NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.

Neurotrophic receptor tyrosine kinase 3 (NTRK3) has pleiotropic functions: it acts not only as an oncogene in breast and gastric cancers but also as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas. However, the role of NTRK3 in upper tract urothelial carcinoma (UTUC) is not well documented. This study investigated the association between NTRK3 expression and outcomes in UTUC patients and validated the results in tests on UTUC cell lines. A total of 118 UTUC cancer tissue samples were examined to evaluate the expression of NTRK3. Survival curves were generated using Kaplan-Meier estimates, and Cox regression models were used for investigating survival outcomes. Higher NTRK3 expression was correlated with worse progression-free survival, cancer-specific survival, and overall survival. Moreover, the results of an Ingenuity Pathway Analysis suggested that NTRK3 may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer. NTRK3 downregulation in BFTC909 cells through shRNA reduced cellular migration, invasion, and activity in the AKT-mTOR pathway. Furthermore, the overexpression of NTRK3 in UM-UC-14 cells promoted AKT-mTOR pathway activity, cellular migration, and cell invasion. From these observations, we concluded that NTRK3 may contribute to aggressive behaviors in UTUC by facilitating cell migration and invasion through its interaction with the AKT-mTOR pathway and the expression of NTRK3 is a potential predictor of clinical outcomes in cases of UTUC.

Merit-Based Incentive Payment System: How Are Plastic Surgeons Performing?

PURPOSE: Merit-based incentive payment system (MIPS) is a payment model implemented to promote high-value care through performance-based adjustments of Medicare reimbursements. Higher scores indicate superior performance in healthcare quality, efficiency, and interoperability, which can result in financial advantages. Given the paucity of literature, we aimed to characterize plastic surgery performance in MIPS. METHOD: The Centers for Medicare and Medicaid Services (CMS) online data repository was queried for data on MIPS performance of plastic surgeons from 2019-2021. Descriptive analyses and multivariable logistic regression were conducted to identify predictors of receiving bonus payment for exceptional performance. RESULTS: Approximately 1400 surgeons were sampled in each year. The median number of Medicare beneficiaries and percent of dually eligible beneficiaries-eligible for Medicare and Medicaid-were higher in 2019 (p<0.001). Beneficiary median HCC risk score, which measures expected healthcare costs and needs based on health status, was lower in 2021 (p<0.001). The most common reporting schema was reporting as a group. Total MIPS score increased from 2019 to 2020 to 2021 (90.2 vs 96.4 vs 98.3, p<0.001), but quality score progressively decreased (98.8 vs 95.5 vs 89.90, p<0.001). Fewer physicians received positive adjustment and bonus payments in 2020 and 2021. Predictors of receiving bonus payments were reporting as an alternative payment model, practice size >24, and having 10-49% of dually eligible beneficiaries (p<0.05). CONCLUSION: Understanding performance of plastic surgeons in MIPS can guide future policy direction and ensure that high-quality care translates into improved patient outcomes across all fields and levels of social vulnerability.

Antibacterial activity of lysozyme after association with carboxymethyl konjac glucomannan.

The unique high isoelectric point of lysozyme (LYZ) restricts its application in composite antibacterial coating due to the unfavorable liability to electrostatic interaction with other components. In this work, the antibacterial activity of a dispersible LYZ-carboxymethyl konjac glucomannan (CMKGM) polyelectrolyte complex was evaluated. Kinetic analysis revealed that, compared with free LYZ, the complexed enzyme exhibited decreased affinity (Km) but markedly increased Vmax against Micrococcus lysodeikticus, and QCM and dynamic light scattering analysis confirmed that the complex could bind with the substrate but in a much lower ratio. The complexation with CMKGM did not alter the antibacterial spectrum of LYZ, and the complex exerted antibacterial function by delaying the logarithmic growth phase and impairing the cell integrity of Staphylococcus aureus. Since the LYZ-CMKGM complex is dispersible in water and could be assembled easily, it has great potential as an edible coating in food preservation.

Multifunctional Lipidated Protein Carrier with a Built-In Adjuvant as a Universal Vaccine Platform Potently Elevates Immunogenicity of Weak Antigens.

