Lycopene promoted M2 macrophage polarization via inhibition of NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to Escherichia coli infection in J744A.1 cells.

Escherichia coli (E. coli) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli-induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 µmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 µmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1ß and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 µmol/L lycopene significantly increased E. coli-induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli-treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli-caused bovine mastitis, providing the new angle of the prevention and management of mastitis.

Metabolic characterization of sphere-derived prostate cancer stem cells reveals aberrant urea cycle in stemness maintenance.

Alteration of cell metabolism is one of the essential characteristics of tumor growth. Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, proliferation, recurrence, and other processes, and play an important role in therapeutic resistance and metastasis. Thus, identification of the metabolic profiles in prostate cancer stem cells (PCSCs) is critical to understanding prostate cancer progression. Using untargeted metabolomics and lipidomics methods, we show distinct metabolic differences between prostate cancer cells and PCSCs. Urea cycle is the most significantly altered metabolic pathway in PCSCs, the key metabolites arginine and proline are evidently elevated. Proline promotes cancer stem-like characteristics via the JAK2/STAT3 signaling pathway. Meanwhile, the enzyme pyrroline-5-carboxylate reductase 1 (PYCR1), which catalyzes the conversion of pyrroline-5-carboxylic acid to proline, is highly expressed in PCSCs, and the inhibition of PYCR1 suppresses the stem-like characteristics of prostate cancer cells and tumor growth. In addition, carnitine and free fatty acid levels are significantly increased, indicating reprogramming of fatty acid metabolism in PCSCs. Reduced sphingolipid levels and increased triglyceride levels are also observed. Collectively, our data illustrate the comprehensive landscape of the metabolic reprogramming of PCSCs and provide potential therapeutic strategies for prostate cancer.

Enhanced ·OH-Scavenging Activity of Cu-CeOx Nanozyme via Resurrecting Macrophage Nrf2 Transcriptional Activity Facilitates Diabetic Wound Healing.

Diabetic wounds are a prevalent and devastating complication of diabetes, which may impede their healing and regeneration. In diabetic wounds, excess reactive oxygen species (ROS) activate the nuclear factor kappa-B pathway, leading to transcriptional silencing of nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in a vicious cycle of oxidative stress and inflammation. Conventional nanozymes have limitations in preventing the continuous production of ROS, including the most oxidizing reactive hydroxyl radical (·OH), although they can remove pre-existing ROS. Herein, a novel antioxidant nanoplatform addresses this challenge by incorporating JSH-23 into the mesoporous of cupric-doped cerium oxide nanozymes. Additionally, for rapid wound adaptability and durable tissue adhesion, a nanozyme hydrogel spray consisting of oxidized sodium alginate and methacrylate gelatin is constructed, named OG@CCJs. This platform resurrects Nrf2 transcriptional activity of macrophages in vitro, curbing the production of ROS at its source, particularly ·OH, while enabling the nanozymes to scavenge previously generated ROS. OG@CCJs significantly alleviate oxidative stress in diabetic wounds in vivo, promoting wound healing. Overall, the proposed nanozyme-hydrogel spray with enhanced ·OH-scavenging activity uses a "two-track" antioxidant strategy to rebuild the antioxidant defense barrier of macrophages. This pioneering approach highlights the tremendous potential of OG@CCJs for facilitating diabetic wound healing.

Why do only some cohort studies find health benefits from low volume alcohol use? A systematic review and meta-analysis of study characteristics that may bias mortality risk estimates.

