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Abstract Background To date, although most thyroid carcinoma (THCA) achieves an excellent prognosis, some patients experience a rapid progression episode, even with differentiated THCA. Nodal metastasis is an unfavorable predictor. Exploring the underlying mechanism may bring a deep insight into THCA. Methods A total of 108 THCA from Chinese patients with next-generation sequencing (NGS) were recruited. It was used to explore the gene alteration spectrum of THCA and identify gene alterations related to nodal metastasis in papillary thyroid carcinoma (PTC). The Cancer Genome Atlas THCA cohort was further studied to elucidate the relationship between specific gene alterations and tumor microenvironment. A pathway enrichment analysis was used to explore the underlying mechanism. Results Gene alteration was frequent in THCA. BRAF, RET, POLE, ATM, and BRCA1 were the five most common altered genes. RET variation was positively related to nodal metastasis in PTC. RET variation is associated with immune cell infiltration levels, including CD8 naïve, CD4 T and CD8 T cells, etc. Moreover, Step 3 and Step 4 of the cancer immunity cycle (CIC) were activated, whereas Step 6 was suppressed in PTC with RET variation. A pathway enrichment analysis showed that RET variation was associated with several immune-related pathways. Conclusion RET variation is positively related to nodal metastasis in Chinese PTC, and anti-tumor immune response may play a role in nodal metastasis triggered by RET variation.

Abstract Background This study aimed to evaluate the efficacy of radiomics signatures derived from polyenergetic images (PEIs) and virtual monoenergetic images (VMIs) obtained through dual-layer spectral detector CT (DLCT). Moreover, it sought to develop a clinical-radiomics nomogram based on DLCT for predicting cancer stage (early stage: stage I-II, advanced stage: stage III-IV) in pancreatic ductal adenocarcinoma (PDAC). Methods A total of 173 patients histopathologically diagnosed with PDAC and who underwent contrast-enhanced DLCT were enrolled in this study. Among them, 49 were in the early stage, and 124 were in the advanced stage. Patients were randomly categorized into training (n = 122) and test (n = 51) cohorts at a 7:3 ratio. Radiomics features were extracted from PEIs and 40-keV VMIs were reconstructed at both arterial and portal venous phases. Radiomics signatures were constructed based on both PEIs and 40-keV VMIs. A radiomics nomogram was developed by integrating the 40-keV VMI-based radiomics signature with selected clinical predictors. The performance of the nomogram was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curves analysis (DCA). Results The PEI-based radiomics signature demonstrated satisfactory diagnostic efficacy, with the areas under the ROC curves (AUCs) of 0.92 in both the training and test cohorts. The optimal radiomics signature was based on 40-keV VMIs, with AUCs of 0.96 and 0.94 in the training and test cohorts. The nomogram, which integrated a 40-keV VMI-based radiomics signature with two clinical parameters (tumour diameter and normalized iodine density at the portal venous phase), demonstrated promising calibration and discrimination in both the training and test cohorts (0.97 and 0.91, respectively). DCA indicated that the clinical-radiomics nomogram provided the most significant clinical benefit. Conclusions The radiomics signature derived from 40-keV VMI and the clinical-radiomics nomogram based on DLCT both exhibited exceptional performance in distinguishing early from advanced stages in PDAC, aiding clinical decision-making for patients with this condition.

Abstract In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Starting from the perspective of RNA sequencing technology, this review outlined the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.

Abstract Largely removed from anthropogenic delivery of nitrogen (N), Antarctica has notably low levels of nitrogen. Though our understanding of biological sources of ammonia have been elucidated, the microbial drivers of nitrate (NO3 −) cycling in coastal Antarctica remains poorly understood. Here, we explore microbial N cycling in coastal Antarctica, unraveling the biological origin of NO3 − via oxygen isotopes in soil and lake sediment, and through the reconstruction of 1968 metagenome-assembled genomes from 29 microbial phyla. Our analysis reveals the metabolic potential for microbial N2 fixation, nitrification, and denitrification, but not for anaerobic ammonium oxidation, signifying a unique microbial N-cycling dynamic. We identify the predominance of complete ammonia oxidizing (comammox) Nitrospira, capable of performing the entire nitrification process. Their adaptive strategies to the Antarctic environment likely include synthesis of trehalose for cold stress, high substrate affinity for resource utilization, and alternate metabolic pathways for nutrient-scarce conditions. We confirm the significant role of comammox Nitrospira in the autotrophic, nitrification process via 13C-DNA-based stable isotope probing. This research highlights the crucial contribution of nitrification to the N budget in coastal Antarctica, identifying comammox Nitrospira clade B as a nitrification driver.

Variations in the mechanical properties and pore structure of granulated blast furnace slag self-compacting concrete were studied. The grey correlation theory established the relationship between mechanical properties and pore structure. The test results show that with the continuous improvement of age, the mechanical properties decreased with the increase of sand replacement rate in the early stage. In the middle and late stages, the compressive strength and splitting tensile strength of granulated blast furnace slag self-compacting concrete are higher than those of ordinary self-compacting concrete, while the elastic modulus continues to decrease with increasing slag content. After standard curing, the change in the pore structure parameters of ordinary self-compacting concrete is relatively stable. The pore structure parameters of granulated blast furnace slag self-compacting concrete change significantly. Because granulated blast furnace slag has a certain hydraulicity, the strength and strength growth rate of granulated blast furnace slag self-compacting concrete are higher than those of ordinary self-compacting concrete, and the corresponding pore structure parameters change. Through grey correlation analysis, the specific surface area and average chord length structure of granulated blast furnace slag self-compacting concrete are essential factors affecting its mechanical properties.

BackgroundIgG4-related disease (IgG4-RD) was characterized by single or multiple masses in organs, which may mimic various inflammatory and malignant diseases. Here, we summarize 4 patients with aggressive manifestations of IgG4-RD that mimic nasopharynx cancer to provide some new sights for the diagnosis of IgG4-RD.Case summaryFour patients were included in our series. The age ranged from 53 to 64 years old, and the duration of the disease ranged from 4 to 6 months. The chief complaints included headache, rhinorrhea, or diplopia. All patients had more than 10 IgG4+ plasma cells/HPF in immunohistochemistry with plasma lgG4 levels ranging from 218 mg/dL to 765 mg/dL. All of them met the diagnostic criteria of lgG4-RD.ConclusionThe described case is highly similar to the clinical manifestations of nasopharyngeal carcinoma. Although pathology is the gold standard, there are still limitations. Serological IgG4 can help confirm the diagnosis. Timely diagnosis of IgG4-RD is of great significance in preventing secondary organ damage in patients with active diseases.

