Nanoparticle-enhanced postbiotics: Revolutionizing cancer therapy through effective delivery.

AIM: Gastric cancer contributes to cancer-related fatalities. Conventional chemotherapy faces challenges due to severe adverse effects, prompting recent research to focus on postbiotics, which are safer biomolecules derived from nonviable probiotics. Despite promising in vitro results, efficient in vivo delivery systems remain a challenge. This study aimed to design a potential nanoparticle (NP) formulation encapsulating the Lacticaseibacillus paracasei GMNL-133 (SGMNL-133) isolate to enhance its therapeutic efficacy in treating gastric cancer. MAIN METHODS: We successfully isolated GMNL-133 (SGMNL-133) by optimizing the lysate extraction and column elution processes for L. paracasei GMNL-133, resulting in substantial enhancement of its capacity to inhibit the proliferation of gastric cancer cells. Additionally, we developed a potential NP utilizing arginine-chitosan and fucoidan encapsulating SGMNL-133. KEY FINDINGS: This innovative approach protected the SGMNL-133 from degradation by gastric acid, facilitated its penetration through the mucus layer, and enabled interaction with gastric cancer cells. Furthermore, in vivo experiments demonstrated that the encapsulation of SGMNL-133 in NPs significantly enhanced its efficacy in the treatment of orthotopic gastric tumors while simultaneously reducing tissue inflammation levels. SIGNIFICANCE: Recent research highlights postbiotics as a safe alternative, but in vivo delivery remains a challenge. Our study optimized the extraction of the lysate and column elution of GMNL-133, yielding SGMNL-133. We also developed NPs to protect SGMNL-133 from gastric acid, enhance mucus penetration, and improve the interaction with gastric cancer cells. This combination significantly enhanced drug delivery and anti-gastric tumor activity.

Targeting nanoparticle-conjugated microbubbles combined with ultrasound-mediated microbubble destruction for enhanced tumor therapy.

The stress of the abnormal stromal matrix of solid tumors is a major limiting factor that prevents drug penetration. Controlled, accurate, and efficient delivery of theranostic agents into tumor cells is crucial. Combining ultrasound with nanocarrierbased drug delivery systems have become a promising approach for targeted drug delivery in preclinical cancer therapy. In this study, to ensure effective tumor barrier penetration, access to the tumor microenvironment, and local drug release, we designed targeted nanoparticle (NP)-conjugated microbubbles (MBs); ultrasound could then help deliver acoustic energy to release the NPs from the MBs. The ultrasound-targeted MB destruction (UTMD) system of negatively charged NPs was conjugated with positively charged MBs using an ionic gelation method. We demonstrated the transfer of targeted NPs and their entry into gastric cancer cells through ligand-specific recognition, followed by enhanced cell growth inhibition owing to drug delivery-induced apoptosis. Moreover, the UTMD system combining therapeutic and ultrasound image properties can effectively target gastric cancer, thus significantly enhancing antitumor activity, as evident by tumor localization in an orthotopic mouse model of gastric cancer. The combination of ultrasound and NP-based drug delivery systems has become a promising approach for targeted drug delivery in preclinical cancer therapy.

Population attributable fraction based on marginal sufficient component cause model for mediation settings.

PURPOSE: Population attributable fraction (PAF), defined as the proportion of the occurrence of a disease which will be reduced by eliminating risk factors in a population, is one of the most common measurements for evaluating the benefit of a health-related policy in epidemiologic study. In this article, we propose an alternative PAF defined based on sufficient cause framework, which decompose the occurrence of a disease into several pathways including mediation and mechanistic interaction. METHODS: We propose a formal statistical definition and regression-based estimator for PAF based on sufficient cause framework within mediation settings. Under monotonicity assumption, the proposed method can decompose the occurrence of a disease into nine PAFs corresponding to all types of mechanisms attributing to exposure and the mediator, including the portion attributing to exposure directly, to mediator, to indirect effect through mediator, to the mechanistic interaction, to both of mediation and interaction, and to none of exposure or mediator. RESULTS: We apply the proposed method to explore the mechanism of a hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) mediated by and/or interacted with alanine aminotransferase (ALT) and hepatitis B virus (HBV). When treating ALT as mediator, 56.77% of diseased subjects can be attributable to either HCV or abnormal ALT. When treating HBV as mediator, HCC is mainly induced by an exogenous high HBV viral load directly. CONCLUSIONS: The proposed method can identify the impact of exposure and pathway effects, and benefit to allocate the resources on intervention strategies.