OBJECTIVE: Assumptions about alcohol's health benefits profoundly influence global disease burden estimates and drinking guidelines. Utilising theory and evidence, we identify and test study characteristics that may bias estimates of all-cause mortality risk associated with low volume drinking. METHOD: We identified 107 longitudinal studies by systematic review with 724 estimates of association between alcohol consumption and all-cause mortality for 4,838,825 participants with 425,564 recorded deaths. "Higher quality" studies had a mean cohort age of ≤55 years, followed-up beyond 55 years, and excluded former and occasional drinkers from abstainer reference groups. "Low volume" alcohol use was defined as between one drink per week (>1.30g ethanol/day) and two drinks per day (<25g ethanol/day). Mixed linear regression was used to model relative risks (RRs) of mortality for subgroups of higher versus lower quality studies. RESULTS: As predicted, studies with younger cohorts and separating former and occasional drinkers from abstainers estimated similar mortality risk for low volume drinkers (RR=0.98, 0.87-1.11) as abstainers. Studies not meeting these quality criteria estimated significantly lower risk for low volume drinkers (RR=0.84, 0.79-0.89). In exploratory analyses, studies controlling for smoking and/or socio-economic status had significantly reduced mortality risks for low volume drinkers. However, mean RR estimates for low volume drinkers in non-smoking cohorts were above 1.0 (RR=1.16, 0.91-1.41). CONCLUSIONS: Studies with lifetime selection biases may create misleading positive health associations. These biases pervade the field of alcohol epidemiology and can confuse communications about health risks. Future research should investigate whether smoking status mediates, moderates or confounds alcohol-mortality risk relationships.

Biomimetic Targeting Nanoadjuvants for Sonodynamic and Chronological Multi-Immunotherapy against Holistic Biofilm-Related Infections.

Biofilm-related infections (BRIs) present significant challenges owing to drug resistance, adverse immune responses, and implant failure; however, current approaches inadequately cater to the diverse therapeutic requirements at different stages of infection. To address this issue, a multi-immunotherapy strategy in combination with sonodynamic therapy is proposed for the chronological treatment of BRIs. Macrophage membrane-decorated targeting sonosensitive nanoadjuvants are fabricated to load cytosine-phosphate-guanine oligodeoxynucleotide (CPG-ODN) or microRNA (miR)-21-5p. In the early stages of BRI (Stage I), CPG-ODN-loaded nanoadjuvants (CPG@HMPN@M) promote the formation of neutrophil extracellular traps to capture and neutralize detached microbes. During the late stage of infection (Stage II), CPG-ODNs redirect macrophage polarization into the M1 phase to combat infections via TLR9/Myd88/TRAF6 pathway. During these stages, CPG@HMPN@M generates singlet oxygen through sonodynamic processes, eradicating the biofilms under US irradiation. Once the BRIs are eliminated, miR-21-5p-loaded nanoadjuvants (miR@HMPN@M) are delivered to the lesions to suppress excessive inflammation and promote tissue integration by evoking macrophage M2 polarization during the repair phase (Stage III) through PTEN/PI3K/Akt pathway. This innovative approach aims to provide comprehensive treatment strategies for the chronological treatment of BRI by effectively eliminating infections, promoting tissue restoration, and implementing different immune regulations at different stages, thus demonstrating promising clinical value.

Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer.

Lung cancer is a malignant tumor with one of the highest morbidity and mortality rates in the world. Approximately 80-85% of lung cancer is diagnosed as non-small lung cancer (NSCLC), and its 5-year survival rate is only 21%. Cisplatin is a commonly used chemotherapy drug for the treatment of NSCLC. Its efficacy is often limited by the development of drug resistance after long-term treatment. Therefore, determining how to overcome cisplatin resistance, enhancing the sensitivity of cancer cells to cisplatin, and developing new therapeutic strategies are urgent clinical problems. Z-ligustilide is the main active ingredient of the Chinese medicine Angelica sinensis, and has anti-tumor activity. In the present study, we investigated the effect of the combination of Z-ligustilide and cisplatin (Z-ligustilide+cisplatin) on the resistance of cisplatin-resistant lung cancer cells and its mechanism of action. We found that Z-ligustilide+cisplatin decreased the cell viability, induced cell cycle arrest, and promoted the cell apoptosis of cisplatin-resistant lung cancer cells. Metabolomics combined with transcriptomics revealed that Z-ligustilide+cisplatin inhibited phospholipid synthesis by upregulating the expression of phospholipid phosphatase 1 (PLPP1). A further study showed that PLPP1 expression was positively correlated with good prognosis, whereas the knockdown of PLPP1 abolished the effects of Z-ligustilide+cisplatin on cell cycle and apoptosis. Specifically, Z-ligustilide+cisplatin inhibited the activation of protein kinase B (AKT) by reducing the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). Z-ligustilide+cisplatin induced cell cycle arrest and promoted the cell apoptosis of cisplatin-resistant lung cancer cells by inhibiting PLPP1-mediated phospholipid synthesis. Our findings demonstrate that the combination of Z-Ligustilide and cisplatin is a promising approach to the chemotherapy of malignant tumors that are resistant to cisplatin.

