Preoperative smoking and robot-assisted radical cystectomy outcomes & complications in multicenter KORARC database.

To investigate the influence of preoperative smoking history on the survival outcomes and complications in a cohort from a large multicenter database. Many patients who undergo radical cystectomy (RC) have a history of smoking; however, the direct association between preoperative smoking history and survival outcomes and complications in patients with muscle-invasive bladder cancer (MIBC) who undergo robot-assisted radical cystectomy (RARC) remains unexplored. We conducted a retrospective analysis using data from 749 patients in the Korean Robot-Assisted Radical Cystectomy Study Group (KORARC) database, with an average follow-up duration of 30.8 months. The cohort was divided into two groups: smokers (n = 351) and non-smokers (n = 398). Propensity score matching was employed to address differences in sample size and baseline demographics between the two groups (n = 274, each). Comparative analyses included assessments of oncological outcomes and complications. After matching, smoking did not significantly affect the overall complication rate (p = 0.121). Preoperative smoking did not significantly increase the occurrence of complications based on complication type (p = 0.322), nor did it increase the readmission rate (p = 0.076). There were no perioperative death in either group. Furthermore, preoperative smoking history showed no significant impact on overall survival (OS) [hazard ratio (HR) = 0.87, interquartile range (IQR): 0.54-1.42; p = 0.589] and recurrence-free survival (RFS) (HR = 1.12, IQR: 0.83-1.53; p = 0.458) following RARC for MIBC. The extent of preoperative smoking (≤ 10, 10-30, and ≥ 30 pack-years) had no significant influence on OS and RFS in any of the categories (all p > 0.05). Preoperative smoking history did not significantly affect OS, RFS, or complications in patients with MIBC undergoing RARC.

Synergistic Effects in LaNiO3 Perovskites between Nickel and Iron Heterostructures for Improving Durability in Oxygen Evolution Reaction for AEMWE.

Perovskite materials that aren't stable during the oxygen evolution reaction (OER) are unsuitable for anion-exchange membrane water electrolyzers (AEMWE). But through manipulating their electronic structures, their performance can further increase. Among the first-row transition metals, nickel and iron are widely recognized as prominent electrocatalysts; thus, the researchers are looking into how combining them can improve the OER. Recent research has actively explored the design and study of heterostructures in this field, showcasing the dynamic exploration of innovative catalyst configurations. In this study, a heterostructure is used to manipulate the electronic structure of LaNiO3 (LNO) to improve both OER properties and durability. Through adsorbing iron onto the LNO (LNO@Fe) as γ iron oxyhydroxide (γ-FeOOH), the binding energy of nickel in the LNO exhibited negative shifts, inferring nickel movement toward the metallic state. Consequently, the electrochemical properties of LNO@Fe are further improved. LNO@Fe showed excellent performance (1.98 A cm-2, 1 m KOH, 50 °C at 1.85 V) with 84.1% cell efficiency in AEMWE single cells, demonstrating great improvement relative to LNO. The degradation for the 850 h durability analysis of LNO@Fe is ≈68 mV kh-1, which is ≈58 times less than that of LNO.

Weighting estimation in the cause-specific Cox regression with partially missing causes of failure.

Complex diseases are often analyzed using disease subtypes classified by multiple biomarkers to study pathogenic heterogeneity. In such molecular pathological epidemiology research, we consider a weighted Cox proportional hazard model to evaluate the effect of exposures on various disease subtypes under competing-risk settings in the presence of partially or completely missing biomarkers. The asymptotic properties of the inverse and augmented inverse probability-weighted estimating equation methods are studied with a general pattern of missing data. Simulation studies have been conducted to demonstrate the double robustness of the estimators. For illustration, we applied this method to examine the association between pack-years of smoking before the age of 30 and the incidence of colorectal cancer subtypes defined by a combination of four tumor molecular biomarkers (statuses of microsatellite instability, CpG island methylator phenotype, BRAF mutation, and KRAS mutation) in the Nurses' Health Study cohort.

Optimal timing for the first cystoscopic follow-up using time-to-treatment initiation analysis of oncologic outcomes in primary non-muscle invasive bladder cancer.

