Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Evaluation of graphical models for multi-group metabolomics data.

Gaussian graphical model is a strong tool for identifying interactions from metabolomics data based on conditional correlation. However, data may be collected from different stages or subgroups of subjects with heterogeneity or hierarchical structure. There are different integrating strategies of graphical models for multi-group data proposed by data scientists. It is challenging to select the methods for metabolism data analysis. This study aimed to evaluate the performance of several different integrating graphical models for multi-group data and provide support for the choice of strategy for similar characteristic data. We compared the performance of seven methods in estimating graph structures through simulation study. We also applied all the methods in breast cancer metabolomics data grouped by stages to illustrate the real data application. The method of Shaddox et al. achieved the highest average area under the receiver operating characteristic curve and area under the precision-recall curve across most scenarios, and it was the only approach with all indicators ranked at the top. Nevertheless, it also cost the most time in all settings. Stochastic search structure learning tends to result in estimates that focus on the precision of identified edges, while BEAM, hierarchical Bayesian approach and birth-death Markov chain Monte Carlo may identify more potential edges. In the real metabolomics data analysis from three stages of breast cancer patients, results were in line with that in simulation study.

DAHOS Study: Efficacy of dapagliflozin in treating heart failure with reduced ejection fraction and obstructive sleep apnea syndrome - A 3-month, multicenter, randomized controlled clinical trial.

BACKGROUND: The recent discovery of new therapeutic approaches to heart failure with reduced ejection fraction (HFrEF), including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as well as improved treatment of co-morbidities has provided much needed help to HFrEF. In addition, dapagliflozin, one of the SGLT-2 inhibitors, serves as a promising candidate in treating obstructive sleep apnea (OSA) of HFrEF patients due to its likely mechanism of countering the pathophysiology of OSA of HFrEF. METHODS: This 3-month multicenter, prospective, randomized controlled trial enrolled participants with left ventricular ejection fraction (LVEF) less than 40% and apnea-hypopnea index (AHI) greater than 15. Participants were randomized into two groups: the treatment group received optimized heart failure treatment and standard-dose dapagliflozin, while the control group only received optimized heart failure treatment. The primary endpoint was the difference in AHI before and after treatment between the two groups. Secondary endpoints included oxygen desaturation index (ODI), minimum oxygen saturation, longest apnea duration, inflammatory factors (CRP, IL-6), quality of life score, and LVEF. RESULTS: A total of 107 patients were included in the final analysis. AHI, LVEF and other baseline data were similar for the dapagliflozin and control groups. After 12 weeks of dapagliflozin treatment, the dapagliflozin group showed significant improvements in sleep parameters including AHI, HI, longest pause time, ODI, time spent with SpO2 < 90%, and average SpO2. Meanwhile, the control group showed no significant changes in sleep parameters, but did demonstrate significant improvements in left ventricular end-diastolic diameter, LVEF, and NT-proBNP levels at 12 weeks. In the experimental group, BMI was significantly reduced, and there were improvements in ESS score, MLHFQ score, and EQ-5D-3L score, as well as significant reductions in CRP and IL-6 levels, while the CRP and IL-6 levels were not improved in the control group. The decrease in LVEF was more significant in the experimental group compared to the control group. There were no significant differences in the magnitude of the decreases between the two groups. CONCLUSIONS: Dapagliflozin may be an effective treatment for heart failure complicated with OSA, and could be considered as a potential new treatment for OSA. (Trial registration  www.chictr.org.cn , ChiCTR2100049834. Registered 10 August 2021).

Vitamin C, vitamin E, ß-carotene and risk of Parkinson's disease: a systematic review and dose-response meta-analysis of observational studies.

OBJECTIVE: This study aimed to explore the relationship between the intake of vitamin C, vitamin E and ß-carotene, and the risk of Parkinson's disease (PD). METHODS: Web of Science, Embase, PubMed, Cochrane library, CNKI, and WanFang databases were searched from inception to 29 August 2022 for observational studies reporting the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by Vitamin C/Vitamin E/ß-carotene intake. Random-effects models, publication bias assessment, subgroup, sensitivity and dose-response analyses were performed, using.Stata version 12.0. RESULTS: A total of 13 studies were included. There was no significant association between high-dose vitamin C intake and the risk of PD compared with low-dose vitamin C intake (RR = 0.98, 95%CI:0.89,1.08). Compared with low-dose intake, high-dose intake of vitamin E can prevent the risk of PD (RR = 0.87, 95%CI:0.77,0.99). Compared with lower ß-carotene intake, there was a borderline non-significant correlation between higher intake and PD risk (RR = 0.91, 95%CI:0.82,1.01), and high dose ß-carotene intake was found to be associated with a lower risk of PD in women (RR = 0.78, 95%CI:0.64,0.96). CONCLUSION: This study shows that vitamin E intake can reduce the risk of PD and play a preventive role.