Introduction: Urothelial carcinoma (UC) is a refractory disease for which achieving satisfactory outcomes remains challenging with current surgical interventions. Antibody–drug conjugates (ADCs) are a novel class of targeted therapeutics that have demonstrated encouraging results for UC. Although there is a limited number of high-quality randomized control trials (RCTs) examining the use of ADCs in patients with UC, some prospective non-randomized studies of interventions (NRSIs) provide valuable insights and pertinent information. We aim to assess the efficacy and safety of ADCs in patients with UC, particularly those with locally advanced and metastatic diseases.Methods: A systematic search was conducted across PubMed, Embase, the Cochrane Library, and Web of Science databases to identify pertinent studies. Outcomes, such as the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events (AEs), and treatment-related adverse events (TRAEs), were extracted for further analyses.Results: Twelve studies involving 1,311 patients were included in this meta-analysis. In terms of tumor responses, the pooled ORR and DCR were 40% and 74%, respectively. Regarding survival analysis, the pooled median PFS and OS were 5.66 months and 12.63 months, respectively. The pooled 6-month PFS and OS were 47% and 80%, while the pooled 1-year PFS and OS were 22% and 55%, respectively. The most common TRAEs of the ADCs were alopecia (all grades: 45%, grades ≥ III: 0%), decreased appetite (all grades: 34%, grades ≥ III: 3%), dysgeusia (all grades: 40%, grades ≥ III: 0%), fatigue (all grades: 39%, grades ≥ III: 5%), nausea (all grades: 45%, grades ≥ III: 2%), peripheral sensory neuropathy (all grades: 37%, grades ≥ III: 2%), and pruritus (all grades: 32%, grades ≥ III: 1%).Conclusion: The meta-analysis in this study demonstrates that ADCs have promising efficacies and safety for patients with advanced or metastatic UC.Systematic review registration:https://www.crd.york.ac.uk/prospero/, identifier: CRD42023460232

Abstract Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf‐1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1‐overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K–AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1‐overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease‐free probability at 3 and 5 years. In summary, DKK1 can promote the PI3K–AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

Rationale and objectives: To investigate alterations in the brain structure in patients with Crohn's disease in activity (CD-A) and in remission (CD-R) compared to healthy controls (HCs) and explore the relationship between gray matter volume (GMV) and psychological disorders. Materials and methods: A total of 127 CD patients (62 CD-A, 65 CD-R) and 92 healthy controls (HCs) were enrolled and analyzed in this study. The Crohn's disease activity index (CDAI) was used as the grouping criteria. Voxel-based morphometry (VBM) was applied to investigate gray matter volume (GMV), white matter volume (WMV) and global cerebrospinal fluid (CSF) volume alterations. Pearson correlation analysis was used to evaluate the relationships. Results: The CSF volume was negatively correlated with the disease duration in CD-R. Increased GMV of CD was observed in the parahippocampal gyrus, precentral gyrus, precuneous cortex, and subcallosal cortex, decreased was located in the occipital pole, precentral gyrus, inferior temporal gyrus, middle frontal gyrus, angular gyrus, frontal pole, lateral occipital cortex, and lingual gyrus. The GMV in the right temporal pole, left precuneous cortex, and left cingulate gyrus had a positive correlation with erythrocyte and hemoglobin in CD groups. The GMV in the right frontal pole, right postcentral gyrus, and left cingulate gyrus had a negative correlation with somatization in the CD groups. The GMV in the right temporal pole had a negative correlation with psychoticism and other in the CD groups. The GMV in the left cingulate gyrus was positive with bowel symptoms and systemic symptoms in the CD groups. Conclusion: Alterations of GMV in CD-A and CD-R and associated correlation with psychological disorders may provide evidence for possible neuro-mechanisms of CD with psychological disorders.

BackgroundThe previous studies have demonstrated that patients with Crohn’s disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn’s disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF).Methods121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn’s disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages.ResultsThere were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors.ConclusionThe results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.

Abstract Background Chronic liver injury contributes to liver fibrosis, which is characterized by the excessive deposition of extracellular matrix (ECM) components. ECM is mainly composed of myofibroblasts. Recently, macrophage-to-myofibroblasts transition (MMT), has been identified as a novel origin for myofibroblasts. However, the potential functions of MMT in chronic liver injury and liver fibrosis remain unknown. Methods To clarify the transformation of fibrotic cells in hepatic fibrosis, liver specimens were collected from people at different stages in the progression of hepatic fibrosis and stained with immunofluorescence. Models of hepatic fibrosis such as the CCL4 model, HFD-induced NAFLD model, MCD-induced NAFLD model and ethanol-induced AFLD model were demonstrated and were stained with immunofluorescence. Results Here, we uncovered macrophages underwent MMT in clinical liver fibrosis tissue samples and multiple animal models of chronic liver injury. MMT cells were found in specimens from patients with liver fibrosis on the basis of co-expression of macrophage (CD68) and myofibroblast (a-SMA) markers. Moreover, macrophages could transform into myofibroblasts in CCL4-induced liver fibrosis model, high-fat diet (HFD) and methionine-choline-deficient diet (MCD)-induced nonalcoholic fatty liver diseases (NAFLD) model, and ethanol-induced alcoholic fatty liver diseases (AFLD) model. In addition, we highlighted that MMT cells mainly had a predominant M2 phenotype in both human and experimental chronic liver injury. Conclusions Taken together, MMT acts a crucial role in chronic liver injury and liver fibrosis.

Molecule hydrogen (H2) has been used to suppress tumor growth. To employ the H2 therapy, it is necessary to use a proper agent for continuous generation of H2. As a biodegradable metal, magnesium (Mg) generates H2 in an aqueous environment, but the H2 release rate is still too low. Here, we design a Mg-Al-Ca (AX) alloy that degrades very rapidly due to the presence of a secondary phase Al2Ca. Having a reduction potential much higher than Mg and any other Mg-based secondary phases, Al2Ca accelerates the corrosion of the Mg matrix by a micro-galvanic process. Al2Ca also enhances the strength and ductility of the AX alloy. AX alloy rods show better anti-tumor efficacy than pure Mg rods in vivo. Moreover, implanted AX alloy rods can be heated under an alternating magnetic field to suppress large-size tumors. This work suggests that the H2 therapy using highly degradable Mg alloys may provide an effective cancer treatment.

Abstract Conventional chemotherapy targets malignant cells without evaluating counter protection from the tumor microenvironment that often causes treatment failure. Herein, we establish chemoresistant fibroblasts (rCAFs) as regulators of neoadjuvant chemotherapeutic (NACT) response in head and neck squamous cell carcinoma (HNSCC). Clinically, high expression of CAF-related gene signature correlates with worse prognosis and chemotherapeutic response in multiple cancers, while the population of CAFs in the residual tumors of chemoresistant HNSCC patients remains unchanged after NACT treatment, compared to chemosensitive patients. Using a murine cancer model or patient-derived organoid, and primary CAFs isolated from chemo-sensitive (sCAFs) or -resistant patients, we show that rCAFs, but not sCAFs, are resistant to chemotherapy-induced apoptosis while reducing HNSCC cell chemosensitivity via paracrine signals. Combined multi-omics and biochemical analyses indicate an elevated PI3K/AKT/p65 driven cell survival and cytokine production in rCAFs, while rCAF-secreted TGFα promotes cancer cell chemoresistance by activating EGFR/Src/STAT3 survival signaling axis. Treatment with anti-EGFR cetuximab restores the chemosensitivity of tumors derived from co-injection of cancer cells and rCAFs in vivo, while the serum level of TGFα determines NACT response in HNSCC patients. Overall, our findings uncover a novel insight whereby the crosstalk between tumor cell and rCAF determines chemotherapeutic response and prognosis in cancer patients.