Various guidelines recommend the first follow-up cystoscopy at 3 months; however, no data exist on the optimal timing for initial follow-up cystoscopy. We tried to provide evidence on the timing of the first cystoscopy after the initial transurethral resection of bladder tumor (TUR-BT) for patients with non-muscle invasive bladder cancer (NMIBC) using big data. This was a retrospective National Health Insurance Service database analysis. The following outcomes were considered: recurrence, progression, cancer-specific mortality, and all-cause mortality. Exposure was the time-to-treatment initiation (TTI), a continuous variable representing the time to the first cystoscopy from the first TUR-BT within 1 year. Additionally, we categorized TTI (TTIc) into five levels: < 2, 2-4, 4-6, 6-8, and 8-12 months. A landmark time of 1 year after the initial TUR-BT was described to address immortal-time bias. We identified the optimal time for the first cystoscopy using Cox regression models with and without restricted cubic splines (RCS) for TTI and TTIc, respectively. Among 26,660 patients, 16,880 (63.3%) underwent cystoscopy within 2-4 months. A U-shaped trend of the lowest risks at TTI was observed in the 2-4 months group for progression, cancer-specific mortality, and all-cause mortality. TTI within 0-2 months had a higher risk of progression (aHR 1.36; 95% confidence intervals [CI] 1.15-1.60; p < 0.001) and cancer-specific mortality (aHR 1.29; 95% CI 1.05-1.58; p = 0.010). Similarly, TTI within 8-12 months had a higher risk of progression (aHR 2.09; 95% CI 1.67-2.63; p < 0.001) and cancer-specific mortality (aHR 1.96; 95% CI 1.48-2.60; p < 0.001). Based on the RCS models, the risks of progression, cancer-specific mortality, and all-cause mortality were lowest at TTI of 4 months. The timing of the first cystoscopy follow-up was associated with oncologic prognosis. In our model, undergoing cystoscopy at 4 months has shown the best outcomes in clinical course. Therefore, patients who do not receive cystoscopy at approximately 4 months for any reason need more careful follow-up to predict a poor clinical course.

Increased risk of diabetes mellitus and hyperlipidemia in patients with differentiated thyroid cancer.

OBJECTIVE: This study aimed to assess the risk of cardiometabolic disease (CMD) in patients with differentiated thyroid cancer (DTC) using a population-based nationwide cohort in Korea. DESIGN: This was a population-based cohort study. METHODS: We selected 2649 patients with DTC and 7947 matched controls. The primary outcome was the composite of CMD including diabetes mellitus (DM), hypertension, hyperlipidemia, cerebrovascular disease, and ischemic heart disease. The secondary outcomes were each individual type of CMD, all-cause mortality, and CMD-specific mortality. The cause-specific hazard ratios (HRs) for each outcome were estimated based on cause-specific Cox proportional hazard regression models. RESULTS: Patients with DTC had an 11% higher risk of the primary composite outcome than controls (HR, 1.11; 95% confidence interval [CI], 1.04-1.19). The risks of DM (HR, 1.22; 95% CI, 1.08-1.38) and hyperlipidemia (HR, 1.36; 95% CI, 1.24-1.48) were higher in patients with DTC. In contrast, the risk of CMD-specific mortality was lower in those with DTC (HR, 0.24; 95% CI, 0.09-0.68). A nonlinear, U-shaped relationship was observed between the daily dose of levothyroxine and the risk of DM (P = .021), but the risk of hyperlipidemia was low with high doses of levothyroxine in patients with DTC (P = .003). CONCLUSIONS: Patients with DTC had an increased risk of CMD, especially DM and hyperlipidemia, but a low risk of CMD mortality. Special attention to metabolic diseases is required in the long-term follow-up of patients with DTC.

Novel Screw Placement Method for Extremely Small Lumbar Pedicles in Scoliosis.

