Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy.

Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.

Bacteroid cerium oxide particles promote macrophage polarization to achieve early vascularization and subsequent osseointegration around implants.

The establishment of an osseointegration is crucial for the long-term stability and functionality of implant materials, and early angiogenesis is the key to successful osseointegration. However, the bioinertness of titanium implants affects osseointegration, limiting their clinical application. In this study, inspired by the rapid polarization of macrophages following the phagocytosis of bacteria, we developed bacteroid cerium oxide particles; these particles were composed of CeO2 and had a size similar to that of Bacillus (0.5 µ m). These particles were constructed on the implant surfaces using a hydrothermal method. In vitro experiments demonstrated that the particles effectively decreased the reactive oxygen species (ROS) levels in macrophages (RAW264.7). Furthermore, these particles exerted effects on M1 macrophage polarization, enhanced nitric oxide (NO) secretion to promote vascular regeneration, and facilitated rapid macrophage transition to the M2 phenotype. Subsequently, the particles facilitated human umbilical vein endothelial cell (HUVEC) migration. In vivo studies showed that these particles rapidly stimulated innate immune responses in animal models, leading to enhanced angiogenesis around the implant and improved osseointegration. In summary, the presence of bacteroid cerium oxide particles on the implant surface regulated and accelerated macrophage polarization, thereby enhancing angiogenesis during the immune response and improving peri-implant osseointegration.

Identification of potential anti-inflammatory components in Moutan Cortex by bio-affinity ultrafiltration coupled with ultra-performance liquid chromatography mass spectrometry.

Moutan Cortex (MC) has been used in treating inflammation-associated diseases and conditions in China and other Southeast Asian countries. However, the active components of its anti-inflammatory effect are still unclear. The study aimed to screen and identify potential cyclooxygenase-2 (COX-2) inhibitors in MC extract. The effect of MC on COX-2 was determined in vitro by COX-2 inhibitory assays, followed by bio-affinity ultrafiltration in combination with ultra-performance liquid chromatography-mass spectrometry (BAUF-UPLC-MS). To verify the reliability of the constructed approach, celecoxib was applied as the positive control, in contrast to adenosine which served as the negative control in this study. The bioactivity of the MC components was validated in vitro by COX-2 inhibitor assay and RAW264.7 cells. Their in vivo anti-inflammatory activity was also evaluated using LPS-induced zebrafish inflammation models. Finally, molecular docking was hired to further explore the internal interactions between the components and COX-2 residues. The MC extract showed an evident COX-2-inhibitory effect in a concentration-dependent manner. A total of 11 potential COX-2 inhibitors were eventually identified in MC extract. The COX-2 inhibitory activity of five components, namely, gallic acid (GA), methyl gallate (MG), galloylpaeoniflorin (GP), 1,2,3,6-Tetra-O-galloyl-ß-D-glucose (TGG), and 1,2,3,4,6-Penta-O-galloyl-ß-D-glucopyranose (PGG), were validated through both in vitro assays and experiments using zebrafish models. Besides, the molecular docking analysis revealed that the potential inhibitors in MC could effectively inhibit COX-2 by interacting with specific residues, similar to the mechanism of action exhibited by celecoxib. In conclusion, BAUF-UPLC-MS combining the molecular docking is an efficient approach to discover enzyme inhibitors from traditional herbs and understand the mechanism of action.

Preventing viral relapse with prophylactic tenofovir in hepatitis B carriers receiving chemotherapy: a phase IV randomized study in Taiwan.