Weak antigens represented by MUC1 are poorly immunogenic, which greatly constrains the development of relevant vaccines. Herein, we developed a multifunctional lipidated protein as a carrier, in which the TLR1/2 agonist Pam3CSK4 was conjugated to the N-terminus of MUC1-loaded carrier protein BSA through pyridoxal 5'-phosphate-mediated transamination reaction. The resulting Pam3CSK4-BSA-MUC1 conjugate was subsequently incorporated into liposomes, which biomimics the membrane structure of tumor cells. The results indicated that this lipidated protein carrier significantly enhanced antigen uptake by APCs and obviously augmented the retention of the vaccine at the injection site. Compared with the BSA-MUC1 and BSA-MUC1 + Pam3CSK4 groups, Pam3CSK4-BSA-MUC1 evoked 22- and 11-fold increases in MUC1-specific IgG titers. Importantly, Pam3CSK4-BSA-MUC1 elicited robust cellular immunity and significantly inhibited tumor growth. This is the first time that lipidated protein was constructed to enhance antigen immunogenicity, and this universal carrier platform exhibits promise for utilization in various vaccines, holding the potential for further clinical application.

Effects of Reishimmune-S, a Fungal Immunomodulatory Peptide Supplement, on the Quality of Life and Circulating Natural Killer Cell Profiles of Patients With Early Breast Cancer Receiving Adjuvant Endocrine Therapy.

OBJECTIVES: To evaluate the effects of Reishimmune-S, a fungal immunomodulatory peptide, on the quality of life (QoL) and natural killer (NK) cell subpopulations in patients receiving adjuvant endocrine therapy (ET) for breast cancer (BC). METHODS: Patients who received adjuvant ET for stage I-III hormone receptor-positive BC without active infection were enrolled in this prospective pilot study. Reishimmune-S was administered sublingually daily for 6 months. QoL scores, circulating immune cell levels, including lymphocyte/NK cell subpopulations, and plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured at baseline and every 4 weeks. Data were analyzed using linear mixed-effect regression models. RESULTS: Nineteen participants were included in the analyses. One patient with underlying asthma did not complete the study owing to the occurrence of skin rashes 15 days after the initiation of Reishimmune-S. No other adverse events were reported. Reishimmune-S supplementation significantly improved the cognitive function at 3 months and significantly decreased the fatigue and insomnia levels at 3 and 6 months, respectively. There was no significant change in the global health/QoL score between baseline and week 4 of treatment. The proportion of CD19+ lymphocytes was significantly higher at 3 and 6 months, and that of NKG2A+ and NKp30+ NK cells was significantly lower at 6 months than at baseline. In addition, fatigue positively correlated with the proportion of NKp30+ NK cells (ß ± standard error: 24.48 ± 8.75, P = .007 in the mixed-effect model). CONCLUSIONS: Short-term supplementation with Reishimmune-S affected the circulating immune cell composition and exerted positive effects on cognitive function, fatigue, and insomnia in patients with BC undergoing adjuvant ET, providing a potential approach for the management of treatment-related adverse reactions in this patient population.

N-Heterocyclic Carbene-Catalyzed Formal Intramolecular [3 + 2] Annulations of Cyclohexadienone-Tethered Ynals.

A formal [3 + 2] annulation of cyclohexadienone-tethered ynals is enabled by an N-heterocyclic carbene (NHC) catalyst, affording a tricyclo[6.2.1.04,11]undecane framework. This study represents the first demonstration of using C═C double bonds as the reaction partner in the NHC-catalyzed annulation of ynals. This strategy is characterized by mild reaction conditions and 100% atom economy as well as high catalytic performance and efficiency.

Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.

The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.

Association between exposure to a mixture of organochlorine pesticides and hyperuricemia in U.S. adults: A comparison of four statistical models.

