Biomimetic Metal-Organic Framework Gated Nanoplatform for Sonodynamic Therapy against Extensively Drug Resistant Bacterial Lung Infection.

Novel antimicrobial strategies are urgently needed to treat extensively drug-resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC-MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic-nano-antimicrobial therapy against gram-negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI29-41) modified hUC-MSCs membrane (MSCm), a sonosensitizer meso-tetra(4-car-boxyphenyl) porphine doped mesoporous organo-silica nanoparticle and an acidity-responsive metal-organic framework ZIF-8. This innovative formulation enables efficient loading of polymyxin B, reduces off-target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI29-41 and the inflammatory chemotaxis of hUC-MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU-mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M2 phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep-tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine.

Mendelian randomization reveals no correlations between herpesvirus infection and idiopathic pulmonary fibrosis.

BACKGROUND: Previous studies have found that the persistence of herpesvirus significantly increases the risk of idiopathic pulmonary fibrosis (IPF), but it is unclear whether this effect is causal. We conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between three herpesvirus infections and IPF. METHODS: We used genome-wide association studies (GWAS) data from three independent datasets, including FinnGen cohort, Milieu Intérieur cohort, and 23andMe cohort, to screen for instrumental variables (IVs) of herpesvirus infection or herpesvirus-related immunoglobulin G (IgG) levels. Outcome dataset came from the largest meta-analysis of IPF susceptibility currently available. RESULTS: In the FinnGen cohort, genetically predicted Epstein-Barr virus (EBV) (OR = 1.105, 95%CI: 0.897-1.149, p = 0.815), cytomegalovirus (CMV) (OR = 1.073, 95%CI: 0.926-1.244, p = 0.302) and herpes simplex (HSV) infection (OR = 0.906, 95%CI: 0.753-1.097, p = 0.298) were not associated with the risk of IPF. In the Milieu Intérieur cohort, we found no correlations between herpesvirus-related IgG EBV nuclear antigen-1 (EBNA1) (OR = 0.968, 95%CI: 0.782-1.198, p = 0.764), EBV viral capsid antigen (VCA) (OR = 1.061, 95CI%: 0.811-1.387, p = 0.665), CMV (OR = 1.108, 95CI%: 0.944-1.314, p = 0.240), HSV-1 (OR = 1.154, 95%CI: 0.684-1.945, p = 0.592) and HSV-2 (OR = 0.915, 95%CI: 0.793-1.056, p = 0.225) and IPF risk. Moreover, in the 23andMe cohort, no evidence of associations between mononucleosis (OR = 1.042, 95%CI: 0.709-1.532, p = 0.832) and cold scores (OR = 0.906, 95%CI: 0.603-1.362, p = 0.635) and IPF were found. Sensitivity analysis confirmed the robustness of our results. CONCLUSIONS: This study provides preliminary evidence that EBV, CMV, and HSV herpesviruses, and herpesviruses-related IgG levels, are not causally linked to IPF. Further MR analysis will be necessary when stronger instrument variables and GWAS with larger sample sizes become available.

Associations between diet and incidence risk of lung cancer: A Mendelian randomization study.

