Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma.

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.

Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis.

Emerging evidence has figured that serum conversion rate of mumps is a crucial link of mumps disease. Nevertheless, a rising number of mumps outbreaks caused our attention and studies examining the serum conversion cases were conducted in small samples previously; this meta-analysis was conducted to assess the immunogenicity and safety of a mumps containing vaccine (MuCV) before 2019. We identified a total of 17 studies from the year of 2002-2017. In the case-control studies, the vaccine effectiveness (VE) of MuCV in preventing laboratory-confirmed mumps was 68% (odds risk: 0.32; 95% confidence interval [CI], 0.14-0.70) while in the cohort studies and randomised control trials, 58% (relative risk [RR]: 0.42; 95% CI, 0.26-0.69). Similar intervals of effectiveness rates were found during non-outbreak periods compared with outbreak periods (VE: 66%; RR: 0.34; 95% CI, 0.18-0.68 versus VE: 49%; RR: 0.51; 95% CI, 0.21-1.27). In addition, the MuCV group with two and three doses did not show enhanced laboratory-confirmed mumps than one dose (VE: 58%; RR: 0.42; 95% CI, 0.20-0.88 versus VE: 65%, RR: 0.35; 95% CI, 0.20-0.61) for the reason of the overlap of 95% CI. MuCV had comparable effectiveness comparing non-outbreak and outbreak period, one dose, and two or three doses. MuCV displayed acceptable adverse event profiles.

Systemic immune-inflammation index (SII) and the risk of all-cause, cardiovascular, and cardio-cerebrovascular mortality in the general population.

BACKGROUND: An elevated systemic immune-inflammation index (SII) is associated with higher mortality in patients with coronary artery disease and other diseases. However, the potential of SII for predicting mortality in the general population has been underexplored. Therefore, this study aimed to analyze the relationship between the SII and all-cause, cardiovascular disease, and cardiocerebrovascular disease mortality in the general population. METHODS: This study involved 26,855 participants (≥ 18 years) from the National Health and Nutrition Examination Survey 1999-2014 who were grouped according to the SII tertiles. Survival differences between the groups were analyzed using log-rank tests and Kaplan-Meier plots. Furthermore, multivariate Cox regression and restricted cubic spline analyses were used to examine the relationship between the SII and all-cause, cardiovascular, and cardio-cerebrovascular mortality. RESULTS: Overall, 1947 (7.425%) participants died following an average follow-up of 87.99 ± 54.04 months. Among these, 325 (1.210%) deaths were related to cardiovascular diseases and 392 (1.459%) to cardio-cerebrovascular mortality. Kaplan-Meier analysis revealed statistically significant differences in all-cause, cardiovascular, and cerebrovascular mortality between the SII tertiles (log-rank test: all P < 0.001). Multi-adjusted models showed that participants in the highest tertile of SII had a higher risk of death from all-cause (hazard ratio [HR] = 1.48, 95% confidence interval [CI] 1.48-1.48) and cardiovascular mortality (HR = 1.60, 95% CI 1.60-1.61) compared with those in the lowest tertile. In addition, the restricted cubic spline curve indicated a nonlinear association between SII and all-cause mortality (P < 0.001), with threshold value of SII at 18.284. There was a 15% decrease in the risk of all-cause mortality for each twofold change in SII on the left flank (HR = 0.85, 95% CI 0.69-1.05) and a 42% increase (HR = 1.42, 95% CI 1.23-1.64) on the right flank of the inflection point. In addition, the risk of cardiovascular mortality increased nonlinearly by 39% per twofold change in SII (HR = 1.39, 95% CI 1.07-1.81). There was also a nonlinear increase in the risk of cardio-cerebrovascular mortality per twofold change in SII (HR = 1.29, 95% CI 1.00-1.66). CONCLUSIONS: In the general population, the SII was significantly associated with all-cause, cardiovascular, and cardio-cerebrovascular mortality, regardless of the established risk factors.

Identification of two novel ferroptosis-associated targets in sepsis-induced cardiac injury: Hmox1 and Slc7a11.

