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Organophosphate esters (OPEs) are emerging pollutants, while data on their occurrence in foods and human dietary intake are limited. Based on the 6th China total diet study conducted in 2016-2019, this study implemented a comprehensive survey of OPEs in plant-derived foods of cereals, potatoes, legumes, fruits, vegetables, and further assessed dietary exposure from both plant- and animal-derived food. The sum concentrations of 15 OPEs in the plant-derived samples ranged from 0.567 to 106 ng/g ww. 2-Ethylhexyl diphenyl phosphate (EHDPP) (median: 1.14 ng/g ww) had the highest level in plant-derived foods, with a proportion of 35.6% in the total median OPEs. Regional distribution analysis showed a higher contamination of OPEs in plant-derived food from northern area of China. Estimated dietary intakes (EDIs) of ∑OPEs for Chinese population were from 109 ng/kg bw/day in Beijing to 1164 ng/kg bw/day in Gansu province, with mean and median of 296 and 222 ng/kg bw/day, respectively. Although animal-derived foods had higher levels of OPEs, plant-derived foods, specifically cereals, was the major source of dietary OPE intake. The EDIs were much lower than reference doses, which suggested the intakes of OPEs via food consumption could not cause significant health risks to the Chinese population at present.
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BACKGROUND: Many studies have demonstrated the effectiveness of chimeric antigen receptor-T (CAR-T) cell therapy for relapsed or refractory multiple myeloma (RRMM), but the hematologic toxicity has not been well characterized. METHODS: A total of 111 adults with RRMM who received BCMA CAR-T cells, BCMA + CD19 CAR-T cells or tandem BCMA/CD19 dual-target (BC19) CAR-T cells infusion were enrolled. We characterized cytopenia and hematologic recovery at different time points after CAR-T-cell therapy, analyzed the effect of cytopenia on prognosis and identified the risk factors. RESULTS: Patients had a high probability of cytopenia, with anemia, neutropenia and thrombocytopenia occurring in 92%, 95% and 73%, respectively. There were 60 (54%) patients had prolonged hematologic toxicity (PHT) after D28. The median hemoglobin and platelet count were significantly lower at D28 post-CAR-T cell therapy than at baseline. Hemoglobin increased to above baseline at D90. The median absolute neutrophil count was lower than baseline at D0 and D28, and it recovered to baseline at D180. The baseline level of lactate dehydrogenase was associated with thrombocytopenia. Extramedullary involvement was associated with hemoglobin recovery, while the baseline level of albumin and types of CAR-T were related to platelet recovery. Patients with anemia at baseline and at D0, D180 and D360 had shorter progression-free survival (PFS), while anemia at D0, D60, D180 and D360 was associated with shorter overall survival (OS). Neutropenia at D0 was associated with shorter PFS and patients with neutropenia at D90 or D180 had shorter OS. Patients with thrombocytopenia at any time had shorter PFS and OS. Compared to patients without PHT, patients with PHT had shorter PFS and OS. CONCLUSIONS: The majority of RRMM patients treated with CAR-T cells experienced cytopenia. Cytopenia occurred at specific time points was associated with a poorer prognosis.
