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Background: Whether hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and acute esophagogastric variceal bleeding (EGVB) can improve the success rate of endoscopic hemostasis and overall survival (OS) from transjugular intrahepatic portosystemic shunt (TIPS) remains controversial., Aim: To compare the clinical outcomes between TIPS and standard treatment for such HCC patients., Methods: This monocenter, retrospective cohort study included patients diagnosed as HCC with PVTT and upper gastrointestinal bleeding. Patients were grouped by the treatment (TIPS or standard conservative treatment). The success rate of endoscopic hemostasis, OS, rebleeding rates, and main causes of death were analyzed., Results: Between July 2015 and September 2021, a total of 77 patients (29 with TIPS and 48 with standard treatment) were included. The success rate of endoscopic hemostasis was 96.6% in the TIPS group and 95.8% in the standard treatment group. All the 29 patients in TIPS group successful underwent TIPS procedure and had a better OS compared with standard treatment within the first 160 days after treatment (68 days vs 43 days, P = 0.022), but shorter OS after 160 days (298 days vs 472 days, P = 0.022). Cheng's Classification of PVTT, total bilirubin and Child-Pugh class were independently negative associated with OS (all P < 0.05). The main causes of death were liver failure or hepatic encephalopathy (75.9%) in the TIPS group and rebleeding (68.8%) in the standard treatment., Conclusion: TIPS could reduce the risk of early death due to rebleeding and prolong short-term survival in HCC patients with PVTT and acute EGVB, which deserves further investigation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Leptomeningeal metastases (LMs) remain a devastating complication of non-small cell lung cancer (NSCLC), particularly following osimertinib resistance. We conducted single-cell RNA sequencing on cerebrospinal fluid (CSF) from EGFR-mutant NSCLC with central nervous system metastases. We found that macrophages of LMs displayed functional and phenotypic heterogeneity and enhanced immunosuppressive properties. A population of lipid-associated macrophages, namely RNASE1&#95;M, were linked to osimertinib resistance and LM development, which was regulated by Midkine (MDK) from malignant epithelial cells. MDK exhibited significant elevation in both CSF and plasma among patients with LMs, with higher MDK levels correlating to poorer outcomes in an independent cohort. Moreover, MDK could promote macrophage M2 polarization with lipid metabolism and phagocytic function. Furthermore, malignant epithelial cells in CSF, particularly after resistance to osimertinib, potentially achieved immune evasion through CD47-SIRPA interactions with RNASE1&#95;M. In conclusion, we revealed a specific subtype of macrophages linked to osimertinib resistance and LM development, providing a potential target to overcome LMs., Competing Interests: Declaration of interests Y.-L.W. has received honoraria from AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, and Sanofi and has consulting or advisory roles with AstraZeneca, Roche, Merck, Boehringer Ingelheim, and Roche outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD., (© 2024. The Author(s).)

Objectives: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein-Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation., Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB-treated PLELC. Viral EBNA-1 and BamHI-W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction., Results: Progression-free survival (PFS) was significantly longer in EBNA-1 high or BamHI-W high groups. A longer PFS was also observed in patients with both high plasma EBNA-1 or BamHI-W and PD-L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA-1 and BamHI-W . Plasma EBV load was negatively associated with intratumoral CD8 + immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months., Conclusions: Plasma EBV DNA could be a useful and easy-to-use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging., Competing Interests: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

The stability of coal pillar is extremely important to the control of rock strata movement and surface subsidence. It is of great significance for mining design to analyze the stability and failure characteristics of coal and rock pillars left after mining and to study the failure characteristics and rheological properties of coal and rock with different shapes. In this paper, based on uniaxial compression and rheological tests on rock samples, the rheological properties of rock samples with different shapes were discussed by using the nonlinear theoretical mechanics and damage theory, and the rheological mechanical characteristics of coarse yellow sandstone samples under the action of different free surface areas and the same loading contact area were investigated by means of experimental research, theoretical analysis and numerical simulation. The following conclusions were drawn: the failure characteristics and dynamic change process of rock samples with different shapes under the same loading contact area are obtained by uniaxial compression test and multi-stage rheological loading. The uniaxial compressive strengths of rock samples with the same loading contact surface area and different free surface areas are inversely proportional to their free surface areas. For the round sample, the stress level in the rheological test is obviously lower than the instantaneous peak uniaxial compression strength, while for the other samples, the stress level in the rheological test is close to the instantaneous peak uniaxial compression strength. For rock all these samples, both the ratio of steady-state rheological time to final failure time and the deformation degree decrease with the increase of free surface area., (© 2023. The Author(s).)

Objective: To analyze and compare the efficacy and safety of pingyangmycin fibrin glue composite (PFG) and pingyangmycin dexamethasone composite (PD) in the treatment of pharyngolaryngeal venous malformation (VM). Methods: The clinical data of 98 patients with pharyngolaryngeal VM who underwent sclerotherapy with pingyangmycin composite in the First Affiliated Hospital of Sun Yat-sen University from June 2013 to November 2022 were retrospectively analyzed. According to their treatment, patients were divided into PFG group ( n =34) and PD group (n=64), among those patients there were 54 males and 44 females, aged 1-77(37.06±18.86)years. The lesion size, total treatment times and adverse events were recorded before and after treatment. And the efficacy was divided into three grades: recovery, effective and invalid. According to the length of VM, all patients were divided into three subgroups, to compare the differences in efficacy and treatment times between each two groups.And finally the adverse events and their treatments were analyzed. SPSS 25.0 software was used for statistical analysis. Results: The efficacy of PFG group was 94.11%(32/34), the recovery rate was 85.29%(29/34).And the efficacy of PD group was 93.75%(60/64), the recovery rate was 64.06%(41/64). No serious adverse eventst occurred in subgroup comparison, there was no statistical difference between the two groups in efficacy and the times of treatments when the length was≤3 cm ( Z efficacy =1.04, t treatment times =2.18, P >0.05); when the length was 3-5 cm, there was no significant efficacy difference between the two groups( Z efficacy =1.17, P >0.05), but the treatment times of PFG were less ( t treatment times =4.87, P <0.01); when the length≥5 cm, efficacy of PFG was significantly better than PD ( Z efficacy =2.94, P <0.01), and had fewer treatments times ( t treatment times =2.16, P <0.01). There were no serious adverse events in either group during treatment and follow-up. Conclusion: Both PFG and PD are safe and effective composite sclerotherapy agent for the treatment of laryngeal VM, but PFG has a higher cure rate and fewer treatment times for massive lesions.