Aldosterone-producing nodules and CYP11B1 signaling correlate in primary aldosteronism.

Autonomous cortisol secretion (ACS) could be found in some patients with unilateral primary aldosteronism (uPA). However, the histopathological patterns of uPA with concurrent ACS have not been well elucidated. The adrenal gland with the adenoma from 61 uPA patients who underwent unilateral adrenalectomy were assessed by immunohistochemistry. Bioinformatics analysis, including the Cancer Genome Atlas (TCGA) and Kyoto Encyclopedia of Genes and Genomes, was applied. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% (40/61) among our uPA patients. Concurrent ACS was identified in 32% of this uPA cohort; they were associated with the interaction of larger tumor size (>1.98 cm) and mAPN/mAPM (odds ratio = 3.08, P = 0.004). Transcriptome analysis uncovered a dominant enrichment of HSD3B7 overexpression (P = 0.004) in the adenomas of the histopathologically classical adrenal uPA lesions with concomitant mAPN/mAPM, compared with those uPA adenomas without concurrent surrounding mAPN/mAPM. We identified a novel linkage of enhanced steroidogenic genes of HSD3B7 expression concurrent with the downstream higher CYP11B1 expression; further relationship was confirmed by immunohistochemical staining and validated by TCGA bioinformatics. The presence of mAPN/mAPM in uPA patients had lower rate for biochemical success after adrenalectomy (P = 0.047). In summary, two-thirds of uPA patients had concomitant mAPN/mAPM; 1/3 of uPA patients had concurrent ACS. Steroidogenic HSD3B7/CYP11B1 signaling was associated with uPA adenomas with surrounding mAPN/mAPM. Interaction of larger adenoma size with the presence of mAPN/mAPM was linked to co-existing ACS. Such uPA patients with concomitant mAPN/mAPM had lower rate of biochemical success.

Stochastic approach for mechanistic interaction under longitudinal studies with noninformative right censoring.

Characterizing the mechanistic interactions between exposures and diseases is one of the most critical issues in epidemiologic studies. Previous studies have proposed a stochastic sufficient component cause framework, under which each sufficient cause is treated as a stochastic process instead of a time-invariant random variable. However, different types of mechanistic interactions such as synergism and agonism cannot be further identified. In this study, we proposed a stochastic marginal sufficient component cause model to conceptualize and identify agonism and synergism by exploiting the additional information. We further provided six approaches to identify and estimate agonism and synergism based on an additive hazard model and a complementary log model. Researchers can easily adjust confounding factors by including appropriate covariates into a regression model. Simulations have proven that approaches under three models are all valid tests. The power of an additive hazard model increases as the total follow-up time increases and is higher than that of the other two models. We applied this method to a Taiwanese cohort data set to investigate the mechanistic interaction among hepatitis B and C viruses on the incidence of hepatocellular carcinoma. The hazard of people with agonistic interaction is 1.28×10-5 (95% CI: 6.97×10-6 , 1.87×10-5 ), and the cumulative hazard of those people is 7.41×10-2 (95% CI: 4.09×10-2 , 1.07×10-1 ), which is approximately 3.5 times stronger than that of synergistic interaction. The proposed method makes it possible to quantify different types of mechanistic interactions in longitudinal studies with censored data.

Cumulative experience of preoperative real-time augmented fluoroscopy-guided endobronchial dye marking for small pulmonary nodules: An analysis of 30 initial patients.