Efficacy and Safety of PD-1/PD-L1 Inhibitor and Chemotherapy in Treatment of Advanced Small Cell Lung Cancer.

Context: SCLC has had few drugs for treatment and a high malignancy rate. About two-thirds of SCLC patients have distant metastasis by the time they receive a diagnosis, and once it occurs, patient's survival time is short. Immunotherapy treatments can block immunosuppression and increase the body's antitumor ability. PD-1 is the main immune checkpoint of tumors' immune response, and PD-L1 is one of the ligands of PD-1. Objective: The study intended to analyze the therapeutic effects of inhibitors of programmed death-1 (PD-1)/ programmed cell death 1 ligand 1 (PD-L1) combined with chemotherapy for patients with advanced small cell lung cancer (SCLC), evaluate the safety of that treatment, and compare it with chemotherapy alone. Design: The research team performed a retrospective randomized controlled study. Setting: The study took place at Cangzhou Central Hospital. Participants: Participants were 72 patients with advanced SCLC who received treatment at the hospital between December 2021 and December 2022. Intervention: The research team divided participants into two groups, each with 36 participants, using the random number method: (1) the control group, which received platinum-etoposide chemotherapy, and (2) the intervention group, which received a PD-1/PD-L1 inhibitor combined with the same chemotherapy that the control group received. Outcome Measures: The research team examined: (1) short-term efficacy; (2) long-term efficacy; (3) tumor-marker levels-neuron-specific enolase (NSE), progastrin releasing peptide (ProGRP), cytokeratin-19-fragment (CYFRA21-1), and squamous cell carcinoma antigen (SCCA); (4) T lymphocyte-subset levels-cluster of differentiation 3+ (CD3+), CD4+, and CD8+; (5) adverse reactions, and (6) Karnofsky performance status (KPS) scores. Results: Compared with the control group, the intervention group's: (1) overall response rate (ORR), with P = .002, and disease control rate (DCR), with P = .041, were significantly higher; (2) median survival time was significantly longer (P = .035); (3) levels of NSE, ProGRP, CYFRA21-1, and SCCA were significantly lower (all P < .001); (4) levels of CD3+ (P = .043) and CD4+ (P < .001) levels were significantly higher; and (5) Karnofsky performance status (KPS) scores were significantly higher than those of the control group (P = .018). No difference existed in the number of adverse reactions between the groups (P > .05). Conclusions: The PD-1/PD-L1 inhibitor combined with chemotherapy can benefit advanced SCLC patients, controlling patients' conditions and improving their quality of life, with good safety.

Targeting CDH17 with Chimeric Antigen Receptor-Redirected T Cells in Small Cell Lung Cancer.

BACKGROUND: Chimeric antigen receptor T cell (CAR-T) therapy stands as a precise and targeted approach in the treatment of malignancies. In this study, we investigated the feasibility of targeting Cadherin 17 (CDH17) with CDH17 CAR-T cells as a therapeutic modality for small cell lung cancer (SCLC). METHODS: CDH17 expression levels were assessed in human SCLC tumor tissues and cell lines using qPCR and Western blot. Subsequently, we established CDH17 CAR-T cells and assessed their cytotoxicity by co-culturing them with various SCLC cell lines at different effector-to-target (E:T) ratios, complemented by ELISA assays. To ascertain the specificity of CDH17 CAR-T cells, we conducted experiments on SCLC cells with and without CDH17 expression (shRNAs). Furthermore, we employed an SCLC xenograft model to evaluate the in vivo efficacy of CDH17 CAR-T cells. RESULTS: Our results revealed a significant upregulation of CDH17 in both SCLC tissues and cell lines. CDH17 CAR-T cells exhibited robust cytotoxic activity against SCLC cells in vitro, while demonstrating no cytotoxicity towards CDH17-deficient SCLC cells and HEK293 cells that lack CDH17 expression. Importantly, the production of IFN-γ and TNF-α by CDH17 CAR-T cells correlated with their cytotoxic potency. Additionally, treatment with CDH17 CAR-T cells significantly decelerated the growth rate of SCLC-derived xenograft tumors in vivo. Remarkably, no significant difference in body weight was observed between the control group and the group treated with CDH17 CAR-T cells. CONCLUSIONS: The preclinical data open further venues for the clinical use of CDH17 CAR-T cells as an immunotherapeutic strategy for SCLC treatment.

