A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

Enhancing precision medicine: a nomogram for predicting platinum resistance in epithelial ovarian cancer.

BACKGROUND: This study aimed to develop a novel nomogram that can accurately estimate platinum resistance to enhance precision medicine in epithelial ovarian cancer(EOC). METHODS: EOC patients who received primary therapy at the General Hospital of Ningxia Medical University between January 31, 2019, and June 30, 2021 were included. The LASSO analysis was utilized to screen the variables which contained clinical features and platinum-resistance gene immunohistochemistry scores. A nomogram was created after the logistic regression analysis to develop the prediction model. The consistency index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the nomogram's performance. RESULTS: The logistic regression analysis created a prediction model based on 11 factors filtered down by LASSO regression. As predictors, the immunohistochemical scores of CXLC1, CXCL2, IL6, ABCC1, LRP, BCL2, vascular tumor thrombus, ascites cancer cells, maximum tumor diameter, neoadjuvant chemotherapy, and HE4 were employed. The C-index of the nomogram was found to be 0.975. The nomogram's specificity is 95.35% and its sensitivity, with a cut-off value of 165.6, is 92.59%, as seen by the ROC curve. After the nomogram was externally validated in the test cohort, the coincidence rate was determined to be 84%, and the ROC curve indicated that the nomogram's AUC was 0.949. CONCLUSION: A nomogram containing clinical characteristics and platinum gene IHC scores was developed and validated to predict the risk of EOC platinum resistance.

Piperine Improves Hyperuricemic Nephropathy by Inhibiting URAT1/GLUT9 and the AKT-mTOR Pathway.

Uncontrolled hyperuricemia often leads to the development of hyperuricemic nephropathy (HN), characterized by excessive inflammation and oxidative stress. Piperine, a cinnamic acid alkaloid, possesses various pharmacological activities, such as antioxidant and anti-inflammatory effects. In this study, we intended to investigate the protective effects of piperine on adenine and potassium oxonate-induced HN mice and a uric-acid-induced injury model in renal tubular epithelial cells (mRTECs). We observed that treatment with piperine for 3 weeks significantly reduced serum uric acid levels and reversed kidney function impairment in mice with HN. Piperine (5 µM) alleviated uric acid-induced damage in mRTECs. Moreover, piperine inhibited transporter expression and dose-dependently inhibited the activity of both transporters. The results revealed that piperine regulated the AKT/mTOR signaling pathway both in vivo and in vitro. Overall, piperine inhibits URAT1/GLUT9 and ameliorates HN by inhibiting the AKT/mTOR pathway, making it a promising candidate for patients with HN.

Exploring a multiparameter MRI-based radiomics approach to predict tumor proliferation status of serous ovarian carcinoma.

OBJECTIVES: To develop a multiparameter magnetic resonance imaging (MRI)-based radiomics approach that can accurately predict the tumor cell proliferation status of serous ovarian carcinoma (SOC). MATERIALS AND METHODS: A total of 134 patients with SOC who met the inclusion and exclusion criteria were retrospectively screened from institution A, spanning from January 2016 to March 2022. Additionally, an external validation set comprising 42 SOC patients from institution B was also included. The region of interest was determined by drawing each ovarian mass boundaries manually slice-by-slice on T2-weighted imaging fat-suppressed fast spin-echo (T2FSE) and T1 with contrast enhancement (T1CE) images using ITK-SNAP software. The handcrafted radiomic features were extracted, and then were selected using variance threshold algorithm, SelectKBest algorithm, and least absolute shrinkage and selection operator. The optimal radiomic scores and the clinical/radiological independent predictors were integrated as a combined model. RESULTS: Compared with the area under the curve (AUC) values of each radiomic signature of T2FSE and T1CE, respectively, the AUC value of the radiomic signature (T1CE-T2FSE) was the highest in the training set (0.999 vs. 0.965 and 0.860). The homogeneous solid component of the ovarian mass was considered the only independent predictor of tumor cell proliferation status among the clinical/radiological variables. The AUC of the radiomic-radiological model was 0.999. CONCLUSIONS: The radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can accurately predict tumor cell proliferation status of SOC which has high repeatability and may enable more targeted and effective treatment strategies. CRITICAL RELEVANCE STATEMENT: The proposed radiomic-radiological model combining radiomic scores and the homogeneous solid component of the ovarian mass can predict tumor cell proliferation status of SOC which has high repeatability and may guide individualized treatment programs. KEY POINTS: • The radiomic-radiological nomogram may guide individualized treatment programs of SOC. • This radiomic-radiological nomogram showed a favorable prediction ability. • Homogeneous slightly higher signal intensity on T2FSE is vital for Ki-67.

