Immunotherapy and liver cancer research trends and the 100 most cited articles: A bibliometric analysis.

BACKGROUND: Bibliometric analysis of liver cancer research, particularly in immunotherapy, reveals crucial insights. The US leads in liver cancer mortality but ranks fifth globally. OBJECTIVE: Scopus database analysis identified 2,349 papers, with the top 100 ranging from 127 to 4,959 citations. Notably, "Microenvironmental Regulation of Tumours Progression and Metastasis" in the Journal of Nature Medicine garnered the highest citations. METHODS: Journals like the Journal of Hepatology, Hepatology, and Nature Reports Clinical Oncology contributed significantly. Understanding molecular mechanisms and prognostic indicators is paramount for advancing combination therapies. RESULTS: For better patient outcomes, research trends in liver cancer immunotherapy point to improved treatment protocols, knowledge of the tumor microenvironment, combining therapies, predicting disease course, international cooperation, sophisticated surgical techniques, early detection, oncolytic virotherapy, and patient-centered care. CONCLUSIONS: This research underscores immunotherapy's pivotal role and encourages further exploration, offering valuable insights into liver cancer treatment trends.

Associations between deep venous thrombosis and thyroid diseases: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach. METHODS: This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran's Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes. RESULTS: This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran's Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods. CONCLUSIONS: This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions.

Epigallocatechin-3-gallate Alleviates Ethanol-Induced Endothelia Cells Injury Partly through Alteration of NF-κB Translocation and Activation of the Nrf2 Signaling Pathway.

Ethanol (alcohol) is a risk factor that contributes to non-communicable diseases. Chronic abuse of ethanol is toxic to both the heart and overall health, and even results in death. Ethanol and its byproduct acetaldehyde can harm the cardiovascular system by impairing mitochondrial function, causing oxidative damage, and reducing contractile proteins. Endothelial cells are essential components of the cardiovascular system, are highly susceptible to ethanol, either through direct or indirect exposure. Thus, protection against endothelial injury is of great importance for persons who chronic abuse of ethanol. In this study, an in vitro model of endothelial injury was created using ethanol. The findings revealed that a concentration of 20.0 mM of ethanol reduced cell viability and Bcl-2 expression, while increasing cell apoptosis, intracellular reactive oxygen species (ROS) levels, mitochondrial depolarization, and the expression of Bax and cleaved-caspase-3 in endothelial cells. Further study showed that ethanol promoted nuclear translocation of nuclear factor kappa B (NF-κB), increased the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 in the culture medium, and inhibited nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway. The aforementioned findings suggest that ethanol has a harmful impact on endothelial cells. Nevertheless, the application of epigallocatechin-3-gallate (EGCG) to the cells can effectively mitigate the detrimental effects of ethanol on endothelial cells. In conclusion, EGCG alleviates ethanol-induced endothelial injury partly through alteration of NF-κB translocation and activation of the Nrf2 signaling pathway. Therefore, EGCG holds great potential in safeguarding individuals who chronically abuse ethanol from endothelial dysfunction.

Identification of fibronectin type III domain containing 3B as a potential prognostic and therapeutic target for pancreatic cancer: a preliminary analysis.

