Integrating single-cell and spatial transcriptomics to elucidate the crosstalk between cancer-associated fibroblasts and cancer cells in hepatocellular carcinoma with spleen-deficiency syndrome.

Background and aim: Most patients with hepatocellular carcinoma (HCC) in China have been diagnosed with spleen deficiency syndrome (SDS), which accelerates the progression of HCC by disrupting the tumor microenvironment homeostasis. This study aimed to investigate the intercellular crosstalk in HCC with SDS. Experimental procedure: An HCC-SDS mouse model was established using orthotopic HCC transplantation based on reserpine-induced SDS. Single-cell data analysis and cancer cell prediction were conducted using Seurat and CopyKAT package, respectively. Intercellular interactions were explored using CellPhoneDB and CellChat and subsequently validated using co-culture assays, ELISA and histological staining. We performed pathway activity analysis using gene set variation analysis and the Seurat package. The extracellular matrix (ECM) remodeling was assessed using a gel contraction assay, atomic force microscopy, and Sirius red staining. The deconvolution of the spatial transcriptomics data using the "CARD" package based on single-cell data. Results and conclusion: We successfully established the HCC-SDS mouse model. Twenty-nine clusters were identified. The interactions between cancer cells and cancer-associated fibroblasts (CAFs) were significantly enhanced via platelet-derived growth factor (PDGF) signaling in HCC-SDS. CAFs recruited in HCC-SDS lead to ECM remodeling and the activation of TGF-ß signaling pathway. Deconvolution of the spatial transcriptome data revealed that CAFs physically surround cancer cells in HCC-SDS. This study reveals that the crosstalk of CAFs-cancer cells is crucial for the tumor-promoting effect of SDS. CAFs recruited by HCC via PDGFA may lead to ECM remodeling through activation of the TGF-ß pathway, thereby forming a physical barrier to block immune cell infiltration under SDS.

Comparison of Clinical and Radiographic Outcomes Between Transforaminal Endoscopic Lumbar Discectomy and Microdiscectomy: A Follow-up Exceeding 5 Years.

OBJECTIVE: To compare the long-term clinical and radiographic outcomes of transforaminal endoscopic lumbar discectomy (TELD) versus microdiscectomy (MD). METHODS: The data of 154 patients with lumbar disc herniation (LDH) who underwent TELD (n = 89) or MD (n = 65) were retrospectively analyzed. The patients' clinical outcomes were evaluated using visual analogue scales for leg and low back pain, the Japanese Orthopaedic Association (JOA) score, and the Oswestry Disability Index (ODI). The evolution of radiographic manifestations was observed during follow-up. Potential risk factors for a poor clinical outcome were investigated. RESULTS: During a mean follow-up of 5.5 years (range, 5-7 years), the recurrence rate was 4.49% in the TELD group and 1.54% in the MD group. All scores significantly improved from preoperatively to postoperatively in both groups (p < 0.01). The improvement in the ODI and JOA scores was significantly greater in the TELD than MD group (p < 0.05). Forty-seven patients (52.8%) in the TELD group and 32 (49.2%) in the MD group had Modic changes before surgery, most of which showed no changes at the last follow-up. The degeneration grades of 292 discs (71.0%) were unchanged at the last follow-up, while 86 (20.9%) showed improvement, mostly at the upper adjacent segment. No significant difference was observed in the intervertebral height index or paraspinal muscle-disc ratio. CONCLUSION: Both TELD and MD provide generally satisfactory long-term clinical outcomes for patients with LDH. TELD can be used as a reliable alternative to MD with less surgical trauma. Modic type II changes, decreased preoperative intervertebral height, and a high body mass index are predictors of a poor prognosis.

α-Terpineol affects social immunity, increasing the pathogenicity of entomopathogenic nematodes to subterranean termites (Isoptera).