Radiomics derived from T2-FLAIR: the value of 2- and 3-classification tasks for different lesions in multiple sclerosis.

Background: White matter (WM) lesions can be classified into contrast enhancement lesions (CELs), iron rim lesions (IRLs), and non-iron rim lesions (NIRLs) based on different pathological mechanism in relapsing-remitting multiple sclerosis (RRMS). The application of radiomics established by T2-FLAIR to classify WM lesions in RRMS is limited, especially for 3-class classification among CELs, IRLs, and NIRLs. Methods: A total of 875 WM lesions (92 CELs, 367 IRLs, 416 NIRLs) were included in this study. The 2-class classification was only performed between IRLs and NIRLs. For the 2- and 3-class classification tasks, all the lesions were randomly divided into training and testing sets with a ratio of 8:2. We used least absolute shrinkage and selection operator (LASSO), reliefF algorithm, and mutual information (MI) for feature selection, then eXtreme gradient boosting (XGBoost), random forest (RF), and support vector machine (SVM) were used to establish discrimination models. Finally, the area under the curve (AUC), accuracy, sensitivity, specificity, and precision were used to evaluate the performance of the models. Results: For the 2-class classification model, LASSO classifier with RF model showed the best discrimination performance with the AUC of 0.893 (95% CI: 0.838-0.942), accuracy of 0.813, sensitivity of 0.833, specificity of 0.781, and precision of 0.851. However, the 3-class classification model of LASSO with XGBoost displayed the highest performance with the AUC of 0.920 (95% CI: 0.887-0.950), accuracy of 0.796, sensitivity of 0.839, specificity of 0.881, and precision of 0.846. Conclusions: Radiomics models based on T2-FLAIR images have the potential for discriminating among CELs, IRLs, and NIRLs in RRMS.

Revolutionizing vascular imaging: trends and future directions of 4D flow MRI based on a 20-year bibliometric analysis.

Background: Four-dimensional flow magnetic resonance imaging (4D flow MRI) is a promising new technology with potential clinical value in hemodynamic quantification. Although an increasing number of articles on 4D flow MRI have been published over the past decades, few studies have statistically analyzed these published articles. In this study, we aimed to perform a systematic and comprehensive bibliometric analysis of 4D flow MRI to explore the current hotspots and potential future directions. Methods: The Web of Science Core Collection searched for literature on 4D flow MRI between 2003 and 2022. CiteSpace was utilized to analyze the literature data, including co-citation, cooperative network, cluster, and burst keyword analysis. Results: A total of 1,069 articles were extracted for this study. The main research hotspots included the following: quantification and visualization of blood flow in different clinical settings, with keywords such as "cerebral aneurysm", "heart", "great vessel", "tetralogy of Fallot", "portal hypertension", and "stiffness"; optimization of image acquisition schemes, such as "resolution" and "reconstruction"; measurement and analysis of flow components and patterns, as indicated by keywords "pattern", "KE", "WSS", and "fluid dynamics". In addition, international consensus for metrics derived from 4D flow MRI and multimodality imaging may also be the future research direction. Conclusions: The global domain of 4D flow MRI has grown over the last 2 decades. In the future, 4D flow MRI will evolve towards becoming a relatively short scan duration with adequate spatiotemporal resolution, expansion into the diagnosis and treatment of vascular disease in other related organs, and a shift in focus from vascular structure to function. In addition, artificial intelligence (AI) will assist in the clinical promotion and application of 4D flow MRI.

Pomalidomide combined with dexamethasone for the treatment of relapsed/refractory multiple myeloma: a systematic review and meta-analysis.