BACKGROUND: Fibronectin type III domain containing 3B (FNDC3B), a member of the fibronectin type III domain-containing protein family, has been indicated in various malignancies. However, the precise role of FNDC3B in the progression of pancreatic cancer (PC) still remains to be elucidated. METHODS: In this study, we integrated data from the National Center for Biotechnology Information, the Cancer Genome Atlas, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets to analyze FNDC3B expression and its association with various clinicopathological parameters. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, along with Gene Set Enrichment Analysis (GSEA), single sample Gene Set Enrichment Analysis (ssGSEA) and estimate analysis were recruited to delve into the biological function and immune infiltration based on FNDC3B expression. Additionally, the prognostic estimation was conducted using Cox analysis and Kaplan-Meier analysis. Subsequently, a nomogram was constructed according to the result of Cox analysis to enhance the prognostic ability of FNDC3B. Finally, the preliminary biological function of FNDC3B in PC cells was explored. RESULTS: The study demonstrated a significantly higher expression of FNDC3B in tumor tissues compared to normal pancreatic tissues, and this expression was significantly associated with various clinicopathological parameters. GSEA revealed the involvement of FNDC3B in biological processes and signaling pathways related to integrin signaling pathway and cell adhesion. Additionally, ssGSEA analysis indicated a positive correlation between FNDC3B expression and infiltration of Th2 cells and neutrophils, while showing a negative correlation with plasmacytoid dendritic cells and Th17 cells infiltration. Kaplan-Meier analysis further supported that high FNDC3B expression in PC patients was linked to shorter overall survival, disease-specific survival, and progression-free interval. However, although univariate analysis demonstrated a significant correlation between FNDC3B expression and prognosis in PC patients, this association did not hold true in multivariate analysis. Finally, our findings highlight the crucial role of FNDC3B expression in regulating proliferation, migration, and invasion abilities of PC cells. CONCLUSION: Despite limitations, the findings of this study underscored the potential of FNDC3B as a prognostic biomarker and its pivotal role in driving the progression of PC, particularly in orchestrating immune responses.

Survival benefit of adjuvant chemotherapy in patients with resected gallbladder adenocarcinoma: An updated retrospective cohort analysis.

BACKGROUND: The rarity yet high malignancy of gallbladder adenocarcinoma (GBA) endows it with a distinctive nature. Radical resection remains the foremost therapeutic approach for GBA, while the impact of early recurrence and metastasis on patient prognosis necessitates the utilization of adjuvant chemotherapy (AC). Despite numerous previous studies on this topic, a consensus regarding the authentic efficacy of AC has yet to be reached. METHODS: We conducted an updated retrospective cohort analysis utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2010 to 2020 to explore the association between AC and survival outcomes in patients with resected GBA. RESULTS: Our study included 2782 patients from the SEER database, with further evaluation of 843 patients in each cohort following meticulous execution of a 1:1 propensity score matching. Remarkably, the AC cohort exhibited a significant survival advantage when juxtaposed against the non-AC cohort. Multivariable Cox regression analysis identified age at diagnosis, year at diagnosis, grade, AJCC T stage, AJCC N stage as well as AC as independent prognostic factors. Furthermore, our findings unveiled that poor/undifferentiated tumor histology, pathological T2 or higher category and pathological N1 category were significantly associated with improved survival when treated with AC while simultaneously observing improved survival across all age categories. CONCLUSION: These results provide additional evidence supporting the survival benefits of AC and offer guidance for personalized therapy in patients with resected GBA.

OTUB1 Targets CHK1 for Deubiquitination and Stabilization to Facilitate Lung Cancer Progression and Radioresistance.

PURPOSE: Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. Ovarian tumor domain ubiquitin aldehyde binding 1 (OTUB1) is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism, and cytokine secretion as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. METHODS AND MATERIALS: The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry. In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and Gene Ontology terms were analyzed based on RNA sequencing. RESULTS: Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiation therapy for lung adenocarcinoma. CONCLUSIONS: These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilization of the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiation therapy in lung cancer.

K+-Dependent Photocycle and Photocurrent Reveal the Uptake of K+ in Light-Driven Sodium Pump.