Abstract Background and aim The literature is sparse on the association between serum liver fibrosis markers and the development of hepatic decompensation in patients with compensated cirrhosis. We aimed to assessed whether the serum liver fibrosis markers are predictive of the occurrence of hepatic decompensation. Methods We ascertained 688 cirrhotic patients with varying etiologies, between December 2015 to December 2019. Serum hyaluronic acid (HA), laminin (LN), collagen IV (CIV), and N-terminal propeptide of type III collagen (PIIINP) levels were measured at enrollment. All subjects were followed for at least 6 months for occurrence of hepatic decompensation. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of hepatic decompensation during follow-up. Results During a median follow-up of 22.0 (13.0–32.0) months, decompensation occurred in 69 (10.0%) patients. Multivariate analysis indicated that higher LN (HR: 1.008, 95% confidence interval [CI]: 1.002–1.014, P = 0.011) and CIV (HR: 1.004, 95% CI: 1.001–1.007, P = 0.003) levels were independently associated with hepatic decompensation. Furthermore, patients in the tertile 2 and tertile 3 groups for CIV levels had HRs of 4.787 (1.419, 16.152) (P = 0.012) and 5.153 (1.508, 17.604) (P = 0.009), respectively, for occurrence of decompensation event compared with those in the tertile 1 group. Conclusion Serum liver fibrosis markers, particularly in CIV, appeared to be reliable biomarkers of disease progression and liver decompensation in patients with compensated cirrhosis with varying etiologies.

Abstract Background Prolyl 4-hydroxylase subunit beta (P4HB) has been reported as a suppressor in ferroptosis. However, no known empirical research has focused on exploring relationships between P4HB and prostate cancer (PCa). In this research, we initially examine the function of P4HB in PCa by thorough analysis of numerous databases and proliferation experiment. Methods We analyzed the correlations of P4HB expression with prognosis, clinical features, mutation genes, tumor heterogeneity, stemness, tumor immune microenvironment and PCa cells using multiple databases and in vitro experiment with R 3.6.3 software and its suitable packages. Results P4HB was significantly upregulated in tumor tissues compared to normal tissues and was closely related to biochemical recurrence-free survival. In terms of clinical correlations, we found that higher P4HB expression was significantly related to older age, higher Gleason score, advanced T stage and residual tumor. Surprisingly, P4HB had highly diagnostic accuracy of radiotherapy resistance (AUC 0.938). TGF beta signaling pathway and dorso ventral axis formation were upregulated in the group of low-expression P4HB. For tumor stemness, P4HB expression was positively related to EREG.EXPss and RNAss, but was negatively associated with ENHss and DNAss with statistical significance. For tumor heterogeneity, P4HB expression was positively related to MATH, but was negatively associated with tumor ploidy and microsatellite instability. For the overall assessment of TME, we observed that P4HB expression was negatively associated with all parameters, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, stromal score, immune score and ESTIMATE score. Spearman analysis showed that P4HB expression was negatively related to TIDE score with statistical significance. In vitro experiment, RT-qPCR and western blot showed that three siRNAs of P4HB were effective on the knockdown of P4HB expression. Furthermore, we observed that the downregulation of P4HB had significant influence on the cell proliferation of six PCa cell lines, including LNCap, C4-2, C4-2B, PC3, DU145 and 22RV1 cells. Conclusions In this study, we found that P4HB might serve as a prognostic biomarker and predict radiotherapy resistance for PCa patients. Downregulation of P4HB expression could inhibit the cell proliferation of PCa cells.

Abstract Background Apolipoprotein F (APOF) has been less studied in cancers. Thus, we aimed to perform a pan-cancer analysis of the oncogenic and immunological effects of APOF on human cancer. Methods A standardized TCGA pan-cancer dataset was downloaded. Differential expression, clinical prognosis, genetic mutations, immune infiltration, epigenetic modifications, tumor stemness and heterogeneity were analyzed. We conducted all analyses through software R (version 3.6.3) and its suitable packages. Results Overall, we found that the common cancers differentially expressed between tumor and normal samples and prognostic-associated were BRCA, PRAD, KIRP, and LIHC in terms of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). The pan-cancer Spearman analysis showed that the mRNA expression of APOF was negatively correlated with four tumor stemness indexes (DMPss, DNAss, ENHss, and EREG-METHss) with statistical significance for PRAD and was positively correlated for LIHC. In terms of BRCA and PRAD patients, we found negative correlation of APOF with TMB, MSI, neo, HRD and LOH. The mutation frequencies of BRCA and LIHC were 0.3%. APOF expression was negatively correlated with immune infiltration and positively correlated with tumor purity for PRAD patients. The mRNA expression of APOF was negatively associated with most TILs for LIHC, B cells, CD4+ T cells, neutrophils, macrophages and dendritic cells, but was positively associated with CD8+ T cells. Conclusions Our pan-cancer study offered a relatively comprehensive understanding of the roles of APOF on BRCA, PRAD, KIRP, and LIHC.

Abstract Current evidence indicate that cancer-associated fibroblasts (CAFs) play an important role in prostate cancer (PCa) development and progression. In this study, we identified CAF-related molecular subtypes and prognostic index for PCa patients undergoing radical prostatectomy through integrating single-cell and bulk RNA sequencing data. We completed analyses using software R 3.6.3 and its suitable packages. Through single-cell and bulk RNA sequencing analysis, NDRG2, TSPAN1, PTN, APOE, OR51E2, P4HB, STEAP1 and ABCC4 were used to construct molecular subtypes and CAF-related gene prognostic index (CRGPI). These genes could clearly divide the PCa patients into two subtypes in TCGA database and the BCR risk of subtype 1 was 13.27 times higher than that of subtype 2 with statistical significance. Similar results were observed in MSKCC2010 and GSE46602 cohorts. In addtion, the molucular subtypes were the independent risk factor of PCa patients. We orchestrated CRGPI based on the above genes and divided 430 PCa patients in TCGA database into high- and low- risk groups according to the median value of this score. We found that high-risk group had significant higher risk of BCR than low-risk group (HR: 5.45). For functional analysis, protein secretion was highly enriched in subtype 2 while snare interactions in vesicular transport was highly enriched in subtype 1. In terms of tumor heterogeneity and stemness, subtype 1 showd higher levels of TMB than subtype 2. In addition, subtype 1 had significant higher activated dendritic cell score than subtype 2. Based on eight CAF-related genes, we developed two prognostic subtypes and constructed a gene prognostic index, which could predict the prognosis of PCa patients very well.