BACKGROUND: To evaluate the efficacy and safety of pomalidomide in combination treatment of relapsed/refractory multiple myeloma (RRMM). METHODS: Published clinical trials were searched in the Cochrane Library, PubMed, EMBASE to February 2023. The literature was screened and evaluated according to the inclusion criteria, and the data were analyzed by a random effect model. Overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and full grade or ≥ 3 adverse events (AEs) were the outcomes. RESULTS: This study included 31 clinical trials, which included 4776 patients. The pooled ORR of the doublet regimens was 33.3% (95%CI: 27-39%) and the triplet regimens was 66% (95%CI: 58-74%). Among the 25 included studies, the median PFS was 8.29 months (95%CI: 7.27-9.31), and nine studies reported median OS of 19.43 months (95%CI: 14.56-24.30). In terms of safety, the most common hematologic AEs of grade ≥ 3 were neutropenia (41%) and anemia (20%); Non-hematologic AEs were pneumonia (14%) and infection/febrile neutropenia (14%). CONCLUSIONS: Pomalidomide combined treatment regimens have shown good clinical efficacy, especially in pomalidomide + dexamethasone combined with other drugs. In terms of safety, it's important to pay attention to the likelihood of hematological adverse events when used clinically. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42023420644.

LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation.

Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott-Aldrich syndrome protein (WASP) recruits the actin-related protein (ARP) 2/3 complex to assemble branched actin networks. The goal of our study was to assess the potential regulatory role exerted by the novel long noncoding RNA (lncRNA) LINC00869 on hepatocellular carcinoma (HCC) cells. We used HCC cells to overexpress or knockdown LINC00869, analyzed patient data from publicly available databases and Cancer Hospital Affiliated with Zhengzhou University, and used a xenograft mouse model of HCC to study the molecular mechanism associated with LINC00869 expression. We found that high levels of LINC00869 expression were associated with poor prognosis in patients with HCC. Next, we detected an interaction between LINC00869 and both WASP and ARP2 in HCC cells, and observed a modulatory effect of LINC00869 on the phosphorylation of WASP at Y291 and the activity of cell division control protein 42 (CDC42). These modulatory roles were required for WASP/CDC42 activity on F-actin polymerization to enhance membrane protrusion formation and maintain persistent cell polarization. This, in turn, promoted the migration and invasion abilities of HCC cells. Finally, we confirmed the role of LINC00869in vivo, using the tumor xenograft mouse model; and identified a positive correlation between LINC00869 expression levels and the phosphorylation levels of WASP in HCC samples. Overall, our findings suggest a unique mechanism by which LINC00869 orchestrates membrane protrusion during migration and invasion of HCC cells. IMPLICATIONS: LncRNA LINC00869 regulates the activity of CDC42-WASP pathway and positively affects protrusion formation in HCC cells, which expands the current understanding of lncRNA functions as well as gives a better understanding of carcinogenesis.

A novel MRI-based deep learning networks combined with attention mechanism for predicting CDKN2A/B homozygous deletion status in IDH-mutant astrocytoma.

OBJECTIVES: To develop a high-accuracy MRI-based deep learning method for predicting cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion status in isocitrate dehydrogenase (IDH)-mutant astrocytoma. METHODS: Multiparametric brain MRI data and corresponding genomic information of 234 subjects (111 positives for CDKN2A/B homozygous deletion and 123 negatives for CDKN2A/B homozygous deletion) were obtained from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) respectively. Two independent multi-sequence networks (ResFN-Net and FN-Net) are built on the basis of ResNet and ConvNeXt network combined with attention mechanism to classify CDKN2A/B homozygous deletion status using MR images including contrast-enhanced T1-weighted imaging (CE-T1WI) and T2-weighted imaging (T2WI). The performance of the network is summarized by three-way cross-validation; ROC analysis is also performed. RESULTS: The average cross-validation accuracy (ACC) of ResFN-Net is 0.813. The average cross-validation area under curve (AUC) of ResFN-Net is 0.8804. The average cross-validation ACC and AUC of FN-Net is 0.9236 and 0.9704, respectively. Comparing all sequence combinations of the two networks (ResFN-Net and FN-Net), the sequence combination of CE-T1WI and T2WI performed the best, and the ACC and AUC were 0.8244, 0.8975 and 0.8971, 0.9574, respectively. CONCLUSIONS: The FN-Net deep learning networks based on ConvNeXt network achieved promising performance for predicting CDKN2A/B homozygous deletion status of IDH-mutant astrocytoma. CLINICAL RELEVANCE STATEMENT: A novel deep learning network (FN-Net) based on preoperative MRI was developed to predict the CDKN2A/B homozygous deletion status. This network has the potential to be a practical tool for the noninvasive characterization of CDKN2A/B in glioma to support personalized classification and treatment planning. KEY POINTS: • CDKN2A/B homozygous deletion status is an important marker for glioma grading and prognosis. • An MRI-based deep learning approach was developed to predict CDKN2A/B homozygous deletion status. • The predictive performance based on ConvNeXt network was better than that of ResNet network.