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BACKGROUND: Care robots have been proposed in response to nursing shortages in assisted living facilities (ALFs) and the growing population of older adults. While the use of care robots may improve the general health and well-being of older adults, their introduction changes the work of nursing staff fundamentally, and it has implications for the entire health care system. In developing such technology, it is important to include end users, but so far, the nursing staff's perspectives have largely been ignored. OBJECTIVE: This study aims to examine the literature on nursing staff's attitudes, needs, and preferences related to the use of care robots in ALFs, in order to discover gaps in the literature and guide future research. METHODS: This review follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 protocol. On May 12, 2023, we searched PubMed, CINAHL Plus with Full Text, PsycINFO, the IEEE Xplore Digital Library, and the ACM Digital Library using predetermined search terms. Included publications, written in English, focused on the predevelopment phase, in which information was gathered on nursing staff's attitudes, needs, and preferences regarding care robots for ALFs. Publications were excluded if they did not provide peer-reviewed empirical data. The studies' findings were summarized, coded, and analyzed into major themes using thematic analysis and narrative synthesis. Their quality was assessed using McGill University's Mixed Methods Appraisal Tool and the Joanna Briggs Institute's critical appraisal tools. RESULTS: The final sample included 15 studies. Most of the studies (n=11, 73%) were rated as good quality; however, there was a general lack of reporting on important methodological decisions and sample characteristics. Nursing staff desired care robots that could assist with physically demanding tasks and reduce their workload but had mixed feelings on whether robots could or should assist with social tasks. In addition, nursing staff are concerned about the ethics of care robots, as well as about their safety, accessibility, and operability. The nursing staff's culture, qualification, and role in the facility may influence their perspectives of care robots. The studies lacked theory-driven designs and large sample sizes. Eight (53%) studies mentioned using a participatory design approach, but a lack of established criteria for what constitutes participatory design leads to varying degrees of methodological quality. CONCLUSIONS: There was consensus among nursing staff that care robots should serve as nursing assistants to reduce workload. Whether robots could or should assist with social tasks remains a question. Further research is needed to mitigate nursing staff's concerns and understand the socioecological factors that influence their perspectives of care robots and their adoption in ALFs. In addition, theory-driven and large sample size study designs are necessary, as well as work to develop clear criteria for related participatory design research.
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Instituciones de Vida Asistida , Actitud del Personal de Salud , Personal de Enfermería , Robótica , Humanos , Personal de Enfermería/psicologíaRESUMEN
Background: The U.S. Food and Drug Administration authorized the sale and marketing of two very low nicotine cigarettes (VLNC) as modified risk tobacco products. The misperception that VLNC are healthier than regular cigarettes is common. This study explores effective message strategies to inform the public about health risks associated with VLNC use, encourage cigarette smokers to try VLNC, and prevent other tobacco users and non-users from product initiation. Methods: Following the Reasoned Action approach, a VLNC educational message was developed based on the salient beliefs associated with behavioral intention. The message was tested in an online survey conducted in 2018, where 410 participants were randomly assigned to one of the two message conditions (no-message, VLNC message). Message effects were assessed across four tobacco-use groups (non-tobacco users, cigarette-only smokers, cigarette dual/poly smokers, other tobacco users). Results: Compared to the no-message control, the VLNC message condition showed lower nicotine risk perception for all participants, lower misbelief in VLNC safety for non-users and cigarette-only smokers, higher belief in VLNC carcinogenicity for other tobacco users, stronger belief in second-hand smoke harm for cigarette dual/poly smokers and other tobacco users, and higher VLNC intention for cigarette-only smokers. Conclusions: Different messages are needed for different types of tobacco users. Both cigarette smokers and other tobacco users could benefit from messages that acknowledge the non-addictiveness but emphasize the health risks of VLNC. Regulators could consider making physical harm statements a requirement for VLNC packaging and marketing. New strategies need to be explored to inform cigarette dual/poly smokers.
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The disruption of per- and polyfluoroalkyl substances (PFASs) on bile acid (BA) homeostasis has raised public concerns, making the evaluation of their effects and underlying mechanisms a high priority. Although the use of perfluorooctanoic acid (PFOA) has been restricted, it remains a widespread legacy PFAS in the environment. Concurrently, the use of its prevalent short-chain alternative, perfluorobutanoic acid (PFBA), is increasing, yet the toxicity assessment of PFBA remains inadequate. In this study, C57BL/6N mice were exposed to PFOA and PFBA (0.4 or 10 mg/kg body weight) by gavage for 28 days. The results showed that both PFOA and PFBA significantly increased hepatic weight, although PFBA exhibited lower bioaccumulation than PFOA in the liver. Targeted metabolomics revealed that PFOA significantly decreased total BA levels and altered their composition. Conversely, PFBA, without significantly altering total BA levels, notably changed their composition, such as increasing the proportion of cholic acid. Further investigations using in vivo and in vitro assays suggested that PFOA inhibited the expression of Cyp7A1, a key BA synthetase, potentially via PPARα activation, thereby reducing BA levels. In contrast, PFBA enhanced Cyp7A1 expression, associated with the inhibition of intestinal Farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) pathway. This study evaluated the differences in the BA-interfering effects of PFOA and PFBA and shed light on the potential mechanisms, which will provide new insights into the health risks of legacy PFASs and their alternatives.