Engineering light-controlled K+ pumps from Na+-pumping rhodopsins (NaR) greatly expands the scope of optogenetic applications. However, the limited knowledge regarding the kinetic and selective mechanism of K+ uptake has significantly impeded the modification and design of light-controlled K+ pumps, as well as their practical applications in various fields, including neuroscience. In this study, we presented K+-dependent photocycle kinetics and photocurrent of a light-driven Na+ pump called Nonlabens dokdonensis rhodopsin 2 (NdR2). As the concentration of K+ increased, we observed the accelerated decay of M intermediate in the wild type (WT) through flash photolysis. In 100 mM KCl, the lifetime of the M decay was approximately 1.0 s, which shortened to around 0.6 s in 1 M KCl. Additionally, the K+-dependent M decay kinetics were also observed in the G263W/N61P mutant, which transports K+. In 100 mM KCl, the lifetime of the M decay was approximately 2.5 s, which shortened to around 0.2 s in 1 M KCl. According to the competitive model, in high KCl, K+ may be taken up from the cytoplasmic surface, competing with Na+ or H+ during M decay. This was further confirmed by the K+-dependent photocurrent of WT liposome. As the concentration of K+ increased to 500 mM, the amplitude of peak current significantly dropped to approximately ~60%. Titration experiments revealed that the ratio of the rate constant of H+ uptake (kH) to that of K+ uptake (kK) is >108. Compared to the WT, the G263W/N61P mutant exhibited a decrease of approximately 40-fold in kH/kK. Previous studies focused on transforming NaR into K+ pumps have primarily targeted the intracellular ion uptake region of Krokinobacter eikastus rhodopsin 2 (KR2) to enhance K+ uptake. However, our results demonstrate that the naturally occurring WT NdR2 is capable of intracellular K+ uptake without requiring structural modifications on the intracellular region. This discovery provides diverse options for future K+ pump designs. Furthermore, we propose a novel photocurrent-based approach to evaluate K+ uptake, which can serve as a reference for similar studies on other ion pumps. In conclusion, our research not only provides new insights into the mechanism of K+ uptake but also offers a valuable point of reference for the development of optogenetic tools and other applications in this field.

Long-distance migration law of radon in overburden of abandoned goaf during coal spontaneous combustion.

The surface isotope radon measurement method (SIRMM) is widely used in fire source detection in abandoned mines. However, studies on the long-distance migration of radon during coal spontaneous combustion are lacking, which hinders the further popularization of this technology in coal fire prevention and control. For this reason, the migration law of radon in overlying strata in fire areas was studied through experiments and numerical simulation. The radon exhalation concentration of coal was found to increase at first and then decrease in the range of 30-350 °C through experiments. The radon concentration reaches the maximum value (557.1 Bq/m3) at 150 °C, which is 6.3 times higher than that at 30 °C. Based on the radon source term obtained by fitting the experimental data, the radon migration model of coal spontaneous combustion in abandoned goaf was constructed, and the dynamic distribution characteristics of the airflow, temperature, and radon concentration fields in the overlying strata area were analyzed. The internal relationship between surface radon and underground fire source was discussed. The simulation results revealed the sharp change in the porosity of the overlying rock causes radon concentration at the interface between the caving and fissure zones to increase continually with the process of spontaneous combustion, providing material and energy support for the long-distance radon migration. When the maximum temperature of the coal pile reaches 70 °C, the concentration of radon released from the coal pile increases rapidly to 13696 Bq/m3, and the radon from the underground space appears on the surface at this temperature. In the range of 70-150 °C, with rapid increase in radon released from coal piles, the surface concentration of radon also increased rapidly to 225 Bq/m3. At the high-temperature stage exceeding 150 °C, the concentration of radon released from coal piles exhibited a downward trend, resulting in a decrease in the rate of increase of radon concentration on the surface. A close relationship between the surface radon concentration and underground fire source temperature in the process of coal spontaneous combustion was observed. In the spatial position, the peak position of radon on the surface was highly consistent with that of the fire source longitudinally, which ensures the accuracy of the SIRMM to determine the location of the hidden fire source. This suggests that the SIRMM can accurately evaluate the fire source's temperature and fire area's development trend.

Discovery of novel TRPV1 modulators through machine learning-based molecular docking and molecular similarity searching.