Biocontrol of subterranean termites is largely impeded by their social immune responses. Studies on biocontrol agents combined with natural insecticides and their possible effects on the immune defense mechanisms of termites are limited. In this study, we investigated the effects of a combined biocontrol strategy using a plant-derived insect ATPase inhibitor, α-terpineol, with the entomopathogenic nematodes (EPNs) Steinernema carpocapsae against the subterranean termite Coptotermes formosanus Shiraki. Survival assays showed that even a low lethal concentration of α-terpineol significantly increased the EPNs-induced virulence in C. formosanus. α-terpineol treatment majorly inhibited the activity of Na+- K+- ATPase, which disturbed the EPNs-induced enhancement of locomotor activity and grooming behavior in termites treated with the combined strategy. Furthermore, the combination treatment had a synergistic inhibitory effect on innate immune responses in C. formosanus, which were measured as changes in the expression of immune-related genes and activities of immune system enzymes. In conclusion, α-terpineol can weaken the immune defense of termites against EPNs at low lethal concentrations, and is a suitable non-synthetic insecticide to prove the biocontrol efficiency of EPNs on C. formosanus. This study provides a theoretical basis and technical reference for a novel biocontrol strategy that promises to overcome the problems of host immune defense in termites.

Single cell and bulk transcriptome analysis identified oxidative stress response-related features of Hepatocellular Carcinoma.

Background: Hepatocellular Carcinoma (HCC) is a common lethal digestive system tumor. The oxidative stress mechanism is crucial in the HCC genesis and progression. Methods: Our study analyzed single-cell and bulk sequencing data to compare the microenvironment of non-tumor liver tissues and HCC tissues. Through these analyses, we aimed to investigate the effect of oxidative stress on cells in the HCC microenvironment and identify critical oxidative stress response-related genes that impact the survival of HCC patients. Results: Our results showed increased oxidative stress in HCC tissue compared to non-tumor tissue. Immune cells in the HCC microenvironment exhibited higher oxidative detoxification capacity, and oxidative stress-induced cell death of dendritic cells was attenuated. HCC cells demonstrated enhanced communication with immune cells through the MIF pathway in a highly oxidative hepatoma microenvironment. Meanwhile, using machine learning and Cox regression screening, we identified PRDX1 as a predictor of early occurrence and prognosis in patients with HCC. The expression level of PRDX1 in HCC was related to dysregulated ribosome biogenesis and positively correlated with the expression of immunological checkpoints (PDCD1LG2, CTLA4, TIGIT, LAIR1). High PRDX1 expression in HCC patients correlated with better sensitivity to immunotherapy agents such as sorafenib, IGF-1R inhibitor, and JAK inhibitor. Conclusion: In conclusion, our study unveiled variations in oxidative stress levels between non-tumor liver and HCC tissues. And we identified oxidative stress gene markers associated with hepatocarcinogenesis development, offering novel insights into the oxidative stress response mechanism in HCC.

Prognostic Role of Unfolded Protein Response-Related Genes in Hepatocellular Carcinoma.

AIMS: To reveal the prognostic role of unfolded protein response (UPR) -related genes in hepatocellular carcinoma (HCC). BACKGROUND: Hepatocellular carcinoma is a genetically heterogeneous tumor, and the prediction of its prognosis remains a challenge. Studies elucidating the molecular mechanisms of UPR have rapidly increased. However, the UPR molecular subtype characteristics of the related genes in HCC progression have yet to be thoroughly studied. OBJECTIVE: Conducting a comprehensive assessment of the prognostic signature of genes related to the UPR in patients with HCC can advance our understanding of the cellular processes contributing to the progression of HCC and offer innovative strategies in precise therapy. METHODS: Based on the gene expression profiles associated with UPR in HCC, we explored the molecular subtypes mediated by UPR-related genes and constructed a UPR-related genes signature that could precisely predict the prognosis for HCC. RESULTS: Using microarray data of HCC patients, differentially expressed UPR-related genes (DEGs) were discovered in malignancies and normal tissues. The HCC was classified into two molecular subtypes by the NMF algorithm based on DEGs modification of the UPR. Moreover, we developed a UPR-related model for predicting HCC patients' prognosis. The robustness of the UPR- related model was confirmed in external validation. Moreover, we analyzed immune responses in different risk groups. Analysis of immune functions revealed that Treg, Macrophages, aDCs, and MHC class-I were significantly up-regulated in high-risk HCC. At the same time, cytolytic activity and type I and II INF response were higher in a low-risk subgroup. CONCLUSION: This study identified two UPR molecular subtypes of HCC and developed a ten-gene HCC prognostic signature model (EXTL3, PPP2R5B, ZBTB17, CCT3, CCT4, CCT5, GRPEL2, HSP90AA1, PDRG1, and STC2), which can robustly forecast the progression of HCC.