Discovery of a novel potential polyphosphate accumulating organism without denitrifying phosphorus uptake function in an enhanced biological phosphorus removal process.

Enhanced biological phosphorus removal (EBPR) is an effective process for phosphorus removal from wastewater. In this study, two lab-scale sequencing batch reactors (SBR) were used to perform EBPR process, in which genus Propioniciclava was unexpectedly accumulated and its relative abundance was over 70 %. A series of tests were conducted to explore the role of Propioniciclava in the two EBPR systems. The two systems performed steadily throughout the study, and the phosphorus removal efficiencies were 96.6 % and 93.5 % for SBR1 and SBR2, respectively. The stoichiometric analysis related to polyphosphate accumulating organisms (PAOs) indicated that polyphosphate accumulating metabolism (PAM) was achieved in the anaerobic phase. It appeared that the Propioniciclava-dominated systems could not perform denitrifying phosphorus removal. Instead, phosphorus was released under anoxic conditions without carbon sources. According to the genomic information from Integrated Microbial Genomes (IMG) database, Propioniciclava owns ppk1, ppk2 and ppx genes that are associated with phosphorus release and uptake functions. By phylogenetic investigation of communities by reconstruction of unobserved states 2 (PICRUSt2) analysis, the abundance of genes related to phosphorus metabolism was much higher than that of genes related to denitrification. Therefore, Propioniciclava was presumed to be a potential PAO without denitrifying phosphorus uptake function. In addition to Propioniciclava, Tessaracoccus and Thiothrix were also enriched in both systems. Overall, this study proposes a novel potential PAO and broadens the understanding of EBPR microbial communities.

A comprehensive investigation to the fate of phosphorus in full-scale wastewater treatment plants using aluminum salts for enhanced phosphorus removal.

This study investigated the fate of phosphorus (P) in 8 full-scale municipal wastewater treatment plants (WWTPs) in Shanghai, China, in which both biological nutrient removal and aluminum-based chemical phosphorus removal were used. The results showed that 83.8-98.9 % P was transferred to the sludge in the 8 WWTPs by both chemical and biological reactions. P speciation analysis indicated that chemical P precipitates accounted for 84.3 % in the activated sludge, of which crystalline AlPO4 and amorphous iron­phosphorus compounds (FePs) were the main components. Sludge with more water-soluble and weakly adsorbed P was generated in the anaerobic-anoxic-oxic (A/A/O) process than in other processes. Among the 8 WWTPs, the one with the largest flow rate and relatively short sludge retention time (SRT) had the best potential to release P from all types of sludge. The recovery potential of P from thickened sludge can be improved by separately thickening the sludge produced in the high-efficiency sedimentation tank or feeding it into the dewatering process directly. Different P removal chemicals and dosing points changed the amount of chemical precipitate formed but had little effect on the composition of P accumulating organisms (PAOs) at the genus level. Although aluminum-based coagulants were applied in the investigated WWTPs, Fe in wastewater had the most positive effect on the proliferation of PAOs. The synthesis of polyphosphate was also related to the metabolism of PAOs as it affected transmembrane inorganic phosphate (Pi) transport and polyhydroxybutyrate (PHB) synthesis. The in-depth understanding of the fate of P is beneficial to improve P recovery efficiency in WWTPs.

Feasibility and effectiveness of automatic deep learning network and radiomics models for differentiating tumor stroma ratio in pancreatic ductal adenocarcinoma.