Evaluation of a multicomponent intervention to shorten thrombolytic door-to-needle time in stroke patients in China (MISSION): A cluster-randomized controlled trial.

BACKGROUND: Rapid intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is crucial for improving outcomes. However, few randomized trials of interventions aimed at reducing in-hospital delay have been carried out in China. We aimed to evaluate the effect of a multicomponent intervention on thrombolytic door-to-needle time (DNT) of AIS patients via video teleconference based on the Behavior Change Wheel (BCW) method. METHODS AND FINDINGS: This cluster-randomized trial, conducted between January 1, 2019 and December 31, 2019, randomly allocated 22 hospitals equally to PEITEM (Persuasion Environment reconstruction Incentivization Training Education Modeling) intervention or routine care plus stroke registry and subsequently enrolled 1,634 AIS patients receiving IVT within 4.5 hours upon stroke onset from participant hospitals. The PEITEM group received a 1-year PEITEM 6-component intervention based on the behavioral theory monthly via video teleconference. The primary outcome was the proportion of patients with a DNT of 60 minutes or less. A total of 987 patients participated in the PEITEM group (mean age, 69 years; female, 411 [41.6%]) and 647 patients in the control group (mean age, 70 years; female, 238 [36.8%]). Of all participants, the proportion of DNT ≤60 minutes in the PEITEM group was higher than in the control group (82.0% versus 73.3%; adjusted odds ratio, 1.77; 95% confidence interval (CI), 1.17 to 2.70; ICC, 0.04; P = 0.007). Among secondary outcomes, the average DNT was 43 minutes in the PEITEM group and 50 minutes in the control group (adjusted mean difference: -8.83; 95% CI, -14.03 to -3.64; ICC, 0.12; P = 0.001). Favorable functional outcome (score of 0 to 1 on the modified Rankin scale (mRS)) was achieved in 55.6% patients of the PEITEM group and 50.4% of the control group (adjusted odds ratio, 1.38; 95% CI, 1.00 to 1.90; ICC, 0.01; P = 0.049). Main study limitations include non-blinding of clinicians, and that specific interventions component responsible for the observed changes could not be determined. CONCLUSIONS: The teleconference-delivered PEITEM intervention resulted in a moderate but clinically relevant shorter DNT and better functional outcome in AIS patients receiving IVT. TRIAL REGISTRATION: Clinicaltrials.gov NCT03317639.

Metabolomics-based molecular signatures reveal the toxic effect of co-exposure to nitrosamines in drinking water.

Nitrosamines, a group of emerging nitrogenous pollutants, are ubiquitously found in the drinking water system. However, less is known about how systemic biological responses resist or tolerate nitrosamines, especially long-term co-exposure at low concentrations. In this study, untargeted metabolomics was used to investigate the metabolic perturbations in human esophageal epithelial Het-1A cells induced by a mixture of nine common nitrosamines in drinking water at environmentally relevant, human-internal-exposure, and genotoxic concentrations. Generally, the disrupted metabolic spectrum became complicated with nitrosamines dose increasing. Notably, two inflammation-associated pathways, namely, cysteine (Cys) and methionine (MET) metabolism, and nicotinate and nicotinamide metabolism, changed significantly under the action of nitrosamines, even at the environmentally relevant level. Furthermore, targeted metabolomics and molecular biology indicators in cells were identified in mice synchronously. For one thing, the up-regulated Cys and MET metabolism provided methyl donors for histone methylation in the context of pro-inflammatory response. For another, the down-regulated NAD+/NADH ratio inhibited the deacetylation of NF-кB p65 and eventually activated the NF-кB signaling pathway. Taken collectively, the metabolomics molecular signatures were important indicative markers for nitrosamines-induced inflammation. The potential crosstalk between the inflammatory cascade and metabolic regulation also requires further studies. These findings suggest that more attention should be paid to long-term co-exposure at low concentrations in the control of nitrosamines pollution in drinking water. Additionally, this study also highlights a good prospect of the combined metabolomic-molecular biology approach in environmental toxicology.

