Comparative analysis of robotic single-site cholecystectomy outcomes between novice and expert surgeons.

Single-incision laparoscopic cholecystectomy (SILC) has declined in popularity, posing a challenge for novice surgeons. However, robotic single-site cholecystectomy (RSSC) has gained popularity in hepatopancreatic surgery, suggesting a paradigm shift in minimally invasive procedures due to the advantages of robotic platforms. The purpose of this study was to compare the surgical outcomes and learning curves between experts and novices without SILC experience, and discuss the utility and potential of RSSC for novice surgeons. A total of 235 patients underwent RSSC between April 2019 and June 2023 at the OOO University Hospital. Among them, 31 cases from novice and expert surgeons were selected to compare their initial experience. Comprehensive demographic and perioperative factors were analyzed and statistical comparisons were made, including cumulative sum analysis (CUSUM) for learning curves. The demographic factors showed no statistically significant differences between the two groups. Although the docking time (P < 0.001) and hospital stay (P = 0.014) were statistically significant, the total operative time and other perioperative factors were comparable. Novice surgeons demonstrated a shorter absolute total operative time, primarily attributed to differences in docking time. The CUSUM analysis indicated a shorter learning curve for novice surgeons. This study shows that the inherent benefits of the robotic platform make it an accessible and reproducible technique for novices. The benefits of integrating observational learning into robotic surgery training programs and the intrinsic advantages of the robotic platform in minimizing the learning curve for RSSC were also highlighted.

Intrahepatic Cholangiocarcinoma in Wilson's Disease: A Case Report.

BACKGROUND Wilson's disease is a rare autosomal recessive disorder characterized by excessive accumulation of copper in the liver, brain, and kidneys. Although it affects only approximately 1 in 30 000 individuals, it leads to progressive liver damage and neurological issue. Wilson's disease presents a wide spectrum of clinical manifestations related to hepatic disease, ranging from asymptomatic cases to acute liver failure. The occurrence of hepatobiliary malignancies, including intrahepatic cholangiocarcinoma, is relatively uncommon in Wilson's disease, even among patients with cirrhosis. Only 14 cases have been published so far, including the present report, and its etiology remains unclear. CASE REPORT We report the successful treatment of intrahepatic cholangiocarcinoma in a 39-year-old woman with Wilson's disease. Twenty-two years after being diagnosed with Wilson's disease, intrahepatic cholangiocarcinoma was diagnosed. She had an intrahepatic mass that was found to be a 4.3-cm ill-defined hypodense lesion in liver segment 3/4, with features suggesting infiltrative intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma. Laboratory results showed slightly elevated liver enzymes and tumor markers. There was no evidence of metastasis on chest computed tomography or positron emission tomography, and the tumor was resectable, so surgery was the first-choice treatment option. Left hepatectomy was performed successfully, and the final pathology confirmed adenocarcinoma with clear resection margins. The patient received adjuvant chemotherapy with capecitabine. To date, the patient has been doing well without evidence of recurrence or metastasis. CONCLUSIONS Despite limited knowledge regarding hepatic malignancy in Wilson's disease, it is crucial to prioritize careful monitoring and develop suitable treatment strategies upon diagnosis to achieve favorable outcomes, considering the potential occurrence of intrahepatic cholangiocarcinoma in Wilson's disease.

Factors influencing re-bleeding after trans-arterial embolization for endoscopically unmanageable peptic ulcer bleeding.