Escherichia coli infection mediates pyroptosis via activating p53-p21 pathway-regulated apoptosis and cell cycle arrest in bovine mammary epithelial cells.

Escherichia coli (E. coli) is a major environmental pathogen that causes mammary tissue damage and cell death, which results in substantial economic losses. Pyroptosis, a novel form of programmed cell death characterized by DNA fragmentation, chromatin condensation, cell swelling and leakage of cell contents, often occurs after inflammatory apoptotic pathways activation. Our objective was to investigate the intraction between E. coli infection and bovine mammary epithelial cells (bMECs) with pyroptosis and to explore the underlying regulatory mechanism. bMECs were infected with E. coli for 6 h. Lactic dehydrogenase activities, interleukin (IL)-10, IL-1ß, IL-18 and tumor necrosis factor-α concentrations, total apoptosis indexes, and protein expressions of P-cdc25c, P-CDK1, cleaved caspase 9, cleaved caspase 3, cleaved PARP, P-NF-κB, NLRP3, ASC, caspase 1, gasdermin D N-terminal, IL-1ß and IL-18 were significantly increased in E. coli infected bMECs. Whereas, cell membrane potential, protein levels of cdc25c, CDK1, cyclin B1, and Bcl-2/Bax level were markedly reduced. Furthermore, Ac-DEVD-CHO (specific inhibitor of apoptosis) dramatically suppressed pyroptosis in bMECs. Moreover, expressions of p53 and p21 promptly improved after E. coli infection, however, Pifithrin-α (specific inhibitor of p53) inhibited p53-p21 pathway, apoptosis, cell cycle arrest and pyroptosis. These results elaborated that E. coli infection of bMECs induced pyroptosis through activating the p53-p21 pathway-mediated apoptosis and cell cycle arrest. Taken together, inhibition of pyroptosis via suppressing of p53-p21 pathway may be an effective therapeutic approach for treating E. coli-induced mastitis, offering efficient theoretical support for the protection and treatment of bovine mastitis.

Metabolomics Reveals Novel Serum Metabolic Signatures in Gastric Cancer by a Mass Spectrometry Platform.

Gastric cancer (GAS) is one of the malignant tumors of the gastrointestinal system. Alterations in metabolite composition can reflect pathological processes of GAS and constitute a basis for diagnosis and treatment improvements. In this study, a total of 301 serum samples from 150 GAS patients at different tumor-node-metastasis (TNM) stages and 151 healthy controls were collected. Mass spectrometry platforms were performed to investigate the changes in GAS-related metabolites and explore the new potential serum biomarkers and the metabolic dysregulation associated with GAS progression. Twelve differential metabolites (ethyl 2,4-dimethyl-1,3-dioxolane-2-acetate, D-urobilinogen, 14-HDoHE, 13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid, 5,6-dihydroxyprostaglandin F1a, 9'-carboxy-gamma-tocotrienol, glutaric acid, alanine, tyrosine, C18:2(FFA), adipic acid, and suberic acid) were identified to establish the diagnosis model for GAS. The defined biomarker panel was also statistically significant for GAS progression with different TNM stages. KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment revealed the metabolic dysregulation associated with GAS progression. In conclusion, a diagnostic panel was established and validated, which could be used to further stage the early and advanced GAS patients from healthy controls. These findings may provide useful information for explaining the GAS metabolic alterations and try to facilitate the characterization of GAS patients in the early stage.