BACKGROUND/PURPOSE: Cone-beam computed tomography-derived augmented fluoroscopy (CBCT-AF) for use in guiding endobronchial dye marking of small pulmonary nodules prior to thoracoscopic surgery is still under development. We sought to evaluate the effect of the cumulative experience on procedural parameters of CBCT-AF-guided endobronchial dye marking for preoperative localization of small pulmonary nodules. METHODS: Clinical variables and treatment outcomes of the 30 initial patients with small pulmonary nodules who were managed with CBCT-AF-guided endobronchial dye marking followed by thoracoscopic resection in our institution were analyzed. Two sequential groups of patients (group I and group II, n = 15 each) were compared with regard to localization time and radiation doses. The Mann-Whitney U test and chi-square test or Fisher exact test were used in the statistical analyses. RESULTS: In the entire cohort, the median size of solitary pulmonary nodules on preoperative computed tomography (CT) images was 9.3 mm (interquartile range, 7.4-13.6 mm), and their median distance from the pleural surface was 15.2 mm (interquartile range, 10.3-27.1 mm). The median tumor depth-to-size ratio was 1.6 (interquartile range, 1.1-2.3). A significant reduction in single DynaCT radiation (3690.4 versus [vs.] 1132.3 µGym2; P < 0.001) and total radiation exposure (median, 4878.8 vs. 1673.8 µGym2; P < 0.001) was noted in group II (late patients) compared with group I. CONCLUSION: Our initial results of CBCT-AF-guided lung marking demonstrate that the cumulative experience with several technical modifications can achieve the same purpose of endobronchial localization with less procedure-related radiation exposure.

Hemojuvelin Predicts Acute Kidney Injury and Poor Outcomes Following Cardiac Surgery.

Acute kidney injury (AKI) is detrimental after cardiac surgery. In this multicenter study, the novel biomarker hemojuvelin (HJV) was evaluated for AKI prediction following cardiac surgery. Urinary HJV, neutrophil gelatinase-associated lipocalin (NGAL), and urinary creatinine were measured in 151 patients after surgery. The outcomes of advanced AKI (KDIGO stages 2 and 3) and all causes of in-hospital mortality as the composite outcome were recorded. Areas under the receiver operator characteristic curves (AUC) and a multivariate generalized additive model (GAM) were applied to predict these outcomes of interest. Urinary HJV differentiated patients with/without AKI, advanced AKI or composite outcome after surgery (p < 0.001, by a generalized estimating equation) in this study. At three hours post-surgery, urinary HJV predicted advanced AKI (p < 0.001) and composite outcome (p < 0.001) with corresponding AUC values of 0.768 and 0.828, respectively. The performance of creatinine-adjusted HJV was also superior to NGAL in predicting advanced AKI (AUC = 0.784 and 0.694; p = 0.037) and composite outcome (AUC = 0.842 and 0.676; p = 0.002). The integration of HJV into the Cleveland Clinic score for advanced AKI led to a significant increase in risk stratification (net reclassification improvement [NRI] = 0.598; p < 0.001).

Development of chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles in chitosan dressings for wound regeneration.

The hydrophobic polyphenol curcumin has anti-inflammatory, antimicrobial, and wound-healing properties that warrant its pharmacological consideration. We report a curcumin nanoparticle with a tripolymeric composite that can be used as a delivery device for wound healing. The present composite nanoparticles were prepared with three biocompatible polymers of chitosan, poly-γ-glutamic acid, and pluronic using a simple ionic gelation technology. Pluronic was used to enhance the solubility of curcumin in chitosan/poly-γ-glutamic acid nanoparticles, leading to the incorporation of chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles into chitosan membranes, and reduced inflammation and bacterial infection during wound regeneration. Nanoparticles were of 193.1 ± 8.9 nm and had a zeta potential of 20.6 ± 2.4 mV. Moreover, in vitro analyses indicated controlled curcumin release in a simulated skin tissue model. Subsequent in vivo studies show that chitosan wound dressing containing chitosan/poly-γ-glutamic acid/pluronic/curcumin nanoparticles promoted neocollagen regeneration and tissue reconstruction. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 81-90, 2017.

Laparoscopic percutaneous jejunostomy with intracorporeal V-Loc jejunopexy in esophageal cancer.