BACKGROUND/AIMS: Acute peptic ulcer bleeding is the most common cause of non-variceal upper gastrointestinal bleeding (NVUGIB). Endoscopic hemostasis is the standard treatment. However, various conditions complicate endoscopic hemostasis. Transarterial visceral embolization (TAE) may be helpful as a rescue therapy. This study aimed to investigate the factors associated with rebleeding after TAE. METHODS: We retrospectively investigated the records of 156 patients treated with TAE between January 2007 and December 2021. Rebleeding was defined as the presence of melena, hematemesis, or hematochezia, with a fall (>2.0 g/dl) in hemoglobin level or shock after TAE. The primary outcomes were rebleeding rate and 30-day mortality. RESULTS: Seventy patients with peptic ulcer bleeding were selected, and rebleeding within a month after TAE occurred in 15 patients (21.4%). Among the patients included in rebleeding group, significant increases were observed in the prevalence of thrombocytopenia (73.3% vs. 16.4%, p<.001) and ulcers >1 cm (93.3% vs 54.5%, p = .014). The mean AIMS65 (albumin, international normalized ratio, mental status, systolic blood pressure, age >65 years) score (2.3 vs 1.4, p = .009) was significantly higher in the rebleeding group. Multivariate logistic analysis revealed that thrombocytopenia (odds ratio 31.92, 95% confidence interval 6.24-270.6, p<.001) and larger ulcer size (odds ratio 27.19, 95% confidence interval 3.27-677.7, p=.010) significantly increased the risk of rebleeding after TAE. CONCLUSION: TAE was effective in the treatment of patients with high-risk peptic ulcer bleeding. AIMS65 score was a significant predictor of rebleeding after TAE, and thrombocytopenia and larger ulcer size increased the risk of rebleeding after TAE.

Propensity Score Matched Comparison of Robotic Single-Site and Laparoscopic Cholecystectomy.

Background and Objectives: To demonstrate the feasibility and potential of robotic single-site cholecystectomy, the study aimed to compare it with conventional laparoscopic cholecystectomy. Methods: In total, 791 consecutive patients underwent conventional laparoscopic cholecystectomy or robotic single-site cholecystectomy at our center between 2019 and 2022. After 1:1 propensity score matching, 117 patients for each group were selected. Results: After propensity score matching, the only statistically significant difference between conventional laparoscopic cholecystectomy and robotic single-site cholecystectomy was operative time, which was 29.15 ±11.45 min in the conventional laparoscopic cholecystectomy group versus 38.57 ± 12.59 min in the robotic single-site cholecystectomy group (P < 0.001). Because the difference in surgical time between the two groups was minimal, it has little clinical relevance. Using cumulative sum analysis, the maturation phase of the total operation and docking times occurred after the 53rd case. To reduce bias, a comparison of results with conventional laparoscopic cholecystectomy and cases of robotic single-site cholecystectomy was performed in the maturation phase, which revealed only total operative time as statistically significant (P < 0.001). Conclusion: Robotic single-site cholecystectomy is a technically feasible and safe method for treating benign gallbladder diseases, with a relatively short learning curve and reasonable operative time.

Small Bowel Variceal Bleeding in Patients with Liver Cirrhosis Treated with Transarterial Embolization: Case Series.

Small bowel variceal bleeding is a rare cause of gastrointestinal hemorrhage, with clinical manifestations ranging from asymptomatic incidental findings to life-threatening conditions. The diagnosis and management of small bowel bleeding are challenging because of the localization of the lesion and the difficulty of the procedure. Trans-arterial embolization (TAE) is a secure and straightforward method for treating ectopic varices. On the other hand, there have been limited local studies on the outcomes of TAE for patients with small bowel variceal hemorrhage. This paper reports patients diagnosed with small bowel variceal bleeding and treated with TAE.

Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants.

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

Association between SLCO1B1 genetic polymorphisms and bleeding risk in patients treated with edoxaban.

Since SLCO1B1 encodes the uptake transporter OATP1B1, which can influence the pharmacokinetic and pharmacodynamic profiles of edoxaban, polymorphisms in SLCO1B1 may affect the edoxaban response. This study aimed to investigate the association between SLCO1B1 gene polymorphisms and the bleeding risk in patients receiving edoxaban. We genotyped 10 single-nucleotide polymorphisms (SNPs) from the SLCO1B1 gene in patients receiving edoxaban. We also analyzed rs3842 of ABCB1 as a confounder. The odds ratio (OR) and adjusted OR (AOR) were calculated from univariate and multivariable analysis, respectively. The area under the receiver operating characteristic curve (AUROC) was constructed for the discrimination of the model. A total of 159 patients receiving edoxaban were analyzed. Overdose and rs4149056 showed significant association with bleeding complications by around 11- and 5.5-fold, respectively. Additionally, patients with the rs4149057 variant allele (C) had a 3.9-fold increased bleeding risk compared with wild-type homozygote carriers (TT), whereas rs2306283 variant homozygote (GG) carriers had a 0.27-fold reduced bleeding risk compared with wild-type allele (A) carriers. Patients with the variant-type homozygote (CC) of ABCB1 rs3842 had a higher bleeding risk than T allele carriers (AOR = 5.3 and 5.9). The final models for multivariable analyses were acceptable based on the AUROC values (> 0.70). These findings may help predict bleeding risk in patients taking edoxaban and help personalize treatment.

Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study.

Warfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable warfarin dose in the Korean population with cardiac valve replacement, using the GWAS approach. This retrospective cohort study was performed from January 1982 to December 2020 at the Severance Cardiovascular Hospital of Yonsei University College of Medicine. GWAS was performed to identify associations between genotypes and the warfarin maintenance dose, by comparing the allele frequency of genetic variants between individuals. Then, the extent of genetic and non-genetic factors on the dose variability was determined by multivariable regression analysis. The study enrolled 214 participants, and the most robust signal cluster was detected on chromosome 16 around VKORC1. Followed by VKORC1, three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) showed an association with stable warfarin dose requirement in univariate analysis. The algorithm was constructed by using multivariable analysis that includes genetic and non-genetic factors, and it could explain 58.5% of the variations in stable warfarin doses. In this variability, VKORC1 rs9934438 and FRAS1 rs4386623 accounted for 33.0% and 9.9%, respectively. This GWAS analysis identified the fact that three novel variants (NKX2-6 rs310279, FRAS1 rs4386623, and FAM201A rs1890109) were associated with stable warfarin doses. Additional research is necessary to validate the results and establish personalized treatment strategies for the Korean population.

Correlation between PPARG Pro12Ala Polymorphism and Therapeutic Responses to Thiazolidinediones in Patients with Type 2 Diabetes: A Meta-Analysis.

Background: Thiazolidinediones (TZDs) are a type of oral drug that are utilized for the treatment of type 2 diabetes mellitus (T2DM). They function by acting as agonists for a nuclear transcription factor known as peroxisome proliferator-activated receptor-gamma (PPAR-γ). TZDs, such as pioglitazone and rosiglitazone, help enhance the regulation of metabolism in individuals with T2DM by improving their sensitivity to insulin. Previous studies have suggested a relationship between the therapeutic efficacy of TZDs and the PPARG Pro12Ala polymorphism (C > G, rs1801282). However, the small sample sizes of these studies may limit their applicability in clinical settings. To address this limitation, we conducted a meta-analysis assessing the influence of the PPARG Pro12Ala polymorphism on the responsiveness of TZDs. Method: We registered our study protocol with PROSPERO, number CRD42022354577. We conducted a comprehensive search of the PubMed, Web of Science, and Embase databases, including studies published up to August 2022. We examined studies investigating the association between the PPARG Pro12Ala polymorphism and metabolic parameters such as hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The mean difference (MD) and 95% confidence intervals (CIs) between pre- and post-drug administration were evaluated. The quality of the studies included in the meta-analysis was assessed by using the Newcastle-Ottawa Scale (NOS) tool for cohort studies. Heterogeneity across studies was assessed by using the I2 value. An I2 value greater than 50% indicated substantial heterogeneity, and a random-effects model was used for meta-analysis. If the I2 value was below 50%, a fixed-effects model was employed instead. Both Begg's rank correlation test and Egger's regression test were performed to detect publication bias, using R Studio software. Results: Our meta-analysis incorporated 6 studies with 777 patients for blood glucose levels and 5 studies with 747 patients for lipid levels. The included studies were published between 2003 and 2016, with the majority involving Asian populations. Five of the six studies utilized pioglitazone, while the remaining study employed rosiglitazone. The quality scores, as assessed with the NOS, ranged from 8 to 9. Patients carrying the G allele exhibited a significantly greater reduction in HbA1C (MD = -0.3; 95% CI = -0.55 to -0.05; p = 0.02) and FPG (MD = -10.91; 95% CI = -19.82 to -2.01; p = 0.02) levels compared to those with the CC genotype. Furthermore, individuals with the G allele experienced a significantly larger decrease in TG levels than those with the CC genotype (MD = -26.88; 95% CI = -41.30 to -12.46; p = 0.0003). No statistically significant differences were observed in LDL (MD = 6.69; 95% CI = -0.90 to 14.29; p = 0.08), HDL (MD = 0.31; 95% CI = -1.62 to 2.23; p = 0.75), and TC (MD = 6.4; 95% CI = -0.05 to 12.84; p = 0.05) levels. No evidence of publication bias was detected based on Begg's test and Egger's test results. Conclusions: This meta-analysis reveals that patients with the Ala12 variant in the PPARG Pro12Ala polymorphism are more likely to exhibit positive responses to TZD treatment in terms of HbA1C, FPG, and TG levels compared to those with the Pro12/Pro12 genotype. These findings suggest that genotyping the PPARG Pro12Ala in diabetic patients may be advantageous for devising personalized treatment strategies, particularly for identifying individuals who are likely to respond favorably to TZDs.