Humans are exposed to a wide variety of natural and engineered nanoparticles (NPs) during their lifetime. However, the effects of pre-exposure to NPs on subsequent uptake of other NPs have not been investigated. In the present study, we investigated the effects of pre-exposure to three NPs (TiO 2 , Fe 2 O 3 , and SiO 2 NPs) on the subsequent uptake of gold NPs (AuNPs) by hepatocellular carcinoma cells (HepG2). When HepG2 cells were pre-exposed to TiO 2 or Fe 2 O 3 NPs, but not SiO 2 NPs for 2 days, their subsequent uptake of AuNPs was inhibited. Such inhibition was also observed in human cervical cancer (HeLa) cells, suggesting that this phenomenon is present in different cell types. The mechanisms underlying the inhibitory effect of NP pre-exposure include altered plasma membrane fluidity due to changes in lipid metabolism and reduced intracellular ATP production due to decreased intracellular oxygen. Despite the inhibitory effects of NP pre-exposure, full recovery was observed after transferring the cells to medium without NPs, even when the pre-exposure time was extended from 2 days to 2 weeks. Overall, the pre-exposure effects observed in the present study should be considered in the biological application and risk evaluation of NPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC., Objectives: We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy., Design: Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection., Methods: This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system., Results: Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC - , KIT - CTC, and KIT + CTC at baseline ( p  = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 versus 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 versus 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95)., Conclusions: CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation., Trial Registration: NCT01740804., Competing Interests: Yi-Long Wu reports receiving speaker bureau fees from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., Roche AG, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, and Sanofi and research grants from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., and Roche AG. Other authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Aquatic organisms are frequently exposed to various nanoparticles (NPs) in the natural environment. Thus, studies of NP bioaccumulation should include organisms that have been previously exposed to NPs. Our study investigated the effects of pre-exposure of Tetrahymena thermophila ( T. thermophila ) to Fe 2 O 3 or TiO 2 NPs on the protozoan's subsequent uptake of 55 Fe-labeled Fe 2 O 3 ( 55 Fe 2 O 3 ) NPs. Molecular mechanisms underlying the pre-exposure effects were explored in transcriptomic and metabolomic experiments. Pre-exposure to either NPs inhibited the subsequent uptake of 55 Fe 2 O 3 NPs. The results of the transcriptomic experiment indicated that NP pre-exposure influenced the expression of genes related to phagosomes and lysosomes and physiological processes such as glutathione and lipid metabolism, which are closely associated with the endocytosis of 55 Fe 2 O 3 NPs. The differentially expressed metabolites obtained from the metabolomic experiments showed an enrichment of energy metabolism and antioxidation pathways in T. thermophila pre-exposed to NPs. Together, these results demonstrate that the pre-exposure of T. thermophila to Fe 2 O 3 or TiO 2 NPs inhibited the protozoan's subsequent uptake of 55 Fe 2 O 3 NPs, possibly by mechanisms involving the alteration of endocytosis-related organelles, the induction of oxidative stress, and a lowering of the intracellular energy supply. Thus, NP pre-exposure represents a scenario which can inform increasingly realistic estimates of NP bioaccumulation.

The increasing incidence and range expansion of tick-borne diseases have caused global threats to human and animal health under the background of climate and socioeconomic changes. As an efficient vector in transmission of tick-borne diseases, a growing burden caused by Ixodes persulcatus and associated pathogens could not be underestimated. This study summarized the distribution, hosts, and pathogens of I. persulcatus , and predicted the suitable habitats of this tick species worldwide. An integrated database involving a field survey, reference book, literature review, and related website was constructed. Location records of I. persulcatus and associated pathogens were incorporated into distribution maps using ArcGIS software. Positive rates for I. persulcatus -associated agents were estimated by meta-analysis. The global distribution of the tick species was predicted using Maxent model. I. persulcatus was distributed in 14 countries across the Eurasian continent, involving Russia, China, Japan, and several Baltic Sea states, which ranged between 21°N to 66°N. The tick species fed on 46 species of hosts, and 51 tick-borne agents could be harbored by I. persulcatus . The predictive model showed that I. persulcatus could be predominantly distributed in northern Europe, western Russia, and northern China. Our study fully clarified the potential public health risks posed by I. persulcatus and I. persulcatus -borne pathogens. Surveillance and control measures of tick-borne diseases should be enhanced to promote the health of humans, animals, and ecosystems., Competing Interests: We declare no competing interests., (© 2023 The Authors. Published by Elsevier B.V.)

The increasing prevalence and expanding distribution of tick-borne viruses globally have raised health concerns, but the full repertoire of the tick virome has not been assessed. We sequenced the meta-transcriptomes of 31 different tick species in the Ixodidae and Argasidae families from across mainland China, and identified 724 RNA viruses with distinctive virome compositions among genera. A total of 1,801 assembled and complete or nearly complete viral genomes revealed an extensive diversity of genome architectures of tick-associated viruses, highlighting ticks as a reservoir of RNA viruses. We examined the phylogenies of different virus families to investigate virome evolution and found that the most diverse tick-associated viruses are positive-strand RNA virus families that demonstrate more ancient divergence than other arboviruses. Tick-specific viruses are often associated with only a few tick species, whereas virus clades that can infect vertebrates are found in a wider range of tick species. We hypothesize that tick viruses can exhibit both 'specialist' and 'generalist' evolutionary trends. We hope that our virome dataset will enable much-needed research on vertebrate-pathogenic tick-associated viruses., (© 2023. The Author(s).)

Cyclophosphamide-induced testosterone deficiency (CPTD) during the treatment of cancers and autoimmune disorders severely influences the quality of life of patients. Currently, several guidelines recommend patients suffering from CPTD receive testosterone replacement therapy (TRT). However, TRT has many disadvantages underscoring the requirement for alternative, nontoxic treatment strategies. We previously reported bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) could alleviate cyclophosphamide (CP)-induced spermatogenesis dysfunction, highlighting their role in the treatment of male reproductive disorders. Therefore, we further investigated whether BMSCs-exos affect autophagy and testosterone synthesis in Leydig cells (LCs). Here, we examined the effects and probed the molecular mechanisms of BMSCs-exos on CPTD in vivo and in vitro by detecting the expression levels of genes and proteins related to autophagy and testosterone synthesis. Furthermore, the testosterone concentration in serum and cell-conditioned medium, and the photophosphorylation protein levels of adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) were measured. Our results suggest that BMSCs-exos could be absorbed by LCs through the blood-testis barrier in mice, promoting autophagy in LCs and improving the CP-induced low serum testosterone levels. BMSCs-exos inhibited cell death in CP-exposed LCs, regulated the AMPK-mTOR signaling pathway to promote autophagy in LCs, and then improved the low testosterone synthesis ability of CP-induced LCs. Moreover, the autophagy inhibitor, 3-methyladenine (3-MA), significantly reversed the therapeutic effects of BMSCs-exos. These findings suggest that BMSCs-exos promote LC autophagy by regulating the AMPK-mTOR signaling pathway, thereby ameliorating CPTD. This study provides novel evidence for the clinical improvement of CPTD using BMSCs-exos., Competing Interests: None

