New options for endoscopic treatment of gastric varices.

BACKGROUND: Gastric venous bleeding is one of the most common adverse events in liver cirrhosis. The therapeutic effect of isolated gastric varices is relatively clear. However, there is no appropriate clinical and endoscopic treatment for extensive variceal bleeding in the gastric fundus and body. METHODS: In this patient with non-isolated gastric varices, we decided to perform endoscopic multi-point ligation of the obvious varices in the gastric fundus and body. RESULTS: In this patient, endoscopic treatment of gastric varices with bleeding after surgery achieved a significant therapeutic effect. Reexamination of gastroscopy at 3 months after operation showed that multiple scars were formed in the gastric fundus and fundus, and no obvious varices were found. CONCLUSIONS: For patients with non-isolated gastric varices, endoscopic multi-point ligation is a safe and effective treatment option for the varices with obvious gastric fundus and body.

Integrating Vision-Language Models for Accelerated High-Throughput Nutrition Screening.

Addressing the critical need for swift and precise nutritional profiling in healthcare and in food industry, this study pioneers the integration of vision-language models (VLMs) with chemical analysis techniques. A cutting-edge VLM is unveiled, utilizing the expansive UMDFood-90k database, to significantly improve the speed and accuracy of nutrient estimation processes. Demonstrating a macro-AUCROC of 0.921 for lipid quantification, the model exhibits less than 10% variance compared to traditional chemical analyses for over 82% of the analyzed food items. This innovative approach not only accelerates nutritional screening by 36.9% when tested amongst students but also sets a new benchmark in the precision of nutritional data compilation. This research marks a substantial leap forward in food science, employing a blend of advanced computational models and chemical validation to offer a rapid, high-throughput solution for nutritional analysis.

Regioselective and enantioselective propargylic hydroxylations catalyzed by P450tol monooxygenases.

Regioselective and enantioselective hydroxylation of propargylic C-H bonds are useful reactions but often lack appropriate catalysts. Here a green and efficient asymmetric hydroxylation of primary and secondary C-H bonds at propargylic positions has been established. A series of optically active propargylic alcohols were prepared with high regio- and enantioselectivity (up to 99% ee) under mild reaction conditions by using P450tol, while the C≡C bonds in the molecule remained unreacted. This protocol provides a green and practical method for constructing enantiomerically chiral propargylic alcohols. In addition, we also demonstrated that the biohydroxylation strategy was able to scaled up to 2.25 mmol scale with the production of chiral propargyl alcohol 2a at a yield of 196 mg with 96% ee, which's an important synthetic intermediate of antifungal drug Ravuconazole.

LncRNA MEG3 Inhibits the Epithelial-mesenchymal Transition of Bladder Cancer Cells through the Snail/E-cadherin Axis.

OBJECTIVE: This study aimed to investigate the role of the long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) in the epithelial-mesenchymal transition (EMT) of bladder cancer cells and the potential mechanisms. METHODS: Cell invasion, migration, and wound healing assays were conducted to assess the effects of MEG3 on the invasive and migratory capabilities of bladder cancer cells. The expression levels of E-cadherin were measured using Western blotting, RT-qPCR, and dual luciferase reporter assays. RNA immunoprecipitation and pull-down assays were performed to investigate the interactions between MEG3 and its downstream targets. RESULTS: MEG3 suppressed the invasion and migration of bladder cancer cells and modulated the transcription of E-cadherin. The binding of MEG3 to the zinc finger region of the transcription factor Snail prevented its ability to transcriptionally repress E-cadherin. Additionally, MEG3 suppressed the phosphorylation of extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and P38, thereby decreasing the expression of Snail and stimulating the expression of E-cadherin. CONCLUSION: MEG3 plays a vital role in suppressing the EMT in bladder cancer cells, indicating its potential as a promising therapeutic target for the treatment of bladder cancer.

Early detection of pancreatic cancer in patients with recurrent pancreatitis: A case report.