Background: Observational studies have revealed associations between diet and lung cancer. However, it is unclear whether the association is disturbed by confounding factors. We used a two-sample Mendelian randomization (MR) method to characterize the associations between diet and the lung cancer risk (including 3 subtypes: lung adenocarcinoma (LA), squamous cell lung carcinoma (SqCLC), and small cell lung cancer (SCLC)). Materials and methods: Data on 20 diets were screened from the UK Biobank. Lung cancer data came from a large meta-analysis of 85,716 individuals. The inverse-variance weighted method was used as the main analysis. Sensitivity analysis was also used to explain the different multiplicity patterns of the final model. Results: Our results showed significant evidence that 3 diets were associated with lung cancer [odds ratio (OR): 0.271, 95% confidence interval (CI): 0.150-0.488, p = 1.46 × 10-4, dried fruit; OR: 3.010, 95% CI: 1.608-5.632, p = 5.70 × 10-4, beer] and SqCLC (OR: 0.135, 95% CI: 0.062-0.293, p = 2.33 × 10-5, dried fruit; OR: 0.485, 95% CI: 0.328-0.717, p = 2.9 × 10-4, cheese). There were also suggestive correlations between 5 dietary intakes and lung cancer (OR: 0.441, 95% CI: 0.250-0.778, p = 0.008, cereal; OR: 2.267, 95% CI: 1.126-4.564, p = 0.022, beef), LA (OR: 0.494, 95% CI: 0.285-0.858, p = 0.012, dried fruit; OR: 3.536, 95% CI: 1.546-8.085, p = 0.003, beer) and SCLC (OR: 0.006, 95% CI: 0.000-0.222, p = 0.039, non-oily fish; OR: 0.239, 95% CI: 0.086-0.664, p = 0.006, dried fruit). No other association between diet and lung cancer was observed. Conclusion: Our study preliminary found that cheese, dried fruit, and beer intake were significantly associated with the risk of lung cancer or its subtypes, while cereal, beef, and non-oily fish intake were suggestively associated with the risk of lung cancer or its subtypes. Well-designed prospective studies are still needed to confirm our findings in the future.

Investigating Causal Associations of Circulating Micronutrients Concentrations with the Risk of Lung Cancer: A Mendelian Randomization Study.

Previous observational studies have suggested that the effect of diet-derived circulating micronutrient concentrations on lung cancer (LC) risk is controversial. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between circulating micronutrient concentrations and the overall risk of LC and three LC subtypes (namely lung adenocarcinoma (LA), squamous cell lung cancer (SqCLC), and small cell lung cancer (SCLC)). The instrumental variables (IVs) of 11 micronutrients (beta-carotene, calcium, copper, folate, lycopene, magnesium, phosphorus, retinol, selenium, zinc, and vitamin B6) were screened from the published genome-wide association studies (GWAS). Summary statistics related to LC and its subtypes came from the largest meta-analysis, including 29,266 cases and 56,450 controls. Inverse-variance weighted (IVW) method is used as the main MR analysis, and the sensitivity analysis is carried out to ensure the MR assumptions. This MR study found suggestive evidence that genetically predicted 6 circulating micronutrient concentrations was correlated with the risk of overall LC (odds ratio (OR): 1.394, 95% confidence interval (CI): 1.041-1.868, p = 0.026, phosphorus), LA (OR: 0.794, 95% CI: 0.634-0.995, p = 0.045, beta-carotene; OR: 0.687, 95%CI: 0.494-0.957, p = 0.026, calcium), SqCLC (OR: 0.354, 95% CI: 0.145-0.865, p = 0.023, retinol), and SCLC (OR: 1.267, 95% CI: 1.040-1.543, p = 0.019, copper; OR: 0.801, 95% CI: 0.679-0.944, p = 0.008, zinc). We found no evidence that other micronutrients are associated with the risk of overall LC or its subtypes. Our study suggested that the increase in circulating beta-carotene, calcium, retinol, and zinc concentration may reduce the risk of LC; the increase in circulating copper and phosphorus concentration may be related to the increased risk of LC. In the future, larger replication samples of LC genetic data and larger micronutrient-related GWAS will be needed to verify our findings.

Diet-Derived Circulating Antioxidants and Risk of Digestive System Tumors: A Mendelian Randomization Study.