Background: Plasma cells as an important component of immune microenvironment plays a crucial role in immune escape and are closely related to immune therapy response. However, its role for prostate cancer is rarely understood. In this study, we intend to investigate the value of a new plasma cell molecular subtype for predicting the biochemical recurrence, immune escape and immunotherapy response in prostate cancer., Methods: Gene expression and clinicopathological data were collected from 481 prostate cancer patients in the Cancer Genome Atlas. Then, the immune characteristics of the patients were analyzed based on plasma cell infiltration fractions. The unsupervised clustering based machine learning algorithm was used to identify the molecular subtypes of the plasma cell. And the characteristic genes of plasma cell subtypes were screened out by three types of machine learning models to establish an artificial neural network for predicting plasma cell subtypes. Finally, the prediction artificial neural network of plasma cell infiltration subtypes was validated in an independent cohort of 449 prostate cancer patients from the Gene Expression Omnibus., Results: The plasma cell fraction in prostate cancer was significantly decreased in tumors with high T stage, high Gleason score and lymph node metastasis. In addition, low plasma cell fraction patients had a higher risk of biochemical recurrence. Based on the differential genes of plasma cells, plasma cell infiltration status of PCa patients were divided into two independent molecular subtypes(subtype 1 and subtype 2). Subtype 1 tends to be immunosuppressive plasma cells infiltrating to the PCa region, with a higher likelihood of biochemical recurrence, more active immune microenvironment, and stronger immune escape potential, leading to a poor response to immunotherapy. Subsequently, 10 characteristic genes of plasma cell subtype were screened out by three machine learning algorithms. Finally, an artificial neural network was constructed by those 10 genes to predict the plasma cell subtype of new patients. This artificial neural network was validated in an independent validation set, and the similar results were gained., Conclusions: Plasma cell infiltration subtypes could provide a potent prognostic predictor for prostate cancer and be an option for potential responders to prostate cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Dou, Luo, Zhang, Liu, Zhou, Huang, Xue, Liang, Ouyang, Ma, Yang, Zhou, Guo, Liu, Zhao and Chen.)

Background: At present, little is known about the risk factors of early postoperative death in patients with hepatocellular carcinoma (HCC)., Methods: We collected the data of patients who were diagnosed with primary liver cancer between 2010 and 2015 in the Surveillance, Epidemiology, and End Results database and further allocated them to the training set and validation set. Univariate and multivariate logistic regression analysis was used to determine the independent influencing factors of early postoperative death of HCC patients. Random forest and Least absolute shrinkage and selection operator regression analysis were used to screen out vital variables for the construction of the nomogram. It was evaluated by receiver operating characteristic curve, calibration curve and decision curve analysis., Results: A total of 4154 patients were selected in this process, including 2647 patients with postoperative early death (outcome1) and 1507 patients with liver cancer-specific postoperative early death (outcome2). Surgery method, age category, marital status and tumor grade were the risk factors for early postoperative death. As for the liver cancer-specific early postoperative death, AJCC, surgery method, chemotherapy and tumor grade were independent prognostic factors. Early death and liver cancer-specific early death nomograms have an area under curves of 0.643 and 0.679 in the training set, respectively, and 0.617 and 0.688 in the validation set. The calibration curve and decision curve analysis shows that the nomograms have good performance., Conclusion: This model provides an intuitive and practical tool for future studies based on large-scale cohorts by exploring the risk factors of early death in patients with HCCs undergoing surgery., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study investigated the correlation between types of posterior upper rotator cuff tears (RCTs) and intramuscular fat infiltration (FI) in magnetic resonance imaging (MRI). Methods: The shoulder joints of 50 adults with a full-thickness posterior upper RCT diagnosed by MRI, from January 2019 to December 2021, were retrospectively analyzed. The patients were divided into three groups according to tear type: 1) an L-shaped tear group; 2) a crescent/U-shaped tear group; 3) a complete tear group. The correlation among age, gender, tear range, trauma history, and the duration of clinical symptoms was analyzed. The MRI images were used by two musculoskeletal imaging physicians to evaluate the type and range of tears, the Goutallier grade of the supraspinatus and infraspinatus, and the correlations and reliability were analyzed. Results: Differences in the tear range ( p < 0.001) and the Goutallier grade of the infraspinatus muscle ( p = 0.036) among the L-shaped, crescent/U-shaped, and complete tear groups were statistically significant; however, differences in the Goutallier grade of the supraspinatus muscle was not statistically significant ( p = 0.356). In the crescent/U-shaped tear group, age was significantly correlated with the Goutallier grade of the supraspinatus muscle (RS = 0.720, p = 0.029) and the infraspinatus muscle (RS = 0.713, p = 0.032). In the complete tear group, tear range was significantly correlated with the Goutallier grade of the supraspinatus muscle (RS = 0.801, p = 0.001) and the infraspinatus muscle (RS = 0.802, p = 0.001). The Goutallier grades of the supraspinatus muscle (kappa, 0.489) and the infraspinatus muscle (kappa, 0.424) presented with interobserver consistency. Conclusion: The type of posterior upper RCT correlates with the degree of FI. There is a positive correlation between the FI of crescent/U-shaped full-thickness RCTs and age. Additionally, the range of complete tears in the posterior upper RC has a positive correlation with FI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Cao, Li, Guo, Zhang and Li.)

