Validation Study of the Newly Proposed Refined Diagnostic Criteria for Malignant Phyllodes Tumor With 136 Borderline and Malignant Phyllodes Tumor Cases.

The World Health Organization (WHO) diagnostic criteria for malignant phyllodes tumor (MPT) may miss a significant number of MPTs with metastatic potential. New refined diagnostic criteria (Refined Criteria) for MPT were recently proposed. The aim of this study is to validate the Refined Criteria. This validation study included 136 borderline (borderline phyllodes tumor [BoPT]) and MPT cases that were not included in the initial study. We evaluated tumor classifications based on both the Refined Criteria and the WHO criteria. The Refined Criteria defines MPT when these criteria are met (1) stromal overgrowth with ≥ 1 feature(s) of marked stromal cellularity, marked stromal cytologic atypia, or ≥10 mitoses per 10 high-power fields (10 mitoses/10 HPFs) or (2) marked stromal cellularity with ≥1 feature(s) of marked stromal cytologic atypia, ≥10 mitoses/10 HPFs or permeative border. The WHO criteria require all 5 morphologic features (stromal overgrowth, permeative border, marked stromal cellularity, marked stromal cytologic atypia, and ≥10 mitoses/10 HPFs) for an MPT diagnosis. Using the Refined Criteria, none of the 61 BoPTs developed metastasis and 40.0% of the 75 MPTs developed metastases; local recurrence was seen in 11.5% BoPTs and 25.3% MPTs. Using the WHO criteria, 9.6% of the 94 BoPTs developed metastases and 50.0% of the 42 MPTs developed metastases; 14.9% of the BoPTs had local recurrence and 28.6% of the MPTs had local recurrence. Nine (30.0%) of the 30 tumors that developed distant metastases were diagnosed as BoPTs by the WHO criteria. When we combined the 75 MPTs from this validation cohort with the 65 MPT cases from the published data using the Refined Criteria, 50 (35.7%) of the 140 MPTs developed metastases, whereas 8 cases with metastases were <5 cm. In the univariate analysis with log-rank test, stromal overgrowth, marked stromal cellularity, marked stromal cytologic atypia, ≥10 mitoses/10 HPFs, presence of heterologous components other than liposarcomatous component, and presence of stromal necrosis were significantly associated with the risk of metastasis (all with P < 0.05). In multivariate analysis with Cox proportional hazard regression, stromal overgrowth and marked stromal cellularity were significantly associated with metastasis (both with P < 0.001). The Refined Criteria are superior to the WHO criteria in predicting the clinical outcomes of BoPTs and MPTs. Using the Refined Criteria, 35.7% of 140 patients with MPT developed metastases, whereas none (0%) of the patients with BoPT developed metastases. Patients with MPT have a high metastatic rate; these patients may benefit from systemic chemotherapy or targeted therapies. In contrast, patients with BoPT may be managed with complete local excision alone without chemotherapy.

Assessing potential benefits of visits to neighborhoods with higher tree canopy coverage using mobility data: Associations with cardiovascular health outcomes in twenty US metropolitan areas.

BACKGROUND: Research on health benefits due to exposure to green space, such as tree canopy coverage, has predominantly focused on canopy coverage in home neighborhoods. Yet exposures to tree canopy coverage in other spaces visited during the week or on weekends outside the home neighborhoods remains largely unexplored. OBJECTIVES: We examined whether differences in coverage levels of tree canopy in neighborhoods visited compared to home neighborhoods was associated with lower prevalence of coronary heart disease (CHD) and stroke, adjusting for exposure to home canopy coverage. We further investigated if the associations varied across levels of home canopy coverage, and if they were more pronounced on weekdays or weekends. METHODS: We used 2018 mobile phone data from the twenty largest U.S. Metropolitan Statistical Areas (MSAs). For each home census tract, we derived a weighted tree canopy coverage exposure from all visited tracts based on the proportion of visits to other tracts by home tract residents. We subtracted home canopy coverage from the weighted canopy coverage in each of the visited tracts to calculate tract-specific differences. We evaluated associations between differences in tree canopy coverage and prevalence of CHD and stroke via spatial error models, adjusting for tract-level home canopy coverage, MSA, socioeconomic and built environment characteristics. RESULTS: For every ten-percentage-point increase in tree canopy coverage in visited tracts relative to home tracts, there was a 0.32-0.34% decrease in stroke prevalence. Association with CHD prevalence was not observed after adjusting for spatial autocorrelation. Variations between weekdays and weekends were minimal. The difference in tree canopy coverage was associated with CHD prevalence only for home tracts with low tree canopy coverage, while the difference was associated with stroke prevalence across home tracts with low, moderate, and high tree canopy coverage, with diminishing effect size. DISCUSSION: This study identified that greater tree canopy coverage in visited neighborhoods relative to home neighborhoods was associated with lower stroke prevalence, and associations varied across home neighborhoods with different tree canopy coverage levels. It emphasized the need to factor in the neighborhood mobility networks in urban planning initiatives to promote cardiovascular health.

Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production.

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.

Multicenter propensity score-matched analysis to compare perioperative morbidity after laparoscopic or robotic complex hepatectomy for solitary hepatocellular carcinoma.

BACKGROUND: Postoperative complications are vital factors affecting the prognosis of patients with hepatocellular carcinoma (HCC), especially for complex hepatectomy. The present study aimed to compare perioperative complications between laparoscopic and robotic complex hepatectomy (LCH vs. RCH). METHODS: Patients with solitary HCC after complex hepatectomy were collected from a multicenter database. Propensity score-matched (PSM) analysis was adopted to control confounding bias. Multivariable analysis was performed to determine the prognostic factors. RESULTS: 436 patients were included. After PSM, 43 patients were included in both the LCH and RCH groups. The results showed that compared to LCH, RCH had lower rates of blood loss and transfusion, and lower postoperative 30-day and major morbidity, and post-hepatectomy liver failure (PHLF) (all P < 0.05). Additionally, the length of hospital stay was shorter in the RCH group (P = 0.026). Multivariable analysis showed RCH is an independent protective factor for reducing the 30-day morbidity, major morbidity and PHLF. CONCLUSION: RCH has advantages over LCH in the minimally invasive treatment of complex HCC, as it can reduce the incidence of postoperative morbidity. Therefore, RCH should be considered for patients with HCC who require complex hepatectomy.

The Relationship between physical activity, nutritional status, and sarcopenia in community- dwelling older adults with type 2 diabetes: a cross-sectional study.

AIM: This study was conducted in Urumqi, Xinjiang, to assess the prevalence of sarcopenia and to determine the relationship between physical activity, nutritional status, and sarcopenia among community-dwelling patients with type 2 diabetes mellitus. METHODS: Four hundred eight cases of older people patients with type 2 diabetes mellitus in the community in Urumqi, Xinjiang, from May to August 2022 were selected for a cross-sectional on-site survey, and general information questionnaires, clinical information surveys, physical function measurements, and criteria developed by the Asian sarcopenia working group in 2019 were selected for diagnosis of sarcopenia, and unifactorial and multifactorial binary Logistic regression were applied to analyze the influencing factors of T2DM combined with sarcopenia in patients with sarcopenia. RESULTS: Among the 408 patients, 84 (20.6%) had sarcopenia, with a prevalence of 12.6%, 32.1%, and 51.9% in those aged 60-70, 71- 80, and 81 or older respectively. The prevalence increased significantly with age. Adjusting for variables, the study found that FFM of the Left Leg (OR: 0.710, 95% CI: 0.612-0.804, P = 0.024), FFM of the Right Arm (OR: 0.710, 95% CI: 0.612-0.804, P < 0.001), Age (OR: 1.246, 95% CI: 1.031-1.505, P = 0.023), Fasting Blood Glucose (OR: 1.649, 95% CI: 1.066-2.550, P = 0.025), and Post-Prandial Blood Glucose (OR: 1.455, 95% CI: 0.999-2.118, P = 0.025) were independent associated factors. An increase in MNA score (OR: 0.398, 95% CI: 0.244-0.6500, P < 0.001), ASMI (OR: 0.000, 95% CI: 0.00-0.01, P < 0.001) walking energy expenditure (MET-min) (OR: 0.998, 95% CI: 0.996-0.999, P = 0.001) reduced the prevalence of sarcopenia. CONCLUSION: This study shows that increased age, increased skeletal muscle mass index, decreased right arm FFM, increased postprandial glucose, increased MNA scores, and increased walking energy expenditure (MET-min) were associated with type 2 diabetes with sarcopenia.

Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis.

Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIFf/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIFf/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.

Inhibition of CC chemokine receptor 1 ameliorates osteoarthritis in mouse by activating PPAR-γ.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage destruction and inflammation. CC chemokine receptor 1 (CCR1), a member of the chemokine family and its receptor family, plays a role in the autoimmune response. The impact of BX471, a specific small molecule inhibitor of CCR1, on CCR1 expression in cartilage and its effects on OA remain underexplored. METHODS: This study used immunohistochemistry (IHC) to assess CCR1 expression in IL-1ß-induced mouse chondrocytes and a medial meniscus mouse model of destabilization of the medial meniscus (DMM). Chondrocytes treated with varying concentrations of BX471 for 24 h were subjected to IL-1ß (10 ng/ml) treatment. The levels of the aging-related genes P16INK4a and P21CIP1 were analyzed via western blotting, and senescence-associated ß-galactosidase (SA-ß-gal) activity was measured. The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan (AGG), and the transcription factor SOX9 were determined through western blotting and RT‒qPCR. Collagen II, matrix metalloproteinase 13 (MMP13), and peroxisome proliferator-activated receptor (PPAR)-γ expression was analyzed via western blot, RT‒qPCR, and immunofluorescence. The impact of BX471 on inflammatory metabolism-related proteins under PPAR-γ inhibition conditions (using GW-9662) was examined through western blotting. The expression of MAPK signaling pathway-related molecules was assessed through western blotting. In vivo, various concentrations of BX471 or an equivalent medium were injected into DMM model joints. Cartilage destruction was evaluated through Safranin O/Fast green and hematoxylin-eosin (H&E) staining. RESULTS: This study revealed that inhibiting CCR1 mitigates IL-1ß-induced aging, downregulates the expression of iNOS, COX-2, and MMP13, and alleviates the IL-1ß-induced decrease in anabolic indices. Mechanistically, the MAPK signaling pathway and PPAR-γ may be involved in inhibiting the protective effect of CCR1 on chondrocytes. In vivo, BX471 protected cartilage in a DMM model. CONCLUSION: This study demonstrated the expression of CCR1 in chondrocytes. Inhibiting CCR1 reduced the inflammatory response, alleviated cartilage aging, and retarded degeneration through the MAPK signaling pathway and PPAR-γ, suggesting its potential therapeutic value for OA.

Basiliximab Treatment for Patients With Steroid-Refractory Acute Graft-Versus-Host Disease Following Matched Sibling Donor Hematopoietic Stem Cell Transplantation.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III-IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67-3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%-72.2%) and 55.4% (95% CI = 44.3%-69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%-29.5%) and 33.8% (95% CI = 21.8%-45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

Efficacy and Postoperative Infection following Super Mini Percutaneous Nephrolithotomy versus Flexible Ureteroscopy for Diabetic Nephrolithiasis: A Comparative Analysis and Risk Factors for Postoperative Infectious Complications.