Abstract Neutralizing antibodies exert a potent inhibitory effect on viral entry; however, they are less effective in therapeutic models than in prophylactic models, presumably because of their limited efficacy in eliminating virus-producing cells via Fc-mediated cytotoxicity. Herein, we present a SARS-CoV-2 spike-targeting bispecific T-cell engager (S-BiTE) strategy for controlling SARS-CoV-2 infection. This approach blocks the entry of free virus into permissive cells by competing with membrane receptors and eliminates virus-infected cells via powerful T cell-mediated cytotoxicity. S-BiTE is effective against both the original and Delta variant of SARS-CoV2 with similar efficacy, suggesting its potential application against immune-escaping variants. In addition, in humanized mouse model with live SARS-COV-2 infection, S-BiTE treated mice showed significantly less viral load than neutralization only treated group. The S-BiTE strategy may have broad applications in combating other coronavirus infections.

Glycyrrhetinic acid (GA) is a saponin compound, isolated from licorice (Glycyrrhiza glabra), which has been wildly explored for its intriguing pharmacological and medicinal effects. GA is a triterpenoid glycoside displaying an array of pharmacological and biological activities, including anti-inflammatory, anti-bacterial, antiviral and antioxidative properties. In this study, we investigated the underlying mechanisms of GA on acne vulgaris through network pharmacology and proteomics. After the intersection of the 154 drug targets and 581 disease targets, 37 therapeutic targets for GA against acne were obtained. A protein–protein interaction (PPI) network analysis highlighted TNF, IL1B, IL6, ESR1, PPARG, NFKB1, STAT3 and TLR4 as key targets of GA against acne, which is further verified by molecular docking. The experimental results showed that GA inhibited lipid synthesis in vitro and in vivo, improved the histopathological damage of skin, prevented mast cell infiltration and decreased the level of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6. This study indicates that GA may regulate multiple pathways to improve acne symptoms, and the beneficial effects of GA against acne vulgaris might be through the regulation of sebogenesis and inflammatory responses.

Abstract Background Prostate cancer (PCa) is usually considered as cold tumor. Malignancy is associated with cell mechanic changes that contribute to extensive cell deformation required for metastatic dissemination. Thus, we established stiff and soft tumor subtypes for PCa patients from perspective of membrane tension. Methods Nonnegative matrix factorization algorithm was used to identify molecular subtypes. We completed analyses using software R 3.6.3 and its suitable packages. Results We constructed stiff and soft tumor subtypes using eight membrane tension-related genes through lasso regression and nonnegative matrix factorization analyses. We found that patients in stiff subtype were more prone to biochemical recurrence than those in soft subtype (HR 16.18; p

Acidification of estuarine and coastal water due to synergistic effects of human induced eutrophication and elevated atmospheric CO2 could inhibit nitrification, a vital link of nitrogen cycle, but increase the release of powerful greenhouse gas N2O.

Abstract Background Head and neck squamous cell carcinomas (HNSCC) are the most common type of head and neck cancer with an unimproved prognosis over the past decades. Although the role of cancer‐associated‐fibroblast (CAF) has been demonstrated in HNSCC, the correlation between CAF‐derived gene expression and patient prognosis remains unknown. Methods A total of 528 patients from TCGA database and 270 patients from GSE65858 database were contained in this study. After extracting 66 CAF‐related gene expression data from TCGA database, consensus clustering was performed to identify different HNSCC subtypes. Limma package was used to distinguish the differentially expression genes (DEGs) between these subtypes, followed by Lasso regression analysis to construct a prognostic model. The model was validated by performing Kaplan‐Meier survival, ROC and risk curve, univariate and multivariate COX regression analysis. GO, KEGG, GSEA, ESTIMATE and ssGSEA analyses was performed to explort the potential mechanism leading to different prognosis. Results Based on the 66 CAF‐related gene expression pattern we stratitied HNSCC patients into two previously unreported subtypes with different clinical outcomes. A prognostic model composed of 15 DEGs was constructed and validated. In addition, bioinformatics analysis showed that the prognostic risk of HNSCC patients was also negatively correlated to immune infiltration, implying the role of tumor immune escape in HNSCC prognosis and treatment option. Conclusions The study develops a reliable prognostic prediction tool and provides a theoretical treatment guidance for HNSCC patients.

Nitrate is mainly converted via aerobic nitrite oxidation during the second step of nitrification, which is catalyzed by nitrite-oxidizing bacteria (NOB) and the recently discovery complete ammonia oxidizers (comammox). Members of the genus Nitrospira are the most diverse and widespread known NOB and comammox. However, the community assembly of Nitrospira in estuary and coastal wetland and the major environmental shaping factors remain understudied. Here in this study, we investigated the geographical distribution pattern of Nitrospira along the large-scale coastal wetlands of China. The results showed that the abundance of Nitrospira ranged from 4.96×106 - 3.88×107 copies/g dry sediment, significantly (more than one order of magnitude) higher than amoA gene of ammonia-oxidizers. The identified Nitrospira belong to Nitrospira lineage IV (50%), lineage I and II. The adaptability of the three lineages to environmental factors (such as temperature, pH, salinity and particle size) are different, which leads to the diversity of its distribution composition in different estuaries. Network analysis showed that the cooperation takes greater portion than competition in the relationship of Nitrospira population. This study revealed the abundance and community composition of Nitrospira bacteria, as well as the major environmental driving factors in coastal wetland ecosystems, which deepens our understanding of the niche separation of Nitrospira with the nitrogen cycling.

Objectives This study aims to assess the relative of social support and psychological distress in disease activity among patients with Crohn’s disease (CD) in China, and explore whether sex moderates the relationship between disease activity and social support and psychological distress in CD.Design Our study has a cross-sectional design.Setting This was a single-centre study, which was conducted in Wuhan, China.Participants A total of 184 patients with CD at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were enrolled in this study; of these,162 patients were included in the final analysis.Primary and secondary outcome measures The main study outcome was the CD patients’ clinical and questionnaire data. The association of disease activity, social support and psychological distress with patients with CD was also evaluated based on the collected data.Results A total of 162 patients with CD were enrolled. Compared with patients with CD in remission (CD-R), the patients with CD in activity (CD-A) had higher C reactive protein (CRP) (p=0.001), anaemia (p

BackgroundPatients with spontaneous bacterial peritonitis (SBP) often just receive empirical antibiotic therapy, as pathogens can be identified in only few patients using the techniques of conventional culture. Metagenomic next generation sequencing (mNGS) is a useful tool for diagnosis of infectious diseases. However, clinical application of mNGS in diagnosis of infected ascites of cirrhotic patients is rarely reported.Case presentationA 53-year-old male with cirrhosis on regular hemodialysis presented with continuous abdominal pain. After treatment with empiric antibiotics, his inflammatory parameters decreased without significant relief of abdominal pain. Finally, based on ascites mNGS detection, he was diagnosed as infection of Staphylococcus cohnii (S.cohnii), a gram-positive opportunistic pathogen. With targeted antibiotic treatment, the bacterial peritonitis was greatly improved and the patient’s abdominal pain was significantly alleviated.ConclusionsWhen conventional laboratory diagnostic methods and empirical antibiotic therapy fail, proper application of mNGS can help identify pathogens and significantly improve prognosis and patients’ symptoms.