BACKGROUND AND AIMS: This study aimed to compare the efficacy of shorter vs. longer tenofovir disoproxil fumarate (TDF) prophylaxis in preventing hepatitis B virus (HBV) relapse in cancer patients with chronic hepatitis B (CHB) undergoing chemotherapy. METHODS: This phase IV, prospective randomized trial enrolled cancer patients with CHB from 2014 to 2019 in Taiwan. Included patients were randomized to receive either 24- (Arm A) or 48-week (Arm B) post-chemotherapy TDF and compared for cumulative incidence of virological and clinical relapse. Logistic regressions were conducted to determine the factors associated with HBV relapse. RESULTS: One hundred patients were randomized, and 41 patients in Arm A and 46 in Arm B completed the TDF treatment. No significant difference was found in cumulative incidence of virological relapse (Arm A: 94.4%, Arm B: 93.1%, p = 0.110) or clinical relapse among patients with baseline HBV DNA > 2000 IU/mL (Arm A: 38.9%, Arm B: 26.7%, p = 0.420) between the two arms. High baseline HBV DNA ≥ 10,000 IU/mL (OR = 51.22) and HBsAg ≥ 1000 IU/mL (OR = 8.64) were independently associated with an increased virological relapse. Alanine aminotransferase (ALT), serum phosphorus, vitamin D, and estimated glomerular filtration rate (eGFR) remained stable throughout the study. CONCLUSIONS: The 24-week preventative TDF has comparable efficacy to the 48-week treatment in virologic and clinical relapse. High baseline HBsAg or HBV DNA is associated with a higher risk of HBV relapse. These findings imply a 24-week duration of TDF treatment with a close monitor for patients with a high baseline viral load. Hepatitis B virus infection is a prominent cause of liver cancer and chronic liver disease and affected millions of people worldwide. When HBV-infected people are exposed to immunosuppressive medication or chemotherapy for cancer, the chance of HBV reactivation rises considerably. This trial showed 24-week tenofovir disoproxil fumarate (TDF) may be sufficient for preventing HBV relapse in cancer patients receiving chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02081469.

Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis.

BACKGROUND AND AIMS: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.

Thiamet G as a Potential Treatment for Polycystic Kidney Disease.

BACKGROUND/AIM: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder primarily caused by mutations in Pkd1 (PC1), which account for the majority of ADPKD cases. These mutations contribute to the formation of cysts in the kidneys and other organs, ultimately leading to renal failure. Unfortunately, there are currently no available preventive treatments for this disease. MATERIALS AND METHODS: In this study, we utilized Pkd1-knockdown mice and cells to investigate the potential involvement of O-GlcNAcylation in the progression of PKD. Additionally, we examined the effects of thiamet G, an inhibitor of O-GlcNAcase (OGA), on PKD mice. RESULTS: Our findings indicate that both O-GlcNAcylation and OGT (O-GlcNAc transferase) were downregulated in the renal tissues of Pkd1-silenced mice. Furthermore, O-GlcNAcylation was shown to regulate the stability and function of the C-terminal cytoplasmic tail (CTT) of PC1. Treatment of PKD mice with thiamet G resulted in a reduction of renal cytogenesis in these animals. CONCLUSION: These results highlight the unique role of O-GlcNAcylation in the development of cyst formation in PKD and propose it as a potential therapeutic target for the treatment of PKD.

Optimization of Continuous Casting for Preventing Surface Peeling Defects on Titanium-Containing Ferrite Stainless Steel.

The surfaces of cold-rolled titanium-containing ferrite stainless steel (TCFSS) strips produced from scrap are prone to severe peeling owing to cracking near slab inclusions during hot rolling. In this study, the Taguchi method was used to prevent peeling defects and clogging of the submerged entrance nozzle, and the optimal casting parameters, such as the degree of casting overheating, casting speed, stirring time, and inclination, were determined. The results showed that increasing the degree of casting overheating and decreasing the casting speed prevented clogging and effectively mitigated peeling defects. Sample A3B1C3D2 had the optimal parameters to reduce the clog thickness to less than 1.5 mm, i.e., a degree of overheating of 60 °C, a casting speed of 0.80 m/min, a stirring time of 12.0 s, and an inclination angle of 6.0°. Sample A3B1C1D3 had the optimal parameters to prevent peeling defects, i.e., a degree of overheating of 60 °C, a casting speed of 0.80 m/min, a stirring time of 10.0 s, and an inclination angle of 6.2°. When casting using these optimal parameters, no peeling defects were observed on the surfaces of the TCFSS strips. The TCFSS strips produced using the optimized parameters exhibited the required mechanical properties and satisfied the design criteria. The parameters included a tensile strength of ≥415 MPa, a yield strength of ≥205 MPa, an elongation of ≥22%, and a hardness of ≤89 HRB.