Fresh fruit consumption, physical activity, and five-year risk of mortality among patients with type 2 diabetes: A prospective follow-up study.

BACKGROUND AND AIMS: We explored the associations among fruit consumption, physical activity, and their dose-response relationship with all-cause and cardiovascular disease (CVD) mortality in type 2 diabetic patients. METHODS AND RESULTS: We prospectively followed 20,340 community-dwelling type 2 diabetic patients aged 21-94 years. Information on diets and physical activity was collected using standardized questionnaires. All-cause and CVD mortality were assessed. Hazard ratios (HRs) for all-cause mortality were estimated with Cox regression models, and HRs for CVD mortality were derived from a competing risk model. Restricted cubic spline regression was used to analyze dose-response relationships. We identified 1362 deaths during 79,844 person-years. Compared to non-consumption, fruit consumption >42.9 g/d was inversely associated with all-cause mortality (HR 0.76; 95% CI 0.64-0.88), CVD mortality (HR 0.69, 0.51-0.94) and stroke mortality (HR 0.57, 0.36-0.89), but not with heart disease mortality (HR 0.93, 0.56-1.52). The HRs comparing the top vs bottom physical activity quartiles were 0.44 (0.37-0.53) for all-cause mortality, 0.46 (0.33-0.64) for CVD mortality, 0.46 (0.29-0.74) for stroke mortality and 0.51 (0.29-0.88) for heart disease mortality. Lower fruit consumption combined with a lower physical activity level was associated with a greater mortality risk. A nonlinear threshold of 80 g fruit/day was identified; all-cause mortality risk was reduced by approximately 24% at this value. A physical activity threshold of eight metabolic equivalents (MET) h/day was also identified, after which the risk of mortality did not decrease. CONCLUSIONS: Fruit consumption and physical activity may reduce all-cause, CVD, and stroke mortality in type 2 diabetic patients.

Comparison of LPS and MS-induced depressive mouse model: behavior, inflammation and biochemical changes.

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.

Effects of sleep apnea hypopnea syndromes on cardiovascular events: a systematic review and meta-analysis.

PURPOSE: Previous studies suggest that sleep apnea hypopnea syndrome (SAHS) is an independent risk factor that contributes to certain cardiovascular events. However, there are studies arguing that patients with SAHS had lower peak troponin levels when suffering cardiovascular events compared to patients without SAHS, which indicates that there may potentially be a protective effect of SAHS. This meta-analysis aimed to assess the impact of SAHS on cardiovascular events. METHODS: Databases were searched for studies that examined cardiac biomarkers or reported angiographic data when patients with SAHS experienced cardiovascular events. The data about peak cardiac biomarkers and angiographic coronary lesion were extracted and then used to compute the pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS: Among 26 studies included in the meta-analysis, there was not a definite difference between the SAHS group and the control group for troponins (SMD, 0.05; 95% CI, [- 0.16, 0.26]), creatine kinase (SMD, - 0.08; 95% CI, [- 0.38, 0.22]), and CK-MB (SMD, - 0.11; 95% CI, [- 0.51, 0.29]). However, patients with SAHS revealed worse coronary lesion condition grading via both Gensini score (SMD, 0.63; 95% CI, [0.31, 0.95]) and SYNTAX score (SMD, 0.99; 95% CI, [0.31-1.67]). CONCLUSIONS: Ischemic preconditioning induced by the intermittent hypoxia at the early stage could generate a cardiac protection effect, which would then benefit SAHS patients encountering a major adverse cardiovascular event.

Metabolomic transition trajectory and potential mechanisms of N-nitrosomethylbenzylamine induced esophageal squamous cell carcinoma in rats.

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.

Eleocharis dulcis corm: phytochemicals, health benefits, processing and food products.

Eleocharis dulcis, an aquatic plant belonging to Cyperaceae family, is indigenous to Asia, and also occurs in tropical Africa and Australia. The edible corm part of E. dulcis is a commonly consumed aquatic vegetable with a planting area of 44.46 × 103 hm2 in China. This work aims to explore the potential of E. dulcis corm for use as a new food source for sufficient nutrients and health benefits by reviewing its nutrients, phytochemicals, functions, processing and food products. Eleocharis dulcis corm contains starches, dietary fibers, non-starch polysaccharides, proteins, amino acids, phenolics, sterols, puchiin, saponins, minerals and vitamins. Among them, phenolics including flavonoids and quinones could be the major bioconstituents that largely contribute to antioxidant, anti-inflammatory, antibacterial, antitumor, hepatoprotective, neuroprotective and hypolipidemic functions. Peel wastes of E. dulcis corm tend to be enriched in phenolics to a much higher extent than the edible pulp. Fresh-cut E. dulcis corm can be consumed as a ready-to-eat food or processed into juice for beverage production, and anti-browning processing is a key to prolonging shelf life. Present food products of E. dulcis corm are centered on various fruit and vegetable beverages, and suffer from single categories and inadequate development. In brief, underutilized E. dulcis corm possesses great potential for use as a new food source for sufficient nutrients and health benefits. © 2021 Society of Chemical Industry.