Purpose: Sepsis-induced cardiac injury is a severe complication of sepsis and has a high mortality. Recent research has implicated ferroptosis as a contributing factor to myocardial cell death. This study is aimed at finding novel ferroptosis-associated targets in sepsis-induced cardiac injury. Methods and results: In our study, a total of two Gene expression omnibus datasets (GSE185754 and GSE171546) were obtained for bioinformatics analysis. GSEA enrichment analysis demonstrated that ferroptosis pathway Z-score rapidly increased in the first 24 h and decreased gradually in the following 24-72 h. Fuzzy analysis was then used to obtain distinct clusters of temporal patterns and find genes in cluster 4 that exhibited the same trend with ferroptosis progression during the time points. After intersecting the differentially expressed genes, genes in cluster 4, and ferroptosis-related genes, three ferroptosis-associated targets were finally selected: Ptgs2, Hmox1, and Slc7a11. While Ptgs2 has been previously reported to be involved in the regulation of septic cardiomyopathy, this study is the first to demonstrate that downregulation of Hmox1 and Slc7a11 can alleviate ferroptosis in sepsis-induced cardiac injury. Conclusion: This study reports Hmox1 and Slc7a11 as ferroptosis-associated targets in sepsis-induced cardiac injury, and both of them may become key therapeutic and diagnostic targets for this complication in the future.

Common variants of RARRES2 and RETN contribute to susceptibility to hand osteoarthritis and related pain.

Aim: To examine the relationship of the RETN and RARRES2 genes with hand osteoarthritis (HOA) susceptibility risk, clinical severity and pain. Methods: A total of 3740 subjects comprising 1180 participants with HOA and 2560 controls were enrolled. Genetic association was evaluated at both single marker and haplotype levels using PLINK. Results: Two significant hits, single-nucleotide polymorphism (SNP) rs4721 from RARRES2 and SNP rs3745368 from RETN, were identified as being related to an increased risk of HOA. Significant associations were obtained for SNP rs3745368 with Kellgren-Lawrence grade in HOA patients and SNP rs4721 with pain analog scales of HOA patients. Conclusion: The authors' results indicate that RARRES2 and RETN affect HOA risk and are associated with clinical features and severity in patients with HOA.

Attenuating oxidized low density lipoprotein (ox-LDL)-induced macrophages damage via inhibiting C-type lectin domain family 2 (CLEC2) expression through janus kinase 1 (JAK1)/ signal transducers and activators of transcription-1 (STAT1) pathway.

Our study aimed to explore the effect of C-type lectin-like receptor 2 (CLEC2) expression level on oxidized low-density lipoprotein (ox-LDL)-induced macrophage damage and the regulatory mechanism of macrophage foaming. Foam cells were derived from RAW264.7 by ox-LDL, and the cell viability was detected by cell counting kit-8 (CCK-8) assay. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of inflammatory cytokines tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), and Interleulin-1ß (IL-1ß). Small interfering CLEC2 (si-CLEC2) was synthesized and transfected into RAW264.7, and the apoptosis rate was analyzed by flow cytometry. Western blotting was employed to detect the protein expressions of Janus kinase 1 (JAK1), Signal transducers and activators of transcription-1 (STAT1), phosphorylation-JAK1 (p-JAK1), phosphorylation-STAT1 (p-STAT1), CLEC2, and the apoptosis-related proteins. The levels of total cholesterol (TC) and free cholesterol (FC) were measured using colorimetric kits. Results showed that ox-LDL could activate the JAK1/STAT1 pathway of macrophages and up-regulate the expression of CLEC2. CLEC2 knockdown could reduce macrophage inflammation and lipid accumulation. Inactivating JAK1/STAT1 pathway with JAK1 inhibitor can significantly reduce the phosphorylation of STAT1 and alleviate the ox-LDL-induced damage in macrophages by regulating the expression of CLEC2. In conclusion, targeting JAK1/STAT1 to inhibit CLEC2 can attenuate ox-LDL-induced macrophage damage. This study enriched the pathogenesis of atherosclerosis and provided the possible treatment targets.

The effect of common variants in GDF5 gene on the susceptibility to chronic postsurgical pain.

BACKGROUND: The growth differentiation factor 5 (GDF5) gene regulates the growth of neuronal axons and dendrites and plays a role in the inflammatory response and tissue damage. The gene may also be associated with chronic postsurgical pain. This study aimed to reveal the relationship between SNPs in the GDF5 gene and orthopedic chronic postsurgical pain in Han Chinese population based on a case-control study. METHODS: We genotyped 8 SNPs within GDF5 gene in 1048 surgical patients with chronic postsurgical pain as the case group and 2062 surgical patients who were pain free as the control group. SNP and haplotypic analyses were performed, and stratified analyses were conducted to determine the correlations between significant SNPs and clinical characteristics. RESULTS: Only rs143384 in the 5'UTR of GDF5 was identified as significantly associated with increased susceptibility to chronic postsurgical pain, and the risk of A allele carriers was increased approximately 1.35-fold compared with that of G allele carriers. Haplotypes AGG and GGG in the LD block rs143384-rs224335-rs739329 also showed similar association patterns. Furthermore, we found that rs143384 was significantly correlated with chronic postsurgical pain in the subgroup aged ≤ 61 years, subgroup with a BMI ≤ 26, subgroup with no-smoking or no pain history, and subgroup with a drinking history. CONCLUSION: Our study provided supportive evidence that genetic variations in the GDF5 gene are potential genetic factors that can increase the risk of chronic postsurgical pain in the Han Chinese population, but further research is necessary to elucidate the underlying mechanism.