Generalizability of machine learning methods in detecting adverse drug events from clinical narratives in electronic medical records.

We assessed the generalizability of machine learning methods using natural language processing (NLP) techniques to detect adverse drug events (ADEs) from clinical narratives in electronic medical records (EMRs). We constructed a new corpus correlating drugs with adverse drug events using 1,394 clinical notes of 47 randomly selected patients who received immune checkpoint inhibitors (ICIs) from 2011 to 2018 at The Ohio State University James Cancer Hospital, annotating 189 drug-ADE relations in single sentences within the medical records. We also used data from Harvard's publicly available 2018 National Clinical Challenge (n2c2), which includes 505 discharge summaries with annotations of 1,355 single-sentence drug-ADE relations. We applied classical machine learning (support vector machine (SVM)), deep learning (convolutional neural network (CNN) and bidirectional long short-term memory (BiLSTM)), and state-of-the-art transformer-based (bidirectional encoder representations from transformers (BERT) and ClinicalBERT) methods trained and tested in the two different corpora and compared performance among them to detect drug-ADE relationships. ClinicalBERT detected drug-ADE relationships better than the other methods when trained using our dataset and tested in n2c2 (ClinicalBERT F-score, 0.78; other methods, F-scores, 0.61-0.73) and when trained using the n2c2 dataset and tested in ours (ClinicalBERT F-score, 0.74; other methods, F-scores, 0.55-0.72). Comparison among several machine learning methods demonstrated the superior performance and, therefore, the greatest generalizability of findings of ClinicalBERT for the detection of drug-ADE relations from clinical narratives in electronic medical records.

Cellular senescence-related gene signature as a valuable predictor of prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a lethal tumor. Its prognosis prediction remains a challenge. Meanwhile, cellular senescence, one of the hallmarks of cancer, and its related prognostic genes signature can provide critical information for clinical decision-making. METHOD: Using bulk RNA sequencing and microarray data of HCC samples, we established a senescence score model via multi-machine learning algorithms to predict the prognosis of HCC. Single-cell and pseudo-time trajectory analyses were used to explore the hub genes of the senescence score model in HCC sample differentiation. RESULT: A machine learning model based on cellular senescence gene expression profiles was identified in predicting HCC prognosis. The feasibility and accuracy of the senescence score model were confirmed in external validation and comparison with other models. Moreover, we analyzed the immune response, immune checkpoints, and sensitivity to immunotherapy drugs of HCC patients in different prognostic risk groups. Pseudo-time analyses identified four hub genes in HCC progression, including CDCA8, CENPA, SPC25, and TTK, and indicated related cellular senescence. CONCLUSIONS: This study identified a prognostic model of HCC by cellular senescence-related gene expression and insight into novel potential targeted therapies.

Merging cultures and disciplines to create a drug discovery ecosystem at Virginia commonwealth university: Medicinal chemistry, structural biology, molecular and behavioral pharmacology and computational chemistry.