OBJECTIVE: To compare the efficacy and postoperative infection rate of super mini percutaneous nephrolithotomy(SMP) and flexible ureteroscopic lithotripsy(FURL) in patients with diabetic nephrolithiasis, and to explore the risk factors associated with postoperative infection following these two procedures. METHODS: The medical history and surgery details of 252 patients with diabetic nephrolithiasis who underwent lithotripsy in our hospital between January 2018 and May 2023, including 144 SMP and 108 FURL, were reviewed and compared. Perioperative outcomes were compared between the two groups. Logistic regression was performed to identify the significant risk factors for infection after each procedure(SMP and FURL). RESULTS: SMP achieved a higher stone-free rate (SFR) on postoperative day 1(POD-1) and postoperative day 30(POD-30) compared to FURL(p<0.05). The mean operative time was shorter in SMP (p<0.01). FURL was associated with less hemoglobin drop (p<0.01) and shorter length of stay (p<0.01). The incident rate of systemic inflammatory response syndrome(SIRS) was higher after SMP (p=0.019), while the incident rate of urinary tract infection(UTI) was higher after FURL (p=0.021). Overall postoperative infection and sepsis rates were similar between the two procedures. Logistic regression analysis revealed that gender (OR: 0.225, 95% CI: 0.079-0.639), HbA1c (OR: 3.516, 95% CI: 1.841-6.716), and operation time (OR: 1.037, 95% CI: 1.008-1.066) were independent risk factors for infection after FURL, while operation time (OR: 1.063, 95% CI: 1.022-1.106) and HbA1c (OR: 7.443, 95% CI: 2.956-18.742) significantly predicted SMP-associated infections. CONCLUSION: In diabetic patients, SMP demonstrated higher SFR and shorter operation time, while FURL was associated with less bleeding and shorter hospitalization. SMP had a higher incident rate of SIRS and FURL had a higher incident rate of UTI. Elevated HbA1c and prolonged operative duration increased infection risk after both procedures, while male gender was an additional risk factor for FURL-related infections.

Development of a Non-Target Screening and Quantitative Analysis Strategy Based on UPLC-Q-TOF/MS and UPLC-QQQ/MS to Improve the Quality Control of Wuling Capsule.

Herbal medicine has been widely valued because of its remarkable efficacy and minimal side effects. The quantitative analysis of herbal medicines is essential to ensure their safety and efficacy. The simultaneous detection of multiple quality markers (Q-markers) has emerged as an important approach and trend in herbal medicine quality control. In recent years, non-targeted screening has become an effective strategy for the discovery and identification of unknown compounds. This study developed a non-targeted screening and quantitative analysis strategy to discover, identify and quantify the multiple components that truly represent the efficacy of Wuling capsule. Within this strategy, 18 types of flavonoids were tentatively discovered and identified from Wuling capsule by analyzing mass cleavage pathways, the precise molecular weights of compounds, and comparing the data with a database. Ten types of flavonoids were determined after the comparison of the standards. Additionally, following the evaluation of the regression equation, linear range, limit of detection (LOD), limit of quantitation (LOQ), precision, repeatability, and recovery of the proposed quantitative method, six flavonoids were quantified. This method successfully screened, identified, and quantified the potential active components in Wuling capsule, providing insights for improving the quality control standards in other herbal medicines.

Corrigendum: Ultrasound-based radiomics analysis for differentiating benign and malignant breast lesions: from static images to CEUS video analysis.

[This corrects the article DOI: 10.3389/fonc.2022.951973.].

Enhanced Prostate-specific Membrane Antigen Targeting by Precision Control of DNA Scaffolded Nanoparticle Ligand Presentation.

Targeted nanoparticles have been extensively explored for their ability to deliver their payload to a selective cell population while reducing off-target side effects. The design of actively targeted nanoparticles requires the grafting of a ligand that specifically binds to a highly expressed receptor on the surface of the targeted cell population. Optimizing the interactions between the targeting ligand and the receptor can maximize the cellular uptake of the nanoparticles and subsequently improve their activity. Here, we evaluated how the density and presentation of the targeting ligands dictate the cellular uptake of nanoparticles. To do so, we used a DNA-scaffolded PLGA nanoparticle system to achieve efficient and tunable ligand conjugation. A prostate-specific membrane antigen (PSMA) expressing a prostate cancer cell line was used as a model. The density and presentation of PSMA targeting ligand ACUPA were precisely tuned on the DNA-scaffolded nanoparticle surface, and their impact on cellular uptake was evaluated. It was found that matching the ligand density with the cell receptor density achieved the maximum cellular uptake and specificity. Furthermore, DNA hybridization-mediated targeting chain rigidity of the DNA-scaffolded nanoparticle offered ∼3 times higher cellular uptake compared to the ACUPA-terminated PLGA nanoparticle. Our findings also indicated a ∼ 3.7-fold reduction in the cellular uptake for the DNA hybridization of the non-targeting chain. We showed that nanoparticle uptake is energy-dependent and follows a clathrin-mediated pathway. Finally, we validated the preferential tumor targeting of the nanoparticles in a bilateral tumor xenograft model. Our results provide a rational guideline for designing actively targeted nanoparticles and highlight the application of DNA-scaffolded nanoparticles as an efficient active targeting platform.