Study Design: Consecutive case series. Objective: To propose a screw placement method in patients with extremely small lumbar pedicles (ESLPs) (<2 mm) to maintain screw density and correction power, without relying on the O-arm navigation system. Summary of Background Data: In scoliosis surgery, ESLPs can hinder probe passage, resulting in exclusion or substitution of the pedicle screws with a hook. Screw density affects correction power, making it necessary to maximize the number of screw placements, especially in the lumbar curve. Limited studies provide technical guidelines for screw placement in patients with ESLPs, independent of the O-arm navigation system. Methods: We enrolled 19 patients who underwent scoliosis correction surgery using our novel screw placement method for ESLPs. Clinical, radiological, and surgical parameters were assessed. After posterior exposure of the spine, the C-arm fluoroscope was rotated to obtain a true posterior-anterior view and both pedicles were symmetrically visualized. An imaginary pedicle outline was presumed based on the elliptical or linear shadow from the pedicle. The screw entry point was established at a 2 (or 10) o'clock position in the presumed pedicle outline. After adjusting the gear-shift convergence, both cortices of the transverse process were penetrated and the tip was advanced towards the lateral vertebral body wall, where an extrapedicular screw was placed with tricortical fixation. Results: Out of 90 lumbar screws in 19 patients, 33 screws were inserted using our novel method, without correction loss or complications during an average follow-up period of 28.44 months, except radiological loosening of one screw. Conclusions: Our new extrapedicular screw placement method into the vertebral body provides an easy, accurate, and safe alternative for scoliosis patients with ESLPs without relying on the O-arm navigation system. Surgeons must consider utilizing this method to enhance correction power in scoliosis surgery, regardless of the small size of the lumbar pedicle.

Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder.

STUDY OBJECTIVES: Adenotonsillectomy (AT) improves short-term symptoms of attention deficit hyperactivity disorder (ADHD) in children; however, its long-term effects remain unclear. We aimed to verify the therapeutic long-term effects of AT in children with ADHD. METHODS: This retrospective control study included children ages < 18 years who were diagnosed with ADHD and receiving ADHD medications. Participants were divided into groups depending on whether AT was performed (AT [+] or AT [-] groups) and matched 1:1 for age, sex, and year and month of diagnosis using randomized nonreplacement selection. RESULTS: Among patients with ADHD (n = 171,112), 3,615 underwent AT. In both groups, the number of drugs taken gradually increased before and decreased after the AT date (ATD). There was no difference in the number of drugs used before (P = .88) and after ATD (P = .06). Before ATD, the average number of outpatient visits (nOV) did not change in both groups (AT [+]: P = .12; AT [-]: P = .71). After ATD, the average number of outpatient visits decreased only in the AT (+) group (P = .001). However, there was no difference in the average number of outpatient visits between the two groups before (P = .47) and after ATD (P = .17). Before ATD, methylphenidate doses between the groups were not different (P = .06); however, a significant increase was noted after ATD in the AT (+) group (P < .001). CONCLUSIONS: AT does not result in significant long-term therapeutic effects in terms of medication use and health care utilization in children with ADHD. CITATION: Lee J, Choi A, Kim S, Kim K. Long-term effects of adenotonsillectomy in children with attention deficit hyperactivity disorder. J Clin Sleep Med. 2024;20(5):727-733.

Density clustering-based automatic anatomical section recognition in colonoscopy video using deep learning.

Recognizing anatomical sections during colonoscopy is crucial for diagnosing colonic diseases and generating accurate reports. While recent studies have endeavored to identify anatomical regions of the colon using deep learning, the deformable anatomical characteristics of the colon pose challenges for establishing a reliable localization system. This study presents a system utilizing 100 colonoscopy videos, combining density clustering and deep learning. Cascaded CNN models are employed to estimate the appendix orifice (AO), flexures, and "outside of the body," sequentially. Subsequently, DBSCAN algorithm is applied to identify anatomical sections. Clustering-based analysis integrates clinical knowledge and context based on the anatomical section within the model. We address challenges posed by colonoscopy images through non-informative removal preprocessing. The image data is labeled by clinicians, and the system deduces section correspondence stochastically. The model categorizes the colon into three sections: right (cecum and ascending colon), middle (transverse colon), and left (descending colon, sigmoid colon, rectum). We estimated the appearance time of anatomical boundaries with an average error of 6.31 s for AO, 9.79 s for HF, 27.69 s for SF, and 3.26 s for outside of the body. The proposed method can facilitate future advancements towards AI-based automatic reporting, offering time-saving efficacy and standardization.

Boston bowel preparation scale score 6 has more missed lesions compared with 7-9.