OBJECTIVE: This study aims to compare the feasibility and effectiveness of automatic deep learning network and radiomics models in differentiating low tumor stroma ratio (TSR) from high TSR in pancreatic ductal adenocarcinoma (PDAC). METHODS: A retrospective analysis was conducted on a total of 207 PDAC patients from three centers (training cohort: n = 160; test cohort: n = 47). TSR was assessed on hematoxylin and eosin-stained specimens by experienced pathologists and divided as low TSR and high TSR. Deep learning and radiomics models were developed including ShuffulNetV2, Xception, MobileNetV3, ResNet18, support vector machine (SVM), k-nearest neighbor (KNN), random forest (RF), and logistic regression (LR). Additionally, the clinical models were constructed through univariate and multivariate logistic regression. Kaplan-Meier survival analysis and log-rank tests were conducted to compare the overall survival time between different TSR groups. RESULTS: To differentiate low TSR from high TSR, the deep learning models based on ShuffulNetV2, Xception, MobileNetV3, and ResNet18 achieved AUCs of 0.846, 0.924, 0.930, and 0.941, respectively, outperforming the radiomics models based on SVM, KNN, RF, and LR with AUCs of 0.739, 0.717, 0.763, and 0.756, respectively. Resnet 18 achieved the best predictive performance. The clinical model based on T stage alone performed worse than deep learning models and radiomics models. The survival analysis based on 142 of the 207 patients demonstrated that patients with low TSR had longer overall survival. CONCLUSIONS: Deep learning models demonstrate feasibility and superiority over radiomics in differentiating TSR in PDAC. The tumor stroma ratio in the PDAC microenvironment plays a significant role in determining prognosis. CRITICAL RELEVANCE STATEMENT: The objective was to compare the feasibility and effectiveness of automatic deep learning networks and radiomics models in identifying the tumor-stroma ratio in pancreatic ductal adenocarcinoma. Our findings demonstrate deep learning models exhibited superior performance compared to traditional radiomics models. KEY POINTS: • Deep learning demonstrates better performance than radiomics in differentiating tumor-stroma ratio in pancreatic ductal adenocarcinoma. • The tumor-stroma ratio in the pancreatic ductal adenocarcinoma microenvironment plays a protective role in prognosis. • Preoperative prediction of tumor-stroma ratio contributes to clinical decision-making and guiding precise medicine.

Febuxostat ameliorates APAP-induced acute liver injury by activating Keap1/Nrf2 and inhibiting TLR4/NF-κB p65 pathways.

Excessive acetaminophen (APAP) application is a major cause of drug-induced liver injury (DILI). Febuxostat (Feb), a drug for reducing uric acid (UA) levels, was demonstrated to relieve hepatic inflammation and reverse organ functions. However, the effect of Feb on APAP-induced DILI and its mechanisms have not been fully explored. In this study, Feb (10 mg/kg) was given to mice by gavage 1 h after APAP (300 mg/kg, i.g.) induction. Serum and liver samples were collected 12 or 3 h after APAP challenge. Feb treatment was found to remarkably improve APAP-induced DILI, as evidenced by reduced serum ALT, AST and UA levels, pathomorphology, inflammatory, and oxidative responses. Consistently, treatment with Feb also reduced the cell injury induced by APAP in LO2 cells. Mechanistically, Feb induced GPX4 expression, activated the Keap1/Nrf2 pathway, and inhibited the TLR4/NF-κB p65 pathway. Feb also inhibited glutathione (GSH) depletion and Jun N-terminal kinase (JNK) activation in the early injury phase. Notably, pretreatment with Feb for 3 days also revealed preventive effects against APAP-induced DILI in mice. Overall, our data revealed a potential health impact of Feb on APAP-mediated DILI in vivo and in vitro, suggesting that Feb might be a potential candidate for treating DILI.

Imaging features of cardioembolic stroke on 4-dimensional computed tomography angiography.