The transient receptor potential vanilloid 1 (TRPV1) channel belongs to the transient receptor potential channel superfamily and participates in many physiological processes. TRPV1 modulators (both agonists and antagonists) can effectively inhibit pain caused by various factors and have curative effects in various diseases, such as itch, cancer, and cardiovascular diseases. Therefore, the development of TRPV1 channel modulators is of great importance. In this study, the structure-based virtual screening and ligand-based virtual screening methods were used to screen compound databases respectively. In the structure-based virtual screening route, a full-length human TRPV1 protein was first constructed, three molecular docking methods with different precisions were performed based on the hTRPV1 structure, and a machine learning-based rescoring model by the XGBoost algorithm was constructed to enrich active compounds. In the ligand-based virtual screening route, the ROCS program was used for 3D shape similarity searching and the EON program was used for electrostatic similarity searching. Final 77 compounds were selected from two routes for in vitro assays. The results showed that 8 of them were identified as active compounds, including three hits with IC50 values close to capsazepine. In addition, one hit is a partial agonist with both agonistic and antagonistic activity. The mechanisms of some active compounds were investigated by molecular dynamics simulation, which explained their agonism or antagonism.

Difference Between Screw Cement Filling and Adequate Osteotomy With Thick Liner for Primary Total Knee Arthroplasty in Patients With Rand IIb Tibial Defects.

BACKGROUND: The effectiveness of 2 treatment options, screw-cement fill, and adequate osteotomy with a thick liner, in treating patients with Rand IIb tibial defects (tibial plateau defects to a depth of 5 to 10 millimeters) in primary total knee arthroplasty (TKA) has not yet been demonstrated. Therefore, we performed a retrospective study to evaluate the differences between these 2 treatments. METHODS: We retrospectively analyzed patients who underwent primary TKA for Rand IIb tibial plateau defects from 2015 to 2020 from a department database. Patients were categorized into the screw-cement and thick liner groups based on the different options used to repair tibial defects. We evaluated Knee Society Score, range of motion (ROM), Insall-Salvati index (ISI), and Forgotten Joint Score (FJS) in both groups. We also compared differences in prosthesis survival, stiffness, myasthenia, and joint clicking between the 2 groups at mean 2 years postoperatively (range, 2 to 2.3). A power analysis was performed on the number of cases in the cohort. RESULTS: Postoperative femur-tibia mechanical axis (FTMA) correction was significantly higher in the screw-cement group than in the thick-liner group: 18.8 (±5.6°) versus 15.4 (±5.9°) (P < .01); At mean 2 years after surgery, the American Knee Society Functional Score improvement values were higher in the thick-liner group than in the screw-cement group: 36.3 (±12.4) versus 42.4 (±16.4) (P = .05). Postoperative ISI scores were 0.95 (±0.12) points in the screw-cement group and 0.89 (±0.13) points in the-thick liner group (P = .03). There were no statistically significant differences in the Knee Society Clinical Score, ROM, FJS, stiffness, myasthenia, joint clicking, and revision rate. CONCLUSION: The results of this study showed no significant difference in clinical outcomes between the 2 reconstruction strategies of the screw cement fill technique and the adequate osteotomy and thick liner technique for Rand IIb tibial plateau defects. However, in patients who have FTMA deformities greater than 20° or in younger patients who need to preserve bone volume, we recommend the screw cement filling technique to ensure stable postoperative results and to prepare these patients for possible later surgery.

Efficacy of cast immobilization versus surgical treatment for distal radius fractures in adults: a systematic review and meta-analysis.