Background: Brain metastases (BM) are common in lung cancer. However, data on the status of immune biomarkers in BM lesions remain limited., Methods: We retrospectively analyzed PD-L1 expression and infiltration levels of CD3 + , CD4 + , CD8 + T cells as biomarkers by immunohistochemistry in both BM lesions and primary lung cancer (PL) lesions of 29 lung cancer (LC) patients. In addition, the correlations between these biomarkers and the clinical outcome were analyzed using log-rank test., Results: Intratumoral heterogeneous expression of PD-L1 was observed on tumor cells (TCs) in 11 cases and on immune cells (ICs) in 10 cases with BM samples from multiple regions. There was a disagreement in PD-L1 expression on TCs between paired BM and PL lesions in 15 cases and on ICs in seven cases. Intraepithelial CD3 + and CD8 + T cell infiltration levels in BM samples were lower than those in the paired PL samples. PD-L1 positivity on both TCs and ICs was associated with a better post-BM-surgery prognosis (p = 0.010; p = 0.041). Notably, PD-L1 positivity on TCs and a high level of intraepithelial CD8 + T cell infiltration could serve as an integrated biomarker that indicates longer survival time (p = 0.004) in LC patients., Conclusion: The heterogeneity in PD-L1 expression was common in both stromal and intraepithelial regions in BM lesions of LC patients, suggesting the need for multiregional PD-L1 testing in clinical practice. More importantly, a combination of PD-L1 expression on TCs with intraepithelial CD8 + T cell infiltration might predict better post-BM-surgery outcomes., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder (MDD), reproducible findings are lacking, probably reflecting mostly small sample sizes and heterogeneity in analytic approaches. To address these issues, the Depression Imaging REsearch ConsorTium (DIRECT) was launched. The REST-meta-MDD project, pooling 2428 functional brain images processed with a standardized pipeline across all participating sites, has been the first effort from DIRECT. In this review, we present an overview of the motivations, rationale, and principal findings of the studies so far from the REST-meta-MDD project. Findings from the first round of analyses of the pooled repository have included alterations in functional connectivity within the default mode network, in whole-brain topological properties, in dynamic features, and in functional lateralization. These well-powered exploratory observations have also provided the basis for future longitudinal hypothesis-driven research. Following these fruitful explorations, DIRECT has proceeded to its second stage of data sharing that seeks to examine ethnicity in brain alterations in MDD by extending the exclusive Chinese original sample to other ethnic groups through international collaborations. A state-of-the-art, surface-based preprocessing pipeline has also been introduced to improve sensitivity. Functional images from patients with bipolar disorder and schizophrenia will be included to identify shared and unique abnormalities across diagnosis boundaries. In addition, large-scale longitudinal studies targeting brain network alterations following antidepressant treatment, aggregation of diffusion tensor images, and the development of functional magnetic resonance imaging-guided neuromodulation approaches are underway. Through these endeavours, we hope to accelerate the translation of functional neuroimaging findings to clinical use, such as evaluating longitudinal effects of antidepressant medications and developing individualized neuromodulation targets, while building an open repository for the scientific community., Competing Interests: One of the authors, Dr Qi-Yong Gong, is also the editor-in-chief of Psychoradiology. He was blinded from reviewing or making decisions on the manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of West China School of Medicine/West China Hospital (WCSM/WCH) of Sichuan University.)

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls., (© 2022. The Author(s).)

Background: Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations., Methods: In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns., Results: As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q < 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs., Conclusions: We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although nanoparticles' (NPs) toxicity has been intensively studied, their effects on bacterial ingestion by protozoans (as an important component of the microbial loop) is unknown. This study investigated the effects of NPs of different chemical composition [hematite (HemNPs), anatase (AnaNPs), and silica (SiNPs) NPs] and size [SiNPs with particle size of 20 (Si-20), 100 (Si-100), and 500 (Si-500) nm] on the ingestion of Escherichia coli by the protozoan Tetrahymena thermophila. Potential differences between pre- vs. co-exposure were also assessed. Pre-exposure to HemNPs had no effects on bacterial ingestion but the other NPs caused a significant inhibition, due to their inhibition of ATP synthesis and the down-regulation of phagocytosis-related genes (ACT1 and CTHB). Contrastively, co-exposure to HemNPs and Si-20 didn't affect bacterial ingestion while co-exposure to AnaNPs (Si-100 and Si-500) induced (inhibited) ingestion. The stimulatory effect of AnaNPs was due to their induction of an increase in the intracellular Ca concentration of T. thermophila whereas the inhibitory effects of Si-100 and Si-500 were attributable to ATP synthesis reduction, enhanced bacterial cell aggregation, and competition between the bacterial cells and the NPs. These findings provide insights into the mechanisms underlying the environmental risks of NPs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The long-lasting co-evolution of ticks with pathogens results in mutual adaptation. Blood-feeding is one of the critical physiological behaviors that have been associated with the tick microbiome; however, most knowledge was gained through the study of laboratory-reared ticks. Here we detached Ixodes persulcatus ticks at different stages of blood-feeding from human patients and performed high-throughput transcriptomic analysis on them to identify their virome and genes differentially expressed between flat and fully fed ticks. We also traced bloodmeal sources of those ticks and identified bats and three other potential mammalian hosts, highlighting the public health significance. We found Jingmen tick virus and 13 putative new viruses belonging to 11 viral families, three of which even exhibited high genetic divergence from viruses previously reported in the same tick species from the same geographic region. Furthermore, differential expression analysis suggested a downregulation of antioxidant genes in the fully fed I. persulcatus ticks, which might be related to bloodmeal-related redox homeostasis. Our work highlights the significance of active surveillance of tick viromes and suggests a role of reactive oxygen species (ROS) in modulating changes in the microbiome during blood-feeding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Ning, Zheng, Chu, Cui, Zhang, Guo, Wei, Liu, Sun, Ye, Jiang, Yuan, Li, Bian, Bell-Sakyi, Wang, Jiang, Song, Cao, Tsan-Yuk Lam, Ni and Jia.)

Background: This study aims to evaluate the incidence of calcific tendinitis (CaT) in rotator cuff tears (RCTs) and to assess the correlation between CaT and RCTs with magnetic resonance imaging (MRI)., Methods: The MRI of 108 patients with rotator cuff CaT admitted to our hospital from January 2019 to January 2021 were retrospectively analyzed. Another retrospective analysis was made of 108 patients with similar age, gender, occupation, and shoulder injury side to those in the first group. The incidence of RCTs and their correlation with CaT were assessed based on an MRI of shoulder joints., Results: There was a statistical difference (p < 0.05) in the incidence of RCTs between the CaT group (23.4%) and the control group (37.2%). No significant difference was observed in the size of the RCTs between the two groups (P = 0.422). In the CaT group, 17.4% of patients had complete tears, compared with 26.3% in the control group. There was no significant correlation between the calcification site and RCTs in the CaT group, and only 3.7% of patients suffered calcification and a tear in the exact location of the same tendon (P > 0.05, r = 0.03)., Conclusions: Compared with patients with shoulder pain without CaT, patients with rotator cuff CaT suffered no increased risk of RCTs on MRI, so CaT and RCTs may have different pathological causes, and there is no significant correlation between the two., (© 2022. The Author(s).)