The Department of Medicinal Chemistry, together with the Institute for Structural Biology, Drug Discovery and Development, at Virginia Commonwealth University (VCU) has evolved, organically with quite a bit of bootstrapping, into a unique drug discovery ecosystem in response to the environment and culture of the university and the wider research enterprise. Each faculty member that joined the department and/or institute added a layer of expertise, technology and most importantly, innovation, that fertilized numerous collaborations within the University and with outside partners. Despite moderate institutional support with respect to a typical drug discovery enterprise, the VCU drug discovery ecosystem has built and maintained an impressive array of facilities and instrumentation for drug synthesis, drug characterization, biomolecular structural analysis and biophysical analysis, and pharmacological studies. Altogether, this ecosystem has had major impacts on numerous therapeutic areas, such as neurology, psychiatry, drugs of abuse, cancer, sickle cell disease, coagulopathy, inflammation, aging disorders and others. Novel tools and strategies for drug discovery, design and development have been developed at VCU in the last five decades; e.g., fundamental rational structure-activity relationship (SAR)-based drug design, structure-based drug design, orthosteric and allosteric drug design, design of multi-functional agents towards polypharmacy outcomes, principles on designing glycosaminoglycans as drugs, and computational tools and algorithms for quantitative SAR (QSAR) and understanding the roles of water and the hydrophobic effect.

A prognostic model based on DNA methylation-related gene expression for predicting overall survival in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) continues to increase in morbidity and mortality among all types of cancer. DNA methylation, an important epigenetic modification, is associated with cancer occurrence and progression. The objective of this study was to establish a model based on DNA methylation risk scores for identifying new potential therapeutic targets in HCC and preventing cancer progression. Methods: Transcriptomic, clinical, and DNA methylation data on 374 tumor tissues and 50 adjacent normal tissues were downloaded from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma database. The gene expression profiles of the GSE54236 liver cancer dataset, which contains data on 161 liver tissue samples, were obtained from the Gene Expression Omnibus database. We analyzed the relationship between DNA methylation and gene expression levels after identifying the differentially methylated and expressed genes. Then, we developed and validated a risk score model based on the DNA methylation-driven genes. A tissue array consisting of 30 human hepatocellular carcinoma samples and adjacent normal tissues was used to assess the protein and mRNA expression levels of the marker genes by immunohistochemistry and qRT-PCR, respectively. Results: Three methylation-related differential genes were identified in our study: GLS, MEX3B, and GNA14. The results revealed that their DNA methylation levels were negatively correlated with local gene expression regulation. The gene methylation levels correlated strongly with the prognosis of patients with liver cancer. This was confirmed by qRT-PCR and immunohistochemical verification of the expression of these genes or proteins in tumors and adjacent tissues. These results revealed the relationship between the level of relevant gene methylation and the prognosis of patients with liver cancer as well as the underlying cellular and biological mechanisms. This allows our gene signature to provide more accurate and appropriate predictions for clinical applications. Conclusion: Through bioinformatics analysis and experimental validation, we obtained three DNA methylation marker: GLS, MEX3B, and GNA14. This helps to predict the prognosis and may be a potential therapeutic target for HCC patients.

Single-cell transcriptomics reveals the role of Macrophage-Naïve CD4 + T cell interaction in the immunosuppressive microenvironment of primary liver carcinoma.

BACKGROUND: Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data. METHODS: Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell-cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets. RESULTS: Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell-cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted. CONCLUSIONS: This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.

Subpathway Analysis of Transcriptome Profiles Reveals New Molecular Mechanisms of Acquired Chemotherapy Resistance in Breast Cancer.