A multi-platform metabolomics reveals possible biomarkers for the early-stage esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent types of upper gastrointestinal malignancies. This work aimed to identify potential biomarkers for early screening for ESCC and characterize the systemic metabolic disturbances underlying ESCC using multi-platform metabolomics analysis. METHODS: We divided 239 patients (the early-stage ESCC patients, n = 132; Healthy controls, n = 107) into discovery and validation sets after matching age and sex. Integrated statistical and multi-platform serum metabolomics analyses were used to screen and validate significant metabolites linked to ESCC patients. RESULTS: Multi-platform metabolomics analyses showed that amino acid and lipid metabolism were crucial in the etiology of ESCC. Five metabolites, tryptophan (Trp), citrulline, l-carnitine, lysine, and acetyl-carnitine, were selected as potential biomarkers to establish a diagnosis panel, which showed high accuracy in distinguishing ESCC patients from healthy controls (area under the receiver operating characteristic curve, 0.873, 95% confidence interval [CI]: 0.825-0.925). CONCLUSIONS: This work laid the groundwork for understanding the etiology of ESCC. The diagnostic panel showed potential usefulness in early-stage ESCC diagnosis in clinical practice.

The beneficial potential of magnesium-based scaffolds to promote chondrogenesis through controlled Mg2+ release in eliminating the destructive effect of activated macrophages on chondrocytes.

Chondral defects caused by osteoarthritis (OA) are common but difficult to manage due to their limited capacity for self-repair. Further, the activated macrophages induced by OA stimulates chondrocytes degradation and inhibits regeneration, further impeding cartilage repair. Therefore, biomaterials with the potential for blocking vicious cycles between activated macrophages and chondrocytes would be promising for use in the treatment of chondral defects caused by OA. In this study, we fabricated porous Mg-Nd-Zn-Zr alloy (denoted JDBM) scaffolds coated with polydopamine (PDA) and investigated their cytocompatibility and impact on immunoregulation. Mesenchymal stem cells (MSCs) were co-cultured in supernatant from M1-polarized macrophages pretreated with extracts from JDBM scaffolds and the anti-inflammatory effect on the NF-κB pathway and reactive oxygen species (ROS) evaluated. JDBM scaffolds could reduce M1 macrophage numbers, while promoting those of M2 macrophages; recruit MSCs; and enhance chondrogenesis. Furthermore, lipopolysaccharide (LPS)-induced p65 translocation to the nucleus was inhibited by JDBM scaffolds, with ROS production and matrix metalloproteinase (MMP) expression also suppressed. These findings suggest that JDBM scaffolds can both promote chondrogenesis and effectively attenuate local inflammatory responses by transforming macrophages from the M1 to M2 subtype and down-regulating NF-κB signaling. Hence, JDBM scaffolds could promote chondrogenesis under inflammatory microenvironment and represent a promising material for treatment of chondral defects caused by OA.

Gas chromatography/mass spectrometry analysis of organic acid profiles in human serum: A protocol of direct ultrasound-assisted derivatization.

RATIONALE: Low-molecular-weight organic acids that generally contain one to three carboxyl groups are involved in many important biological processes; therefore, it is important to develop a quantitative method for analyzing organic acids in serum in order to allow an evaluation of metabolic changes. In this study, we evaluated a protocol for detecting 26 organic acids in serum based on ultrasound-assisted derivatization by gas chromatography/mass spectrometry (GC/MS). METHODS: Serum samples were prepared using ultrasound-assisted silane derivatization before GC/MS analysis to quantify concentrations of organic acids. Additionally, we investigated the variables affecting derivatization yields, including the extraction solvent, derivatization reagents, and derivatization conditions (reaction temperature, duration, and sonication parameters). The protocol was ultimately applied to detect organic acid profiles related to obesity. RESULTS: We used acetone as the extraction solvent and determined suitable derivatization conditions, as follows: BSTFA + 1% TMCS, 50°C, 10 min, and 100% ultrasound power. The protocol showed satisfactory linearity (r = 0.9958-0.9996), a low limit of detection (0.04-0.42 µmol/L), good reproducibility (coefficient of variation (CV) %: 0.32-13.76%), acceptable accuracy (recovery: 82.97-114.96%), and good stability within 5 days (CV%: 1.35-12.01% at room temperature, 1.24-14.09% at 4°C, and 1.01-11.67% at -20°C). Moreover, the protocol was successfully applied to obtain the organic acid profiles from obese and healthy control subjects. CONCLUSIONS: We identified and validated a protocol for ultrasound-assisted derivatization prior to GC/MS analysis for detecting 26 kinds of organic acids in serum. The results suggest the efficacy of this protocol for clinical applications to determine metabolic changes related to fluctuations in organic acid profiles.