Microplastics (MPs) and nanoplastics (NPs) in the environment pose significant risks to organisms of different trophic levels. While the toxicity of MPs and NPs have been extensively investigated, it remains unknown whether these particles affect microbial transformation of organic pollutants. Here, we show that 20 and 100 nm polystyrene NPs (PS-NPs) can inhibit the transformation of tetrabromobisphenol A (TBBPA) by Gram-positive bacterium Rhodococcus jostii in a concentration-dependent manner. We found that smaller PS-NPs were more inhibitory than larger ones and that both PS-NPs affected biotransformation in several ways. PS-NPs adsorbed TBBPA on their surface and reduced the bioavailable concentration of TBBPA for transformation by R. jostii . Furthermore, PS-NPs induced oxidative stress, increased membrane permeability, and downregulated O -methyltransferase enzymes that transform TBBPA into their methylated derivatives. Our results demonstrate that PS-NPs can impact microbial transformation of organic pollutants, and these effects should be accounted for in future environmental risk assessments.

Objective: While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure., Method: Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms., Results: There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P < 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P < 0.01, voxel-P < 0.001). While these changed brain areas had significantly association with GI symptoms (P < 0.001), they were not correlated with depressive symptoms (P > 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p < 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe., Conclusion: MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients., (Copyright © 2021. Published by Elsevier Inc.)

Atrial septal defects (ASDs) are the most common types of cardiac septal defects in congenital heart defects. In addition to traditional therapy, interventional closure has become the main treatment method. However, the molecular events and mechanisms underlying the repair progress by occlusion device remain unknown. In this study, we aimed to characterize differentially expressed genes (DEGs) in the blood of patients treated with occlusion devices (metal or poly-L-lactic acid devices) using RNA-sequencing, and further validated them by qRT-PCR analysis to finally determine the expression of key mediating genes after closure of ASD treatment. The result showed that total 1,045 genes and 1,523 genes were expressed differently with significance in metal and poly-L-lactic acid devices treatment, respectively. The 115 overlap genes from the different sub-analyses are illustrated. The similarities and differences in gene expression reflect that the body response process involved after interventional therapy for ASDs has both different parts that do not overlap and the same part that crosses. The same portion of body response regulatory genes are key regulatory genes expressed in the blood of patients with ASDs treated with closure devices. The gene ontology enrichment analysis showed that biological processes affected in metal device therapy are immune response with CXCR4 genes and poly-L-lactic acid device treatment, and the key pathways are nuclear-transcribed mRNA catabolic process and proteins targeting endoplasmic reticulum process with ribosomal proteins (such as RPS26). We confirmed that CXCR4, TOB1, and DDIT4 gene expression are significantly downregulated toward the pre-therapy level after the post-treatment in both therapy groups by qRT-PCR. Our study suggests that the potential role of CXCR4, DDIT4, and TOB1 may be key regulatory genes in the process of endothelialization in the repair progress of ASDs, providing molecular insights into this progress for future studies., Competing Interests: AC, Y-JL and Z-XZ were employed by the company Guangzhou Mendel Genomics and Medical Technology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Tang, Tan, Yan, Sun, Guo, Qian, Chen, Luo, Zheng, Zhang, Jia and Liu.)

Objective: To investigate the prevalence and associated risk factors of metabolic syndrome (MS) in patients with obstructive sleep apnea (OSA). Methods: From July 2007 to June 2017, a total of 8 155 adult subjects, including 6 484 males and 1 671 females, aged 18-90 (43.13±12.28), body mass index 14.61~59.56 (25.59±3.98) kg/m 2 ,who were admitted to the Department of Otorhinolaryngology head and Neck surgery of The Sixth People's Hospital affiliated to Shanghai Jiao Tong University, were retrospectively analyzed. All patients underwent polysomnography and biochemical tests. Subjects were divided into four groups (non-OSA, mild OSA, moderate OSA, and severe OSA) according to OSA severity. The prevalence of MS was expressed as percentage, and the correlation between OSA and MS and its characteristic pathophysiological indicators was evaluated by logistic regression model after adjusting for factors such as gender, age, BMI, neck circumference, hip circumference, smoking and alcohol consumption, and was expressed by odds ratio (OR). SPSS 25.0 software was used for statistical analysis. Results: The overall prevalence of MS was 43.6%, and that of non-/mild/moderate/severe OSA group was 18.6%, 30.4%, 43.8%, 57.1%.Logistic regression showed that patients with mild/moderate/severe OSA had an increased risk of MS compared with non-OSA patients, with adjusted OR values and confidence intervals of 1.27 (1.05-1.54), 1.84 (1.53-2.22), and 2.08 (1.76-2.46), respectively ( P <0.01).In addition, indicators of OSA anoxic burden [oxygen drop index(T oxygen =7.1), minimum blood oxygen(T minimum =56.3), blood oxygen saturation below 90% cumulative time ratio (T CT90 =10.6) ]were closely associated with MS disease( P <0.01), but sleep fragmentation index (arousals index) was not significantly associated with MS disease. Conclusion: The risk of MS gradually increases with the severity of OSA, and the indicators reflecting OSA hypoxia burden are closely related to MS disease.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks., (© 2021. The Author(s).)

Objective: To investigate the association between magnetic resonance imaging (MRI) classification and symptom relief after uterine artery embolization (UAE) in patients with adenomyosis., Methods: Totally, 73 patients with symptomatic adenomyosis who underwent UAE were retrospectively analyzed. Preoperative MRI classification was defined as: type I, high signal on both T2-weighted images (T2WI) and T1-weighted images (T1WI); type III, high signal only on T2WI, and type II, high signal on neither T1WI nor T2WI. Dysmenorrhea was measured with the visual-analog scales and the degree of menorrhagia was measured according to the number of sanitary pads used in one menstrual cycle. Dysmenorrhea and menorrhagia were measured before UAE and 12 months after UAE., Results: The number of the type I, II, III cases was 23, 37, and 13, respectively. The baseline characteristics of the three groups exhibited no significant difference. The alleviation rates of dysmenorrhea among type I, II, III cases were 73.9%, 89.2%, and 84.6%, respectively (P=0.455). The alleviation rates of menorrhagia for type I, II, III were 69.6%, 78.4%, and 92.3%, respectively (P=0.714)., Conclusion: Pre-procedure MRI classification and symptom relief after UAE exhibited no significant association. UAE has a favorable mid-term control on dysmenorrhea and menorrhagia among patients with adenomyosis. Preoperative MRI classification might not indicate symptom relief. More research is needed before changing clinical practice., (© 2021. Huazhong University of Science and Technology.)