ObjectivesTumor grading is important for prognosis of pancreatic ductal adenocarcinoma (PDAC). In this study, we developed preoperative clinical-radiomics nomograms using features from contrast-enhanced CT (CECT), to discriminate high-grade and low-grade PDAC and predict overall survival (OS).MethodsIn this single-center, retrospective study conducted from February 2014 to April 2021, consecutive PDAC patients who underwent CECT and had pathologically identified grading were randomized to training (n=200) and test (n=84) cohorts for development of model to predict histological grade based on radiomics scores from CECT (HGrad). Another 42 patients were used as external validation cohort of HGrad. A nomogram (HGnom) was constructed using radiomics score, CA12-5 and smoking to predict histological grade. A second nomogram (Pnom) was constructed using radiomics score, CA12-5, TNM, adjuvant treatment, resection margin and microvascular invasion to predict OS in radical resection patients (217 of 284).ResultsAmong 326 patients, 122 were high-grade (120 poorly differentiated and 2 undifferentiated). The HGrad yielded AUCs of 0.75 (95% CI: 0.64, 0.85) and 0.76 (95% CI: 0.60, 0.91) in test and validation cohorts. The HGnom achieved AUCs of 0.77 (95% CI: 0.66, 0.87), and the predicted grades calibrated well with actual grades (P=.13). OS was different between the grades predicted by radiomics scores (P=.01). The integrated AUC of the Pnom for predicting OS was 0.80 (95% CI: 0.75, 0.88).ConclusionCompared with the HGrad using features from CECT, the HGnom demonstrated higher performance for predicting histological grade. The Pnom helped identify patients with high survival outcome in pancreatic ductal adenocarcinoma.

Coastal soil microbiomes play a key role in coastal ecosystem functioning and are intensely threatened by land reclamation. However, the impacts of coastal reclamation on soil microbial communities, particularly on their assembly processes, co-occurrence patterns, and the multiple soil functions they support, remain poorly understood. This impedes our capability to comprehensively evaluate the impacts of coastal reclamation on soil microbiomes and to restore coastal ecosystem functions degraded by reclamation. Here, we investigated the temporal dynamics of bacterial and fungal communities, community assembly processes, co-occurrence patterns, and ecosystem multifunctionality along a 53-year chronosequence of paddy soil following reclamation from tidal flats. Reclamation of tidal flats to paddy soils resulted in decreased β-diversity, increased homogeneous selection, and decreased network complexity and robustness of both bacterial and fungal communities, but caused contrasting α-diversity response patterns of them. Reclamation of tidal flats to paddy soils also decreased the multifunctionality of coastal ecosystems, which was largely associated with the fungal network complexity and α-diversity. Collectively, this work demonstrates that coastal reclamation strongly reshaped the soil microbiomes at the level of assembly mechanisms, interaction patterns, and functionality level, and highlights that soil fungal community complexity should be considered as a key factor in restoring coastal ecosystem functions deteriorated by land reclamation.

Abstract Background N7-methylguanosine (m7G) is closely associated with tumor prognosis and immune response in many cancer types. The correlation between m7G and bladder cancer (BC) needs further study. We aimed to orchestrate molecular subtypes and identify key genes for BC from the perspective of m7G. Methods RNA-seq and clinical data of BC patients were extracted from TCGA and GSE13507 datasets. The patients were subtyped by “ConsensusClusterPlus” and “limma.” The clusters were validated by the Kaplan‒Meier curves, univariable and multivariate Cox regression models, the concordance index, and calibration curves. The immunotherapy response was evaluated by immune checkpoints, immune infiltration, TIDE score, and IMvigor210 cohort. Genomics of Drug Sensitivity in Cancer was utilized to predict the chemotherapy response between the clusters. Results The m7G-related cluster was ultimately established by EIF4G1, NUDT11, NUDT10, and CCNB1. The independent prognostic value of the m7G-related cluster was validated by the TCGA and GSE13507 datasets. The cluster was involved in immune-associated pathways, such as neutrophil degranulation, antigen processing cross-presentation, and signaling by interleukins pathways. Meanwhile, cluster 2 was positively correlated with many immune checkpoints, such as CD274, CTLA4, HAVCR2, LAG3, PDCD1, and PDCD1LG2. The cluster 2 was significantly correlated with a higher TIDE score than the cluster 1. Furthermore, in the IMvigor210 cohort, patients in the cluster 1 had a higher response rate than those in the cluster 2. Patients in the cluster 2 were sensitive to many chemotherapies. Conclusions We successfully determined molecular subtypes and identified key genes for BC from the perspective of m7G, thereby providing a roadmap for the evolution of immunotherapy and precision medicine.

The resistive microbolometer fabricated by using CMOS technology can be monolithically integrated with the readout circuit but usually performs poorly in responsivity and detectivity. In this paper, the salicide poly-Si microbolometer with Al grating structure is demonstrated in the standard CMOS process. The simulation results show that not only are surface plasmon polaritons generated at the interface of the Al grating and SiO2, Al grating also provides the infrared resonant cavity required for the absorber, which improves the responsivity of the microbolometer. According to the experimental results, the maximum detectivity of the microbolometer with the grating structure reaches up to 2.26 × 109 cmHz1/2/W at 10 μm, which means an increase by 27.8% compared to the one without the Al grating. Moreover, the average detectivity of the microbolometer is also improved when the wavelength ranges from 7 μm to 13 μm. It is effortless to implement the proposed high-performance microbolometer in a unit structure based on CMOS technology, which is favorable to high-density array integration.

Abstract At present, the insufficient supply of land resources has seriously hindered the sustainable development of regional economy. Improving the urban green land use efficiency (UGLUE) has become a key issue on the road to sustainable development. As an important feature of economic development, industrial agglomeration has an impact on the UGLUE that cannot be ignored. This paper uses the Global Malmquist–Luenberger Index (GMLI) to measure UGLUE of 107 cities in the Yangtze River Economic Belt (YREB) from 2007 to 2016, and uses a dynamic panel model (DPM) to empirically analyze the effects of industrial specialization agglomeration and diversification agglomeration on UGLUE. On this basis, the heterogeneous impact of industrial agglomeration in different regions on UGLUE is further discussed. The results illustrate that: (1) The UGLUE shows a general downward trend. (2) Different modes of industrial agglomeration have different impacts on UGLUE. The impact of industrial specialization agglomeration on UGLUE was inverted U-shaped. Industrial diversification agglomeration has a positive effect on UGLUE. (3) The impact of industrial agglomeration in different regions on UGLUE is heterogeneous. The relationship between the industrial agglomeration and UGLUE in the YREB revealed in this paper will provide a reference for promoting UGLUE.