Analysis of Combined Indicators for Risk of Osteoporotic Hip Fracture in Elderly Women.

OBJECTIVE: To compare the accuracy of combined independent risk factors in assessing the risk of hip fractures in elderly women. METHODS: Ninety elderly females who sustained hip fractures (including femoral neck fractures and intertrochanteric fractures) and 110 female outpatients without a hip fracture were included in our cross-sectional study from 24 November 2017 to 20 May 2019. The age of subjects in the present study was ≥65 years, with the mean age of 78.73 ± 7.77 and 78.09 ± 5.03 years for women with and without elderly hip fractures, respectively. Bone mineral density (BMD), Beta-carboxy terminal telopeptide (ß-CTX), N-terminal/mid region (N-MID), and 25(OH)D levels were analyzed. A novel evaluation model was established to evaluate combined indicators in assessing hip fractures in elderly women. RESULTS: Compared with the control group, taller height (155.68 ± 6.40 vs 150.97 ± 6.23, P < 0.01), higher levels of ß-CTX (525.91 ± 307.38 vs 330.94 ± 289.71, P < 0.01), and lower levels of total hip BMD (0.662 ± 0.117 vs 0.699 ± 0.111, P = 0.022), femoral neck BMD (0.598 ± 0.106 vs 0.637 ± 0.100, P = 0.009), and 25(OH)D (15.67 ± 7.23 vs 29.53 ± 10.57, P < 0.01) were found in the facture group. After adjustment for confounding factors, logistic regression analysis revealed that 25(OH)D (adjusted OR 0.837 [95% CI 0.790-0.886]; P < 0.01), femoral neck BMD (adjusted OR 0.009 [95% CI 0.000-0.969]; P = 0.048) and height (adjusted OR 1.207 [95% CI 1.116-1.306]; P < 0.01) remained risk factors for hip fractures in elderly women. Then a model including independent risk factors was established. A DeLong test showed the area under the receiver operator characteristic (ROC) (Area under the curve [AUC]) of 25(OH)D was significantly greater than that for femoral neck BMD (P < 0.01) and height (P < 0.01). The AUC of model including 25(OH)D and height was significantly greater than that of other combinations (P < 0.01). CONCLUSION: 25(OH)D, femoral neck BMD and height were associated with the occurrence of hip fractures in elderly women even after adjustment for confounding factors, and a model including 25(OH)D and height could provide better associated power than other combinations in the assessment of elderly hip fractures.

Serum metabolite signatures of epithelial ovarian cancer based on targeted metabolomics.

BACKGROUND: Epithelial ovarian cancer (EOC) is a common gynecological cancer with high mortality rates. The main objective of this study was to investigate the serum amino acid and organic acid profiles to distinguish key metabolites for screening EOC patients. METHODS: In total, 39 patients with EOC and 31 healthy controls were selected as the training set. Serum amino acid and organic acid profiles were determined using the targeted metabolomics approach. Metabolite profiles were processed via multivariate analysis to identify potential metabolites and construct a metabolic network. Finally, a test dataset derived from 29 patients and 28 healthy controls was constructed to validate the potential metabolites. RESULTS: Distinct amino acid and organic acid profiles were obtained between EOC and healthy control groups. Methionine, glutamine, asparagine, glutamic acid and glycolic acid were identified as potential metabolites to distinguish EOC from control samples. The areas under the curve for methionine, glutamine, asparagine, glutamic acid and glycolic acid were 0.775, 0 778, 0.955, 0.874 and 0.897, respectively, in the validation study. Metabolic network analysis of the training set indicated key roles of alanine, aspartate and glutamate metabolism as well as D-glutamine and D-glutamate metabolism in the pathogenesis of EOC. CONCLUSIONS: Amino acid and organic acid profiles may serve as potential screening tools for EOC. Data from this study provide useful information to bridge gaps in the understanding of the amino acid and organic acid alterations associated with epithelial ovarian cancer.