Impact of Coronary Artery Disease on The Outcomes of Catheter Ablation in Patients with Atrial Fibrillation.

INTRODUCTION: The objective of this study is to investigate the possible impact of coronary artery disease (CAD) on clinical outcomes of catheter ablation in patients with atrial fibrillation (AF). METHODS: Patients with AF who underwent coronary computed tomography and catheter ablation were enrolled. The presence of stenotic severity and plaque, characteristics of coronary arteries, clinical data, and adverse outcomes of catheter ablation were analysed. RESULTS: A total of 243 patients were enrolled, 100 (41%) patients with CAD. The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65-74 years, and sex category) score of AF patients with CAD was significantly (P<0.001) higher than of those without CAD. Presence of stenotic artery and plaques increased significantly with increase of CHA2DS2-VASc score (P<0.05). There was no significant (P=0.342) difference in AF recurrence between patients with and without CAD (30% versus 24%). Age, AF type, duration of AF, heart failure, CHA2DS2-VASc score, left ventricular ejection fraction, and left atrial diameter were significantly (P<0.05) correlated with AF recurrence in univariant analysis. Multivariable analysis revealed that duration of AF (hazard ratio [HR] 1.769), heart failure (HR 1.821), and left atrial diameter (HR 1.487, P=0.022) remained significant independent predictors of AF recurrence. Patients with AF and concomitant CAD were significantly (P=0.030) associated with a worse outcome. CONCLUSION: CAD concomitant with AF may be associated with a worse clinical outcome even though CAD does not significantly affect the risk of AF recurrence after ablation therapy.

TiO2nanotubes induce early mitochondrial fission in BMMSCs and promote osseointegration.

Nanotopography can promote osseointegration, but how bone marrow mesenchymal stem cells (BMMSCs) respond to this physical stimulus is unclear. Here, we found that early exposure of BMMSCs to nanotopography (6 h) caused mitochondrial fission rather than fusion, which was necessary for osseointegration. We analyzed the changes in mitochondrial morphology and function of BMMSCs located on the surfaces of NT100 (100 nm nanotubes) and ST (smooth) by super-resolution microscopy and other techniques. Then, we found that both ST and NT100 caused a significant increase in mitochondrial fission early on, but NT100 caused mitochondrial fission much earlier than those on ST. In addition, the mitochondrial functional statuses were good at the 6 h time point, this is at odds with the conventional wisdom that fusion is good. This fission phenomenon adequately protected mitochondrial membrane potential (MMP) and respiration and reduced reactive oxygen species. Interestingly, the MMP and oxygen consumption rate of BMMSCs were reduced when mitochondrial fission was inhibited by Mdivi-1(Inhibition of dynamin-related protein 1 fission) in the early stage. In addition, the effect on osseointegration was significantly worse, and this effect did not improve with time. Taken together, the findings indicate that early mitochondrial fission plays an important role in nanotopography-mediated promotion of osseointegration, which is of great significance to the surface structure design of biomaterials.

Evaluation of computational fluid dynamics models for predicting pediatric upper airway airflow characteristics.

Computational fluid dynamics (CFD) has the potential for use as a clinical tool to predict the aerodynamics and respiratory function in the upper airway (UA) of children; however, careful selection of validated computational models is necessary. This study constructed a 3D model of the pediatric UA based on cone beam computed tomography (CBCT) imaging. The pediatric UA was 3D printed for pressure and velocity experiments, which were used as reference standards to validate the CFD simulation models. Static wall pressure and velocity distribution inside of the UA under inhale airflow rates from 0 to 266.67 mL/s were studied by CFD simulations based on the large eddy simulation (LES) model and four Reynolds-averaged Navier-Stokes (RANS) models. Our results showed that the LES performed best for pressure prediction; however, it was much more time-consuming than the four RANS models. Among the RANS models, the Low Reynolds number (LRN) SST k-ω model had the best overall performance at a series of airflow rates. Central flow velocity determined by particle image velocimetry was 3.617 m/s, while velocities predicted by the LES, LRN SST k-ω, and k-ω models were 3.681, 3.532, and 3.439 m/s, respectively. All models predicted jet flow in the oropharynx. These results suggest that the above CFD models have acceptable accuracy for predicting pediatric UA aerodynamics and that the LRN SST k-ω model has the most potential for clinical application in pediatric respiratory studies.