Abstract In this study, we established a novel immunologic gene prognostic index (IGPI) to predict metastasis and provided new insights into tumor immune microenvironment (TIME) for PCa patients receiving radical radiotherapy. GBP2 and IGF1 were independent factors associated with metastasis-free survival. IGPI score was calculated based on GBP2 and IGF1 and this score was an independent risk factor for PCa patients undergoing radical radiotherapy. Patients with higher IGPI score were at higher risk of metastasis and biochemical recurrence, which were externally validated in the TCGA database and other GEO datasets. IGPI score had demonstrated moderate diagnostic ability of radiation resistance (AUC: 0.889). This score increased with the augment of Gleason score and T stage, as well as biochemical recurrence. Using EPIC, ESTIMATE and immunophenoscore (IPS) algorithms, cancer associated fibroblasts (CAFs), macrophages, stromal score, and estimate score were significantly higher in patients with metastasis group compared to their counterpart. Besides, for CAFs, macrophages, stromal score, and estimate score, patients with higher scores were at higher risk of metastasis, and the HRs were 3.65, 4.01, 4.27, and 3.78, respectively. IGPI score was highly positively associated with stromal score (coefficient: 0.39), immune score (coefficient: 0.43), estimate score (coefficient: 0.45), CAFs (coefficient: 0.42) and macrophages (coefficient: 0.42), while showing the opposite relationship with tumor purity (coefficient: − 0.45). In conclusion, we found that IGPI based on GBP2 and IGF1 might serve as a biomarker predicting metastasis for PCa patients. Besides, the current data further highlight the importance of CAFs in the metastatic process of PCa.

(1) Background: To assess the efficacy of the quantitative parameters of intravoxel incoherent motion (IVIM) diffusion-weighted imaging for hepatocellular carcinoma (HCC) diagnosis after transarterial chemoembolization (TACE). (2) Methods: Fifty HCC patients after TACE were included and underwent MRI. All of the patients were scanned with the IVIM-DWI sequence and underwent TACE retreatment within 1 week. Referring to digital subtraction angiography (DSA) and MR enhanced images, two readers measured the f, D, and D* values of the tumor active area (TAA), tumor necrotic area (TNA), and adjacent normal hepatic parenchyma (ANHP). Then, the distinctions of the TAA, TNA, and ANHP were compared and we analyzed the differential diagnosis of the parameters in three tissues. (3) Results: For values of f and D, there were significant differences between any of the TAA, TNA, and ANHP (p < 0.05). The values of f and D were the best indicators for identifying the TAA and TNA, with AUC values of 0.959 and 0.955, respectively. The values of f and D performed well for distinguishing TAA from ANHP, with AUC values of 0.835 and 0.753, respectively. (4) Conclusions: Quantitative IVIM-DWI was effective for evaluating tumor viability in HCC patients treated with TACE and may be helpful for non-invasive monitoring of the tumor viability.

Context The swim bladder of the croceine croaker is believed to have a therapeutic effect on various diseases. However, there is no research about its effect on mammalian spermatogenesis. Objective We investigated the swim bladder peptides (SBPs) effect on busulfan-induced oligoasthenospermia in mice. Materials and methods We first extracted SBP from protein hydrolysate of the croceine croaker swim bladder, and then five groups of ICR male mice were randomly assigned: control, control + SBP 60 mg/kg, busulfan, busulfan + SBP 30 mg/kg and busulfan + SBP 60 mg/kg. Mice received bilateral intratesticular injections of busulfan to establish oligoasthenospermia model. After treatment with SBP for 4 weeks, testis and epididymis were collected from all mice for further analysis. Results After treatment with SBP 30–60 mg/kg for 4 weeks, epididymal sperm concentration and motility increased by 3.9–9.6- and 1.9–2.4-fold than those of oligoasthenospermia mice induced by busulfan. Meanwhile, histology showed that spermatogenic cells decreased, leading to increased lumen diameters and vacuolization in the busulfan group. These features were reversed by SBP treatment. RNA-sequencing analysis revealed that, compared with the busulfan group, Lin28b and Igf2bp1 expression related to germ cell proliferation, increased with a >1.5-fold change after SBP treatment. Additionally, PGK2 and Cfap69 mRNAs associated with sperm motility, also increased with a >1.5-fold change. Furthermore, these findings were validated by quantitative real-time PCR and Western blotting. Discussion and conclusions This is the first reported evidence for the therapeutic effect of SBP on oligoasthenospermia. SBP may be a promising drug for oligoasthenospermia in humans.

Background: To investigate the prognostic significance of systemic inflammation score (SIS) in upper tract urothelial carcinoma (UTUC) in patients undergoing radical nephroureterectomy (RNU). Methods: A total of 313 UTUC patients who underwent RNU at West China Hospital from May 2014 to June 2019 were retrospectively analyzed. The predictive value of SIS for relevant endpoints, including overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS), was assessed by Kaplan–Meier curves and the Cox proportional hazards model. Results: According to inclusion and exclusion criteria, 218 UTUC patients were ultimately included in this cohort study. Statistical analysis shows that increased SIS was significantly associated with higher TNM stage (p = 0.017), lower BMI (p = 0.037), absence of hemoglobin (p < 0.001), and pathologic necrosis (p = 0.007). Kaplan–Meier survival curves clearly visually stratified survival for the three outcomes. After adjusting for tumor grade, the multivariate Cox proportional hazards model results showed that SIS was an independent risk factor for poor OS and CSS (HR = 1.89, 95% CI: 1.11–3.21, p = 0.0183, HR = 1.89, 95% CI: 1.07–3.33, p = 0.0285) in the advanced group. Conclusions: SIS was an independent risk factor for OS and CSS after RNU in patients with high-grade UTUC. It may be a novel and conducive tool for preoperative risk stratification and guiding individualized therapy for high-risk UTUC patients.

Objectivegastrointestinal stromal tumors (GISTs) with KIT exon 11 deletions have more malignant clinical outcomes. A radiomics model was constructed for the preoperative prediction of KIT exon 11 deletion in GISTs.MethodsOverall, 126 patients with GISTs who underwent preoperative enhanced CT were included. GISTs were manually segmented using ITK-SNAP in the arterial phase (AP) and portal venous phase (PVP) images of enhanced CT. Features were extracted using Anaconda (version 4.2.0) with PyRadiomics. Radiomics models were constructed by LASSO. The clinical-radiomics model (combined model) was constructed by combining the clinical model with the best diagnostic effective radiomics model. ROC curves were used to compare the diagnostic effectiveness of radiomics model, clinical model, and combined model. Diagnostic effectiveness among radiomics model, clinical model and combine model were analyzed in external cohort (n=57). Statistics were carried out using R 3.6.1.ResultsThe Radscore showed favorable diagnostic efficacy. Among all radiomics models, the AP-PVP radiomics model exhibited excellent performance in the training cohort, with an AUC of 0.787 (95% CI: 0.687-0.866), which was verified in the test cohort (AUC=0.775, 95% CI: 0.608-0.895). Clinical features were also analyzed. Among the radiomics, clinical and combined models, the combined model showed favorable diagnostic efficacy in the training (AUC=0.863) and test cohorts (AUC=0.851). The combined model yielded the largest AUC of 0.829 (95% CI, 0.621–0.950) for the external validation of the combined model. GIST patients could be divided into high or low risk subgroups of recurrence and mortality by the Radscore.ConclusionThe radiomics models based on enhanced CT for predicting KIT exon 11 deletion mutations have good diagnostic performance.