In aquatic ecosystems, the calcium (Ca) concentration varies greatly. It is well known that Ca affects the aggregation of nanoparticles (NPs) and thus their bioaccumulation. Nevertheless, Ca also plays critical roles in various biological processes, whose effects on NP accumulation in aquatic organisms remain unclear. In this study, the effects of Ca on the uptake of polyacrylate-coated hematite NPs (HemNPs) by the aquatic ciliate Tetrahymena thermophila were investigated. At all of the tested Ca concentrations, HemNPs were well dispersed in the experimental medium, excluding the possibility of Ca to influence HemNP bioaccumulation by aggregating the NPs. Instead, Ca was shown to induce the clathrin-mediated endocytosis and phagocytosis of HemNPs. Manipulation of the Ca speciation in the experimental medium as well as the influx and intracellular availability of Ca in T. thermophila indicated that HemNP uptake was regulated by the intracellular Ca level. The results of the proteomics analyses further showed that the binding of intracellular Ca to calmodulin altered the activity of proteins involved in clathrin-mediated endocytosis (calcineurin and dynamin) and phagocytosis (actin). Overall, the biologically inductive effects of Ca on NP accumulation in aquatic organisms should be considered when evaluating the environmental risks of NPs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The potential effects of engineered nanoparticles (NPs) on metal bioaccumulation in aquatic organisms have been the focus of increasing research attention. However, while NPs typically aggregate, the role of aggregation in NP-mediated metal bioaccumulation is largely unknown. The present study investigated the effects of polyacrylate-coated TiO 2 (anatase) NPs (AnaNPs) on Cd bioaccumulation in zebrafish. The Ca concentration in the experimental medium was manipulated to regulate AnaNP aggregation. At the low Ca concentration, the AnaNPs were well-dispersed and there was little bioaccumulation. Under this condition, Cd bioaccumulation was mainly via the uptake of free ions (Route 1), with only a minor contribution from NP-Cd complexes (Route 2). Therefore, AnaNPs decreased Cd bioaccumulation, as their inductive carrier effect could not offset the inhibition induced by the decrease in the free Cd ion concentration as a result of NP adsorption. At the high Ca concentration, the AnaNPs aggregated and their bioaccumulation increased. Accordingly, Cd bioaccumulation was equally accounted for by Routes 1 and 2 but the overall amount of Cd remained unchanged because the inductive effect of the AnaNPs offset their inhibitory effect. Thus, during risk evaluations of NPs, the contribution of aggregation to metal bioaccumulation should be considered., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Src homology region 2 domain-containing phosphatase 2 (SHP2) is a novel target for Kirsten rat sarcoma oncogene (KRAS) mutant cancer. We retrospectively studied the significance of SHP2 in KRAS mutant non-small cell lung cancer (NSCLC) treated with immunotherapy and its relationship with tumor microenvironment (TME)., Methods: Sixty-one advanced KRAS mutant NSCLC patients who underwent immunotherapy were enrolled. Next-generation sequencing (NGS) was used to profile mutation status. The expression of SHP2, phospho-SHP2 (pSHP2), and programmed death ligand 1 (PD-L1) were analyzed by immunohistochemistry (IHC). Quantitative multiplexed immunofluorescence cytochemistry (mIFC) analysis was conducted to describe the TME., Results: SHP2 was heterogeneously expressed in 32 samples in both tumor cells and immune cells and highly expressed (H-score >10) in 25 (78.1%) samples. The expression levels of SHP2 and pSHP2 were positively correlated. Stromal SHP2 (s-SHP2) was higher in tumors with PD-L1 ≥50% versus PD-L1 <50% (p = 0.039). By quantitative mIFC analysis, the expression of s-SHP2 had positive correlation with CD8, CD4, CD68, and PD-L1 levels in stromal area. Patients with high SHP2 expression made up 100.0% of the partial respond (PR) and 80.0% of the stable disease (SD), whereas 50.0% of the progress disease (PD). High SHP2 expression was associated with longer progression-free survival (PFS) and overall survival (OS) (p < 0.001, p = 0.013). Patients with high expression of both SHP2 and PD-L1 had longer PFS (p < 0.001)., Conclusion: High SHP2 expression could predict the efficacy of immunotherapy and better survival in advanced KRAS mutant NSCLC. SHP2 may function in both tumor cells and immune cells, warranting further study on the potential diverse effects of SHP2 inhibition in TME., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: The burden of non-communicable diseases (NCDs) has increased in China. However, the contribution of dietary risks to the NCD burden has not been evaluated. This study aimed to estimate the burden of ischemic heart disease (IHD) and colorectal cancer (CRC) attributable to a diet low in fiber in China from 1990 to 2017., Methods: China data from the Global Burden of Disease Study (GBD) 2017 were used to assess the age-, sex-, and province-specific mortality and disability-adjusted life-years (DALYs) of IHD and CRC related to a diet low in fiber., Results: In 2017, a diet low in fiber contributed 170,143 [95% uncertainty interval (UI): 99,623-256,806] IHD deaths and 25,561 (95% UI: 13,726-39,215) CRC deaths, with the population attributable fractions (PAFs) were 9.7 and 13.7%, respectively. Males had higher risk-attributable mortality and DALY rates for IHD and CRC than females. An upward trend with age in rates of mortality and DALY was observed. All-age risk-attributable mortality and DALY rates increased significantly by 111.4 and 53.2% for IHD, and 94.4 and 59.6% for CRC from 1990 to 2017, respectively; however, the corresponding age-standardized rates for IHD and CRC showed relatively stable trends. Heilongjiang, Xinjiang, and Inner Mongolia were ranked as the top three provinces in terms of total risk-attributable NCD burden in 2017., Conclusions: China has a large and growing NCD burden attributable to a diet low in fiber. Greater priority in disease prevention and control should be given to male and older adults throughout China, particularly in some western provinces., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