Chemoresistance has been a major challenge in the treatment of patients with breast cancer. The diverse omics platforms and small sample sizes reported in the current studies of chemoresistance in breast cancer limit the consensus regarding the underlying molecular mechanisms of chemoresistance and the applicability of these study findings. Therefore, we built two transcriptome datasets for patients with chemotherapy-resistant breast cancers­one comprising paired transcriptome samples from 40 patients before and after chemotherapy and the second including unpaired samples from 690 patients before and 45 patients after chemotherapy. Subsequent conventional pathway analysis and new subpathway analysis using these cohorts uncovered 56 overlapping upregulated genes (false discovery rate [FDR], 0.018) and 36 downregulated genes (FDR, 0.016). Pathway analysis revealed the activation of several pathways in the chemotherapy-resistant tumors, including those of drug metabolism, MAPK, ErbB, calcium, cGMP-PKG, sphingolipid, and PI3K-Akt, as well as those activated by Cushing's syndrome, human papillomavirus (HPV) infection, and proteoglycans in cancers, and subpathway analysis identified the activation of several more, including fluid shear stress, Wnt, FoxO, ECM-receptor interaction, RAS signaling, Rap1, mTOR focal adhesion, and cellular senescence (FDR < 0.20). Among these pathways, those associated with Cushing's syndrome, HPV infection, proteoglycans in cancer, fluid shear stress, and focal adhesion have not yet been reported in breast cancer chemoresistance. Pathway and subpathway analysis of a subset of triple-negative breast cancers from the two cohorts revealed activation of the identical chemoresistance pathways.

Correction: The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on the Pressure Overload-Induced Progression of Cardiac Hypertrophy to Cardiac Failure.

[This corrects the article DOI: 10.1371/journal.pone.0091834.].

Radiographic risk factors for degenerative lumbar spondylolisthesis: A comparison with healthy control subjects.

Objective: To evaluate the radiologic parameters of degenerative lumbar spondylolisthesis (DLS) and determine the radiographic risk factors for DLS by making comparisons with healthy control subjects. Methods: Seventy-five patients with L4/5 DLS (Meyerding grade I) and 53 healthy control subjects were analyzed. The L1-S1 disc height index (DHI), L4/5 facet joint angle (FJA), and relative cross-sectional area (RCSA) of paravertebral muscles were measured in both groups. The initial L4/5 DHI (iDHI) before the onset of DLS were estimated based on the L3/4 DHI of the DLS group and DHI of the control group. The sagittal parameters of DLS were also included in this study. Results: The DHI of L4/5 was lower in the DLS group than in the control group (P < 0.05), but the DHI of the L1-L4 segments were much higher than in the control group (P < 0.05). The initial L4/5 DHI and FJA of the DLS group were significantly higher than those of the control group (P < 0.05). The RCSA of the paravertebral muscles were smaller in the DLS group than in the control group (P < 0.05). Binary logistic regression analysis showed that iDHI, FJA, and RCSA of the total paraspinal muscles were risk factors for DLS. The cutoff values for iDHI, FJA, and RCSA were 0.504, 56.968°, and 1.991 respectively. The iDHI was associated with lumbar lordosis (LL), while L4/5 DHI was associated with the RCSA of the multifidus muscle and psoas major muscle (P < 0.05). Conclusion: A large initial lumbar disc height, large FJA, and paravertebral muscle atrophy may be risk factors for DLS.

Several non-salt and solid thienopyridine derivatives as oral P2Y12 receptor inhibitors with good stability.

A series of novel thienopyridine derivatives were designed and synthesized as P2Y12 receptor inhibitors. Several solid compounds were assessed for inhibitory effect where they exhibited stronger potency than clopidogrel. Compound 6b and 6g were evaluated for metabolism to verify that they could overcome clopidogrel resistance and for toxicity where they showed lower toxicity than prasugrel. Compound 6b exhibited lower risk of bleeding than prasugrel and showed good stability under stress testing. Overall, as a promising antiplatelet agent, representative compound 6b showed the following advantages: (1) no drug resistance for CYP2C19 poor metabolizers; (2) higher potency than clopidogrel; (3) lower toxicity than prasugrel; (4) lower risk of bleeding than prasugrel; (5) good stability as a non-salt solid.

Catechol-containing compounds are a broad class of protein aggregation inhibitors: Redox state is a key determinant of the inhibitory activities.