The SiO2–B2O3–Al2O3–Na2O system glass samples and the ceramic binder samples with different B2O3 contents were prepared. The density and the microhardness of different glass samples, the bending strength, the micro morphology and the thermal expansion coefficient of ceramic binder samples were measured by electronic multifunctional experimental machine, scanning electron microscope, microhardness instrument, plane flow method and thermal expansion coefficient tester. The structures and the compositions of the ceramic binder were analyzed by X-ray diffractometer and Fourier transform infrared spectrometer. The results show that the introduction of B2O3 into the ceramic binder can effectively reduce its sintering temperature, improve its thermal stability and adjust its thermal expansion coefficient. When B2O3 with mole fraction of 15% is added to the ceramic binder, the maximum bending strength of the spline is 78.11 MPa, and the maximum density and hardness are 2.45 g/cm3 and 856 MPa respectively, and the thermal expansion coefficient of the ceramic binder is the best match with that of diamond. The results of X-ray diffraction analysis show that the ceramic binder is a typical glass phase structure and has a good coating effect on the abrasives.

Abstract Spindle and kinetochore-associated complex subunit 3 (SKA3) is a microtubule-binding subcomplex of the outer kinetochore that is required for proper chromosomal segregation and cell division. However, little is known regarding the probable mechanism of SKA3, particularly in terms of prostate cancer (PCA) progression. Multiple databases, including TCGA and GTEx, were utilized to examine the expression of SKA3 in PCA patients and to shed light on the clinical significance and potential mechanism of SKA3 in the onset and progression of PCA. The biological function of SKA3 was evaluated in vitro using RT–qPCR and the CCK8 assay. For statistical analysis, the R 3.6.3 software and its associated packages were utilized. SKA3 was shown to be considerably elevated in PCA patients and was linked to a shorter progress free interval (PFI). Furthermore, we discovered that SKA3 mRNA expression was higher in PCA cells than in normal cells, and inhibition of SKA3 could clearly reduce PCA cell proliferation using the CCK8 assay. Finally, SKA3 could be used as a predictive biomarker in PCA patients.

Background: While radiotherapy has been studied in the treatment of locally advanced pancreatic ductal adenocarcinoma (PDAC), few studies have analyzed the effects of radiotherapy on PDAC in patients with liver metastases. This study aimed to determine whether PDAC patients with liver metastases have improved survival after radiotherapy treatment. Methods: The data of 8535 patients who were diagnosed with PDAC with liver metastases between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Survival analysis and Cox proportional hazards regression analysis of cancer-specific mortality and overall survival were performed, and propensity score matching (PSM) was used to reduce selection bias. Results: After PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) in the radiotherapy group were longer than those in the nonradiotherapy group (OS: 6 months vs. 4 months; mCSS: 6 months vs. 5 months, both p < 0.05), respectively. The multivariate analysis showed that cancer-specific mortality rates were higher in the nonradiotherapy group than in the radiotherapy group (HR: 1.174, 95% CI: 1.035–1.333, p = 0.013). The Cox regression analysis according to subgroups showed that the survival benefits (OS and CSS) of radiotherapy were more significant in patients with tumor sizes greater than 4 cm (both p < 0.05). Conclusions: PDAC patients with liver metastases, particularly those with tumor sizes greater than 4 cm, have improved cancer-specific survival (CSS) rates after receiving radiotherapy.

Abstract Background This study aimed to evaluate the artificial intelligence (AI)-based coronary artery calcium (CAC) quantification and regional distribution of CAC on non-gated chest CT, using standard electrocardiograph (ECG)-gated CAC scoring as the reference. Methods In this retrospective study, a total of 405 patients underwent non-gated chest CT and standard ECG-gated cardiac CT. An AI-based algorithm was used for automated CAC scoring on chest CT, and Agatston score on cardiac CT was manually quantified. Bland-Altman plots were used to evaluate the agreement of absolute Agatston score between the two scans at the patient and vessel levels. Linearly weighted kappa (κ) was calculated to assess the reliability of AI-based CAC risk categorization and the number of involved vessels on chest CT. Results The AI-based algorithm showed moderate reliability for the number of involved vessels in comparison to measures on cardiac CT (κ = 0.75, 95% CI 0.70–0.79, P

Abstract In this study, we aimed to perform a pan-cancer analysis of leucine zipper protein 2 (LUZP2). A standardized TCGA pan-cancer dataset was downloaded. Differential expression, clinical prognosis, genetic mutations, immune infiltration, epigenetic modifications, tumor stemness and heterogeneity were analyzed. We conducted all analyses through software R 3.6.3 and its suitable packages. Compared to normal samples, we observed that the LUZP2 mRNA expression was significantly upregulated in LGG, PRAD, LUSC and downregulated in KIRC and other eleven cancer species patients. In terms of overall survival, low-expression of LUZP2 was significantly associated with poor prognosis in lower grade glioma (LGG), lung squamous cell carcinoma (LUSC), kidney renal clear cell carcinoma (KIRC) and prostate adenocarcinoma (PRAD). For progression-free survival, we observed that downregulation of LUZP2 was significantly related to LGG, KIRC, LUSC, and PRAD. Our results observed negative correlations of the stemness of LGG and PRAD with the mRNA expression of LUZP2, whose downregulation was closely associated with poor prognosis. The mutation frequencies of LGG, PRAD, KIRC, and LUSC were 0.4%, 0.4%, 0.3%, and 2.1%, respectively. We detected that the LUZP2 level was negatively associated with TILs in most cancers, including LGG, LUSC, PRAD, and KIRC, while the LUZP2 methylation showed the opposite results. In conclusion, the results of our initial pan-cancer investigation provided a somewhat thorough understanding of the functions of LUZP2 on KIRC, LGG, PRAD, and LUSC.