Magneto-Based Synergetic Therapy for Implant-Associated Infections via Biofilm Disruption and Innate Immunity Regulation.

Implant-associated infections (IAIs) are a common cause of orthopedic surgery failure due to microbial biofilm-induced antibiotic-resistance and innate immune inactivation. Thus, the destruction of microbial biofilm plays a key role in reducing IAIs. Herein, first, a magneto-based synergetic therapy (MST) is proposed and demonstrated against IAIs based on biofilm destruction. Under an alternating magnetic field (AMF), CoFe2O4@MnFe2O4 nanoparticles (MNPs), with a rather strong magnetic hyperthermal capacity, can generate sufficient thermal effect to cause dense biofilm dispersal. Loosened biofilms provide channels through which nitrosothiol-coated MNPs (MNP-SNOs) can penetrate. Subsequently, thermosensitive nitrosothiols rapidly release nitric oxide (NO) inside biofilms, thus efficiently killing sessile bacteria under the magnetothermal effect of MNPs. More importantly, MNP-SNOs can trigger macrophage-related immunity to prevent the relapse of IAIs by exposing the infected foci to a consistent innate immunomodulatory effect. The notable anti-infection effect of this nanoplatform is also confirmed in a rat IAI model. This work presents the promising potential of combining magnetothermal therapy with immunotherapy, for the effective and durable control and elimination of IAIs.

A novel ISM-SAM strategy, based on gas chromatography/mass spectrometry analysis, to compensate for matrix effects in the determination of pyruvic acid.

RATIONALE: The matrix effect is tricky in gas chromatography/mass spectrometry (GC/MS) analyses. Although several methods have been proposed to solve this problem, the results were unsatisfactory. Even fewer studies have assessed the performance of corrective methods. Hence, our study focused on assessing several common corrective methods, and then proposed a new strategy to correct for the matrix effect in GC/MS analyses. METHODS: In GC/MS analyses, the internal standard method (ISM) was employed to overcome the matrix effect during the detection of pyruvic acid (PA) in serum samples from a healthy adult female. The accuracy of the ISM was evaluated by comparing it with the standard addition method (SAM). To employ the ISM-SAM strategy, correction factors (CFs) were established by combining the ISM and the SAM based on different groups. The CFs were used to normalize data onto the results of subsequent analyses. RESULTS: When using the ISM to detect levels of PA, a serious bias is observed, thereby affecting the conclusions reached. In contrast, more reliable data can be obtained after normalizing results by undertaking the ISM-SAM strategy. The feasibility of this strategy was verified by comparing it with the results of the SAM alone. The ISM-SAM strategy was successfully applied to quantify the PA levels in healthy people and nephrotic syndrome patients. CONCLUSIONS: Our results indicated that a false outcome was presented when only the ISM was used to adjust the data, and important information would be missed if the correction strategy was not carried out. Therefore, ISM-SAM, as an available correction method, should be adapted to improve the reliability of research results.

Abundance, morphology, and removal efficiency of microplastics in two wastewater treatment plants in Nanjing, China.

Municipal wastewater treatment plants (WWTPs) are considered to be major contributors of microplastics to the aquatic environment. Detailed research in China, which is relevant to the local situation, remains in the initial stage. Herein, the microplastic abundance, morphology, and removal efficiency of two WWTPs (C and P) equipped with tertiary treatment processes in different districts of Nanjing, an important city in the Yangtze River Basin, were investigated. The influence of technology, operational parameters, daily capacity, and sewage source and its proportion were discussed. Observations by optical microscope and FT-IR analysis and systematic calculation revealed that the microplastics have four shapes, including fragments, granules, film, and fibers, with various sizes and proportions, which were dependent on wastewater source. The total removal rates of 97.67% and 98.46% for WWTP C and WWTP P, respectively, indicated their highly efficient reduction of microplastics. Treatment technology had a considerable influence on the removal rate, especially the secondary and tertiary processes. However, a large number of microplastics from WWTPs were still released into the environmental waters due to the huge daily capacity. Sewage source determined the concentration, morphology feature, and chemical composition of microplastics to a certain extent. Compared with industrial wastewater, domestic wastewater possibly contained smaller microplastics of polyethylene and polypropylene with lower abundance. Furthermore, additional attention was provided on the flocculation process, drainage system, and treatment efficiency of microplastics with different shapes. This work is expected to provide some technical supports to guide the operation and management of WWTPs.