A range of neurodegenerative and related aging diseases, such as Alzheimer's disease and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based inhibitor design. Herein we employed a parallel small molecule library-screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Aß and tau. One remarkable class of inhibitors identified from these screens against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Secondary assays validated most of the identified inhibitors. In vivo efficacy evaluation of a selected catechol-containing compound, rosmarinic acid, demonstrated its strong mitigating effects of amylin amyloid deposition and related diabetic pathology in transgenic HIP rats. Further systematic investigation of selected class of inhibitors under aerobic and anaerobic conditions revealed that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. The molecular insights we gained not only explain why a large number of catechol-containing polyphenolic natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases.

Combined cadmium and fluorine inhibit lettuce growth through reducing root elongation, photosynthesis, and nutrient absorption.

Cadmium (Cd) and fluorine (F) often coexist in environment and are toxic to organisms; however, their combined effects on plants are still not well documented. In this study, the co-effects of Cd and F on germination, biomass, photosynthesis, and nutrients uptake of lettuce were carried out in hydroponic culture. The results showed that the seed germination and seedling biomass decreased with an increase in Cd and F supplementation. The root morphology verified these effects as excess combined Cd and F diminished the root tips and surface area of lettuce, while single Cd and F inhibited the growth by decreasing root length and average diameter, respectively. These effects were also consistence with a reduction in photosynthesis which was mainly regulated by reducing the quantum yield of PS II, electron transport activity, stomatal conductance, intercellular CO2 concentration, and transpiration rate in response to the pollutants. Moreover, when lettuce exposed to Cd and F stress, the accumulation of several essential elements in shoot decreased. In a sum, the synergistic negative effects of Cd and F on the seed germination and seedling growth of lettuce were observed, and these might be owed to nutrient absorption and translocation in the plant. These findings aid in understanding the harmful effects and specific mechanisms of action of Cd and F on plants.

Is it important to measure the internal spermatic vein diameter after varicocelectomy? A self-controlled trial.

To analyse spermatic vein parameters and post-varicocelectomy diagnostic ultrasound methods by comparing pre- and post-operative ultrasound parameters and semen quality in patients undergoing varicocelectomy. Ultrasound and semen analyses were performed within 1 week before surgery and 3 months after surgery in 125 patients who underwent varicocelectomy for infertility. Patients were divided into three groups according to the post-operative internal diameter of the spermatic vein and reflux: recovery, dilatation, and reflux. Changes in semen quality before and after surgery were compared between groups. Sperm concentration, motility, and morphology were significantly improved (p < 0.05); however, semen volume did not improve (p > 0.05) in patients in the recovery and dilatation groups compared to those in patients before surgery. Sperm concentration, motility, and semen volume did not improve in patients in the reflux group compared with those in patients before surgery (p > 0.05). Logistic regression analysis revealed that the internal diameter of the spermatic vein and reflux duration were risk factors for post-operative spermatic vein dilatation without reflux. Ultrasonography after varicocelectomy should primarily be used to observe reflux, and should not be used as a diagnostic criterion for varicocele based on the internal diameter of the spermatic vein alone.

Evaluation of Occupational Health Risk Management and Performance in China: A Case Study of Gas Station Workers.

China has a large number of gas stations, with which thousands of workers are associated. There is abundant online literature documenting the various occupational health risks these workers face. However, this literature has many flaws to address, and it falls short of suggesting measures to manage these risks. This study strives to fill that gap, and aims to improve the occupational health of gas station workers through comprehensive risk management and performance analysis. To this end, a reasonable volume of reliable data, i.e., 208 completed questionnaires, were analyzed through current statistical routines, viz., fuzzy Analytical Hierarchy Process (AHP) and Importance Performance Analysis (IPA). These methods were employed to hierarchically organize the main factors and sub-factors of physical risk management, chemical risk management, biological risk management, physiological risk management and psychological risk management according to their appraised importance, and screen out the risk management stratagem for priority improvement. Research findings reveal that chemical risk and biological risk response schemes have the lowest performance, and need to be prioritized for improvement. Furthermore, this study argues that we can safeguard the occupational health of gas station workers through appropriate risk management strategies. It also elaborates on implications, limitations and future research directions.