Accurate methods for identifying pelvic lymph node metastasis (LNM) of prostate cancer (PCa) prior to surgery are still lacking. We aimed to investigate the predictive value of peripheral monocyte count (PMC) for LNM of PCa in this study. Two hundred and ninety-eight patients from three centers were divided into a training set (n = 125) and a validation set (n = 173). In the training set, the independent predictors of LNM were analyzed using univariate and multivariate logistic regression analyses, and the optimal cutoff value was calculated by the receiver operating characteristic (ROC) curve. The sensitivity and specificity of the optimal cutoff were authenticated in the validation cohort. Finally, a nomogram based on the PMC was constructed for predicting LNM. Multivariate analyses of the training cohort demonstrated that clinical T stage, preoperative Gleason score, and PMC were independent risk factors for LNM. The subsequent ROC analysis showed that the optimal cutoff value of PMC for diagnosing LNM was 0.405 × 109 l -1 with a sensitivity of 60.0% and a specificity of 67.8%. In the validation set, the optimal cutoff value showed significantly higher sensitivity than that of conventional magnetic resonance imaging (MRI) (0.619 vs 0.238, P < 0.001). The nomogram involving PMC, free prostate-specific antigen (fPSA), clinical T stage, preoperative Gleason score, and monocyte-to-lymphocyte ratio (MLR) was generated, which showed a robust predictive capacity for predicting LNM before the operation. Our results indicated that PMC as a single agent, or combined with other clinical parameters, showed a robust predictive capacity for LNM in PCa. It can be employed as a complementary factor for the decision of whether to conduct pelvic lymph node dissection., Competing Interests: None

Spermatogenic dysfunction caused by cyclophosphamide (CP) chemotherapy has seriously influenced the life quality of patients. Unfortunately, treatments for CP-induced testicular spermatogenic dysfunction are limited, and the molecular mechanisms are not fully understood. For the first time, here, we explored the effects of bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) on CP-induced testicular spermatogenic dysfunction in vitro and in vivo. BMSC-exos could be taken up by spermatogonia (GC1-spg cells). CP-injured GC1-spg cells and BMSC-exos were cocultured at various doses, and then, cell proliferation was measured using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. In addition, photophosphorylation of extracellular-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38MAPK), and protein kinase B (AKT) proteins was evaluated by western blotting as well as apoptosis in GC1-spg cells measured using flow cytometry. Treatment with BMSC-exos enhanced cell proliferation and reduced apoptosis of CP-injured GCI-spg cells. Phosphorylated levels of ERK, AKT, and p38MAPK proteins were reduced in CP-injured spermatogonia when co-treated with BMSC-exos, indicating that BMSC-exos acted against the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways. In experiments in vivo, CP-treated rats received BMSC-exos by injection into the tail vein, and testis morphology was compared between treated and control groups. Histology showed that transfusion of BMSC-exos inhibited the pathological changes in CP-injured testes. Thus, BMSC-exos could counteract the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways. The findings provide a potential treatment for CP-induced male spermatogenic dysfunction using BMSC-exos., Competing Interests: None

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.

Bacterial accumulation of engineered nanoparticles (NPs) result in their transfer along the food chain. However, there are a lot of NPs not associated with bacteria. Whether bacteria, as representative biotic particles, influence the biological uptake of these non-associated NPs in aquatic ecosystems is unclear. In the present study, we examined the effects of four bacterial species on the uptake kinetics of polyacrylate-coated hematite nanoparticles (HemNPs) by the ciliate Tetrahymena thermophila. The HemNPs were well dispersed. Their adsorption on the bacteria was low with negligible uptake by T. thermophila through bacterial ingestion. This result demonstrated the feasibility of examining the effects of bacteria on the uptake of non-associated HemNPs. Our study further showed that all four bacterial species inhibited the uptake of HemNPs by T. thermophila; however, the effects of the bacterial cells on the physiological activities of the ciliate with respect to its uptake of HemNPs were negligible. In the absence of phagocytosis by T. thermophila, none of the bacteria inhibited HemNP uptake. This observation suggested that bacterial cells competed with the HemNPs for uptake via phagocytosis. Therefore, in evaluations of the environmental risks of NPs, their competition with biotic particles should be taken into account., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Spotted fever group rickettsiae, mainly maintained and transmitted by ticks, are important etiological agents of (re)emerging zoonotic diseases worldwide. It is of great significance to investigate spotted fever group rickettsiae in ticks in different areas for the prevention and control of rickettsioses. In this study, a total of 305 ticks were collected from wild and domestic animals in Chongqing, Guizhou, Yunnan, and Guangxi provinces of southwestern China during 2017-2019 and examined for the presence of spotted fever group rickettsiae by PCR with primers targeting the partial gltA, ompA, rrs, and htrA genes. Results showed that two spotted fever group rickettsiae species, including the pathogenic Candidatus Rickettsia jingxinensis (Rickettsiales: Rickettsiaceae) and a potential novel species Rickettsia sp. sw (Rickettsiales: Rickettsiaceae), were identified. The Ca. R. jingxinensis sequences were recovered from Rhipicephalus microplus (Ixodida: Ixodidae) and Haemaphysalis longicornis (Ixodida: Ixodidae) ticks and phylogenetically clustered with previous Ca. R. jingxinensis, Ca. R. longicornii (Rickettsiales: Rickettsiaceae), and Rickettsia sp. XY118 (Rickettsiales: Rickettsiaceae) strains. Rickettsia sp. sw was detected in Amblyomma geoemydae (Ixodida: Ixodidae) and Rh. microplus. Interestingly, as far as we know, this was the first report of Rickettsia (Rickettsiales: Rickettsiaceae) in A. geoemydae. Phylogenetic analyses indicated that this potential novel species was closely related to R. aeschlimannii (Rickettsiales: Rickettsiaceae) with gltA and ompA genes and grouped in a cluster composed of R. montanensis (Rickettsiales: Rickettsiaceae), R. raoultii (Rickettsiales: Rickettsiaceae), R. aeschlimannii, R. massiliae (Rickettsiales: Rickettsiaceae), and R. rhipicephali (Rickettsiales: Rickettsiaceae) with htrA, while formed a separate clade with rrs. The pathogenicity of Rickettsia sp. sw should be further confirmed. These results expand the knowledge of the geographical distribution and vector distribution of spotted fever group rickettsiae in China and are useful for assessing the potential public health risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dermacentor silvarum is an obligate blood sucking arthropod and transmits various pathogens to humans and domestic animals. Recently several new viruses were detected in D. silvarum as an emerging disease threat. In this study, we aimed to analyze its geographical distribution and associated pathogens. Data were collected from multiple sources, including a field survey, reference book, and literature review. We searched various electronic databases with the terms " Dermacentor silvarum " OR " D. silvarum " for studies published since 1963 and the positive rates for Dermacentor silvarum -associated pathogens were estimated by meta-analysis. D. silvarum was found only in four countries in Eurasia, ranging from 22° N to 57° N latitude. At least 20 human pathogens were associated with D. silvarum , including five species of spotted fever group rickettsiae, three species in the family of Anaplasmataceae, three genospecies in the complex Borrelia burgdorferi sensu lato, Francisella tularensis, Babesia venatorum, Coxiella buenetii, Borrelia miyamotoi, and five species of virus. Among them, Rickettsia raoultii was widely detected in D. silvarum , showing the highest pooled positive rate (25.15%; 95% CI 13.31-39.27). Our work presents the most comprehensive data and analysis (to our knowledge) for the geographical distribution of D. silvarum and associated pathogens, revealing an emerging threat to public health and stocking farming. Continued surveillance and further investigations should be enhanced.