BACKGROUND: Pancreatic cancer presents a challenge with its low early diagnosis and treatment rates, leading to high metastasis and mortality rates. The median survival time for advanced pancreatic cancer is a mere 3 months. However, there's hope: small pancreatic cancers diagnosed at an early stage (T1) or those less than or equal to 1 cm in diameter boast an impressive 5-year survival rate of nearly 100%. This underscores the critical importance of early pancreatic cancer detection for significantly improving prognosis. CASE SUMMARY: Pancreatic cancer, a malignant tumor of the digestive tract, poses challenges in both diagnosis and treatment due to its occult and atypical clinical symptoms. Clinically, patients with recurrent pancreatitis should be vigilant, as it may be indicative of pancreatic cancer, particularly in middle-aged and elderly patients. Here, we presented the case of a patient who experienced recurrent acute pancreatitis within a span of 2 months. During the initial episode of pancreatitis, routine imaging failed to identify the cause of pancreatic cancer. However, upon recurrence of acute pancreatitis, endoscopic ultrasonography (EUS) revealed a space-occupying lesion approximately 1 cm in size in the pancreatic body. Subsequent EUS coupled with fine-needle aspiration examination demonstrated atypical pancreatic gland epithelium. Ultimately, the patient underwent surgery and was diagnosed with an intraductal papillary mucinous tumor of the pancreas (severe epithelial dysplasia, focal cancer). CONCLUSION: We recommend EUS for patients with recurrent pancreatitis of unknown etiology to exclude early pancreatic cancer.

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Synthesis of 6/5/3-Fused Tricyclic Scaffolds via Multistep Cascade Cyclization of α-Aryl Vinylsulfoniums with para-Quinamines and para-Quinols.

Herein, we present a straightforward approach to access hydroindoline-5-one-based 6/5/3-fused polycyclic ring structures through multistep cascade reactions involving α-aryl vinylsulfoniums and para-quinamines. The reactions proceed smoothly under mild conditions to deliver the desired products in generally good isolated yields. This protocol is also applicable to the cascade cycloaddition reactions of α-aryl vinylsulfoniums and para-quinols, effectively generating complex tricyclic scaffolds. In addition, the scale-up synthesis and further derivatizations demonstrate the potential synthetic application of the protocol.

Increased risk of chronic fatigue syndrome following pneumonia: A population-based Cohort study.

BACKGROUND: Chronic fatigue syndrome (CFS) has been linked to several conditions, including infections, immune system changes, or emotional stress. Our study aimed to assess the risk of CFS after a pneumonia diagnosis using data from National Health Insurance Research Database of Taiwan. METHODS: In this nested case-control study, we identified 2,000,000 adult patients from a nationwide population-based health insurance claims database spanning from January 1, 2000, to December 31, 2017. Each case diagnosed with a pathogenic infection was matched with a corresponding control using propensity scores. We excluded individuals under 20 years of age, those with a history of pathogenic infections before the index date, or those with more than one potential pathogen. To estimate hazard ratios (HR) and the adjusted hazard ratio (aHR) with their respective 95 % confidence intervals (CI), we applied univariable and multivariable Cox proportional hazard models. The multivariable analysis incorporated adjustments for age, sex, and comorbidity-related confounders. RESULTS: The relationship between infection and the subsequent risk of CFS was assessed using Cox proportional hazards regression analysis. The incidence density rates were 6.13 and 8.70 per 1000 person-years among the non-pulmonary infection and pulmonary infection populations, respectively (adjusted hazard ratio [HR] = 1.4, 95 % confidence interval [CI] 1.32-1.5). Patients infected with Pseudomonas, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, and influenza virus exhibited a significantly higher risk of CFS than those without these pathogens (p < 0.05). Additionally, patients with pneumonia had a significantly increased risk of thromboembolism compare with control group (p < 0.05).

Plasma SCUBE2 as a novel biomarker associates with survival outcomes in patients with sepsis-associated acute kidney injury.