Previous observational case-control studies have shown significant controversy over the impact of dietary intake-related circulating antioxidants on the risk of digestive system tumors. We conducted a two-sample Mendelian randomized (MR) analysis to determine whether there was a significant causal relationship between increased levels of circulating antioxidants and digestive system tumors. Our circulating antioxidants (vitamin C, carotenoids, vitamin A, and vitamin E) were derived from absolute circulating antioxidants and circulating antioxidant metabolites, and their corresponding instrumental variables were screened from published studies. The digestive system tumors we studied included colorectal, gastric, pancreatic, liver, and esophageal cancer, and the corresponding summary GAWS (genome-wide association study) data were obtained from the UK Biobank database. We first evaluated the causal relationship between each tumor and circulating antioxidants and then used meta-analysis to summarize the results of MR analysis of different tumors. No significant associations were noted for genetically predicted circulating antioxidants and higher risk of digestive system tumors in our study. The pooled ORs (odds ratio) are 0.72 (95% CI: 0.46-1.11; ß-carotene), 0.93 (95% CI: 0.81-1.08; lycopene), 2.12 (95% CI: 0.31-14.66; retinol), and 0.99 (95% CI: 0.96-1.02; ascorbate) for absolute circulating antioxidants; for circulating antioxidant metabolites, the pooled ORs for digestive system tumors risk per unit increase of antioxidants were 1.29 (95% CI: 0.39-4.28; α-tocopherol), 1.72 (95% CI: 0.85-3.49; γ-tocopherol), 1.05 (95% CI: 0.96-1.14; retinol), and 1.21 (95% CI: 0.97-1.51; ascorbate), respectively. Our study suggested that increased levels of dietary-derived circulating antioxidants did not reduce the risk of digestive system tumors.

Effects of endoscopic therapy and surgical resection on long-term survival outcomes in patients with duodenal gastrointestinal stromal tumors: a surveillance, epidemiology, and end result program analysis.

BACKGROUND: With the rapid development of endoscopic technology, endoscopic therapy (ET) has gradually become a new treatment choice for gastrointestinal stromal tumors (GISTs). However, due to the low incidence of duodenal GIST and the difficulty of ET, there is a lack of data to compare the long-term results of ET and surgical resection. METHODS: Duodenal GIST patients from 2004 to 2015 were selected from the surveillance, epidemiology, and end result (SEER) database. We used the Kaplan-Meier method and log-rank test to describe the 5- and 10-year survival differences between the ET and the surgery groups. The multivariate Cox proportional hazard model was used for analyzing the risk factors influencing the prognosis of patients. We used a 1:1 propensity score-matched (PSM) to reduce confounding factors, and then we compared survival differences between the two groups again. RESULTS: A total of 294 patients with duodenal GIST were enrolled, including 41 (13.9%) patients with ET and 253 (86.1%) patients with surgical resection. Before PSM, the long-term survival of patients with duodenal GIST after ET and surgical resection was similar [5-year overall survival (OS) (79.7 vs. 79.3%, p = 0.876), 10-year OS (66.5 vs. 68.1%, p = 0.876)]. After adjusting the relevant variables using multivariate Cox analysis, we found that the ET and surgery groups were comparable in OS and cancer-specific survival (CSS). After PSM, there was also no significant difference between ET and surgical resection for long-term OS and CSS. CONCLUSION: Our study found no significant difference in long-term survival between ET and surgical resection in patients with duodenal GIST. However, to obtain high-quality evidence, more extensive sample size studies are needed in the future to evaluate the long-term effects of ET on patients.

Relationship between Primary Tumor Resection for Metastatic Small Intestine Neuroendocrine Tumors and Survival: A Propensity Score-Matched Analysis.

BACKGROUND: At present, it has been controversial whether primary tumor resection (PTR) can bring survival advantage to patients with metastatic small intestine neuroendocrine tumors (SI-NETs). To answer this question, we conducted a retrospective cohort study to evaluate the effect of PTR on the survival of patients with metastatic SI-NETs. METHODS: Information on SI-NETs patients from 2004 to 2015 was extracted from Surveillance, Epidemiology, and End Results (SEER) databases. Demographics, tumor characteristics, treatment, and survival were compared. Propensity score-matched (PSM) was used 1:1 in the filtered queue. Cox proportional hazard regression model was used to evaluate the correlation between PTR and treatment results. RESULTS: Before PSM, survival analysis showed that PTR significantly prolonged the survival of metastatic SI-NETs patients. After PSM, there was no significant difference in overall survival (OS) and cancer-specific survival (CSS) between the PTR group and the non-PTR group. Multivariate analysis showed no significant difference in OS and CSS between the two groups (p > 0.05). CONCLUSION: Our study shows that OS and CSS are comparable between the PTR group and the non-PTR group. Thus, we believe that PTR should not be actively performed on such patients. Meanwhile, it is undeniable that properly selected patients may also benefit from PTR. Therefore, prospective randomized controlled trials are still needed to verify the effect of PTR on patients in the future.