Adequate bowel preparation is an important factor in high-quality colonoscopy. It is generally accepted that a Boston Bowel Preparation Scale (BBPS) score ≥ 6 is adequate, but some reports suggest ≥ 7. Subjects who underwent colonoscopy at least twice within 3 years from August 2015 to December 2019 were included. Polyp detection rates (PDRs), adenoma detection rates (ADRs), and number of polyps including adenomas were compared stratified by baseline colonoscopy (C1) BBPS score. Among 2352 subjects, 529 had BBPS 6 (group 1) and 1823 had BBPS 7-9 (group 2) at C1. There was no significant difference in PDR or ADR at C1 and follow-up colonoscopy (C2) between the two groups. However, the numbers of polyps (1.84 vs. 1.56, P = 0.001) and adenomas (1.02 vs. 0.88, P = 0.034) at C2 were significantly higher in group 1 than group 2, respectively. Segmental BBPS score 2 in group 1 compared to group 2, especially, showed higher PDR (P = 0.001) and ADR (P = 0.007) at C2. BBPS 6 is associated with a higher number of polyps and adenomas in short-term follow-up colonoscopy than BBPS 7-9. To reduce the risk of missed polyps, a thorough examination is necessary for BBPS 6.

Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy.

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.

Methyl Syringate Stimulates Glucose Uptake by Inhibiting Protein Tyrosine Phosphatases Relevant to Insulin Resistance.

Several protein tyrosine phosphatases (PTPs), particularly PTPN1, PTPN2, PTPN6, PTPN9, PTPN11, PTPRS, and DUSP9, are involved in insulin resistance. Therefore, these PTPs could be promising targets for the treatment of type 2 diabetes. Our previous studies revealed that PTPN2 and PTPN6 are potential antidiabetic targets. Therefore, the identification of dual-targeting inhibitors of PTPN2 and PTPN6 could be a potential therapeutic strategy for the treatment or prevention of type 2 diabetes. In this study, we demonstrate that methyl syringate inhibits the catalytic activity of PTPN2 and PTPN6 in vitro, indicating that methyl syringate acts as a dual-targeting inhibitor of PTPN2 and PTPN6. Furthermore, methyl syringate treatment significantly increased glucose uptake in mature 3T3-L1 adipocytes. Additionally, methyl syringate markedly enhanced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in 3T3L1 adipocytes. Taken together, our results suggest that methyl syringate, a dual-targeting inhibitor of PTPN2 and PTPN6, is a promising therapeutic candidate for the treatment or prevention of type 2 diabetes.

Cutaneous warmth and hotness thresholds to radiation heat exposure at a distance of 10 cm from 17 body regions.

The purpose of the present study was to evaluate body regional differences in cutaneous warmth and hotness thresholds in relation to radiant heat exposure. Fourteen male subjects participated in this study (age: 25 ± 5 y, height: 176.6 ± 5.5 cm, body weight: 70 ± 5.8 kg). Cutaneous warmth and hotness thresholds were measured on the forehead, neck, chest, abdomen, upper back, lower back, upper arm, forearm, palm, back of hand, front thigh, shin, top of foot, buttock, back thigh, calf, and sole. The forehead (34.8 ± 0.2 °C), lower back (34.1 ± 1.2 °C) and palm (34.3 ± 0.7 °C) had the highest warmth thresholds, whereas the foot (29.8 ± 1.9 °C) and sole (28.0 ± 2.1 °C) had the lowest values among the 17 regions (P<0.001). Higher warmth thresholds were related to higher initial skin temperatures (Tsk) (r=0.972, P<0.001). Increases in Tsk for detecting warmth sensation were smaller for the lower back with a rise of 0.2 ± 0.4 °C and the abdomen (0.3 ± 0.3 °C) than for the buttock (0.9 ± 0.8 °C) and sole (0.8 ± 0.6 °C) (P<0.05). Increases in Tsk for detecting hotness sensation ranged from 0.5 to 1.5 °C. Warmth and hotness thresholds on the abdomen or sole had significant relationships with body mass index, indicating that the overweight are less sensitive to detecting radiant heat on the abdomen or sole. Thermal thresholds from radiant heat exposure of 100 cm2 were lower than the values from conductive heat exposure of 6.25 cm2, which might be explained by the effect of spatial summation.

Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study.

BACKGROUND: We aimed to assess the trends in urinary tract infections (UTIs) and prognosis of patients with prostate cancer after radical prostatectomy (RP) and radiation therapy (RT) as definitive treatment options. METHODS: The data of patients diagnosed with prostate cancer between 2007 and 2016 were collected from the National Health Insurance Service database. The incidence of UTIs was evaluated in patients treated with RT, open/laparoscopic RP, and robot-assisted RP. The proportional hazard assumption test was performed using the scaled Schoenfeld residuals based on a multivariable Cox proportional hazard model. Kaplan-Meier analysis were performed to assess survival. RESULTS: A total of 28,887 patients were treated with definitive treatment. In the acute phase (< 3 months), UTIs were more frequent in RP than in RT; in the chronic phase (> 12 months), UTIs were more frequent in RT than in RP. In the early follow-up period, the risk of UTIs was higher in the open/laparoscopic RP group (aHR, 1.63; 95% CI, 1.44-1.83; p < 0.001) and the robot-assisted RP group (aHR, 1.26; 95% CI, 1.11-1.43; p < 0.001), compared to the RT group. The robot-assisted RP group had a lower risk of UTIs than the open/laparoscopic RP group in the early (aHR, 0.77; 95% CI, 0.77-0.78; p < 0.001) and late (aHR, 0.90; 95% CI, 0.89-0.91; p < 0.001) follow-up periods. In patients with UTI, Charlson Comorbidity Index score, primary treatment, age at UTI diagnosis, type of UTI, hospitalization, and sepsis from UTI were risk factors for overall survival. CONCLUSIONS: In patients treated with RP or RT, the incidence of UTIs was higher than that in the general population. RP posed a higher risk of UTIs than RT did in early follow-up period. Robot-assisted RP had a lower risk of UTIs than open/laparoscopic RP group in total period. UTI characteristics might be related to poor prognosis.

Sex-specific risk factors associated with graves' orbitopathy in Korean patients with newly diagnosed graves' disease.

OBJECTIVE: To assess sex-specific risk factors for Graves' orbitopathy (GO) in newly diagnosed Graves' disease (GD) patients. METHODS: A retrospective cohort study was conducted using the National Health Insurance Service's sample database, which consisted of 1,137,861 subjects from 2002 to 2019. The international classification of disease-10 codes was used to identify those who developed GD (E05) and GO (H062). A multivariable Cox proportional hazards model was used to estimate the effect of risk factors on GO development. RESULTS: Among 2145 male and 5047 female GD patients, GO occurred in 134 men (6.2%) and 293 women (5.8%). A multivariable Cox regression model revealed that GO development was significantly associated with younger age (HR = 0.84, 95% CI = 0.73-0.98), low income (HR = 0.55, 95% CI = 0.35-0.86), and heavy drinking (HR = 1.79, 95% CI = 1.10-2.90) in men, and with younger age (HR = 0.89, 95% CI = 0.81-0.98), lower body mass index (HR = 0.55, 95% CI = 0.33-0.90), high total cholesterol (HR = 1.04, 95% CI = 1.01-1.06), hyperlipidaemia (HR = 1.37, 95% CI = 1.02-1.85), and lower statin dose (HR = 0.37, 95% CI = 0.22-0.62) in women. There was no association between smoking and GO development in both men and women. CONCLUSIONS: The risk factors for GO development were sex-dependent. These results show the need for more sophisticated attention and support considering sex characteristics in GO surveillance.

Selective cytotoxicity of a novel mitochondrial complex I inhibitor, YK-135, against EMT-subtype gastric cancer cell lines due to impaired glycolytic capacity.

Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemoresistance compared to those of other molecular subtypes. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development. [BMB Reports 2022; 55(12): 645-650].

Therapeutic strategies for liver diseases based on redox control systems.