BACKGROUND: Barbed sutures are widely used in various laparoscopic digestive surgeries. The purpose of this paper is to present our initial experience of laparoscopic percutaneous jejunostomy with unidirectional barbed sutures in esophageal cancer patients and compare it with our early cases using traditional transabdominal sutures. METHODS: A total of 118 esophageal cancer patients who underwent laparoscopic percutaneous jejunostomy were identified in a single institution in Taiwan from June 2014 to May 2016. The authors' traditional technique consisted of using transabdominal sutures with bolsters to fix a jejunum loop onto the anterior abdominal wall. A novel technique was introduced using intracorporeal suturing with knotless unidirectional barbed monofilament absorbable sutures (V-Loc) to attain a seal around the feeding catheter. A comparison between these two techniques was performed. RESULTS: Twenty cases with barbed V-Loc sutures and 98 cases with transabdominal sutures were identified. The V-Loc sutures appeared to reduce peristomal skin ulcers (19.4 vs. 0 %, p = 0.040), postoperative pain scores during the first 24 h (1.8 ± 1.4 vs. 0.9 ± 1.1, p = 0.007) and on postoperative day 2 (1.7 ± 1.4 vs. 1.0 ± 0.8, p = 0.026) when compared to patients receiving transabdominal sutures. The mean suturing time using V-Loc sutures was 22 min (14-60 min). The mean onset to resumption of enteral feeding was 1.8 ± 0.8 days and the mean duration of postoperative hospital stay was 8 ± 5.1 days, both of which were comparable in the two groups. There was no surgical mortality in our series. CONCLUSIONS: In the study cohort, the use of knotless unidirectional barbed sutures instead of traditional transabdominal sutures had similar outcomes and appears to be a feasible option for intracorporeal jejunopexy when performing laparoscopic jejunostomy in patients with esophageal cancer.

Nanoparticle Targeting CD44-Positive Cancer Cells for Site-Specific Drug Delivery in Prostate Cancer Therapy.

Prostate cancer is one of the leading causes of cancer death in adult men and is a multistage disease with therapeutic challenges of local recurrent advanced tumors and distant metastatic disease. CD44 is a multifunctional and multistructural cell surface glycoprotein that is involved in cell-cell interactions, cell proliferation, and cell migration. In the study, we produced negatively charged and biocompatible hyaluronic acid-based nanoparticles as a therapeutic system for targeting CD44-positive cancer cells. Subsequently, we confirmed the delivery of bioactive epigallocatechin-3-gallate and site-specific inhibition of prostate tumor growth. In this study, hyaluronic acid-based nanoparticles successfully encapsulated epigallocatechin-3-gallate and were efficiently internalized into cancer cells via CD44 ligand receptor recognition, induced cell cycle arrest at G2/M phase, and inhibited prostate cancer cell growth. Furthermore, in vivo assays indicated that these nanoparticles specifically bind CD44 receptors and increase apoptosis of cancer cells, leading to significant decreases in prostate tumor activity and tumor tissue inflammation.

Environmental NO2 level is associated with 2-year mortality in patients undergoing peritoneal dialysis.

An ongoing issue related to global urbanization is the association of air pollution with increased incidences of morbidity and mortality. However, no in-depth study has investigated this issue focusing on peritoneal dialysis (PD) patients. Therefore, this study assessed the effects of traffic-related air pollutants and other important mortality-associated factors on 2-year mortality in PD patients.A total of 160 PD patients were recruited in this 2-year retrospective observational study. Differences in air quality were analyzed with respect to the patients' living areas. The PD patients were categorized into 2 groups according to high (n = 65) and low (n = 95) nitrogen dioxide (NO2) exposure. Demographic, hematological, nutritional, inflammatory, biochemical, air pollutants, and dialysis-related data were analyzed. Univariate and multivariate Cox regression analyses were used for 2-year mortality analysis.A total of 160 PD patients (38 men and 122 women) were enrolled. Fourteen patients (8.8%) died within 2 years; among them, the causes of death were infection (n = 10), malignancy (n = 1), and cardiovascular events (n = 3). Among the 10 patients who died from infection, 5, 4, and 1 died from pneumonia, PD-related peritonitis, and sepsis of unknown origin, respectively. All patients who died from pneumonia were living in high environmental NO2 exposure areas. Multivariate Cox regression analysis showed that age (hazard ratio [HR] 1.073, 95% confidence interval [CI] [1.013-1.137]; P = 0.017), white blood cell count (HR 1.41, 95% CI [1.116-1.781]; P = 0.004), log normalized protein nitrogen appearance (HR 0.0001, 95% CI [0-0.073]; P = 0.005), high cardiothoracic ratio (HR 14.28, 95% CI [1.778-114.706]; P = 0.012), and high environmental NO2 exposure (HR 3.776, 95% CI [1.143-12.47]; P = 0.029) were significantly associated with 2-year mortality.PD patients with high environmental NO2 exposure had a higher 2-year mortality rate than those with low exposure. Therefore, air pollution may be associated with 2-year mortality in such patients.