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Ácidos y Sales Biliares , Caprilatos , Fluorocarburos , Hígado , Ratones Endogámicos C57BL , Fluorocarburos/toxicidad , Caprilatos/toxicidad , Animales , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ácidos y Sales Biliares/metabolismo , Contaminantes Ambientales/toxicidad , MasculinoRESUMEN
We examined whether prenatal exposure to two classes of endocrine-disrupting chemicals (EDCs) was associated with infant epigenetic age acceleration (EAA), a DNA methylation biomarker of aging. Participants included 224 maternal-infant pairs from a Canadian pregnancy cohort study. Two bisphenols and 12 phthalate metabolites were measured in maternal second trimester urines. Buccal epithelial cell cheek swabs were collected from 3 month old infants and DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The Pediatric-Buccal-Epigenetic tool was used to estimate EAA. Sex-stratified robust regressions examined individual chemical associations with EAA, and Bayesian kernel machine regression (BKMR) examined chemical mixture effects. Adjusted robust models showed that in female infants, prenatal exposure to total bisphenol A (BPA) was positively associated with EAA (B = 0.72, 95% CI: 0.21, 1.24), and multiple phthalate metabolites were inversely associated with EAA (Bs from -0.36 to -0.66, 95% CIs from -1.28 to -0.02). BKMR showed that prenatal BPA was the most important chemical in the mixture and was positively associated with EAA in both sexes. No overall chemical mixture effects or male-specific associations were noted. These findings indicate that prenatal EDC exposures are associated with sex-specific deviations in biological aging, which may have lasting implications for child health and development.
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Background: The understanding of the prevalence and early predictive factors of scoliosis in children and adolescents is limited, which poses challenges to developing preventative strategies. This systematic review and meta-analysis aimed to clarify the prevalence and predictors of scoliosis among children and adolescents. Methods: We conducted a comprehensive search in PubMed, Cochrane, Embase, and Web of Science through October 2023. The quality of included studies was evaluated using the Joanna Briggs Institute scale or the Newcastle-Ottawa Scale. Subgroup analyses were performed to examine different types of scoliosis and specific demographic groups. Results: From 32 studies encompassing 55,635,351 children and adolescents, we identified 284,114 cases of scoliosis, resulting in a prevalence rate of 3.1% (95% CI: 1.5%-5.2%). This rate varied by gender, degrees of scoliosis severity, and between idiopathic vs. congenital forms. Notable predictors included gender, age, Body Mass Index (BMI), race, environmental factors, and lifestyle choices. Conclusion: Scoliosis is a significant condition affecting a minority of children and adolescents, particularly adolescent girls and individuals who are overweight. It is recommended that guardians and schools enhance educational efforts towards its prevention. Systematic Review Registration: https://www.crd.york.ac.uk/, Identifier CRD42023476498.