Protective Effect of Curcumin on the Tight Junction Integrity and Cellular Senescence in Human Retinal Pigment Epithelium of Early Diabetic Retinopathy.

Diabetic retinopathy (DR) is a secondary complication of diabetes that can lead to visual impairment and blindness. The retinal pigment epithelium (RPE) is a monolayer of pigment cells that forms the blood-retinal barrier (BRB) via tight junction (TJ) proteins and plays a crucial role in the physiological function of the retina. Hyperglycemia induces RPE death and BRB breakdown, which accelerates the process of DR. Curcumin, an active extract of Curcuma longa , has anti-inflammatory, antioxidant, antiapoptotic, and neuroprotective properties. However, the effect of Curcumin on the BRB under high glucose conditions remains unknown. This study aimed to investigate the protective effects of Curcumin on RPE physiology in vitro and in vivo . Curcumin significantly alleviated cell viability inhibition under high glucose conditions. Moreover, high glucose reduced extracellular signal-regulated kinase and Akt pathways activation to diminish RPE cell growth but reversed by Curcumin treatment. Curcumin protected not only TJ integrity but also retinoid regeneration through TJ proteins and isomerase modulation in diabetic retina. Furthermore, Curcumin decreased the expression of angiogenic factor to inhibit retinal neovascularization. Finally, Curcumin treatment markedly reduced apoptosis during hyperglycemia. In conclusion, Curcumin can alleviate the progression of DR by promoting RPE survival, TJ integrity, retinoid isomerase activity, RPE senescence inhibition, and neovascularization. Therefore, Curcumin exhibits high potential for use as a therapeutic agent for early DR.

Association of podocyte ultrastructural changes with proteinuria and pathological classification in type 2 diabetic nephropathy.

AIMS: Podocyte injury plays an essential role in the progression of diabetic nephropathy (DN). The associations between the ultrastructural changes of podocyte with proteinuria and the pathological classification of DN proposed by Renal Pathology Society (RPS) have not been clarified in patients with type 2 diabetic nephropathy (T2DN). METHODS: We collected 110 patients with kidney biopsy-confirmed T2DN at Peking University First Hospital from 2017 to 2022. The morphometric analysis on the podocyte foot process width (FPW) and podocyte detachment (PD) as markers of podocyte injury was performed, and the correlations between the ultrastructural changes of podocytes with severity of proteinuria and the RPS pathological classification of DN were analyzed. RESULTS: Mean FPW was significantly broader in the group of T2DN patients with nephrotic proteinuria (565.1 nm) than those with microalbuminuria (437.4 nm) or overt proteinuria (494.6 nm). The cut-off value of FPW (> 506 nm) could differentiate nephrotic proteinuria from non-nephrotic proteinuria with a sensitivity of 75.3% and a specificity of 75.8%. Percentage of PD was significantly higher in group of nephrotic proteinuria (3.2%) than that in microalbuminuria (0%) or overt proteinuria (0.2%). FPW and PD significantly correlated with proteinuria in T2DN (r = 0.473, p < 0.001 and r = 0.656, P < 0.001). FPW and PD correlated with RPS pathological classification of T2DN (r = 0.179, P = 0.014 and r = 0.250, P = 0.001). FPW value was increased significantly with more severe DN classification (P for trend =0.007). The percentage of PD tended to increase with more severe DN classification (P for trend = 0.017). CONCLUSIONS: Podocyte injury, characterized by FPW broadening and PD, was associated with the severity of proteinuria and the pathological classification of DN.

Association between serum vitamin E and bacterial vaginitis in women: a cross-sectional study.

