an independent predictor of survival (adjusted hazard ratio [aHR] = 2.34, 95% CI 1.20-4.64, p= 0.002), while intermittent pericardial effusion was not a predictor of survival (aHR = 0.89, 95% CI 0.52-1.56, p= 0.68), in a multivariable-adjusted analysis. CONCLUSION: Persistent pericardial effusion, but not ever having had pericardial effusion or intermittent pericardial effusion, was independently associated with poorer survival. Incorporating information from serial echocardiograms may help clinicians better prognosticate survival in their SSc-PH patients.