Inflammatory Response-Related Long Non-Coding RNA Signature Predicts the Prognosis of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a high mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting prognosis challenging. Meanwhile, the inflammatory response is an indispensable player in the tumorigenesis process and regulates the tumor microenvironment, which can affect the prognosis of tumor patients. Methods: Using HCC samples in the TCGA-LIHC dataset, we explored lncRNA expression profiles associated with the inflammatory response. The inflammatory response-related lncRNA signature was constructed by univariate Cox regression, LASSO regression, and multivariate Cox regression methods based on inflammatory response-related differentially expressed lncRNAs in HCC. Results: Seven inflammatory response-related lncRNA signatures were identified in predicting HCC prognosis. Kaplan-Meier (K-M) survival analysis indicated that high-risk group HCC patients were associated with poor prognosis. The utility of the inflammatory response-related lncRNA signatures was proved by the AUC and DCA analysis. The nomogram further confirmed the accuracy of the novel signature in predicting HCC patients' prognoses. In validation, our novel signature is more accurate than traditional clinicopathological performance for prognosis prediction of HCC patients. GSEA analysis further elucidated the underlying mechanisms and pathways of HCC progression in the low- and high-risk groups. Moreover, immune cells infiltration responses and immune function analyses revealed a significant difference between high- and low-risk groups in cytolytic activity, MHC class I, type I INF response, type II INF response, inflammation-promoting, and T cell coinhibition. Finally, HHLA2, NRP1, CD276, TNFRSF9, TNFSF4, CD80, and VTCN1 were expressed higher in high-risk groups in the immune checkpoint analysis. Conclusions: A novel inflammatory response-related lncRNA signature (AC145207.5, POLHAS1, AL928654.1, MKLN1AS, AL031985.3, PRRT3AS1, and AC023157.2) is capable of predicting the prognosis of HCC patients and providing new immune targeted therapies insight.

Therapeutic Effect of Catgut Implantation at Acupoint in a Mouse Model of Hepatocellular Carcinoma by Suppressing Immune Escape.

BACKGROUND: The occurrence and development of hepatocellular carcinoma (HCC) are closely related to immune function, as is the capacity of hepatoma cells to escape. Immunosurveillance is a key mechanism. Catgut implantation at acupoint (CIAA) is a promising acupuncture improvement method that can regulate immunity and has been widely used in the clinical treatment of a variety of diseases. The aim of this study is to observe the therapeutic effect of CIAA on HCC and to investigate the potential mechanism of immune escape. MATERIALS AND METHODS: A total of 40 mice were randomly divided into three groups: the HCC model group (n = 15), the CIAA treatment group (n = 15), and the control group (n = 10). HCC was chemically induced in 30 mice by the combination of DEN, carbon tetrachloride, and ethanol for 150 days. Among them, 15 were selected for CIAA treatment to ascertain the therapeutic effect. The mRNA expression levels of AFP, IL-10, PD-1, and CTLA-4 in three groups were examined by using RT-PCR. AFP and AKT expressions were measured by using western blotting. PD1, CTLA-4, IL-10, CD4+, and CD8+ protein expression levels were evaluated by using IHC. The mortality rate, body weight, and psychological conditions of three groups were also compared. RESULTS: The mRNA and protein expression levels of AFP, PD-1, CTLA-4, and IL-10 were significantly downregulated in the CIAA-treated mice in comparison with HCC mice. IHC assay shows that CD4+ and CD8+ expression levels were notably upregulated after CIAA treatment. Western blotting assay shows that AKT pathway was deactivated in CIAA-treated mice. CIAA notably reduced the mortality rate and inhibited weight loss caused by HCC and improved the overall psychological condition of the mice. CONCLUSIONS: Taken together, our data corroborate the effective potency of CIAA in the treatment of HCC by and inhibiting immune escape and deactivating the AKT pathway.