The association between the exposure of organochlorine pesticides (OCPs) and serum uric acid (UA) levels remained uncertain. In this study, to investigate the combined effects of OCP mixtures on hyperuricemia, we analyzed serum OCPs and UA levels in adults from the National Health and Nutrition Examination Survey (2005-2016). Four statistical models including weighted logistic regression, weighted quantile sum (WQS), quantile g-computation (QGC), and bayesian kernel machine regression (BKMR) were used to assess the relationship between mixed chemical exposures and hyperuricemia. Subgroup analyses were conducted to explore potential modifiers. Among 6,529 participants, the prevalence of hyperuricemia was 21.15%. Logistic regression revealed a significant association between both hexachlorobenzene (HCB) and trans-nonachlor and hyperuricemia in the fifth quintile (OR: 1.54, 95% CI: 1.08-2.19; OR: 1.58, 95% CI: 1.05-2.39, respectively), utilizing the first quintile as a reference. WQS and QGC analyses showed significant overall effects of OCPs on hyperuricemia, with an OR of 1.25 (95% CI: 1.09-1.44) and 1.20 (95% CI: 1.06-1.37), respectively. BKMR indicated a positive trend between mixed OCPs and hyperuricemia, with HCB having the largest weight in all three mixture analyses. Subgroup analyses revealed that females, individuals aged 50 years and above, and those with a low income were more vulnerable to mixed OCP exposure. These results highlight the urgent need to protect vulnerable populations from OCPs and to properly evaluate the health effects of multiple exposures on hyperuricemia using mutual validation approaches.

Promotion of 14-3-3ζ/Heme Oxygenase-1 Axis on Endotoxin-Induced Uveitis and Microglia Ferroptosis in Mice.

PURPOSE: Uveitis is a common, sight-threatening inflammatory ocular disease and is the main cause of blindness, which is caused by autoimmune response, infection, and injury. The contribution of 14-3-3ζ in uveitis remains obscure. This study aims to investigate the role of 14-3-3ζ in regulating ferroptosis in retinal inflammation and its contribution to uveitis. METHODS: A lipopolysaccharide (LPS)-induced uveitis mouse model and BV-2 cell line were used to examine the effect of LPS stimulation on the expression of 14-3-3ζ and ferroptosis in microglia. The expression of heme oxygenase-1 (HO-1) was also analyzed to understand its role in promoting microglial ferroptosis. RESULTS: We found that LPS stimulation increased the expression of 14-3-3ζ and promoted ferroptosis in microglia. Additionally, 14-3-3ζ was found to promote microglial ferroptosis by stabilizing the expression of HO-1. These findings suggest that the 14-3-3ζ/HO-1 axis plays a crucial role in promoting microglial ferroptosis in retinal inflammation. CONCLUSION: The study provides valuable insights into the mechanisms underlying uveitis and highlights the potential of the 14-3-3ζ/HO-1 axis as a therapeutic target for the disease. Further research in this area could lead to the development of preventive and therapeutic strategies for uveitis.

[Research progress on the role of microglia in sepsis-associated encephalopathy].

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by sepsis, which is characterized by decreased attention, directional impairment, being prone to irritation, and in severe cases the patient will experience drowsiness and coma. The pathogenesis of SAE mainly includes neuroinflammation, damage of blood-brain barrier, cerebral vascular dysfunction, and neurometabolic changes, among which neuroinflammation is the core pathological process. Microglia are considered to be important immune cells of the central nervous system and play an important role in neuroinflammation. This article systematically describes the role of microglia in the development of SAE, and discusses the phenotype and related signaling pathways of microglia, in order to clarify the role of microglia in SAE and provide a theoretical basis for clinical treatment of SAE.

Esophageal cancer screening, early detection and treatment: Current insights and future directions.

Esophageal cancer ranks among the most prevalent malignant tumors globally, primarily due to its highly aggressive nature and poor survival rates. According to the 2020 global cancer statistics, there were approximately 604000 new cases of esophageal cancer, resulting in 544000 deaths. The 5-year survival rate hovers around a mere 15%-25%. Notably, distinct variations exist in the risk factors associated with the two primary histological types, influencing their worldwide incidence and distribution. Squamous cell carcinoma displays a high incidence in specific regions, such as certain areas in China, where it meets the cost-effectiveness criteria for widespread endoscopy-based early diagnosis within the local population. Conversely, adenocarcinoma (EAC) represents the most common histological subtype of esophageal cancer in Europe and the United States. The role of early diagnosis in cases of EAC originating from Barrett's esophagus (BE) remains a subject of controversy. The effectiveness of early detection for EAC, particularly those arising from BE, continues to be a debated topic. The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses. In areas with higher incidences, such as China and Japan, early diagnosis is more common, which has led to the advancement of endoscopic methods as definitive treatments. These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality. Early screening, prompt diagnosis, and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.