Background: Identifying cardioembolic stroke is important for the decision-making of endovascular treatment and anticoagulation therapy. We aimed to explore the features of cardioembolic stroke on 4-dimensional (4D) computed tomography angiography (4D-CTA) and assess whether these features can assist in classifying stroke etiology. Methods: In this retrospective study, we analyzed the images of 294 patients with acute ischemic stroke (AIS) from July 2020 to February 2022 at the First Affiliated Hospital of Chongqing Medical University, which had been consecutively collected. The data of 110 patients with occlusion of the M1/M2 segment of the middle cerebral artery (MCA) with/without intracranial internal carotid artery (ICA) occlusion were analyzed to calculate the clot burden score (CBS) and collateral score (CS), and the data of 88 patients with a clear origin and distal part were analyzed to measure clot length. Maximum intensity projection (MIP) and time MIP (tMIP) post-processing were used to assess the clot features. The Mann-Whitney U test was used to compare the clot characteristics between the 2 groups. Binary logistic regression was performed to assess the association between the image characteristics and cardioembolic stroke. Moreover, the receiver operating characteristic (ROC) curve was used to test the diagnostic efficacy of MIP/tMIP clot features in classifying cardioembolic stroke. Results: Age, high-risk factors for cerebrovascular disease, high/medium-risk sources of cardioembolic stroke, clot length, CBS, and CS were significantly different between the cardioembolic stroke group and non-cardioembolic stroke group (P<0.05). In the cardioembolic stroke group, the median MIP and tMIP clot length was 12 mm [interquartile range (IQR), 8.3-17.4 mm] and 9.3 mm (IQR, 6.8-14.3 mm), respectively. In the non-cardioembolic stroke group, the median MIP and tMIP clot length was 6.5 mm (IQR, 4.7-11.5 mm) and 5.8 mm (IQR, 3.9-10.6 mm), respectively. Binary logistic regression showed that cardioembolic stroke was significantly associated with MIP-clot length [odds ratio (OR), 1.15; 95% confidence interval (CI): 1.02-1.29; P<0.05], tMIP-clot length (OR, 1.18; 95% CI: 1.02-1.36; P<0.05), and tMIP-CBS (OR, 3.96; 95% CI: 1.08-14.58; P<0.05). The area under the ROC curve (AUC) values of MIP clot length for identifying cardioembolic stroke were 0.75 (95% CI: 0.65-0.84, P<0.05), with a cut-off value of >7.4 mm [sensitivity: 84.62% (95% CI: 69.50-94.10%); specificity: 59.18% (95% CI: 44.20-73.00%)]. The AUC value of tMIP clot length was 0.72 (95% CI: 0.61-0.81, P<0.05), with a cut-off value of >5.4 mm [sensitivity: 92.31% (95% CI: 79.10-98.40%); specificity: 48.98% (95% CI: 34.40-63.70%)]. Conclusions: Clot length and CBS were overestimated on MIP images. Among the clot characteristics, clot length could identify cardioembolic stroke.

A novel approach to enhance methane production during anaerobic digestion of waste activated sludge by combined addition of trypsin, nano-zero-valent iron and activated carbon.

A novel approach with a combination of trypsin, nano-zero-valent iron (NZVI) and activated carbon (AC) was conducted to promote the methane production of waste activated sludge (WAS) during the anaerobic digestion (AD) processes. Results showed that the combined addition of trypsin-NZVI-AC exhibited the synergistic effect during different AD stages. Trypsin mainly facilitated the hydrolysis process and the acetic acid conversion, while NZVI-AC enhanced the substrate metabolism and the electronic transfer to subsequently produce methane. A dose of 1000 mg/L trypsin was optimal to maximize this synergistic effect. Metagenomic analysis showed that trypsin-NZVI-AC addition effectively improved the relative abundance of acetyl-CoA carboxylase, and then strengthened both acetoclastic methanogenesis (M00357) and hydrogenotrophic methanogenesis (M00567). Hydrogenotrophic methanogens such as Methanobacterium, Methanoculleus, and Methanosarcina were greatly enriched with trypsin-NZVI-AC compared with trypsin or NZVI-AC addition. Moreover, electroactive bacteria G. sulfurreducens and G. metallireducens were also enriched by this method to conduct direct interspecies electron transfer among methanogens, leading to the better improvement of methane production. These findings supply a promising way to optimize the enzyme pretreatment technology and elevate the methanogenic efficiency of WAS.

Circulating Non-coding RNAs and Exosomes: Liquid Biopsies for Monitoring Preeclampsia.

Preeclampsia (PE) remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. The early prediction or accurate diagnosis of PE is a concern of researchers. Liquid biopsy can be analyzed for cell-free nucleic acids and exosomes. Because circulating non-coding RNAs (ncRNAs) and peripheral blood exosomes can be detected in the peripheral blood of women in early pregnancy, these vesicles and their contents have become the focus of research on early predictive and diagnostic biomarkers for preeclampsia. In this review, we focus on recent studies addressing the roles of circulating ncRNAs and exosomes in PE, with particular attention paid to the potential application value of placenta-derived exosomes and circulating ncRNAs as PE-specific biomarkers.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.