Effectiveness of telemedicine for pregnant women with gestational diabetes mellitus: an updated meta-analysis of 32 randomized controlled trials with trial sequential analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is now a global health problem. Poor blood glucose control during pregnancy may lead to maternal and neonatal/foetal complications. Recently, the development of information and communication technology has resulted in new technical support for the clinical care of GDM. Telemedicine is defined as health services and medical activities provided by healthcare professionals through remote communication technologies. This study aimed to update the systematic review of the effectiveness of telemedicine interventions on glycaemic control and pregnancy outcomes in pregnant women with GDM. METHODS: We searched the Web of Science, PubMed, Scopus, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, Wan-fang Database, China Biology Medicine and VIP Database for randomized controlled trials (RCTs) related to the effectiveness of telemedicine interventions for GDM from database inception to July 31st, 2019. Languages were limited to English and Chinese. Literature screening, data extraction and assessment of the risk of bias were completed independently by two reviewers. Meta-analysis and trial sequential analysis were conducted in Stata 14.0 and TSA v0.9.5.10 beta, respectively. RESULTS: A total of 32 RCTs were identified, with a total of 5108 patients. The meta-analysis showed that telemedicine group had significant improvements in controlling glycated haemoglobin (HbA1c) [mean difference (MD) = - 0.70, P < 0.01], fasting blood glucose (FBG) (MD = -0.52, P < 0.01) and 2-h postprandial blood glucose (2hBG) (MD = -1.03, P = 0.01) compared to the corresponding parameters in the standard care group. In the telemedicine group, lower incidences of caesarean section [relative risk (RR) = 0.82, P = 0.02], neonatal hypoglycaemia (RR = 0.67, P < 0.01), premature rupture of membranes (RR = 0.61, P < 0.01), macrosomia (RR = 0.49, P < 0.01), pregnancy-induced hypertension or preeclampsia (RR = 0.48, P < 0.01), preterm birth (RR = 0.27, P < 0.01), neonatal asphyxia (RR = 0.17, P < 0.01), and polyhydramnios (RR = 0.16, P < 0.01) were found. The trial sequential analyses conclusively demonstrated that the meta-analytic results of the change in HbA1c, the change in 2hBG, the change in FBG, the incidence rates of caesarean section, pregnancy-induced hypertension or preeclampsia, premature rupture of membranes, premature birth, neonatal asphyxia, and polyhydramnios were stable. CONCLUSIONS: Compared to standard care, telemedicine interventions can decrease the glycaemic levels of patients with GDM more effectively and reduce the risk of maternal and neonatal/foetal complications.

Circulating tumor cells in peripheral blood of pancreatic cancer patients and their prognostic role: a systematic review and meta-analysis.

BACKGROUND: It has been shown that circulating tumor cells in peripheral blood can be used to predict survival in patients with breast, prostate and other epithelial tumors. In the present study, we performed a meta-analysis to evaluate the prognostic role of circulating tumor cells (CTCs) in patients with pancreatic cancer. METHODS: A systematic literature search of the databases was conducted from the inception to Jul 20, 2019. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated under a fixed or random effect model. RESULTS: A total of 19 studies with 1320 confirmed individuals were included. Our meta-analysis showed that patients in the CTC-positive group had a significantly shorter overall survival (OS) (RR = 0.47, 95%CI = 0.33-0.61, P < 0.001) and progression-free survival (PFS) (P = 0.003) than CTC-negative patients. Moreover, subgroup analysis by ethnicity indicated that CTC-positive patients had a significantly shorter OS in both Asian and Western populations. Further subgroup analysis by detection methods, treatments, and Tumor Node Metastasis (TNM) stages also indicated that CTC-positive patients were associated with significant decreases in both OS and PFS  in most subgroups. CONCLUSION: Our meta-analysis indicates that CTC-positive patients have a worse OS and PFS than CTC-negative patients, which suggests that CTCs may act as predictive biomarkers for pancreatic cancer patients before treatment.