In the liver, reactive oxygen species (ROS) are constantly released during cellular metabolic processes, and excess ROS production can cause redox stress. The redox stress is both beneficial for and harmful to the survival of cells since it modulates the cellular redox control system. The redox control system is a series of cellular responses that are responsible for maintaining a balanced oxidation-reduction status. Many cellular processes including growth, proliferation, and senescence are sensitively regulated by the redox control system. Imbalance of redox induces redox stress and damages DNA, proteins, and lipids in cells, and further contributes to the pathogenesis of severe diseases and disorders like cancer. However, the cellular redox control system also utilizes redox stress-responsive pathways and increases antioxidant enzymes to aid cell survival. Therefore, a deeper understanding of the connection between the redox control system and liver disease is likely to pave the way for the future development of new therapeutic strategies. This review will examine the redox control systems in liver with responsive regulating molecules, current knowledge of the redox control system and liver disease, and suggest potential therapeutic targets for liver diseases.

Clinical factors and dopamine transporter availability for the prediction of outcomes after globus pallidus deep brain stimulation in Parkinson's disease.

We aimed to investigate the predictive value of preoperative clinical factors and dopamine transporter imaging for outcomes after globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with advanced Parkinson's disease (PD). Thirty-one patients with PD who received bilateral GPi DBS were included. The patients underwent preoperative [18F] FP-CIT positron emission tomography before DBS surgery. The Unified Parkinson's Disease Rating Scale (UPDRS) were used to assess outcomes 12 months after DBS. Univariate and multivariate linear regression analysis were performed to investigate the association between clinical variables including sex, age at onset of PD, disease duration, cognitive status, preoperative motor severity, levodopa responsiveness, daily dose of dopaminergic medication, and dopamine transporter availability in the striatum and outcomes after GPi DBS. Younger age at onset of PD was associated with greater DBS motor responsiveness and lower postoperative UPDRS III score. Greater levodopa responsiveness, lower preoperative UPDRS III score and lower striatal dopamine transporter availability were associated with lower postoperative UPDRS III score. Younger age at onset was also associated with greater decrease in UPDRS IV score and dyskinesia score after GPi DBS. Our results provide useful information to select DBS candidates and predict therapeutic outcomes after GPi DBS in advanced PD.

Predictive Model for Graves' Ophthalmopathy in Patients with New-Onset Graves' Disease.

Background: The most prevalent extrathyroidal manifestation of Graves' disease (GD) is Graves' ophthalmopathy (GO). However, only few methods allow for predictions of GO occurrence or progression in patients with GD. Methods: We retrospectively analyzed 1,074 patients with new-onset GD, and divided them into a derivation and a validation cohort based on the date of their GD diagnosis. We then separately analyzed clinical risk factors affecting the occurrence and progression of GO using multivariable regression analysis and created a predictive model based on the factors we identified as significant. Results: Of the 853 GD patients included in the derivation cohort, 101 (11.8%) developed GO. Those who developed GO were more likely to be smokers (25.7% vs. 8.5%, p < 0.001), were younger at the time of their GD diagnosis (35.0 years vs. 42.0 years, p < 0.001), more commonly had a family history of GD (27.7% vs. 17.2%, p = 0.015), and had higher thyrotropin-binding inhibitor immunoglobulin (TBII) levels at the time of their diagnosis (13.5 IU/L vs. 10.0 IU/L, p = 0.020) than those who did not develop GO. Of the 101 GO patients in the derivation cohort, after excluding 8 who initially had active and moderate-to-severe GO, 11 of the remaining 93 had progressed to more active or severe GO. GO patients with confirmed progression had a higher proportion of those older than 45 years (54.5% vs. 19.8%, p = 0.031), and they had a different initial clinical activity score distribution. The multivariable regression analysis identified age at GD diagnosis, sex, smoking history, family history of GD, total cholesterol level, and TBII level at the time of the diagnosis as significant risk factors of GO occurrence, and a predictive model including these risk factors was built to create a nomogram. Conclusions: The predictors of GO occurrence in patients with new-onset GD were female sex, positive smoking history, young age, family history of GD, high cholesterol level, and high TBII level. The predictive nomogram developed in this study may be useful in patient counseling and facilitating informed treatment decision-making.

Snail acetylation by autophagy-derived acetyl-coenzyme A promotes invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells.