This articl e includes high-quality randomized controlled trials in recent years and updates the past meta-analysis. It has been proved that cast immobilization can achieve similar functional results, reduce economic burden in the long-term compared with surgery, and provide a basis for doctors to make treatment choices. PURPOSE: The efficacy of conservative and surgical treatment of distal radius fractures (DRFs) in adults is still controversial. Recently, some high-quality randomized controlled trials (RCTs) evaluated the efficacy of both treatments. We hypothesized that treatment of DRFs with closed reduction and cast immobilization would achieve functional outcomes similar to surgery. METHODS: This study is a systematic review and summary of RCTs comparing conservative and surgical management of DRFs from 2005 to March 2022. Patients were evaluated for functional and imaging outcomes and complications. RESULTS: A total of 11 studies [1-11] included 1775 cases of DRFs. At 1-year follow-up, the cast group had lower mean differences (MDs) in DASH scores than the surgery group by - 2.55 (95% CI = - 5.02 to - 0.09, P = 0.04); with an MD of 1.63 (95% CI = 1.08-2.45, P = 0.02), while the surgery group had a lesser complication rate than the cast group. CONCLUSIONS: At 1-year follow-up, the lower DASH scores of the cast group showed advantages of this treatment, but the complication rate was higher than that of the surgery group. There was no massive distinction in other scoring methods.

m6A regulator-mediated methylation modification highlights immune infiltration patterns for predicting risk in hepatocellular carcinoma.

BACKGROUND: Increasing studies have demonstrated the biological function of RNA N6-methyladenosine (m6A) modifications in tumorigenesis. However, the potential role of m6A modifications in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) remains unclear. METHODS: Herein, 23 m6A regulators were fetched and introduced into consensus clustering to identify distinct m6A modification patterns and develop m6A-based molecular signatures. Then, a principal component analysis algorithm was employed to construct an m6A-based scoring system to further quantify m6A modification patterns in individual tumors. Immunophenoscore (IPS) was used to estimate the immunotherapeutic response of patients. RESULTS: Three different m6A modification patterns with distinct prognoses and biological signatures were identified among 611 HCC samples. The TIME characteristics of these three patterns were consistent with three known immune profiles: immune-oasis, immune-excluded, and immune-inflamed phenotypes. Identifying m6A modification patterns within individual tumors based on the m6Ascore, developed under the m6A-related signature genes, contributed to elaborating biological processes, clinical outcomes, immune cell infiltration, immunotherapeutic effects, and genetic variations. The low-m6Ascore subtype, characterized by immunosuppression, suggested an immune-suppressed phenotype and a low probability of benefiting from immunotherapy. Finally, the potential function of PRDM4 in HCC was explored. CONCLUSION: This study comprehensively elucidated the indispensable role of m6A modification patterns in the complexity of TIME. The quantitative identification of m6A modification patterns in individual tumors will contribute to optimizing precision immunotherapy.

USPs in Pancreatic Ductal Adenocarcinoma: A Comprehensive Bioinformatic Analysis of Expression, Prognostic Significance, and Immune Infiltration.

Pancreatic ductal adenocarcinoma (PDAC), as an intractable malignancy, still causes an extremely high mortality worldwide. The ubiquitin-specific protease (USP) family constitutes the major part of deubiquitinating enzymes (DUBs) which has been reported to be involved in initiation and progression of various malignancies via the function of deubiquitination. However, the biological function and clinical values of USPs in PDAC have not been comprehensively elucidated. In this study, Gene Expression Profiling Interactive Analysis (GEPIA), Gene Expression Omnibus (GEO) datasets, UALCAN database, and the Human Protein Atlas (HPA) online tool were used to analyze the expression level and the relationship between USP expression and clinicopathological features in PDAC. Survival module of HPA and Kaplan-Meier plotter (KMP) databases was recruited to explore the prognostic value of USPs. Tumor Immune Estimation Resource (TIMER) online tool and KMP databases were utilized to elucidate tumor immune infiltration and immune-related survival of USPs. CBioPortal online tool was used to identify the gene mutation level of USPs in PDAC. Both cBioPortal and LinkedOmics were used to confirm the potential biological functions of USPs in PDAC. Our study showed that USP10, USP14, USP18, USP32, USP33, and USP39 (termed as six-USPs) expressions were significantly elevated in tumor tissues. The high expression of the four USPs (USP10, USP14, USP18, and USP39) indicated a poor prognosis. A significant relationship was indicated between the expression of six-USPs and clinicopathological features. Also, the expression of six-USPs was related to promoter methylation level. Moreover, more than 40% genetic alterations and mutations were discovered in six-USPs. Furthermore, the six-USP expression was correlated with immune infiltration and immune-related prognosis. The functional analysis found that the six-USPs were involved in various biological processes and signaling pathways, such as nucleocytoplasmic transport, choline metabolism in cancer, cell cycle, ErbB signaling pathway, RIG-I-like receptor signaling pathway, TGF-ß signaling pathway, and TNF signaling pathway. In conclusion, the results showed that six-USPs are potential prognostic biomarkers and can be recruited as possible therapeutic targets of PDAC.