Abstract Background Tumor cells detachment from primary lesions is an early event for hepatocellular carcinoma (HCC) metastasis, in which cell adhesion molecules play an important role. The role of mechanical crowding has attracted increasing attention. Previous studies have found that overcrowding can induce live cells extrusion to maintain epithelial cell homeostasis, and normally, live extruded cells eventually die through a process termed anoikis, suggesting the potential of tumor cells resistant to anoikis might initiate metastasis from primary tumors by cell extrusion. We have demonstrated transmembrane adhesion molecule blood vessel epicardial substance (BVES) suppression as an early event in HCC metastasis. However, whether its suppression is involved in HCC cell extrusion, especially in HCC metastasis, remains unknown. This study aims to investigate the role of BVES in tumor cells extrusion in HCC metastasis, as well as the underlying mechanisms. Methods Cells extrusion was observed by silicone chamber, petri dish inversion, and three-dimensional cell culture model. Polymerase chain reaction, western blotting, immunohistochemistry, immunofluorescence, co-immunoprecipitation, and RhoA activity assays were used to explore the underlying mechanisms of cell extrusion regulated by BVES. An orthotopic xenograft model was established to investigate the effects of BVES and cell extrusion in HCC metastasis in vivo. Results Tumor cell extrusion was observed in HCC cells and tissues. BVES expression was decreased both in HCC and extruded tumor cells. BVES overexpression led to the decrease in HCC cells extrusion in vitro and in vivo. Moreover, our data showed that BVES co-localized with ZO-1 and GEFT, regulating ZO-1 expression and localization, and GEFT distribution, thus modulating RhoA activity. Conclusion The present study revealed that BVES downregulation in HCC enhanced tumor cells extrusion, thus promoting HCC metastasis, which contributed to a more comprehensive understanding of tumor metastasis, and provided clues for developing novel HCC therapy strategies. Video abstract

Abstract Non-muscle invasive bladder cancer (NMIBC) is a major type of bladder cancer with a high incidence worldwide, resulting in a great disease burden. Treatment and surveillance are the most important part of NIMBC management. In 2018, we issued “Treatment and surveillance for non-muscle-invasive bladder cancer in China: an evidence-based clinical practice guideline”. Since then, various studies on the treatment and surveillance of NMIBC have been published. There is a need to incorporate these materials and also to take into account the relatively limited medical resources in primary medical institutions in China. Developing a version of guideline which takes these two issues into account to promote the management of NMIBC is therefore indicated. We formed a working group of clinical experts and methodologists. Through questionnaire investigation of clinicians including primary medical institutions, 24 clinically concerned issues, involving transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and intravesical immunotherapy of NMIBC, and follow-up and surveillance of the NMIBC patients, were determined for this guideline. Researches and recommendations on the management of NMIBC in databases, guideline development professional societies and monographs were referred to, and the European Association of Urology was used to assess the certainty of generated recommendations. Finally, we issued 29 statements, among which 22 were strong recommendations, and 7 were weak recommendations. These recommendations cover the topics of TURBT, postoperative chemotherapy after TURBT, Bacillus Calmette–Guérin (BCG) immunotherapy after TURBT, combination treatment of BCG and chemotherapy after TURBT, treatment of carcinoma in situ, radical cystectomy, treatment of NMIBC recurrence, and follow-up and surveillance. We hope these recommendations can help promote the treatment and surveillance of NMIBC in China, especially for the primary medical institutions.

Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared.

Type 2 diabetes (T2DM) clinically exhibits a higher incidence of hepatocellular carcinoma (HCC), contributing to a lousy prognosis in patients harboring both diseases. Microflora-based therapy draws attention with low side effects. Accumulating evidence shows that Lactobacillus brevis can improve blood glucose and body weight of the T2DM mice model and reduce several cancer incidences. However, the therapeutic effect of Lactobacillus brevis in affecting the prognosis of T2DM+HCC remains unknown. In this study, we aim to explore this question via an established T2DM+HCC mice model. We observed a significant alleviation after the probiotic intervention. Lactobacillus brevis improves blood glucose and insulin resistance and ameliorates Mechanically. Combined with a multi-omics approach including 16SrDNA, GC-MS, and RNA-seq, we identified distinct intestinal microflora composition and metabolites after Lactobacillus brevis intervention. Furthermore, we found that Lactobacillus brevis delayed disease progression by regulating MMP9 and NOTCH 1 signaling pathways, potentially through gut microflora and BA interaction. This study indicates that Lactobacillus brevis may improve the prognosis of T2DM + HCC, providing novel therapeutic opportunities via targeting intestinal flora for patients with T2DM+HCC.

BackgroundObesity is a prevalent health problem in patients with schizophrenia, and calorie restriction diet (CRD) achieved effective weight loss and metabolic improvement; however, these have not been rigorously evaluated in obese patients with schizophrenia.ObjectiveTo measure the effects of CRD on weight loss and metabolic status in hospitalized obese women with schizophrenia during a 4-week period.MethodsParticipants were randomly assigned to two groups in a 1:1 ratio. The intervention group (n = 47) was asked to follow a CRD and the control group (n = 48) a normal diet for 4 weeks. Outcomes of body weight, body composition, as well as metabolic parameters were measured at baseline and following the intervention period.ResultsForty-five participants completed the 4-week research in both the intervention and control groups. Compared to the normal diet, adherence to the CRD significantly decreased body weight (2.38 ± 1.30 kg), body mass index (0.94 ± 0.52 kg/m2), waist circumference (4.34 ± 2.75 cm), hip circumference (3.37 ± 2.36 cm), mid-upper circumferences, triceps skin-fold thickness, fat mass and free fat mass with large effect sizes (p = 0.05).ConclusionCRD is preventative of weight gain, but not apparent in intervention for metabolic status in hospitalized obese women with schizophrenia.Clinical trial registration: http://www.chictr.org.cn, ChiCTR-INR-16009185.

Background: Previous studies have demonstrated that both vitamin C (VC) and vitamin D3 (VD3) have therapeutic potential against metabolic disorders, including obesity, diabetes, and metabolic-associated fatty liver disease (MAFLD). However, it is unclear whether VC supplementation is associated with improving the intestinal flora and regulating the metabolism of bile acids via the gut-liver axis in MAFLD. There is still no direct comparison or combination study of these two vitamins on these effects.Methods: In this study, we employed biochemical, histological, 16S rDNA-based microbiological, non-targeted liver metabolomic, and quantitative real-time polymerase chain reaction analyses to explore the intervening effect and mechanism of VC and VD3 on MAFLD by using a high-fat diet (HFD)-induced obese mouse model.Results: Treatment of mice with VC and VD3 efficiently reversed the characteristics of MAFLD, such as obesity, dyslipidemia, insulin resistance, hepatic steatosis, and inflammation. VC and VD3 showed similar beneficial effects as mentioned above in HFD-induced obese mice. Interestingly, VC and VD3 reshaped the gut microbiota composition; improved gut barrier integrity; ameliorated oxidative stress and inflammation in the gut-liver axis; inhibited bile acid salt reflux-related ASBT; activated bile acid synthesis-related CYP7A1, bile acid receptor FXR, and bile acid transportation-related BSEP in the gut-liver axis; and improved bile secretion, thus decreasing the expression of FAS in the liver and efficiently ameliorating MAFLD in mice.Conclusion: Together, the results indicate that the anti-MAFLD activities of VC and VD3 are linked to improved gut-liver interactions via regulation of the gut microbiota and bile acid metabolism, and they may therefore prove useful in treating MAFLD clinically.