Metabolic utilization of human osteoblast cell line hFOB 1.19 under normoxic and hypoxic conditions: A phenotypic microarray analysis.

Osteoblasts play an important role in bone regeneration and repair. The hypoxia condition in bone occurs when bone undergoes fracture, and this will trigger a series of biochemical and mechanical changes to enable bone repair. Hence, it is interesting to observe the metabolites and metabolism changes when osteoblasts are exposed to hypoxic condition. This study has looked into the response of human osteoblast hFOB 1.19 under normoxic and hypoxic conditions by observing the cell growth and utilization of metabolites via Phenotype MicroArrays™ under these two different oxygen concentrations. The cell growth of hFOB 1.19 under hypoxic condition showed better growth compared to hFOB 1.19 under normal condition. In this study, osteoblast used glycolysis as the main pathway to produce energy as hFOB 1.19 in both hypoxic and normoxic conditions showed cell growth in well containing dextrin, glycogen, maltotriose, D-maltose, D-glucose-6-phospate, D-glucose, D-mannose, D-Turanose, D-fructose-6-phosphate, D-galactose, uridine, adenosine, inosine and α-keto-glutaric acid. In hypoxia, the cells have utilized additional metabolites such as α-D-glucose-1-phosphate and D-fructose, indicating possible activation of glycogen synthesis and glycogenolysis to metabolize α-D-glucose-1-phosphate. Meanwhile, during normoxia, D-L-α-glycerol phosphate was used, and this implies that the osteoblast may use glycerol-3-phosphate shuttle and oxidative phosphorylation to metabolize glycerol-3-phosphate.

Hypoxic-Mediated Oxidative Stress Condition and Hydroxyapatite-Inducing Osteogenic Differentiation of Human Mesenchymal Stem Cells: A Mathematical Modeling Study.

Avascular necrosis (AVN) of the bones remains a major clinical challenge. Fractures in the talus, the scaphoid, and the neck of the femur are especially challenging to heal due to the low blood vessel network and the lack of collateral blood supply. These fractures are associated with high rates of nonunion and increased infections that require repeated operations. Conventional treatments by autografting or allografting bone replacement and synthetic bone implants have limitations, including the invasiveness of operative procedures, tissue supply insufficiency, and the risk of host rejection. The advancement in tissue engineering has revealed the potential of stem cells as restorative agents for bone injuries. The administration of mesenchymal stem cells (MSCs) into the talus, the scaphoid, and the neck of the femur could produce enhanced osteogenesis via the manipulation of MSC culture conditions. In this study, we used hydroxyapatite as the nanomaterial, and hypoxic milieu to enhance MSC differentiation capacity into the osteogenic lineage, allowing for more rapid and efficient bone cell replacement treatment. Our results demonstrate 1% oxygen and 12.5 µg/mL of hydroxyapatite (HAP) as the optimal conditions to incorporate the osteogenic medium for the osteogenic induction of MSCs. We also established a proof of concept that the addition of HAP and hypoxic conditions could augment the osteoinductive capacity of MSCs. We also developed an accurate mathematical model to support future bone cell replacement therapy.

Bone breaking infections - A focus on bacterial and mosquito-borne viral infections.

The recent global resurgence of arthritogenic alphaviruses, including Ross River, chikungunya, and dengue, highlights an urgency for the development of therapeutic strategies. Currently, dengue represents the most rapidly transmitting mosquito-borne viral disease worldwide. By contracting bone breaking diseases, patients experience devastating clinical manifestations involving muscle pain and bone loss. The bone self-repair and regeneration mechanisms can be damaged by the presence of viruses and bacteria. The rapid establishment of dengue epidemic and the severity of bacterial and viral infections affecting the bone stress the urgent need of developing effective interventions. Herein, we review current knowledge on bone breaking infections, covering both bacterial and mosquito-borne viral ones. The mechanisms exploited by these diseases to significantly affect the bone, including interferences with self-repair and regeneration routes, were discussed. In the final section, challenges for future research aimed to treat and prevent bacterial and mosquito-borne bone-breaking infections have been outlined.

The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: A meta-analysis.