Effective natural inhibitors targeting granzyme B in rheumatoid arthritis by computational study.

Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients. Objectives: This study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and to screen desirable compounds with potential inhibitory effects on GZMB. Methods: We performed differential gene analysis on GSE55235 and GSE55457 from Gene Expression Omnibus (GEO) and then obtained the intersection of the two differentially expressed genes (DEGs) lists by drawing Venn diagrams. Then we performed protein-protein interaction (PPI) network analysis, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the DEGs of the intersection. Next, we downloaded the crystal structure of Granzyme B (GZMB). Molecular docking technology was used to screen potential inhibitors of GZMB in subsequent experiments, and we then analyzed the toxicity and water solubility of these potential inhibitors for future drug experiments. Finally, whether the docking of these small molecules with GZMB is stable is tested by molecular dynamics. Results: A total of 352 mutual DEGs were identified. Twenty hub genes were obtained according to PPI network analysis, among which the GZMB gene attracted the attention of our research. Three potent natural compounds, ZINC000004557101, ZINC000012495776, and ZINC000038143593, bound to GZMB, show better binding affinity. Furthermore, they are predicted to own low Ames mutagenicity, developmental toxicity potential, rodent carcinogenicity, and high tolerance to cytochrome P4502D6. Molecular dynamics simulations show that ZINC000004557101 and GZMB have more advantageous potential energy and can exist stably in a natural environment. Moreover, we finally verified the inhibitory effect of ZINC000004557101 on granzyme B by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blotting experiment. Conclusion: RA patients showed increased GZMB expression. ZINC000004557101 is a potential drug targeting GZMB for treating RA.

Modified Brostrom-Gould surgical procedure for chronic lateral ankle instability compared with other operations: a systematic review and meta-analysis.

BACKGROUND: This study performed a randomized trial data meta-analysis to assess The Modified Brostrom-Gould (MBG) for proven chronic lateral ankle instability (CLAI). METHODS: All published randomized clinical trials comparing MBG and other operations were found by searching the Cochrane Library, EMBASE, and PubMed databases. The Review Manager 5.4 software was used to compare the two groups regarding postoperative functional score, ankle stability, and complications. Risk Ratio (RR) and Mean Differences (MD) were used in meta-analyses. RESULTS: 8 experiments are suitable for it, 426 patients were enrolled, and 222 patients underwent other operations surgery. Among the six outcome indicators, in terms of FAOS scores, the other operations group has an advantage, 6.53 points higher than MBG; others show no significant differences. CONCLUSIONS: Based on this meta-analysis, the authors believe that other surgical groups can achieve better outcomes than MBG in some aspects of CLAI treatment.

Role of extracellular vesicles in osteosarcoma.