Comparing Predictability of Non-invasive Tools for Hepatocellular Carcinoma in Treated Chronic Hepatitis C Patients.

BACKGROUND: Non-invasive tools including liver stiffness measurement (LSM) or FIB-4, assessed before or after direct acting antivirals (DAA), have been suggested to predict hepatocellular carcinoma (HCC). AIMS: This study aims to compare predictability of HCC by these methods at different time points, to validate the HCC surveillance suggestion by guidelines, and to propose personalized strategy. METHODS: Chronic hepatitis C whose LSM and FIB-4 were available at pretherapy and after sustained virological response (SVR) were enrolled. Advanced chronic liver disease (ACLD) was defined as pretherapy LSM ≥ 10 kPa or FIB-4 index ≥ 3.25 or ultrasound signs of cirrhosis plus platelet count < 150,000/µL. The predictabilities were compared by area under ROC. The cumulative HCC incidences were calculated by Kaplan-Meier analysis. RESULTS: Among 466 ACLD patients, 40 patients developed HCC during a follow-up duration of 26.8 months. Comparable predictive performances for HCC between LSM and FIB-4 at pretherapy and SVR were noted. By guidelines suggestion using pretherapy LSM = 10 kPa (advanced fibrosis) and 13 kPa (cirrhosis) for risk stratification, the annual HCC incidences of those with LSM of < 10, 10-12.9 and ≥ 13 kPa were 1.1, 3.6, and 5.0%, respectively. Combination of baseline LSM < 12 kPa and SVR FIB-4 < 3.7 could further stratify relatively low risk of HCC in ACLD patients of annal incidence of 1.2%. CONCLUSIONS: ACLD patients who met advanced fibrosis but not cirrhosis by guidelines' cut-offs still posed high risk of HCC. Baseline LSM with SVR FIB-4 can be applied to stratify low, intermediate, and high risk of HCC for personalizing surveillance strategies after SVR.

Polypeptide Bilayer Assembly-Mediated Gene Delivery Enhances Chemotherapy in Cancer Cells.

Developing gene vectors with high transfection efficiency and low cytotoxicity to humans is crucial to improve gene therapy outcomes. This study set out to investigate the use of cationic polypeptide bilayer assemblies formed by coil-sheet poly(l-lysine)-block-poly(l-benzyl-cysteine) (PLL-b-PBLC) as gene vectors that present improved transfection efficiency, endosomal escape, and biocompatibility compared to PLL. The formation of the polyplexes was triggered by hydrogen bonding, hydrophobic interactions, and electrostatic association between the cationic PLL segments and the negatively charged plasmid encoding p53, resulting in self-assembled polypeptide chains. Transfection efficiency of these polyplexes increased with increments of PLL-to-PBLC block ratios, with PLL15-b-PBLC5 bilayers exhibiting the best in vitro transfection efficiency among all, suggesting that PLL-b-PBLC bilayer assemblies are efficient in the protection and stabilization of genes. The polypeptide bilayer gene vector reversed the cisplatin sensitivity of p53-null cancer cells by increasing apoptotic signaling. Consistent with in vitro results, mouse xenograft studies revealed that PLL15-b-PBLC5/plasmid encoding p53 therapy significantly suppressed tumor growth and enhanced low-dose cisplatin treatment, while extending survival of tumor-bearing mice and avoiding significant body weight loss. This study presents a feasible gene therapy that, combined with low-dose chemotherapeutic drugs, may treat genetically resistant cancers while reducing side effects in clinical patients.

Comparison of quantitative susceptibility mapping methods for iron-sensitive susceptibility imaging at 7T: An evaluation in healthy subjects and patients with Huntington's disease.