INTRODUCTION: Bacterial vaginitis (BV) is a common vaginal disease. Vitamin E has been shown to reduce BV by enhancing immune function, but no studies have analyzed the relationship between vitamin E and BV at different BMIs and ages. METHOD: This study used 2242 participants from four cycles of NHANES 1999-2006 in American. Participants' vitamin E levels were divided into four groups, and analyses such as study population description, stratified analysis, multiple logistic regression analysis, and curve fitting were performed. To perform data processing, the researchers used the statistical package R (The R Foundation; http://www.r-project.org ; version 3.6.3) and Empower Stats software ( www.empowerstats.net , X&Y solutions, Inc. Boston, Massachusetts). RESULT: The concentrations of serum vitamin E were negatively correlated with the risk of BV, especially when vitamin E were at 1198-5459ug/dL with (OR = -0.443, 95%CI = 0.447-0.923, P = 0.032) or without (OR = -0.521, 95%CI = 0.421-0.837, P = 0.006) adjustment for variables. At the same time, at lower levels, there was no significant association. Vitamin E supplementation may significantly reduce the risk of BV (p < 0.001). In addition, the risk of having BV decreased and then increased with increasing vitamin E concentrations at high BMI levels (p < 0.01). CONCLUSION: Vitamin E at moderate to high concentrations may significantly reduce BV risk, says the study, providing clinical evidence for the prevention and the treatment of BV.

Mechanism of Guigan Longmu Decoction in the Treatment of Arrhythmias Based on Network Pharmacology and Untargeted Metabolomics Assays.

BACKGROUND: Guigan longmu decoction (GGLM), a traditional Chinese medicine compound, has demonstrated efficacy in treating rapid arrhythmia clinically. Nevertheless, its mechanism of action remains elusive. This study aims to elucidate the molecular mechanism underlying the efficacy of GGLM in treating arrhythmia utilizing non-targeted metabolomics, widely-targeted metabolomics, and network pharmacology, subsequently validated through animal experiments. METHODS: Initially, network pharmacology analysis and widely-targeted metabolomics were performed on GGLM. Subsequent to that, rats were administered GGLM intervention, and nontargeted metabolomics assays were utilized to identify metabolites in rat plasma postadministration. The primary signaling pathways, core targets, and key active ingredients of GGLM influencing arrhythmia were identified. Additionally, to validate the therapeutic efficacy of GGLM on arrhythmia rat models, a rat model of rapid arrhythmia was induced via subcutaneous injection of isoproterenol, and alterations in pertinent pathogenic pathways and proteins in the rat model were assessed through qRT-PCR and Western blot following GGLM administration. RESULTS: The results of network pharmacology showed that 99 active ingredients in GGLM acted on 249 targets and 201 signaling pathways, which may be key to treating arrhythmia. Widelytargeted metabolic quantification analysis detected a total of 448 active ingredients in GGLM, while non-targeted metabolomics identified 279 different metabolites and 10 major metabolic pathways in rats. A comprehensive analysis of the above results revealed that the core key active ingredients of GGLM in treating arrhythmia include calycosin, licochalcone B, glabridin, naringenin, medicarpin, formononetin, quercetin, isoliquiritigenin, and resveratrol. These active ingredients mainly act on the relevant molecules and proteins upstream and downstream of the MAPK pathway to delay the onset of arrhythmia. Animal experimental results showed that the heart rate of rats in the model group increased significantly, and the mRNA and protein expression of p38, MAPK, JNK, ERK, NF-kb, IL-1ß, and IL-12 in myocardial tissue also increased significantly. However, after intervention with GGLM, the heart rate of rats in the drug group decreased significantly, while the mRNA and protein expression of p38 MAPK, JNK, ERK1, NF-kb, IL-1ß, and IL-12 in myocardial tissue decreased significantly. CONCLUSION: GGLM, as an adjunctive therapy in traditional Chinese medicine, exhibits favorable therapeutic efficacy against arrhythmia. This can be attributed to the abundant presence of bioactive compounds in the formulation, including verminin, glycyrrhizin B, glabridine, naringenin, ononin, quercetin, isorhamnetin, and kaempferol. The metabolites derived from these active ingredients have the potential to mitigate myocardial inflammation and decelerate heart rate by modulating the expression of proteins associated with the MAPK signaling pathway in vivo.

BRAF-V600E mutations in plasma and peripheral blood mononuclear cells correlate with prognosis of pediatric Langerhans cell histiocytosis treated with first-line therapy.