Osteosarcoma is a malignant bone tumor characterized by the direct production of osteoid tissue from tumor cells. Extracellular vesicles are membranous vesicles released by cells into the extracellular matrix, which exist widely in various body fluids and cell supernatants, and stably carry some important signaling molecules. They are involved in cell communication, cell migration, angiogenesis and tumor cell growth. Increasing evidence has shown that extracellular vesicles play a significant role in osteosarcoma development, progression, and metastatic process, indicating that extracellular vesicles can be use as biomarker vehicles in the diagnosis and prognosis of osteosarcoma. This review discusses the basic biological characteristics of extracellular vesicles and focuses on their application in osteosarcoma.

The independent and interactive effects of phthalates exposure and hypertension on the indicators of early renal injury in US adults: Evidence from NHANES 2001-2004.

The association between phthalates and early renal injury is largely unknown in adults. We aim to explore the associations of phthalates and hypertension with early renal injury, and the interactive effects of phthalate and hypertension on the early renal injury. This study enrolled 3283 U.S. adults from NHANES 2001-2004. We detected nine phthalate metabolites in spot urine. We also measured the multiple indicators of early renal injury, including albumin-to-creatinine (Cr) ratio (ACR), ß2-microglobulin (B2M), cystatin C (CYST), and calculated the estimated glomerular filtration rate (eGFR), including Cr-based eGFR, CYST-based eGFR, and Cr-CYST-based eGFR. Multiple linear regression and multivariable logistic regression were used to explore the associations among urinary phthalate metabolites, hypertension, and the indicators of early renal injury. The results showed that monobenzyl phthalate (MBzP), mono (3-carboxypropyl) phthalate (MCPP), and mono (2-ethylhexyl) phthalate (MEHP) were positively associated with ACR, B2M, CYST and negatively associated with three eGFR. Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) was positively associated with ACR, with a ß value of 0.099 (95% CI: 0.046, 0.152). Meanwhile, MEHP was associated with a higher risk of ACR abnormality, with an OR value of 1.258 (95% CI: 1.067, 1.482). MBzP, MCPP, and MEOHP increased the risks of ACR, B2M, CYST, and eGFR abnormality. Hypertension was positively associated with ACR, with a ß value of 0.460 (95% CI: 0.360, 0.561). We also found interactive effects of monoethyl phthalate (MEP), MCPP, MBzP, monobutyl phthalate (MnBP), and hypertension on B2M, CYST, and three kinds of eGFR. Our results indicated that certain phthalate metabolites might contribute to increased risks of early renal injury. The hypertension population may be more sensitive to the early renal injury caused by phthalates exposure than the non-hypertension population.

Associations of exposure to melamine, cyanuric acid, phthalates with markers of early kidney impairment, and their interactions in US adults: analyses of NHANES 2003-2004 data.

Melamine (MEL), cyanuric acid (CYA), and phthalates have kidney toxicity, respectively. Still, no study has explored whether there is an interaction of co-exposure to MEL, CYA, and phthalates on early kidney impairment, including cystatin C (CYST), beta 2-microglobulin (ß2-MG), albumin creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Urine samples were collected from 333 adults in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, and urinary MEL, CYA, and ten metabolites of phthalates were quantified. The multiple markers of early kidney impairment were also measured, including serum CYST, ß2-MG, urinary ACR, and eGFR. Their associations were explored by multiple linear and multivariate logistic regression models. Meanwhile, the interactions of co-exposure to MEL, CYA, and phthalates on early kidney impairment were analyzed by Wilcoxon rank-sum test combined with the LSD test. In the multiple linear regression model, urinary concentrations of monobenzyl phthalate (MBzP), mono(3-carboxypropyl) phthalate (MCPP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-ethylhexyl) phthalate (MEHP) were positively associated with urinary ACR, serum ß2-MG, and CYST, respectively. Urinary concentrations of MBzP and MCPP were negatively associated with eGFR. In the multivariate logistic regression model, increased urinary CYA concentration was the risk factor of CYST abnormality with an odds ratio (OR) (95% confidence interval, 95% CI) of 2.38 (1.01, 5.60) (P = 0.047) and increased urinary MBzP concentration was the risk factor of ACR abnormality with an OR of 2.59 (1.41, 4.75) (P = 0.002). The co-exposure to MEL, CYA, and four phthalate metabolites (MEHP, MBzP, MCPP, and MECPP) presented significantly interactive effects on the markers of early kidney impairment, respectively. There were the independent and interactive effects of exposure to MEL, CYA, and specific phthalate metabolites on early kidney impairment. Due to co-exposure to multiple environmental chemicals in our daily life, more attention should be paid to the health damage raised by the synergistic effects of environmental chemicals.