BACKGROUND: The adverse effects of sepsis-associated acute kidney injury (SA-AKI) highlight the need for new biomarkers. Signal Peptide-Complement C1r/C1s, Uegf, Bmp1-Epidermal Growth Factor-like Domain-Containing Protein 2 (SCUBE2), important for angiogenesis and endothelial integrity, has been linked to increased mortality in models of lipopolysaccharide-induced lung injury. This research aimed to assess the utility of plasma SCUBE2 levels as a prognostic indicator for SA-AKI in intensive care unit (ICU) patients. METHODS: Between September 2020 and December 2022, our study enrolled ICU patients diagnosed with stage 3 SA-AKI. We collected demographic information, illness severity indices, and laboratory data, including plasma SCUBE2 and sepsis-triggered cytokine levels. We employed receiver operating characteristic curves and DeLong tests to assess the predictive accuracy for survival, Kaplan-Meier curves to evaluate the relative risk of death, and multivariate logistic regression to identify independent mortality predictors. RESULTS: Among the total of 200 participants, the survivors had significantly higher plasma SCUBE2 levels (115.9 ng/mL) compared to those who died (35.6 ng/mL). SCUBE2 levels showed a positive correlation with the anti-inflammatory cytokine IL-10 and a negative correlation with the APACHE II score, SOFA score, C-reactive protein, and monocyte chemoattractant protein-1. Multivariate analysis revealed that elevated SCUBE2 and IL-10 levels were independently protective against mortality, and associated with the most favorable 30-day survival outcomes. CONCLUSIONS: In ICU patients with stage 3 SA-AKI, lower plasma levels of SCUBE2 were correlated with elevated pro-inflammatory factors, which impacted survival outcomes. This suggests that SCUBE2 could be a potential biomarker for predicting prognosis in patients with SA-AKI.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Rate of graft retear is higher in over-the-top superior capsular reconstruction for massive posterosuperior rotator cuff tears with subscapularis tear.

PURPOSE: To compare side-to-side superior capsular reconstruction (SCR) with over-the-top SCR in terms of functional outcomes, pain relief and allograft survival rates. METHODS: Patients who had undergone arthroscopic dermal allograft SCR for massive irreparable rotator cuff tears and clinical follow-up for ≥2 years were recruited. All patients underwent postoperative assessment with routine radiographic analysis for acromiohumeral distances, ultrasound imaging 1 and 3 months after SCR and magnetic resonance imaging (MRI) at least 12 months after SCR. The outcome measures were visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES), Constant and Single Assessment Numeric Evaluation (SANE) scores. RESULTS: SCR was performed in 56 patients including side-to-side SCR in 32 and over-the-top SCR in 24. Postoperative MRI showed that the grafts were intact in 46 patients (82.1%; 26 who underwent side-to-side SCR and 20 who underwent over-the-top SCR). The proportion of nonhealing grafts in the over-the-top group was significantly higher with concomitant subscapularis tears (60% vs. 5.3%; p = 0.02). VAS scores and functional outcomes improved postoperatively in both groups and postoperative VAS (1.4 vs. 1.7; n.s.), Constant (74.8 vs. 76.0; n.s.), mean ASES (87.4 vs. 89.1; n.s.) and mean SANE (81.7 vs. 84.3; n.s.) scores did not differ significantly. CONCLUSION: For massive rotator cuff tears, over-the-top and side-to-side SCR achieve similar pain relief and functional improvement, and the rate of healing allografts is high. However, over-the-top SCR is not recommended for massive posterosuperior rotator cuff tears with repairable subscapularis tendon tears due to a higher nonhealing rate. LEVEL OF EVIDENCE: Level III.

Impact of Healthy Lifestyle Factors on Life Expectancy and Lifetime Health Care Expenditure: Nationwide Cohort Study.