Conditional survival in patients with spontaneous tumor rupture of hepatocellular carcinoma after partial hepatectomy: a propensity score matching analysis.

BACKGROUND: Spontaneous tumor rupture (STR) of hepatocellular carcinoma (HCC) is a life-threatening condition. This study investigates the influences of STR on the observed survival and conditional survival of patients received hepatectomy. METHODS: A retrospective cohort of patients who underwent hepatectomy from 2009 to 2013 was divided into tumor rupture group and non-rupture group. Propensity score matching (PSM) was used for comparison of the observed survival and conditional survival probabilities between these two groups. RESULTS: 89 pairs of patients who had comparable background and tumor characteristics were created using PSM analysis. There was significant association between STR and increased risk of OS no matter when before or after PSM (p < 0.01). STR was significantly associated with increased risks of PFS before, while not after PSM. Multivariate Cox regression analyses demonstrated that STR was an independent risk factor associated with OS. There were significant differences in two groups for conditional probabilities of OS and PFS for an additional 6 months and 1 year before PSM, while not after PSM. CONCLUSIONS: This study identified STR but not PFS as an independent risk factor influencing OS, in patients with HCC following hepatectomy. In selected patients with STRHCC, hepatectomy should be performed with acceptable outcomes.

Optimization of Purification, Identification and Evaluation of the in Vitro Antitumor Activity of Polyphenols from Pinus Koraiensis Pinecones.

In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93 ± 0.14% (n = 3), which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line), A549 (human lung cancer cell line), SH-SY5Y (human neuroblastoma cell line), LOVO (human colon cancer stem cell line), MCF-7 (human breast cancer cell line), HeLa (human cervical cancer line), and HT29 (human colon cancer line), were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC50 value of 0.317 ± 0.0476 mg/mL. Finally, Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS) was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstrate that Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods.

Smoking and smoking cessation in relation to the development of co-existing non-small cell lung cancer with chronic obstructive pulmonary disease.

Previous studies have identified a mixed-phenotype of non-small cell lung cancer (NSCLC) with co-existing chronic obstructive pulmonary disease (COPD). Although NSCLC and COPD share a common risk factor in smoking, whether and how smoking may contribute to the coexistence of NSCLC with COPD (NSCLC-COPD) is unclear. Our study suggests that cigarette smoking is the major risk factor for the development of NSCLC-COPD, especially in females and among patients with squamous cell carcinoma subtype.

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction.

Gene therapy (GT) for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada(-/-)). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

Contamination Status and Acute Dietary Exposure Assessment of Paralytic Shellfish Toxins in Shellfish in the Dalian Area of the Yellow-Bohai Sea, China.

The Yellow-Bohai Sea is an important semi-enclosed continental shelf marginal seas with an intensive aquaculture industry in China. The current study analyzed the contamination status and the time variations of paralytic shellfish toxins (PSTs) in shellfish between 2019 and 2020 from the Yellow-Bohai Sea in the Dalian area and estimated the acute health risks to consumers in China. A total of 199 shellfish samples (including 34 Pacific oysters, 25 Mediterranean blue mussels, 34 Manila clams, 36 bay scallops, 34 veined rapa whelks and 36 bloody clams) were analyzed from four representative aquaculture zones around the Yellow-Bohai Sea in Dalian. Among the samples, scallops and blood clams were the shellfish species with the highest detection rate of PSTs (94.4%), and the highest level of PSTs was detected in scallops with 3953.5 µg STX.2HCl eq./kg (µg STX.2HCL equivalents per kg shellfish tissue), followed by blood clams with 993.4 µg STX.2HCl eq./kg. The contents of PSTs in shellfish showed a time variation trend, and autumn was the season of concern for PST contamination in Dalian. For general Chinese consumers, the probability of acute health risks to shellfish consumers from dietary exposure to PSTs was around 13%. For typical consumers in coastal areas of China, especially those with higher shellfish intake, there was an acute health risk associated with exposure to PSTs through shellfish consumption during the occurrence of harmful algal blooms. It is suggested that the government continue to strengthen the monitoring of the source of PSTs and the monitoring of harmful algal blooms and give reasonable advice on shellfish consumption for consumers in coastal areas, such as not eating scallop viscera.

Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. METHODS: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. RESULTS: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. CONCLUSIONS: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.