Polyostotic Fibrous Dysplasia Complicated by Pathological Fracture of Right Femoral Shaft with Nonunion: A Case Report.

Introduction: Fibrous dysplasia is a benign fibrous bone tumor that accounts for 5% to 10% of benign bone tumors. It can manifest as simple fibrous dysplasia (70%-80%), polyostotic fibrous dysplasia (20%-30%), with approximately the same incidence in men and women. We report a patient with a rare case of multiple fibrous dysplasia combined with proximal femoral shepherd deformity with pathological fracture of the femoral shaft complicated by nonunion. It is necessary to understand the disease in more detail to avoid overtreatment of benign lesions or misdiagnosis of malignant tumors and other diseases. Case presentation: A 58-year-old man with polyostotic fibrous dysplasia, bilateral proximal femur deformity, Shepherd's angle deformity, right femoral shaft pathological fracture complicated by nonunion, we under fluoroscopy, in the obvious proximal fracture, take osteotomy, and process the shape of the cut bone fragment to adapt it to the corrected force line, and then restore it back to its original position, using intramedullary nailing technology complete the operation. Three months after the operation, he came to the hospital for re-examination, and an X-ray of the right femur was taken. It was found that the fractured end had a tendency to heal. The patient was instructed to gradually bear weight. After six months of re-examination, the patient could walk with a walker. One year after the operation, the patient could walk without a walker and take care of himself at home. However, there was still stretch-like pain in the right lower back, but it was tolerable. Conclusions: For patients with polyostotic fibrous dysplasia combined with proximal femoral shepherd deformity and pathological fracture of the femoral shaft with nonunion, osteotomy combined with intramedullary nailing is a simple and convenient way to correct the deformity and obtain correct fracture alignment.

Integrated Analysis of MATH-Based Subtypes Reveals a Novel Screening Strategy for Early-Stage Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a frequently diagnosed cancer type, and many patients have already reached an advanced stage when diagnosed. Thus, it is crucial to develop a novel and efficient approach to diagnose and classify lung adenocarcinoma at an early stage. In our study, we combined in silico analysis and machine learning to develop a new five-gene-based diagnosis strategy, which was further verified in independent cohorts and in vitro experiments. Considering the heterogeneity in cancer, we used the MATH (mutant-allele tumor heterogeneity) algorithm to divide patients with early-stage LUAD into two groups (C1 and C2). Specifically, patients in C2 had lower intratumor heterogeneity and higher abundance of immune cells (including B cell, CD4 T cell, CD8 T cell, macrophage, dendritic cell, and neutrophil). In addition, patients in C2 had a higher likelihood of immunotherapy response and overall survival advantage than patients in C1. Combined drug sensitivity analysis (CTRP/PRISM/CMap/GDSC) revealed that BI-2536 might serve as a new therapeutic compound for patients in C1. In order to realize the application value of our study, we constructed the classifier (to classify early-stage LUAD patients into C1 or C2 groups) with multiple machine learning and bioinformatic analyses. The 21-gene-based classification model showed high accuracy and strong generalization ability, and it was verified in four independent validation cohorts. In summary, our research provided a new strategy for clinicians to make a quick preliminary assisting diagnosis of early-stage LUAD and make patient classification at the intratumor heterogeneity level. All data, codes, and study processes have been deposited to Github and are available online.