Six-Transmembrane Epithelial Antigen of Prostate 4: An Indicator of Prognosis and Tumor Immunity in Hepatocellular Carcinoma.

Purpose: The six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been linked to tumor progression via its involvement in inflammatory responses, oxidative stress, and metabolism. However, STEAP4 has rarely been studied in hepatocellular carcinoma (HCC). We explored STEAP4 expression associated with tumor prognosis to understand its role in tumor biology in HCC. Patients and Methods: STEAP4 mRNA and protein expressions were primarily analyzed using bioinformatics tools based on The Cancer Genome Atlas database to understand the expression pattern, molecular mechanism, prognostic impact, and association with immune cell infiltration. We further investigated the association between STEAP4 protein expression and clinicopathological parameters and their predictive value in HCC patients using immunohistochemical staining of tissue microarrays. Results: The expression of STEAP4 mRNA and protein in HCC tissues was significantly lower than in normal liver tissues. Reduced expression of STEAP4 was linked to advanced HCC stages, poor recurrence-free survival (RFS), and overall survival. Furthermore, reduced STEAP4 expression was a significant predictor of worse RFS in univariate and multivariate analyses in the immunohistochemical cohort. GO, KEGG, and GSEA analyses revealed that STEAP4 is related to numerous biological processes and pathways, including drug metabolism, DNA replication, RNA metabolism, and immune response. In terms of the immune system, the decreased level of STEAP4 was correlated with the immunosuppressive microenvironment. Conclusion: Our data indicated that reduced STEAP4 expression was significantly associated with tumor aggressiveness and poor prognosis, possibly because of its link to various biological processes and induction of HCC immune evasion. Therefore, STEAP4 expression may serve as a potential prognostic biomarker for cancer progression and immunity, as well as a therapeutic target in HCC.

Effectiveness and Safety of Recombinant Human Follicle-Stimulating Hormone (Follitrope™) in Inducing Controlled Ovarian Stimulation in Infertile Women in Real-World Practice: a Prospective Cohort Study.

To evaluate the safety and effectiveness of recombinant human follicle-stimulating hormone (rhFSH [Follitrope™]) in infertile women undergoing in vitro fertilization (IVF). To identify predictors of ovarian response that induce optimal clinical outcomes. This multicenter prospective study enrolled infertile women who were scheduled to undergo IVF after ovarian stimulation with rhFSH (Follitrope™) following the gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist protocol. Predictive factors for ovarian response were identified in the GnRH antagonist group based on the number of oocytes retrieved. A total of 516 infertile women were enrolled, among whom 136 (except one who withdrew before administration) received rhFSH using the GnRH agonist protocol and 379 using the antagonist protocol. The mean number of oocytes retrieved was 13.4 in the GnRH agonist group and 13.6 in the GnRH antagonist group. The clinical pregnancy rates were 32.3% (30/93) and 39.9% (115/288) in the GnRH agonist and antagonist groups, respectively. The incidence of ovarian hyperstimulation syndrome was 1.8% and 3.4% in the GnRH agonist and antagonist groups, respectively. No other significant safety risks associated with rhFSH administration were identified. Body mass index, basal serum FSH and anti-Müllerian hormone levels, and antral follicle count were identified as predictors of ovarian response by multiple regression with backward elimination, and the final regression model accounted for 26.5% of the response variability. In real-world practice, rhFSH (Follitrope™) is safe and effective in inducing ovarian stimulation in infertile women. Patient characteristics identified as predictors can be considered to be highly related to optimal clinical outcomes.