Using machine learning to identify key subject categories predicting the pre-clerkship and clerkship performance: 8-year cohort study.

BACKGROUND: Medical students need to build a solid foundation of knowledge to become physicians. Clerkship is often considered the first transition point, and clerkship performance is essential for their development. We hope to identify subjects that could predict the clerkship performance, thus helping medical students learn more efficiently to achieve high clerkship performance. METHODS: This cohort study collected background and academic data from medical students who graduated between 2011 and 2019. Prediction models were developed by machine learning techniques to identify the affecting features in predicting the pre-clerkship performance and clerkship performance. Following serial processes of data collection, data pre-processing before machine learning, and techniques and performance of machine learning, different machine learning models were trained and validated using the 10-fold cross-validation method. RESULTS: Thirteen subjects from the pre-med stage and ten subjects from the basic medical science stage with an area under the ROC curve (AUC) greater than 0.7 for either pre-clerkship performance or clerkship performance were found. In each subject category, medical humanities and sociology in social science, chemistry and physician scientist-related training in basic science, and pharmacology, immunology-microbiology, and histology in basic medical science have predictive abilities for clerkship performance above the top tertile. Using a machine learning technique based on random forest, the prediction model predicted clerkship performance with 95% accuracy and 88% AUC. CONCLUSION: Clerkship performance was predicted by selected subjects or combination of different subject categories in the pre-med and basic medical science stages. The demonstrated predictive ability of subjects or categories in the medical program may facilitate students' understanding of how these subjects or categories of the medical program relate to their performance in the clerkship to enhance their preparedness for the clerkship.

Association of dietary intake of B vitamins with glaucoma.

This cross-sectional study investigated the association between glaucoma and B vitamin dietary intake. A total of 5025 enrolled individuals participated in self-reported glaucoma questionnaire and 3264 participated in International Society Geographical and Epidemiological Ophthalmology (ISGEO) criteria. In self-reported glaucoma, the risk of having self-reported glaucoma was lower in the third quartile of vitamin B1 intake (odds ratio [odds ratio [OR] 0.63, 95% confidence interval [CI] 0.40-0.97), and P trend (P trend = 0.004) for vitamin B12 was significant; in males, the third quartile of vitamin B1 intake (OR 0.44, 95% CI 0.24-0.83) and the fourth quartile of vitamin B2 intake (OR 0.39, 95% CI 0.17-0.89) were associated with a lower risk. In glaucoma based on ISGEO criteria, the increase of niacin intake (OR 0.94, 95% CI 0.89-0.99) was negatively associated with the odds of self-reported glaucoma. After sex-stratified analysis, the third quartile of vitamin B6 intake (OR 0.21, 95% CI 0.08-0.60) in males were associated with reduced odds of glaucoma. The restricted cubic spline analysis revealed a nonlinear association of vitamin B2 (p for nonlinearity = 0.04) and B9 (p for nonlinearity = 0.024) intake with glaucoma diagnosed by ISGEO criteria in females.

ODF3B affects the proliferation and apoptosis of glioma via the JAK/STAT pathway.

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.

Comprehensive evaluation of cytomorphologic, histologic, and molecular features of DICER1-altered thyroid lesions on FNA: A multipractice experience.

BACKGROUND: DICER1 mutations, though infrequent, are encountered on preoperative molecular testing of indeterminate adult and pediatric thyroid fine-needle aspiration (FNA) specimens. Yet, published cytomorphologic features of DICER1-altered thyroid lesions are limited. Cytomorphological features of DICER1-altered thyroid lesions were examined in a multipractice FNA cohort with clinical, radiological, and histologic data. METHODS: The cohort comprised 18 DICER1-altered thyroid FNAs, with 14 having slides available and eight having corresponding surgical resections. Smears, ThinPrep, and formalin-fixed cell block slides were reviewed and correlated with histology, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: Most DICER1-altered FNAs were classified as atypia of undetermined significance (94.4%). DICER1 mutations occurred in codons 1709 (50%), 1810 (27.8%), and 1813 (22.2%). One patient had an additional DICER1 p.D1822N variant in both of their FNAs. Lesions were often hypoechoic (35.3%) and solid (47.1%) on ultrasound. Notable cytomorphologic features include mixed but prominent microfollicular or crowded component, variable colloid, and insignificant nuclear atypia. On resection (n = 10), histologic diagnoses ranged from benign follicular adenoma and low-risk follicular thyroid carcinoma to high-grade follicular-derived nonanaplastic thyroid carcinoma. Subcapsular infarct-type change was the most common histologic change. There was no evidence of recurrence or metastasis in eight patients on limited follow-up. CONCLUSION: DICER1-altered thyroid lesions occurred frequently in young females and FNAs show RAS-like cytomorphology including crowded, mixed macro-/microfollicular pattern, and bland nuclear features. On resection, DICER1-altered thyroid lesions include benign (50%), low-risk lesions (30%), or high-risk malignancies (20%).

