Feasibility Assessment of Robotic Major Hepatectomy and Bile Duct Resection in Klatskin Type IIIB Tumor with Concomitant Gallbladder Cancer.

BACKGROUND: Radical resection is the only curative treatment for perihilar cholangiocarcinoma (Klatskin tumor), the most common type of bile duct cancer.1,2 Because Klatskin tumors require major hepatectomy including segment 1, extensive lymphadenectomy, and bile duct reconstruction, laparoscopic surgery has technical challenges, especially with small and multiple bile ducts.2-5 The robotic platform has great freedom of movement, making it effective for dissection and suturing in minimally invasive Klatskin tumor resection.2,3,6 However, few cases have been reported, prompting this video demonstration. METHODS: A 74-year-old woman was referred to surgery after biliary drainage due to obstructive jaundice. Adenocarcinoma was diagnosed via endobiliary brushing, with magnetic resonance imaging and computed tomography (CT) showing a polypoid mass in the gallbladder and a 3-cm enhancing mass in the perihilar area. No signs of distant metastasis were present. Thus, robotic left hepatectomy including segment 1, partial hepatectomy of segment 5, and bile duct resection were performed (see video). RESULTS: The total operative time was 419 min, with an estimated blood loss of 300 ml. Computed tomography on postoperative day 5 showed no abnormal findings, and the patient was discharged on postoperative day 10 without complications. The final pathologic results confirmed the double primary adenocarcinomas with clear resection margins of 6.4 cm and 3.8 cm, respectively, and 11 lymph nodes all were negative for malignancy. CONCLUSIONS: This case exemplifies the safety and effectiveness of robotic surgery for Klatskin tumors, even with concomitant gallbladder cancer, and demonstrates the benefits and potential of this technique in complex surgical procedures.

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.

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.

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.

Salinomycin ameliorates oxidative hepatic damage through AMP-activated protein kinase, facilitating autophagy.

Salinomycin, a monocarboxylic ionophore in Streptomyces albus, has been studied as an anti-cancer agent. However, we wondered whether salinomycin has another effect such as an anti-oxidant and hepatic protectant, because some chemical drugs treating human diseases were sometimes related with their toxic effects. Therefore, this study was conducted to examine the effects of salinomycin against oxidative stress and mitochondrial impairment in vivo and in vitro as well as the cellular mechanisms of action. In hepatocyte, salinomycin inhibited arachidonic acid (AA) + iron-induced apoptosis, mitochondrial dysfunction and ROS production. As a molecular mechanism, salinomycin induced autophagy through AMP-activated protein kinase (AMPK) activation, as assessed by the accumulation of acidic vesicle organelles, p62 and LC3-II. Moreover, these protective effects were blocked by AMPK inhibition, which indicates the importance of AMPK in the process of salinomycin's effects. In mice, oral administration of salinomycin protected against carbon tetrachloride (CCl4)-induced oxidative stress and liver injury, and also activated AMPK as well as autophagy-related proteins in the liver. Collectively, salinomycin had the ability to protect hepatocytes against AA+iron-induced reactive oxygen species production and mitochondrial dysfunction, as well as CCl4-induced liver injury. Although this beneficial effect was demonstrated under severe oxidative stress, this study showed that salinomycin protected the liver against the oxidative stress and liver damage through AMPK and autophagy, and suggest that salinomycin has a possibility to treat a broad range of diseases.

Fucoxanthin, the constituent of Laminaria japonica, triggers AMPK-mediated cytoprotection and autophagy in hepatocytes under oxidative stress.

BACKGROUND: Laminaria japonica has frequently been used as a food supplement and drug in traditional oriental medicine. Among the major active constituents responsible for the bioactivities of L. japonica, fucoxanthin (FX) has been considered as a potential antioxidant. This study was conducted to examine the effects of L. japonica extract (LJE) or FX against oxidative stress on hepatocytes and to elucidate the overall their cellular mechanisms of the effects. METHODS: We constructed an in vitro model with the treatment of arachidonic acid (AA) + iron in HepG2 cells to stimulate the oxidative damage. The cells were pre-treated with LJE or FX for 1 h, and incubated with AA + iron. The effect on oxidative damage and cellular mechanisms of LJE or FX were assessed by cytological examination and several biochemical assays under conditions with or without kinase inhibitiors. RESULTS: LJE or FX pretreatment effectively blocked the pathological changes caused by AA + iron treatment, such as cell death, altered expression of apoptosis-related proteins such as procaspase-3 and poly (ADP-ribose) polymerase, and mitochondria dysfunction. Moreover, FX induced AMPK activation and AMPK inhibitor, compound C, partially reduced the protective effect of FX on mitochondria dysfunction. Consistent with AMPK activation, FX increased the protein levels of autophagic markers (LC3II and beclin-1) and the number of acridine orange stained cells, and decreased the phosphorylation of mTOR and simultaneously increased the phosphorylation of ULK1. And the inhibition of autophagy by 3-methylanine or bafilomycin A1 partially inhibited the protective effect of FX on mitochondria dysfunction. CONCLUSION: These findings suggest that FX have the function of being a hepatic protectant against oxidative damages through the AMPK pathway for the control of autophagy.