Quantitative susceptibility mapping (QSM) is a promising tool for investigating iron dysregulation in neurodegenerative diseases, including Huntington's disease (HD). Many diverse methods have been proposed to generate accurate and robust QSM images. In this study, we evaluated the performance of different dipole inversion algorithms for iron-sensitive susceptibility imaging at 7T on healthy subjects of a large age range and patients with HD. We compared an iterative least-squares-based method (iLSQR), iterative methods that use regularization, single-step approaches, and deep learning-based techniques. Their performance was evaluated by comparing: (1) deviations from a multiple-orientation QSM reference; (2) visual appearance of QSM maps and the presence of artifacts; (3) susceptibility in subcortical brain regions with age; (4) regional brain susceptibility with published postmortem brain iron quantification; and (5) susceptibility in HD-affected basal ganglia regions between HD subjects and healthy controls. We found that single-step QSM methods with either total variation or total generalized variation constraints (SSTV/SSTGV) and the single-step deep learning method iQSM generally provided the best performance in terms of correlation with iron deposition and were better at differentiating between healthy controls and premanifest HD individuals, while deep learning QSM methods trained with multiple-orientation susceptibility data created QSM maps that were most similar to the multiple orientation reference and with the best visual scores.

Impact of Coronary Artery Disease on The Outcomes of Catheter Ablation in Patients with Atrial Fibrillation

ABSTRACT Introduction: The objective of this study is to investigate the possible impact of coronary artery disease (CAD) on clinical outcomes of catheter ablation in patients with atrial fibrillation (AF). Methods: Patients with AF who underwent coronary computed tomography and catheter ablation were enrolled. The presence of stenotic severity and plaque, characteristics of coronary arteries, clinical data, and adverse outcomes of catheter ablation were analysed. Results: A total of 243 patients were enrolled, 100 (41%) patients with CAD. The CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65-74 years, and sex category) score of AF patients with CAD was significantly (P<0.001) higher than of those without CAD. Presence of stenotic artery and plaques increased significantly with increase of CHA2DS2-VASc score (P<0.05). There was no significant (P=0.342) difference in AF recurrence between patients with and without CAD (30% versus 24%). Age, AF type, duration of AF, heart failure, CHA2DS2-VASc score, left ventricular ejection fraction, and left atrial diameter were significantly (P<0.05) correlated with AF recurrence in univariant analysis. Multivariable analysis revealed that duration of AF (hazard ratio [HR] 1.769), heart failure (HR 1.821), and left atrial diameter (HR 1.487, P=0.022) remained significant independent predictors of AF recurrence. Patients with AF and concomitant CAD were significantly (P=0.030) associated with a worse outcome. Conclusion: CAD concomitant with AF may be associated with a worse clinical outcome even though CAD does not significantly affect the risk of AF recurrence after ablation therapy.

A neglected cervicovesical fistula diagnosed and repaired by combined hysteroscopy and laparoscopy: A case report and review of literature.

Objective: To analyze a case of neglected cervicovesical fistula with intrauterine adhesions caused by cesarean section. Methods: A 36-year-old female patient with a history of two previous cesarean sections complained of the absence of menstruation for the last 18 months. The diagnosis of the cervicovesical fistula was made through hysteroscopy and cystoscopy. The reconstruction of the uterus and bladder was achieved by a laparoscopic repair technique. Results: The patient resumed normal menstruation postoperatively without complaining of any complications. Uterine continuity and cavity had been restored to normal at the second look of hysteroscopy. Conclusions: Cervicovesical fistula with intrauterine adhesions is very rare in our clinical work. Hysteroscopy might play an essential role in diagnosing cervicovesical fistula and IUA. In our literature review, a surgical approach was the mainstay and definitive management of the cervicovesical fistula following a cesarean section.

Association of Common Variants in OLA1 Gene with Preclinical Atherosclerosis.