The Effects of Alcohol Warning Labels on Population Alcohol Consumption: An Interrupted Time Series Analysis of Alcohol Sales in Yukon, Canada.

OBJECTIVE: There is limited evidence that alcohol warning labels (AWLs) affect population alcohol consumption. New evidence-informed AWLs were introduced in the sole government-run liquor store in Whitehorse, Yukon, that included a cancer warning (Ca), low-risk drinking guidelines (LRDGs) and standard drink (SD) messages. These temporarily replaced previous pregnancy warning labels. We test if the intervention was associated with reduced alcohol consumption. METHOD: An interrupted time series study was designed to evaluate the effects of the AWLs on consumption for 28 months before and 14 months after starting the intervention. Neighboring regions of Yukon and Northwest Territories served as control sites. About 300,000 labels were applied to 98% of alcohol containers sold in Whitehorse during the intervention. Multilevel regression analyses of per capita alcohol sales data for people age 15 years and older were performed to examine consumption levels in the intervention and control sites before, during, and after the AWLs were introduced. Models were adjusted for demographic and economic characteristics over time and region. RESULTS: Total per capita retail alcohol sales in Whitehorse decreased by 6.31% (t test p < .001) during the intervention. Per capita sales of labeled products decreased by 6.59% (t test p < .001), whereas sales of unlabeled products increased by 6.91% (t test p < .05). There was a still larger reduction occurring after the intervention when pregnancy warning labels were reintroduced (-9.97% and -10.29%, t test p < .001). CONCLUSIONS: Applying new AWLs was associated with reduced population alcohol consumption. The results are consistent with an accumulating impact of the addition of varying and highly visible labels with impactful messages.

Baseline Assessment of Alcohol-Related Knowledge of and Support for Alcohol Warning Labels Among Alcohol Consumers in Northern Canada and Associations With Key Sociodemographic Characteristics.

OBJECTIVE: Evidence-informed alcohol warning labels (AWLs) are a promising, well-targeted strategy to increase consumer awareness of health risks. We assessed consumers' baseline knowledge of alcohol-related cancer risk, standard drinks, and low-risk drinking guidelines as well as levels of support for AWLs. We further assessed associations with sociodemographic factors. METHOD: Forming part of a larger study testing new evidence-informed AWLs in a northern Canadian territory compared with a neighboring territory, baseline surveys were completed among liquor store patrons systematically selected in both sites. Chi-square and multivariable logistic regression analyses were performed to assess outcomes. RESULTS: In total, 836 liquor store patrons (47.8% female) completed baseline surveys across both sites. Overall, there was low knowledge of alcohol-related cancer risk (24.5%), limited ability to calculate a standard drink (29.5%), and low knowledge of daily (49.5%) and weekly (48.2%) low-risk drinking guideline limits. There was moderate support for AWLs with a health warning (55.9%) and standard drink information (51.4%), and lower support for low-risk drinking guideline labels (38.7%). No sociodemographic characteristics were associated with cancer knowledge. Identifying as female and having adequate health literacy were associated with support for all three AWLs; high alcohol use was associated with not supporting standard drink (adjusted odds ratio = 0.60, 95% CI [0.40, 0.88]) and low-risk drinking guideline (adjusted odds ratio = 0.57, 95% CI [0.38, 0.87]) labels. CONCLUSIONS: Few consumers in this study had key alcohol-related health knowledge; however, there was moderate support for AWLs as a tool to raise awareness. Implementation of information-based interventions such as evidence-informed AWLs with health messages including alcohol-related cancer risk, standard drink information, and national drinking guidelines is warranted.