BACKGROUND: The association between lifestyle risk factors and the risk of mortality and chronic diseases has been established, while limited research has explored the impact of healthy lifestyle factors on lifetime health care expenditure using longitudinal individual data. OBJECTIVE: We aimed to determine the individual and combined effects of 5 healthy lifestyle factors on life expectancy and lifetime health care expenditure in Taiwan. METHODS: Using data from the National Health Interview Survey cohort, 5 healthy lifestyle behaviors were defined and analyzed: nonsmoking, avoiding excessive alcohol consumption, engaging in sufficient physical activity, ensuring sufficient fruit and vegetable intake, and maintaining a normal weight. We used a rolling extrapolation algorithm that incorporated inverse probability of treatment weighting to estimate the life expectancy and lifetime health care expenditure of the study populations with and without healthy lifestyle factors. RESULTS: A total of 19,893 participants aged ≥30 (mean age 48.8, SD 13.4) years were included, with 3815 deaths recorded during a median follow-up period of 15.6 years. The life expectancy and per capita estimated lifetime health care expenditures for the overall study population were 35.32 years and US $58,560, respectively. Multivariable-adjusted hazard ratios for all-cause mortality in participants adhering to all 5 healthy lifestyle factors, compared with those adhering to none, were 0.37 (95% CI 0.27-0.49). We found significant increases in life expectancy for nonsmokers (2.31 years; 95% CI 0.04-5.13; P=.03), those with sufficient physical activity (1.85 years; 95% CI 0.25-4.34; P=.02), and those with adequate fruit and vegetable intake (3.25 years; 95% CI 1.29-6.81; P=.01). In addition, nonsmokers experienced a significant reduction in annual health care expenditure (-9.78%; 95% CI -46.53% to -1.45%; P=.03), as did individuals maintaining optimal body weight (-18.36%; 95% CI -29.66% to -8.57%; P=.01). Overall, participants adhering to all 5 healthy lifestyle behaviors exhibited a life gain of 7.13 years (95% CI 1.33-11.11; P=.02) compared with those adhering to one or none, with a life expectancy of 29.19 years (95% CI 25.45-33.62). Furthermore, individuals adopting all 5 healthy lifestyle factors experienced an average annual health care expenditure reduction of 28.12% (95% CI 4.43%-57.61%; P=.02) compared with those adopting one or none. CONCLUSIONS: Adopting a healthy lifestyle is associated with a longer life expectancy and a reduction of health care expenditure in Taiwanese adults. This contributes to a more comprehensive understanding of the impact of healthy lifestyle factors on the overall health and economic burden.

Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer.

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

Risks of KD and MIS-C in pediatric patients with COVID-19 infection: A TriNetX based cohort study.

BACKGROUND: The associations of COVID-19 with Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) remain unclear. Few large-scale studies have estimated the cumulative incidence of MIS-C and KD after COVID-19 in children. METHODS: Data were obtained from TriNetX. After propensity score matching was completed, data from 258,645 patients with COVID-19 (COVID-19 group) and 258,645 patients without COVID-19 (non-COVID-19 group) were analyzed using Cox regression. Hazard ratio (HR), 95% confidence interval (CI), and cumulative incidence of MIS-C and KD were calculated for both groups. Stratified analysis was performed to validate the results. RESULTS: After matching for age at baseline and sex, the risks of MIS-C and KD were higher in the COVID-19 group than in the non-COVID-19 group (HR: 3.023 [95% CI: 2.323 to 3.933] and 1.736 [95% CI: 1.273 to 2.369], respectively). After matching for age at baseline, sex, race, ethnicity, and comorbidities, the risks of MIS-C and KD remained significantly higher in the COVID-19 group than in the non-COVID-19group (HR: 2.899 [95% CI: 2.173 to 3.868] and 1.435 [95% CI: 1.030 to 2.000]). When stratified by age, the risk of MIS-C was higher in the COVID-19 group-for patients aged > 5 years and ≤ 5 years (HR: 2.399 [95% CI: 1.683 to 3.418] and 2.673 [95% CI: 1.737 to 4.112], respectively)-than in the non-COVID-19 group. However, the risk of KD was elevated only in patients aged ≤ 5 years (HR: 1.808; 95% CI: 1.203 to 2.716). When stratified by COVID-19 vaccination status, the risks of MIS-C and KD were elevated in unvaccinated patients with COVID-19 (HR: 2.406 and 1.835, respectively). CONCLUSION: Patients with COVID-19 who are aged < 18 and ≤ 5 years have increased risks of MIS-C and KD, respectively. Further studies are required to confirm the role of COVID-19 in the pathogenesis of MIS-C and KD.