Anti-Melanogenic Activity of Gagunin D, a Highly Oxygenated Diterpenoid from the Marine Sponge Phorbas sp., via Modulating Tyrosinase Expression and Degradation.

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge Phorbas sp., has exhibited cytotoxicity toward human leukemia cells. However, the effect of GD on normal cells and the molecular mechanisms remain to be elucidated. In the present study, we identified for the first time the anti-melanogenic activity of GD and its precise underlying mechanisms in mouse melan-a cells. GD significantly inhibited melanin synthesis in the melan-a cells and a reconstructed human skin model. Further analysis revealed that GD suppressed the expression of tyrosinase and increased the rate of tyrosinase degradation. GD also inhibited tyrosinase enzymatic activity. In addition, GD effectively suppressed the expression of proteins associated with melanosome transfer. These findings suggest that GD is a potential candidate for cosmetic formulations due to its multi-functional properties.

Wogonin, a plant flavone from Scutellariae radix, attenuated ovalbumin-induced airway inflammation in mouse model of asthma via the suppression of IL-4/STAT6 signaling.

Bronchial asthma is a chronic inflammatory disease of the airways characterized by a marked infiltration of eosinophils at the site of inflammation. Eotaxins are potent chemoattractants for eosinophils and play important roles in pathogenesis of asthma. In the course of screening for eotaxin-3 inhibitors, we found that wogonin showed potent inhibitory activity of interleukin-4 (IL-4)-induced eotaxin-3 expression in BEAS-2B cells. In this study, we examined the effects of wogonin on IL-4/STAT6 signaling pathway and biological implication in a mouse model of asthma. Wogonin inhibited IL-4-induced activation and nuclear translocation of STAT6 which plays a key role in either the transcription of STAT6-response genes or Th2 cytokine-mediated inflammation. Oral administration of wogonin significantly reduced activation of STAT6 in the lung and the expression of eotaxin and RANTES in bronchoalveolar lavage fluids. Histological examination of lung tissue demonstrated that wogonin significantly inhibited allergen-induced eosinophilic inflammation. Administration of wogonin reduced the total IgE and ovalbumin-specific IgE levels compared with the ovalbumin-challenged group. All of these data demonstrated that wogonin could alleviate airway inflammation through inhibition of STAT6 activation induced by Th2 cytokines. Our finding implicates a potential therapeutic value of wogonin in the treatment of asthma through regulation of IL-4/STAT6 signaling pathway.

Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome.

BACKGROUND: Endoscopic ampullectomy is increasingly performed in patients with familial adenomatous polyposis (FAP)-associated ampullary adenomas. We sought to define the procedure-associated morbidities and long-term outcomes. METHODS: We performed a retrospective chart review of patients with FAP who underwent endoscopic ampullectomy at two tertiary institutions between 1999 and 2010. The severity of duodenal polyposis was classified according to Spigelman's classification. RESULTS: Of 26 FAP patients who underwent endoscopic ampullectomy, 21 arose in the setting of Spigelman's stage II duodenal polyposis. Adverse events associated with endoscopic ampullectomy included acute pancreatitis (19.2%), abdominal pain (7.6%), and bleeding (3.8%). The mean resected adenoma size was 0.99 ± 0.34 cm. Three adenomas (12.0%) contained foci of high-grade dysplasia. Follow-up data were available for 24 patients. The mean follow-up duration was 84.5 ± 36.2 months. Adenoma recurrence was observed in 14 patients (58.3%; 14/24) at a mean of 38.3 months after initial ampullectomy. Adenomas ≥10 mm recurred more frequently than smaller adenomas (76.9 vs. 36.4%; p = 0.002). Positive margins were not associated with higher recurrence rates. No cancers were observed during long-term follow-up. Three patients underwent a Whipple procedure, but none was performed for a recurrent ampullary adenoma. CONCLUSIONS: Endoscopic ampullectomy in FAP can be performed safely. Because ampullary adenomas frequently recur after endoscopic ampullectomy, close surveillance is essential. Smaller tumors are less likely to recur, suggesting a benefit for early recognition of these lesions.

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.

Exploring the feasibility of robotic liver resection in a limited resource setting.