Circ-Bptf Ameliorates Learning and Memory Impairments via the miR-138-5p/p62 Axis in APP/PS1 Mice.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy.

Comparison of different medical treatments for primary hyperaldosteronism: a systematic review and network meta-analysis.

Background: The effectiveness and side effects between different medical treatments in patients with primary hyperaldosteronism have not been systematically studied. Objective: To analyze the efficacy between different mineralocorticoid receptor antagonists (MRAs) and epithelial sodium channel (ENaC) inhibitors in a network meta-analysis (NMA) framework, while also evaluating adverse events. Design: Systematic review and NMA. Data sources and methods: The systematic review and NMA was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, MEDLINE, the Cochrane library, and Excerpta Medica database (EMBASE) were searched for randomized controlled trials (RCTs) involving adult patients with primary hyperaldosteronism until 23 June 2023. Studies that compared the efficacy and side effects of different medical treatments of primary hyperaldosteronism were included. The primary outcomes included the effect on blood pressure, serum potassium, and major adverse cardiovascular events. The secondary outcomes were adverse events related to MRAs (hyperkalemia and gynecomastia). Frequentist NMA and pairwise meta-analysis were conducted. Results: A total of 5 RCTs comprising 392 participants were included. Eplerenone, esaxerenone, and amiloride were compared to spironolactone and demonstrated comparable effect on the reduction of systolic blood pressure. In comparison to spironolactone, eplerenone exhibited a less pronounced effect on reducing diastolic blood pressure [-4.63 mmHg; 95% confidence interval (CI): -8.87 to -0.40 mmHg] and correcting serum potassium (-0.2 mg/dL; 95% CI: -0.37 to -0.03 mg/dL). Spironolactone presented a higher risk of gynecomastia compared with eplerenone (relative risk: 4.69; 95% CI: 3.58-6.14). Conclusion: The present NMA indicated that the blood pressure reduction and potassium-correcting effects of the three MRAs may demonstrate marginal differences, with confidence levels in the evidence being very low. Therefore, further research is needed to explore the efficacy of these MRAs, especially regarding their impact on mortality and cardiovascular outcomes. Trial registration: PROSPERO (CRD: 42023446811).

Quantum spin liquid signatures in monolayer 1T-NbSe2.

Quantum spin liquids (QSLs) are in a quantum disordered state that is highly entangled and has fractional excitations. As a highly sought-after state of matter, QSLs were predicted to host spinon excitations and to arise in frustrated spin systems with large quantum fluctuations. Here we report on the experimental observation and theoretical modeling of QSL signatures in monolayer 1T-NbSe2, which is a newly emerging two-dimensional material that exhibits both charge-density-wave (CDW) and correlated insulating behaviors. By using scanning tunneling microscopy and spectroscopy (STM/STS), we confirm the presence of spin fluctuations in monolayer 1T-NbSe2 by observing the Kondo resonance as monolayer 1T-NbSe2 interacts with metallic monolayer 1H-NbSe2. Subsequent STM/STS imaging of monolayer 1T-NbSe2 at the Hubbard band energy further reveals a long-wavelength charge modulation, in agreement with the spinon modulation expected for QSLs. By depositing manganese-phthalocyanine (MnPc) molecules with spin S = 3/2 onto monolayer 1T-NbSe2, new STS resonance peaks emerge at the Hubbard band edges of monolayer 1T-NbSe2. This observation is consistent with the spinon Kondo effect induced by a S = 3/2 magnetic impurity embedded in a QSL. Taken together, these experimental observations indicate that monolayer 1T-NbSe2 is a new promising QSL material.