Polymer Dispersed Liquid Crystal Imprinted by Microlens Array for Enhanced Outcoupling Efficiency of Organic Light Emitting Diode.

In this paper, we demonstrate the use of polymer dispersed liquid crystal (PDLC) imprinted with a microlens array (MLA) via solution process to improve the outcoupling efficiency of organic light emitting diodes (OLEDs). The PDLC, well known for its scattering effect, is an excellent technology for improving the outcoupling efficiency of OLEDs. Additionally, we introduce a simple spin-coating process to fabricate PDLC which is adaptable for future solution-processed OLEDs. The MLA-imprinted PDLC applied OLED shows an enhancement factor of 1.22 in outcoupling efficiency which is a 37.5% increase compared to the existing PDLC techniques without changing the electrical properties of the OLED. Through this approach, we can expect the roll-to-roll based extremely flexible OLED, and with further research on pattering PDLC by various templates, higher outcoupling efficiency is achievable through a simple UV irradiation process.

Early Experience of Pure Robotic Right Hepatectomy for Liver Donors in a Small-Volume Center.

Background and Objectives: Living donor right hepatectomy has become the most common method of liver transplantation. With minimally invasive surgery, laparoscopic donor hepatectomy became possible, but with some limitations. Advancements in robotic technology made it possible to overcome these shortcomings and maximize the advantages of minimally invasive surgery in transplantation. For this reason, some centers have started robotic donor hepatectomy. Our study aimed to introduce our early experience of robotic donor right hepatectomy and investigate the feasibility of this surgery. Methods: This study included 10 (30%) living donors who underwent pure robotic donor right hepatectomy at Dong-A University Hospital from January 1, 2020 to December 31, 2021. The medical records were analyzed to determine the short-term outcomes of these patients. Results: The total operation time and warm ischemic time were 396.6 min ± 62.7 min and 19.7 min± 5.6 min, respectively. Moreover, there was no transfusion during the operation and no other port use and open conversion. The average real graft volume was 590 mL ± 73.5 mL, and the mean hospital stay was 8.7 d ± 2.6 d. There have been no specific complications noted in the donor group. Conclusions: Based on our positive experience with pure robotic right hepatectomy for a liver donor, the robotic technique may be a new option for achieving minimally invasive surgery for a liver donor.

α-Iso-cubebene attenuates neointima formation by inhibiting HMGB1-induced monocyte to macrophage differentiation via suppressing ROS production.

α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis, a medicinal herb used to improve cardiovascular symptoms. To investigate the mechanisms involved, the effects of ICB on cellular production of reactive oxygen species (ROS) was determined using cultured human THP-1 cells. When THP-1 cells were stimulated with HMGB1, cellular concentration of ROS was increased in dose- and time-dependent manners. These increases were significantly attenuated in cells pretreated with NADPH oxidase inhibitors, diphenyleneiodonium chloride and apocynin, but not by other inhibitors related to ROS generation in monocytes. The expression of constitutively expressed NADPH oxidase (NOX) subunits including NOX1, NOX2, NOX4 and NOX5 was not affected by HMGB1, but HMGB1-induced ROS production was exclusively attenuated in NOX2-deficient cells using siRNA, suggesting an enhanced NOX2 complex assembly. When cells were stimulated with HMGB1, p47phox phosphorylation at ser345, ser359 and ser370 was increased in dose- and time-dependent manners, which were significantly attenuated in ICB (3-10 µg/mL)-pretreated cells. In addition, HMGB1-induced monocyte-macrophage differentiation (MMD) in bone marrow-derived cells isolated from mice were significantly attenuated in cells treated with apocynin and ICB. Also, macrophage infiltration and intimal hyperplasia in the wire-injured femoral artery were significantly attenuated in ICB-treated mice compared to wild-type control mice. The results of this study show that ICB inhibits HMGB1-induced MMD by suppressing ROS production in monocytes, thus suggest that ICB has therapeutic potential for vascular inflammation with subsequent intimal hyperplasia related to vascular injury.