Endoscopic and surgical treatment of T1N0M0 colorectal neuroendocrine tumors: a population-based comparative study.

BACKGROUND: With the rapid advances in endoscopic technology, endoscopic therapy (ET) is increasingly applied to the treatment of small (≤ 20 mm) colorectal neuroendocrine tumors (NETs). However, long-term data comparing ET and surgery for management of T1N0M0 colorectal NETs are lacking. The purpose of this work was to compare overall survival (OS) and cancer-specific survival (CSS) of such patients with ET or surgery. METHODS: Patients with T1N0M0 colorectal NETs were identified within the Surveillance Epidemiology and End Results (SEER) database (2004-2016). Demographics, tumor characteristics, therapeutic methods, and survival were compared. Propensity score matching (PSM) was used 1:3 and among this cohort, Cox proportional hazards regression models were performed to evaluate correlation between treatment and outcomes. RESULTS: Of 4487 patients with T1N0M0 colorectal NETs, 1125 were identified in the matched cohort, among whom 819 (72.8%) underwent ET and 306 (27.2%) underwent surgery. There was no difference in the 5-year and 10-year OS and CSS rates between the 2 treatment modalities. Likewise, analyses stratified by tumor size and site showed that patients did not benefit more from surgery compared with ET. Moreover, multivariate analyses found no significant differences in OS [Hazard Ratio (HR) = 0.857, 95% Confidence Interval (CI): 0.513-1.431, P = 0.555] and CSS (HR = 0.925, 95% CI: 0.282-3.040, P = 0.898) between the 2 groups. Similar results were observed when comparisons were limited to patients with different tumor size and site. CONCLUSIONS: In this population-based study, patients with lesions < 10 mm treated endoscopically had comparable long-term survival compared with those treated surgically, which demonstrates ET as an alternative to surgery in T1N0M0 colorectal NETs of < 10 mm. Further high-quality prospective studies are warranted to comprehensively evaluate the role of ET in patients with tumors 10 to 20 mm.

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: An increasing number of studies have described the aberrant expression of homeobox (HOX) proteins in gastric cancer (GC), which is critically associated with the prognosis and clinicopathological characteristics of GC. This study was conducted to investigate the clinical value and action mechanisms of HOX proteins in GC. METHODS: A comprehensive search of PubMed, Embase, Web of Science and Cochrane Library was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) and the pooled odds ratio (OR) with its 95% CI were used to assess the effect of HOX protein expression on the prognosis and clinicopathological features of GC, respectively. RESULTS: Nineteen studies containing 3775 patients were selected for this study. Heterogeneity among HRs of overall survival (OS) was markedly high (I2 = 90.5%, p = 0.000). According to the subgroup analysis, increased expression of HOX protein in the downregulated subgroup was associated with a good prognosis for patients with GC (pooled HR: 0.46, 95% CI: 0.36-0.59, I2 = 3.1%, p = 0.377), while overexpression of HOX protein in the upregulated subgroup was correlated with a reduced OS (pooled HR: 2.59, 95% CI: 1.79-3.74, I2 = 73.5%, p = 0.000). The aberrant expression of HOX protein was crucially related to the TNM stage, depth of tumour invasion, tumour size, lymph node metastasis, distant metastasis, vascular invasion, histological differentiation and Lauren classification in patients with GC. In addition, the molecular mechanisms by which HOX proteins regulate tumorigenesis and development of GC were also explored. CONCLUSIONS: HOX proteins play vital roles in GC progression, which might serve as prognostic markers and therapeutic targets for GC.