BACKGROUND: The clinical relevance of BRAF-V600E alleles in peripheral blood mononuclear cells (PBMCs) and the prognostic impact of the mutants in cell-free (cf) and PBMC DNAs of Langerhans cell histiocytosis (LCH) have not been fully clarified in pediatric LCH. METHODS: We retrospectively determined the levels of BRAF-V600E mutation in paired plasma and PBMC samples at the time of diagnosis of LCH. Subsequently, we performed a separate or combined analysis of the clinical and prognostic impact of the mutants. RESULTS: We assessed BRAF-V600E mutation in peripheral blood from 94 patients of childhood LCH. Our data showed that cfBRAF-V600E was related to young age, multiple-system (MS) disease, involvements of organs with high risk, increased risk of relapse, and worse progression-free survival (PFS) of patients. We also observed that the presence of BRAF-V600E in PBMCs at baseline was significantly associated with MS LCH with risk organ involvement, younger age, and disease progression or relapse. The coexisting of plasma(+)/PBMC(+) identified 36.2% of the patients with the worst outcome, and the hazard ratio was more significant than either of the two alone or neither, indicating that combined analysis of the mutation in plasma and PBMCs was more accurate to predict relapse than evaluation of either one. CONCLUSIONS: Concurrent assessment of BRAF-V600E mutation in plasma and PBMCs significantly impacted the prognosis of children with LCH. Further prospective studies with larger cohorts need to validate the results of this study.

Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives.

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

Care needs for urinary incontinence in older adults: Latent profile analysis.

AIM: This study utilized latent profile analysis to investigate care needs subgroups among older adults with urinary incontinence. METHODS: The "Elderly Urinary Incontinence Care Needs Inventory" surveyed 510 participants in two Guangzhou City hospitals from July 2022 to June 2023. Latent profile analysis created a classification model, and variance and correlation analysis assessed influencing factors. RESULTS: A total of 510 older adults with urinary incontinence participated. The standardized total care needs score was 78.77 ± 5.03, with variations across dimensions: social participation needs scored (71.16 ± 10.32), daily life care needs (78.80 ± 5.51), medical care needs (77.33 ± 12.17), psychological comfort needs (76.97 ± 6.51) and health education needs scored highest (82.67 ± 6.77). Three distinct profiles emerged: "medium," "high SPN-PCN" and "high DLCN-MCN-HEN". The majority belonged to the "high SPN-PCN" profile. Significant correlations were found with age, education, leaks and frequency of micturitions. CONCLUSION: Research findings showed the existence of three distinct categories, with a notable majority of participants belonging to the "high SPN-PCN" group. The significance of having these classes identified lies in the move away from a one-size-fits-all approach to a more nuanced understanding of care needs. Customized nursing interventions can be devised based on specific factors, such as age, education level, urinary incontinence-related symptoms and potential category. For instance, for the "high SPN-PCN" group, our nursing strategy can encompass heightened psychological support and expanded opportunities for social engagement.Furthermore, in the training and education of healthcare professionals, recognizing and meeting the needs of each potential category of older adults might require more attention. Geriatr Gerontol Int 2024; ••: ••-••.

Intermittent hydroxylamine dosing to strengthen stability of partial nitrification and nitrogen removal efficiency through continuous-flow anaerobic-aerobic-anoxic reactor treating municipal wastewater.

Intermittent hydroxylamine (NH2OH) dosing strategy was applied to enhance the stability of partial nitrification and total nitrogen (N) removal efficiency (TNRE) in a continuous-flow process. The results showed 2 mg/L of NH2OH dosing (once every 6 h) could maintain stably partial nitrification with nitrite accumulation rate (NAR) of 91.6 % and TNRE of 92.6 %. The typical cycle suggested NH2OH dosing could promote simultaneous nitrification-denitrification (SND) and endogenous denitrification (END) while inhibit exogenous denitrification (EXD). Nitrification characteristics indicated the NH2OH dosing enhanced stability of partial nitrification by suppressing specific nitrite oxidation rate (SNOR), Nitrospira and nitrite oxidoreductase enzyme (Nxr). The microbial community suggested the aerobic denitrfiers, denitrifying glycogen accumulating organisms (DGAOs) and traditional denitrfiers were the potential contributor for advanced N removal. Moreover, NH2OH dosage was positively associated with NAR, SND and END. Overall, this study offers a feasible strategy to maintain sustainably partial nitrification that has great application potential.