BACKGROUND: Autophagy is elevated in metastatic tumors and is often associated with active epithelial-to-mesenchymal transition (EMT). However, the extent to which EMT is dependent on autophagy is largely unknown. This study aimed to identify the mechanisms by which autophagy facilitates EMT. METHODS: We employed a liquid chromatography-based metabolomic approach with kirsten rat sarcoma viral oncogene (KRAS) and liver kinase B1 (LKB1) gene co-mutated (KL) cells that represent an autophagy/EMT-coactivated invasive lung cancer subtype for the identification of metabolites linked to autophagy-driven EMT activation. Molecular mechanisms of autophagy-driven EMT activation were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting analysis, immunoprecipitation, immunofluorescence staining, and metabolite assays. The effects of chemical and genetic perturbations on autophagic flux were assessed by two orthogonal approaches: microtubule-associated protein 1A/1B-light chain 3 (LC3) turnover analysis by Western blotting and monomeric red fluorescent protein-green fluorescent protein (mRFP-GFP)-LC3 tandem fluorescent protein quenching assay. Transcription factor EB (TFEB) activity was measured by coordinated lysosomal expression and regulation (CLEAR) motif-driven luciferase reporter assay. Experimental metastasis (tail vein injection) mouse models were used to evaluate the impact of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) or ATP citrate lyase (ACLY) inhibitors on lung metastasis using IVIS luciferase imaging system. RESULTS: We found that autophagy in KL cancer cells increased acetyl-coenzyme A (acetyl-CoA), which facilitated the acetylation and stabilization of the EMT-inducing transcription factor Snail. The autophagy/acetyl-CoA/acetyl-Snail axis was further validated in tumor tissues and in autophagy-activated pancreatic cancer cells. TFEB acetylation in KL cancer cells sustained pro-metastatic autophagy in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner. Pharmacological inhibition of this axis via CAMKK2 inhibitors or ACLY inhibitors consistently reduced the metastatic capacity of KL cancer cells in vivo. CONCLUSIONS: This study demonstrates that autophagy-derived acetyl-CoA promotes Snail acetylation and thereby facilitates invasion and metastasis of KRAS-LKB1 co-mutated lung cancer cells and that inhibition of the autophagy/acetyl-CoA/acetyl-Snail axis using CAMKK2 or ACLY inhibitors could be a potential therapeutic strategy to suppress metastasis of KL lung cancer.

Inverse correlation between gastroesophageal reflux disease and atrophic gastritis assessed by endoscopy and serology.

BACKGROUND: Helicobacter pylori (H. pylori) infection is known to prevent the occurrence of gastroesophageal reflux disease (GERD) by inducing gastric mucosal atrophy. However, little is known about the relationship between atrophic gastritis (AG) and GERD. AIM: To confirm the inverse correlation between AG and the occurrence and severity of GERD. METHODS: Individuals receiving health checkups who underwent upper gastrointestinal endoscopy at Seoul National University Healthcare System Gangnam Center were included. The grade of reflux esophagitis was evaluated according to the Los Angeles classification. Endoscopic AG (EAG) was categorized into six grades. Serologic AG (SAG) was defined as pepsinogen I ≤ 70 ng/mL and pepsinogen I/II ratio ≤ 3.0. The association between the extent of EAG and SAG and the occurrence and severity of GERD was evaluated using multivariate logistic regression analysis. RESULTS: In total, 4684 individuals with GERD were compared with 21901 healthy controls. In multivariate logistic regression analysis, advanced age, male sex, body mass index > 23 kg/m2, presence of metabolic syndrome, current smoking, and alcohol consumption were associated with an increased risk of GERD. Seropositivity for H. pylori immunoglobulin G antibodies was associated with a decreased risk of GERD. There was an inverse correlation between the extent of EAG and occurrence of GERD: Odds ratio (OR), 1.01 [95% confidence interval (CI): 0.90-1.14] in C1, 0.87 (0.78-0.97) in C2, 0.71 (0.62-0.80) in C3, 0.52 (0.44-0.61) in O1, 0.37 (0.29-0.48) in O2, and 0.28 (0.18-0.43) in O3. Additionally, the extent of EAG showed an inverse correlation with the severity of GERD. The presence of SAG was correlated with a reduced risk of GERD (OR = 0.49, 95%CI: 0.28-0.87, P = 0.014). CONCLUSION: The extent of EAG and SAG exhibited strong inverse relationships with the occurrence and severity of GERD. AG followed by H. pylori infection may be independently protect against GERD.