Notopterygium Incisum Extract Promotes Apoptosis by Preventing the Degradation of BIM in Colorectal Cancer.

OBJECTIVE: Colorectal cancer (CRC), a prevalent malignancy worldwide, has prompted extensive research into anticancer drugs. Traditional Chinese medicinal materials offer promising avenues for cancer management due to their diverse pharmacological activities. This study investigated the effects of Notopterygium incisum, a traditional Chinese medicine named Qianghuo (QH), on CRC cells and the underlying mechanism. METHODS: The sulforhodamine B assay and colony formation assay were employed to assess the effect of QH extract on the proliferation of CRC cell lines HCT116 and Caco-2. Propidium iodide (PI) staining was utilized to detect cell cycle progression, and PE Annexin V staining to detect apoptosis. Western blotting was conducted to examine the levels of apoptotic proteins, including B-cell lymphoma 2-interacting mediator of cell death (BIM), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (BAX) and cleaved caspase-3, as well as BIM stability after treatment with the protein synthesis inhibitor cycloheximide. The expression of BAX was suppressed using lentivirus-mediated shRNA to validate the involvement of the BIM/BAX axis in QH-induced apoptosis. The in vivo effects of QH extract on tumor growth were observed using a xenograft model. Lastly, APCMin+ mice were used to study the effects of QH extract on primary intestinal tumors. RESULTS: QH extract exhibited significant in vitro anti-CRC activities evidenced by the inhibition of cell proliferation, perturbation of cell cycle progression, and induction of apoptosis. Mechanistically, QH extract significantly increased the stability of BIM proteins, which undergo rapid degradation under unstressed conditions. Knockdown of BAX, the downstream effector of BIM, significantly rescued QH-induced apoptosis. Furthermore, the in vitro effect of QH extract was recapitulated in vivo. QH extract significantly inhibited the tumor growth of HCT116 xenografts in nude mice and decreased the number of intestinal polyps in the APCMin+ mice. CONCLUSION: QH extract promotes the apoptosis of CRC cells by preventing the degradation of BIM.

Stiphodon chlorestes, a new species of sicydiine goby (Teleostei: Gobioidei) from Taiwan and Luzon.

Stiphodon chlorestes sp. nov. is described based on seven specimens collected from Taiwan and Luzon. It is a large-sized Stiphodon species sharing the second dorsal-fin rays 9-10 and pectoral-fin rays 14-16 with similar-sized congeners. However, it differs from them by the wider interorbital width and almost complete lack of scales on the occipital region in males. In addition, the new species can be further distinguished from all congeners by seven to eight oval bands or a black longitudinal band on the lower body, black and white spots on pectoral fins, and a short red or orange line on posterior upper edge of caudal fin. Molecular analysis based on the 680-bp mitochondrial cytochrome oxidase subunit I (COI) fragments also supports it as a distinct species belonging to the "Stiphodon elegans group" and a sister group of the clade consisting of Stiphodon multisquamus and Stiphodon palawanensis.

Palladium-Catalyzed Cycloaddition Reactions of π-Allylpalladium 1,4-Dipoles with 1,3,5-Triazinanes: Access to Hexahydropyrimidines, 1,3-Oxazinanes, and 1,5-Diazocanes.

Palladium-catalyzed decarboxylation of 5-methylene-1,3-oxazinan-2-ones and 5-methylene-1,3-dioxan-2-ones to generate aza-π-allylpalladium and oxa-π-allylpalladium 1,4-dipoles for [4 + 2] cycloaddition reaction with 1,3,5-triazinanes was developed, affording a wide range of hexahydropyrimidine and 1,3-oxazinane derivatives in good to excellent yields (up to 99%). The acyclic sulfonamido-substituted allylic carbonates as aza-π-allylpalladium 1,4-dipole precursors also apply to the developed synthesized strategy, achieving the synthesis of hexahydropyrimidines. Moreover, the in situ-generated aza-π-allylpalladium 1,4-dipoles undergoing dimeric [4 + 4] cycloaddition were also demonstrated by the construction of 1,5-diazocane derivatives.

Recent Advances in the Domino Annulation Reaction of Quinone Imines.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.