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in OLA1 genes on preclinical atherosclerosis. A total of 564 and 746 subjects who had thicker and normal carotid intima-media thickness (cIMT), respectively, were enrolled. Among 55 screened SNPs, rs35145102, rs201641962, rs12466587, rs4131583, and rs16862482 in OLA1 showed significant associations with cIMT. SNP rs35145102 is a 3'-utr variant and correlates with the differential expression of OLA1 in immune cells. These five genetic markers form a single closely linked block and H1-ATTGT and H2-GCCTC were the top two most prevalent 5-locus haplotypes. The H1 + H1 genotype negatively and H1 + H2 genotype positively correlated with thicker cIMT. The five identified SNPs in the OLA1 gene showed significant correlations with cIMT. Furthermore, we found that OLA1 was required for migration and proliferation of human aortic endothelial and smooth muscle cells and regulated vascular tube formation by human aortic endothelial cells. Therefore, these genetic variants in the OLA1 gene may serve as markers for risk prediction of atherosclerotic diseases.

Optimization of Hot Rolling Scheduling of Steel Strip with High Bending Performance.

Poor formability in hot-rolled strips may be attributed to the many pearlite-banded structures (PBSs) that develop in steel during the hot-rolling process. The challenge of manufacturing strips with minimum PBSs is that multiple factors influence the amount and distribution of the PBSs. This study used the Taguchi method to find the optimum hot-rolling parameters to obtain strips with a reduced number of PBSs. The strips were then subjected to bending tests to evaluate their ductility. The first part analyzes the contribution of selected parameters to the hot-rolling process: (1) finishing rolling temperature, (2) finishing rolling speed, (3) coiling temperature, and (4) coiling speed. The second part confirms, using bending tests, the influence of the finishing rolling temperatures 780, 800, 820, 840, 860, 870, and 880 °C on the formability of an A36 hot-rolled strip. Based on the experimental protocol for the study, the optimal process parameters were determined to be the finishing rolling speed (0.80 m/s), finishing rolling temperature (870 °C), coiling speed (2.80 m/s), and coiling temperature (650 °C). When the A36 strip was prepared at the optimum parameters, the average length and thickness of the PBS were 108.61 ± 0.11 µm and 10.18 ± 0.12 µm, respectively. According to the Taguchi analysis, the finishing rolling temperature had the most significant influence on the dimensions of the PBS. In tests where the hot-rolled A36 strip was bent to 90° and 180°, at the finishing rolling temperatures of 870 °C and 880 °C, no cracking was observed at the R angle.

Innate-like bystander-activated CD38+ HLA-DR+ CD8+ T cells play a pathogenic role in patients with chronic hepatitis C.

BACKGROUND AND AIMS: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS: The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS: The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.

Comparison of quantitative susceptibility mapping methods on evaluating radiation-induced cerebral microbleeds and basal ganglia at 3T and 7T.

Quantitative susceptibility mapping (QSM) has the potential for being a biomarker for various diseases because of its ability to measure tissue susceptibility related to iron deposition, myelin, and hemorrhage from the phase signal of a T2 *-weighted MRI. Despite its promise as a quantitative marker, QSM is faced with many challenges, including its dependence on preprocessing of the raw phase data, the relatively weak tissue signal, and the inherently ill posed relationship between the magnetic dipole and measured phase. The goal of this study was to evaluate the effects of background field removal and dipole inversion algorithms on noise characteristics, image uniformity, and structural contrast for cerebral microbleed (CMB) quantification at both 3T and 7T. We selected four widely used background phase removal and five dipole field inversion algorithms for QSM and applied them to volunteers and patients with CMBs, who were scanned at two different field strengths, with ground truth QSM reference calculated using multiple orientation scans. 7T MRI provided QSM images with lower noise than did 3T MRI. QSIP and VSHARP + iLSQR achieved the highest white matter homogeneity and vein contrast, with QSIP also providing the highest CMB contrast. Compared with ground truth COSMOS QSM images, overall good correlations between susceptibility values of dipole inversion algorithms and the COSMOS reference were observed in basal ganglia regions, with VSHARP + iLSQR achieving the susceptibility values most similar to COSMOS across all regions. This study can provide guidance for selecting the most appropriate QSM processing pipeline based on the application of interest and scanner field strength.