BACKGROUND: Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). PURPOSE: To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. METHODS: 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. RESULTS: CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p = 0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r = 0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r = 0.45, p = 0.003), and IRLs volume (r = 0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r = -0.30, p = 0.006), deep gray matter (r = -0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p = 0.011); the larger CP volume was associated with higher EDSS scores (r = 0.25, p = 0.014) and lower SDMT Z scores in RRMS (r = -0.26, p = 0.014). CONCLUSION: The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.

Obesity induces male mice infertility via oxidative stress, apoptosis, and glycolysis.

In brief: The current declining trend in male fertility parallels the increasing prevalence of obesity worldwide. This paper revealed that the poor in vitro fertilization rates and decreased sperm motility in obese mice due to excessive oxidative stress enhanced apoptosis and impaired glucose metabolism in the testes. Abstract: Obesity is an urgent public health problem in recent decades, linked to reduced reproductive potential, and negatively affects the success of assisted reproduction technology. The aim of this study is to investigate the mechanisms underlying impaired male fertility caused by obesity. Male C57BL/6 mice fed a high-fat diet for 20 weeks served as mouse models with moderate (20% < body fat rate (BFR) < 30%) and severe obesity (BFR > 30%). Our results showed poor in vitro fertilization rates and decreased sperm motility in obese mice. Abnormal testicular structures were identified in male mice with moderate and severe obesity. The expression level of malondialdehyde increased with obesity severity. This finding indicates that oxidative stress plays a role in male infertility caused by obesity, which was further confirmed by the decreased expression of nuclear factor erythroid 2-related factor 2, superoxide dismutase, and glutathione peroxidases. Our study also found that the expression of cleaved caspase-3 and B-cell lymphoma-2 showed an obesity severity-dependent manner indicating that apoptosis is highly correlated with male infertility caused by obesity. Moreover, the expression of glycolysis-related proteins, including glucose transporter 8, lactate dehydrogenase A, monocarboxylate transporter 2 (MCT2), and MCT4, decreased significantly in the testes of obese male mice, suggesting energy supply for spermatogenesis is impaired by obesity. Taken together, our findings provide evidence that obesity impairs male fertility through oxidative stress, apoptosis, and blockage of energy supply in the testes and suggest that male obesity influences fertility through complex and multiple mechanisms.

Dual-energy CT of the pancreas: comparison between virtual non-contrast images and true non-contrast images in the detection of pancreatic lesion.

PURPOSE: To evaluate the image quality and diagnostic performance for pancreatic lesion between true non-contrast (TNC) and virtual non-contrast (VNC) images obtained from the dual-energy computed tomography (DECT). METHODS: One hundred six patients with pancreatic mass underwent contrast-enhanced DECT examinations were retrospectively included in this study. VNC images of the abdomen were generated from late arterial (aVNC) and portal (pVNC) phases. For quantitative analysis, the attenuation differences and reproducibility of abdominal organs were compared between TNC and aVNC/pVNC measurements. Qualitatively image quality was assessed by two radiologists using a five-point scale, and they independently compared the detection accuracy of pancreatic lesions between TNC and aVNC/pVNC images. The volume CT dose index (CTDIvol) and size-specific dose estimates (SSDE) were recorded to evaluate the potential dose reduction when using VNC reconstruction to replace the unenhanced phase. RESULTS: A total of 78.38% (765/976) of the attenuation measurement pairs were reproducible between TNC and aVNC images, and 71.0% (693/976) between TNC and pVNC images. In triphasic examinations, a total of 108 pancreatic lesions were found in 106 patients, and no significant difference in detection accuracy was found between TNC and VNC images (p = 0.587-0.957). Qualitatively, image quality was rated diagnostic (score ≥ 3) in all the VNC images. Calculated CTDIvol and SSDE reduction of about 34% could be achieved by omitting the non-contrast phase. CONCLUSION: VNC images of DECT provide diagnostic image quality and accurate pancreatic lesions detection, which are a promising alternative to unenhanced phase with a substantial reduction of radiation exposure in clinical routine.