The transition from open hepatectomy to minimally invasive techniques has reduced morbidity and mortality. However, laparoscopic liver resection (LLR) requires substantial expertise. Robotic liver resection (RLR) combines minimal invasiveness with open surgical precision. It may facilitate complex procedures without the learning required for LLR. We evaluated RLR outcomes in a limited resource setting and assessed its efficacy and practicality. This retrospective study analyzed 67 robotic hepatectomies conducted from 2020 to 2023. Demographic, perioperative factors, and surgical outcomes were analyzed. Major hepatectomies were required in 46/67 (68.7%) patients who underwent RLR. No open conversions, 30-day mortalities, or readmissions occurred. Complications occurred in 7.4% of patients; major complications occurred in 5.9%. Learning curve analysis showed a negative correlation between operation sequence and operative time. Effective use of robotic technology combined with the expertise of well-trained surgeons facilitates successful execution of RLR with feasible surgical outcomes, even at smaller centers.

The method of using robotic Harmonic ACE curved shears for parenchymal transection in robotic hepatectomy.

Robotic liver surgery is emerging as a minimally invasive surgery to overcome the disadvantages of laparoscopy. The two biggest barriers to the uptake of robotic hepatectomy are the high cost and instrument limitations. Transection of the liver parenchyma is the main issue in robotic hepatectomy. Nonetheless, with adequate experience and the aid of reliable and enhanced three-dimensional visualization, many robotic surgeons have successfully used robotic Harmonic ACE curved shears (Intuitive Surgical Inc.) for parenchymal transection of the liver. Herein, we share a method of using robotic Harmonic ACE curved shears for parenchymal transection using a video clip.

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.

Advancing treatment for perihilar cholangiocarcinoma: role of hepatopancreaticoduodenectomy in small-volume centers.

Hepatopancreaticoduodenectomy (HPD) is a controversial surgical technique for the treatment of perihilar cholangiocarcinoma. This study aimed to clarify the mortality, morbidity, and survival outcomes in patients with perihilar cholangiocarcinoma who underwent HPD at a small-volume hepatobiliary-pancreatic center. This retrospective study included 78 patients with perihilar cholangiocarcinoma who underwent HPD (n = 18) or major liver resection with bile duct resection (n = 60) at our center between October 2013 and December 2022. The primary endpoints were the in-hospital morbidity and 90-day mortality rates. The secondary endpoints included the recurrence-free and overall survival rates in both groups. Major complications (Clavien-Dindo grade ≥3) were more common in the HPD group (Group 1, 61.1%) than in the major liver resection group (Group 2; 23.3%, p = 0.03). The 1-, 3- and 5-year overall survival rates for Groups 1 and 2 were 66.7%, 41.7%, and 27.8% and 79.9%, 44.5%, and 22.7%, respectively (p = 0.89). The 1-, 3-, and 5-year recurrence-free survival rates for Groups 1 and 2 were 64.2%, 53.5%, and 35.6% and 85.3%, 46.8%, and 25.0%, respectively (p = 0.41). Although morbidity and mortality after HPD are higher than those after other surgeries, our findings suggest that HPD is a feasible treatment option for perihilar cholangiocarcinoma, even in small-volume centers. However, meticulous pre- and perioperative evaluation of the patient's overall health status, quality of life, and prospective advantages are required.

Stanford type A aortic dissection secondary to infectious aortitis: a case report.

Nowadays, infectious aortitis has become a rare disease thanks to antibiotics, but remains life-threatening. We present a case of a patient with acupuncture-induced infectious aortitis leading to aortic dissection. Chest computed-tomogram scan revealed Stanford type A dissection with pericardial effusion. Under the impression of an impending rupture, emergent surgery was performed. During surgery, infectious aortitis was identified incidentally, so she underwent resection of the infected aorta including surrounding tissues. Then the ascending aorta and hemi-arch were replaced with a prosthetic graft as an in situ fashion. The resected tissue and blood cultures revealed Staphylococcus aureus, so prolonged antibiotherapy was prescribed.

Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway.

BACKGROUND: Korean ginseng (Panax ginseng C.A. Meyer) has been used as a botanical medicine throughout the history of Asian traditional Oriental medicine. Formulated red ginseng (one form of Korean ginseng) has been shown to have antioxidant and chemopreventive effects. METHODS: This study investigated the cytoprotective effects and mechanism of action of Korean red ginseng extract (RGE) against severe ROS production and mitochondrial impairment in a cytotoxic cell model induced by AA + iron. RESULTS: RGE protected HepG2 cells from AA + iron-induced cytotoxicity by preventing the induction of mitochondrial dysfunction and apoptosis. Moreover, AA + iron-induced production of ROS and reduction of cellular GSH content (an important cellular defense mechanism) were remarkably attenuated by treatment with RGE. At the molecular level, treatment with RGE activated LKB1-dependent AMP-activated protein kinase (AMPK), which in turn led to increased cell survival. The AMPK pathway was confirmed to play an essential role as the effects of RGE on mitochondrial membrane potential were reversed upon treatment with compound C, an AMPK inhibitor. CONCLUSIONS: Our results demonstrate that RGE has the ability to protect cells from AA + iron-induced ROS production and mitochondrial impairment through AMPK activation.

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.

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.

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.

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.