OBJECTIVE: This meta-analysis aimed to illustrate the efficacy and safety of preganalin for pain management in patients with postherpetic neuralgia (PHN). METHODS: In July 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, and Google database. Data on patients with PHN that compared pregabalin versus placebo were retrieved. The endpoints were the visual analog scale (VAS) at 8 weeks, the percentage of 30% and 50% pain responders; sleep interference score and improvement in patient global impression of change (PGIC). After testing for publication bias and heterogeneity between studies, data were aggregated for random-effects models when necessary. RESULTS: Seven clinical studies with 2192 patients (pregabalin group = 1381, control group = 811) were finally included in the meta-analysis. Pregabalin was associated with reduced pain scores at 8 weeks, corresponding to a reduction of 11.23 points (95% CI, -14.33, -8.13, P = .000) on a 100-point VAS. Pregabalin was also associated with a more percentage of 30% and 50% pain responders than controls (P < .05). Meanwhile, pregabalin can decrease sleep interference score and improvement in PGIC than control groups (P < .05). CONCLUSIONS: Pregabalin was efficacious in the reduction of postoperative pain and improvement the sleep quality in patients with PHN.

An elevated level of BNP in plasma is related to the development of good collateral circulation in coronary artery disease.

OBJECTIVE: B-type natriuretic peptide (BNP) was recently demonstrated to be a potential stimulator of angiogenesis and arteriogenesis. The correlation between BNP level and collateral formation in patients with coronary artery disease (CAD) has not been reported. METHODS AND RESULTS: The study included 311 consecutive patients who underwent coronary angiography were divided into three groups according to coronary angiography and collateral formation: normal group (100 patients with normal coronary angiographic findings); poor collateral group (116 patients with at least one coronary stenosis of ≥75% without visible collateral circulation); and good collateral group (95 patients with at least one coronary stenosis of ≥75% with well-developed collateral circulation). Collateral score was analyzed using the Cohen-Rentrop classification. Plasma BNP levels were 45.77 ± 4.66 pg/ml, 116.40 ± 28.15 pg/ml, and 254.20 ± 42.85 pg/ml for patients in normal, poor collateral, and good collateral groups, respectively. Plasma BNP levels in the latter were significantly higher than in the normal group (p < 0.01) and poor collateral group (p < 0.05). There were no significant differences between the good collateral group and poor collateral group when compared with left ventricular ejection fraction (LVEF), left ventricular dimensions at end diastole (LVEDd), age, severity of angiographic disease, and other cardiovascular risk factors. After adjustment in the multiple ordinal logistic regression model, plasma BNP levels showed a strong independent association with collateral Cohen-Rentrop score (χ(2 )= 5.636, OR = 1.002, 95% CI 1.000-1.004, p = 0.018). CONCLUSIONS: An elevated level of BNP in plasma is independently associated with collateral development; patients with good collaterals tend to have a higher BNP level.

Plasma hyaluronan and collateral development in patients with coronary artery disease.

OBJECTIVE: In-vivo studies have shown that hyaluronan (HA) can promote angiogenesis and arteriogenesis, which results in accelerated collateral development. This study is aimed at investigating the association between plasma HA levels and the extent of coronary collaterals, in patients with coronary artery disease. METHODS: A total of 253 consecutive patients, who underwent coronary angiography, were divided into three groups according to coronary angiograms: normal group, 81 patients with normal coronary angiographic findings; poor collateral group, 98 patients with at least one coronary stenosis of at least 75%, but without visible collateral circulation; good collateral group, 74 patients with at least one coronary stenosis of at least 75% with well-developed collateral circulation. Plasma HA levels were measured by radioimmunoassay. The correlation between HA levels and the extent of coronary collaterals according to the Cohen-Rentrop classification was calculated by cumulative logits models. RESULTS: Plasma HA levels were 43.71+/-2.91, 61.77+/-4.10, and 131.97+/-11.76 ng/ml, for patients in the normal, poor collateral, and good collateral groups, respectively. The good collateral group had significantly higher plasma HA levels than the poor collateral (P<0.001) and normal group (P<0.001), whereas there was no significant difference between the normal and poor collateral group. HA levels elevated with increasing Rentrop score, and the cumulative logits model showed a strong graded association between plasma HA levels and the collateral Cohen-Rentrop score (odds ratio=1.021, chi2=17.811, 95% confidence interval: 1.011-1.031, P=0.000). CONCLUSION: This study suggests that elevated plasma HA levels are associated with a significant enhancement in coronary collateralization. HA may serve as a novel potential biomarker for collateral formation in patients with coronary artery disease.

Surface acoustic wave velocity in single-crystal AlN substrates.

The surface acoustic wave velocity has been measured on a-plane (c-propagation) and c-plane oriented bulk aluminum nitride (AlN) single crystals using the S11-parameter method in the frequency range 160-360 MHz. The SAW velocity is 5760 m/s for both orientations. From comparison of this value with the simulations using various elastic constants of AlN available in literature, we estimated the elastic constant C44 to be 122 +/- 1 GPa.