HMGB1 increases RAGE expression in vascular smooth muscle cells via ERK and p-38 MAPK-dependent pathways.

The increased expression of receptors for advanced glycation end-product (RAGE) is known as a key player in the progression of vascular remodeling. However, the precise signal pathways regulating RAGE expression in vascular smooth muscle cells (VSMCs) in the injured vasculatures are unclear. Given the importance of mitogen-activated protein kinase (MAPK) signaling in cell proliferation, we investigated the importance of MAPK signaling in high-mobility group box 1 (HMGB1)-induced RAGE expression in VSMCs. In HMGB1 (100 ng/ml)-stimulated human VSMCs, the expression of RAGE mRNA and protein was increased in association with an increase in AGE-induced VSMC proliferation. The HMGB1-induced RAGE expression was attenuated in cells pretreated with inhibitors for ERK (PD98059, 10 µM) and p38 MAPK (SB203580, 10 µM) as well as in cells deficient in ERK and p38 MAPK using siRNAs, but not in cells deficient of JNK signaling. In cells stimulated with HMGB1, the phosphorylation of ERK, JNK, and p38 MAPK was increased. This increase in ERK and p38 MAPK phosphorylation was inhibited by p38 MAPK and ERK inhibitors, respectively, but not by JNK inhibitor. Moreover, AGE-induced VSMC proliferation in HMGB1-stimulated cells was attenuated in cells treated with ERK and p38 MAPK inhibitors. Taken together, our results indicate that ERK and p38 MAPK signaling are involved in RAGE expression in HMGB1-stimulated VSMCs. Thus, the ERK/p38 MAPK-RAGE signaling axis in VSMCs was suggested as a potential therapeutic target for vascular remodeling in the injured vasculatures.

Associations of GNAS and RGS Gene Polymorphisms with the Risk of Ritodrine-Induced Adverse Events in Korean Women with Preterm Labor: A Cohort Study.

Ritodrine, a ß2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide polymorphisms in GNAS, RGS2, and RGS5 with the risk of ritodrine-induced adverse events (AEs) and develop a risk scoring system to identify high-risk patients. This is the prospective cohort study conducted at the Ewha Woman's University Mokdong Hospital between January 2010 and October 2016. Pregnant women were included if they were treated with ritodrine for preterm labor with regular uterine contractions (at least 3 every 10 min) and cervical dilation. A total of 6, 3, and 5 single nucleotide polymorphisms (SNPs) of GNAS, RGS2, and RGS5 genes were genotyped and compared in patients with and without ritodrine-induced AEs. A total of 163 patients were included in this study. After adjusting confounders, GNAS rs3730168 (per-allele odds ratio (OR): 2.1; 95% confidence interval (95% CI): 1.0-4.3) and RGS2 rs1152746 (per-allele OR: 2.6, 95% CI: 1.1-6.5) were significantly associated with ritodrine-induced AEs. According to the constructed risk scoring models, patients with 0, 1, 2, 3, 4, and 5 points showed 0%, 13%, 19%, 31%, 46%, and 100% risks of AEs. This study suggested that GNAS and RGS2 polymorphisms could affect the risk of AEs in patients treated with ritodrine.

Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.

PDGFR-ß signaling mediates HMGB1 release in mechanically stressed vascular smooth muscle cells.

Mechanically stressed vascular smooth muscle cells (VSMCs) have potential roles in the development of vascular complications. However, the underlying mechanisms are unclear. Using VSMCs cultured from rat thoracic aorta explants, we investigated the effects of mechanical stretch (MS) on the cellular secretion of high mobility group box 1 (HMGB1), a major damage-associated molecular pattern that mediates vascular complications in stressed vasculature. Enzyme-linked immunosorbent assay (ELISA) demonstrated an increase in the secretion of HMGB1 in VSMCs stimulated with MS (0-3% strain, 60 cycles/min), and this secretion was markedly and time-dependently increased at 3% MS. The increased secretion of HMGB1 at 3% MS was accompanied by an increased cytosolic translocation of nuclear HMGB1; the acetylated and phosphorylated forms of this protein were significantly increased. Among various inhibitors of membrane receptors mediating mechanical signals, AG1295 (a platelet-derived growth factor receptor (PDGFR) inhibitor) attenuated MS-induced HMGB1 secretion. Inhibitors of other receptors, including epidermal growth factor, insulin-like growth factor, and fibroblast growth factor receptors, did not inhibit this secretion. Additionally, MS-induced HMGB1 secretion was markedly attenuated in PDGFR-ß-deficient cells but not in cells transfected with PDGFR-α siRNA. Likewise, PDGF-DD, but not PDGF-AA, directly increased HMGB1 secretion in VSMCs, indicating a pivotal role of PDGFR-ß signaling in the secretion of this protein in VSMCs. Thus, targeting PDGFR-ß-mediated secretion of HMGB1 in VSMCs might be a promising therapeutic strategy for vascular complications associated with hypertension.