Background: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied., Methods: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes)., Results: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities., Limitations: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results., Conclusions: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Tick-borne bacteria and protozoa can cause a variety of human and animal diseases in China. It is of great importance to monitor the prevalence and dynamic variation of these pathogens in ticks in ever-changing natural and social environment. Materials and Methods: Ticks were collected from Heilongjiang and Jilin provinces of northeastern China during 2018-2019 followed by morphological identification. The presence of Rickettsia spp., Anaplasma spp., Ehrlichia spp., Borrelia spp., Babesia spp., and Theileria spp. was examined by PCR and Sanger sequencing. The obtained sequences were subjected to phylogenetic analysis through Mega 7.0. Statistical analysis was performed using SPSS 24.0. Results: A total of 250 ticks from 5 species of 3 genera were collected. Ixodes and Haemaphysalis ticks carried more species of pathogens than Dermacentor , and the pathogens detected in Haemaphysalis japonica varied significantly among different sampling sites. The infection rates of Rickettsia spp., Anaplasma spp., Ehrlichia spp., Borrelia spp., Babesia spp., and Theileria spp. were 41.2%, 0, 2.0%, 7.2%, 1.2%, and 7.2%, respectively. Twelve pathogens were identified, among which Rickettsia raoultii (29.6%), Candidatus Rickettsia tarasevichiae (9.2%), and Theileria equi (4.4%) were the three most common ones. Rickettsia had its dominant vector, that is, R. raoultii had high infection rates in Dermacentor nuttalli and Dermacentor silvarum , Ca. R. tarasevichiae in Ixodes persulcatus , and Rickettsia heilongjiangensis in H. japonica . Interestingly, unclassified species were observed, including a Rickettsia sp., an Ehrlichia sp., a Borrelia sp., and a Babesia sp. Coinfections with different pathogens were identified in 9.2% of all tested ticks, with I. persulcatus most likely to be coinfected (23.8%) and Rickettsia spp. and Borrelia spp. as the most common combination (16.7%). Conclusions: The results of this study reflect high diversity and complexity of pathogens in ticks, which are useful for designing more targeted and effective control measures for tick-borne diseases in China.

Microplastics (MPs) are an environmental hazard of growing concern, including their potential toxic effects on the biota of different trophic levels. Nevertheless, the molecular mechanisms underlying MP-induced toxicity remain largely unknown. In the present study, Tetrahymena thermophila was exposed to polystyrene nanoplastics (PS-NPs) and the responses of this relatively sensitive ciliate were then followed using transcriptome analysis together with several other verification methods. The results showed that PS-NPs perturbed calcium (Ca) homeostasis, by inducing the inositol-1,4,5-trisphosphate-dependent liberation of Ca from the endoplasmic reticulum into the cytosol. The high cytosolic concentration of Ca induced Ca accumulation in mitochondria, which increased mitochondrial permeability and the generation of reactive oxygen species, finally leading to growth inhibition. Such toxicity is the so-called direct effects of PS-NPs. By contrast, PS-NPs also inhibited the activity of multixenobiotic resistance transporter, by down-regulating the ATP-binding cassette transporter genes Abcb15 and Abcc52. This additional effect may alter cellular responses to other pollutants and implicates PS-NPs in the risks to the organism posed by subsequent toxic exposures, which was named as the indirect effects of PS-NPs. Our study highlights the importance of considering both direct and indirect biological effects of MPs in evaluations of their environmental and health risks., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer (CRC) has emerged as a major public health concern. However, little is known about the burden attributable to specific risk factors. The present study aimed to estimate the temporal trends and geographical variation of CRC burden attributable to a diet low in milk in China., Methods: Following the general analytic strategy used in the 2017 Global Burden of Disease study, we assessed the age-, sex-, and province-specific mortality and disability-adjusted life-years (DALYs) of CRC caused by a diet low in milk in China from 1990 to 2017., Results: In 2017, a diet low in milk contributed 32 032 [95% uncertainty interval (UI) = 11 350-53 806] deaths and 726 710 (95% UI = 256 651-1 218 153) DALYs for CRC with a population attributable fraction of 17.1%. The age-standardised mortality and DALY rates per 100 000 were 1.7 (95% UI = 0.6-2.9) and 36.8 (95% UI = 13.0-61.7), respectively. An upward trend with age in rates of mortality and DALYs was observed. Males had higher age-standardised rates than females. The number of deaths and DALYs increased significantly from 1990 to 2017, whereas the corresponding age-standardised rates showed relatively stable trends. In 2017, Hunan and Liaoning were ranked as the top two provinces in terms of disease burden. Socio-demographic index had a weak correlation with the age-standardised mortality (r = 0.348, P = 0.047)., Conclusions: The present study shows a substantial increase in the CRC burden attributable to a diet low in milk over the past three decades. Greater priority in CRC prevention should be given to males and the elderly population throughout China, particularly in less-developed provinces., (© 2020 The British Dietetic Association Ltd.)

Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: The effective use of MSCs for the treatment of some B cell-mediated immune diseases is quite limited. The main reason is that the immunomodulatory effects of mesenchymal stem cells (MSCs) on B cells are unclear, and their underlying mechanisms have not been fully explored., Methods and Results: By co-culturing B cells with MSCs without (MSC/CTLsh) or with suppressor of cytokine signaling 1 (SOCS1) knockdown (MSC/SOCS1sh), we found that MSCs inhibited B cell proliferation, activation and terminal differentiation. Remarkably, the highest inhibition of B cell proliferation was observed in MSC/SOCS1sh co-culture. Besides, MSC/SOCS1sh reversed the inhibitory effect of MSCs in the last stage of B cell differentiation. However, MSC/SOCS1sh had no effect on inhibiting B cell activation by MSCs. We also showed that IgA + B cell production was significantly higher in MSC/SOCS1sh than in MSC/CTLsh, although no difference was observed when both MSCs co-cultures were compared to isolated B cells. In addition, MSCs increased PGE2 production after TNF- α /IFN- γ stimulation, with the highest increase observed in MSC/SOCS1sh co-culture., Conclusions: Our results highlighted the role of SOCS1 as an important new mediator in the regulation of B cell function by MSCs. Therefore, these data may help to develop new treatments for B cell-mediated immune diseases.