Humoral and Cellular Responses to COVID-19 Vaccines in SARS-CoV-2 Infection-Naïve and -Recovered Korean Individuals.

In the face of a global COVID-19 vaccine shortage, an efficient vaccination strategy is required. Therefore, the immunogenicity of single or double COVID-19 vaccination doses (ChAdOX1, BNT162b2, or mRNA-1273) of SARS-CoV-2-recovered individuals was compared to that of unvaccinated individuals with SARS-CoV-2 infection at least one year post-convalescence. Moreover, the immunogenicity of SARS-CoV-2-naïve individuals vaccinated with a complete schedule of Ad26.CoV2.S, ChAdOX1, BNT162b2, mRNA-1273, or ChAdOX1/BNT162b2 vaccines was evaluated. Anti-SARS-CoV-2 S1 IgG antibody (S1-IgG), pseudotyped virus-neutralizing antibody titer (pVNT50), and IFN-γ ELISpot counts were measured. Humoral immune responses were significantly higher in vaccinated than in unvaccinated recovered individuals, with a 43-fold increase in the mean pVNT50 values. However, there was no significant difference in the pVNT50 and IFN-γ ELISpot values between the single- and double-dose regimens. In SARS-CoV-2-naïve individuals, antibody responses varied according to the vaccine type: BNT162b2 and mRNA-1273 induced similar levels of S1-IgG to those observed in vaccinated, convalescent individuals; in contrast, pVNT50 was much lower in SARS-CoV-2-naïve vaccinees than in vaccinated recovered individuals. Therefore, a single dose of ChAdOX1, BNT162b2, or mRNA-1273 vaccines would be a good alternative for recovered individuals instead of a double-dose regimen.

A Pivotal Role for AP-1-Mediated Osteopontin Expression in the Increased Migration of Vascular Smooth Muscle Cells Stimulated With HMGB1.

Migration of vascular smooth muscle cells (VSMCs) plays an essential role in the development of vascular remodeling in the injured vasculatures. Previous studies have identified high-mobility group box 1 (HMGB1) as a principal effector mediating vascular remodeling; however, the mechanisms involved have not been fully elucidated. Thus, this study investigated the role of HMGB1 on VSMC migration and the underlying molecular mechanisms involved. VSMCs were ex plant cultured using rat thoracic aorta, and the cellular migration was measured using wound-healing assay. Osteopontin (OPN) mRNA and protein were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. The OPN promoter was cloned into pGL3 basic to generate a pLuc-OPN-2284 construct. Migration of VSMCs stimulated with HMGB1 (100ng/ml) was markedly increased, which was significantly attenuated in cells pretreated with MPIIIB10 (100-300ng/ml), a neutralizing monoclonal antibody for OPN as well as in cells deficient of OPN. In VSMCs stimulated with HMGB1, OPN mRNA and protein levels were significantly increased in association with an increased promotor activity of OPN gene. Putative-binding sites for activator protein 1 (AP-1) and CCAAT/enhancer-binding protein beta (C/EBPß) in the indicated promoter region were suggested by TF Search, and the HMGB1-induced expression of OPN was markedly attenuated in cells transfected with siRNA for AP-1. VSMC stimulated with HMGB1 also showed an increased expression of AP-1. Results of this study suggest a pivotal role for AP-1-induced OPN expression in VSMC migration induced by HMGB1. Thus, the AP-1-OPN signaling axis in VSMC might serve as a potential therapeutic target for vascular remodeling in the injured vasculatures.