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Fear memory is essential for survival and adaptation, yet excessive fear memories can lead to emotional disabilities and mental disorders. Despite previous researches have indicated that histamine H1 receptor (H1R) exerts critical and intricate effects on fear memory, the role of H1R is still not clarified. Here, we show that deletion of H1R gene in medial septum (MS) but not other cholinergic neurons selectively enhances contextual fear memory without affecting cued memory by differentially activating the dentate gyrus (DG) neurons in mice. H1R in cholinergic neurons mediates the contextual fear retrieval rather than consolidation by decreasing acetylcholine release pattern in DG. Furthermore, selective knockdown of H1R in the MS is sufficient to enhance contextual fear memory by manipulating the retrieval-induced neurons in DG. Our results suggest that H1R in MS cholinergic neurons is critical for contextual fear retrieval, and could be a potential therapeutic target for individuals with fear-related disorders.
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Neuronas Colinérgicas , Giro Dentado , Miedo , Receptores Histamínicos H1 , Animales , Miedo/fisiología , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/fisiología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H1/genética , Giro Dentado/metabolismo , Ratones , Masculino , Ratones Endogámicos C57BL , Memoria/fisiología , Ratones Noqueados , Acetilcolina/metabolismo , Núcleos Septales/metabolismo , Núcleos Septales/fisiología , Núcleos Septales/citologíaRESUMEN
Wound healing in diabetic patients presents significant challenges in clinical wound care due to high oxidative stress, excessive inflammation, and a microenvironment prone to infection. In this study, we successfully developed a multifunctional tandem dynamic covalently cross-linked hydrogel dressing aimed at diabetic wound healing. This hydrogel was constructed using cyanoacetic acid functionalized dextran (Dex-CA), 2-formylbenzoylboric acid (2-FPBA) and natural oligomeric proanthocyanidins (OPC), catalyzed by histidine. The resulting Dex-CA/OPC/2-FPBA (DPOPC) hydrogel can be dissolved triggered by cysteine, thereby achieving "controllable and non-irritating" dressing change. Furthermore, the incorporation of OPC as a hydrogel building block endowed the hydrogel with antioxidant and anti-inflammatory properties. The cross-linked network of the DPOPC hydrogel circumvents the burst release of OPC, enhancing its biosafety. In vivo studies demonstrated that the DPOPC hydrogel significantly accelerated the wound healing process in diabetic mice compared to a commercial hydrogel, achieving an impressive wound closure rate of 98 % by day 14. The DPOPC hydrogel effectively balanced the disrupted inflammatory state during the healing process. This dynamic hydrogel based on natural polyphenols is expected to be an ideal candidate for dressings intended for chronic wounds.
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Diabetes Mellitus Experimental , Hidrogeles , Proantocianidinas , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Proantocianidinas/química , Proantocianidinas/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Reactivos de Enlaces Cruzados/química , Antioxidantes/farmacología , Antioxidantes/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Dextranos/químicaRESUMEN
The colonic fermentation metabolites of resistant starch (RS) are recognized to have various health benefits. However, the relationship between the structural variation of RS and the colonic fermentation properties, remains inadequately studied, especially for type 3 resistant starch. The in vitro fecal fermentation properties with multi-structure evolution of A- and B-type polymorphic resistant starch spherulites (RSS) were investigated. Both polymorphic types of RSS showed similar fermentation rate and total short-chain fatty acid profiles, while the butyrate concentration of the A-type RSS subjected to 24 h of fermentation was significantly higher compared to B-type RSS. In the case of recrystallized starch spherulites, irrespective of the polymorphic type, gut bacteria preferentially degraded the intermediate chains and crystalline regions, as the local molecule-ordered area potentially serves as suitable attachment sites or surfaces for microbial enzymes.
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Ácidos Grasos Volátiles , Heces , Fermentación , Almidón , Heces/microbiología , Heces/química , Almidón/metabolismo , Almidón/química , Ácidos Grasos Volátiles/metabolismo , Humanos , Microbioma Gastrointestinal/fisiología , Almidón Resistente/metabolismo , Colon/microbiología , Colon/metabolismo , Butiratos/metabolismoRESUMEN
Mycobacterium abscessus (M. abscessus) is a multidrug-resistant nontuberculous mycobacterium (NTM) that is responsible for a wide spectrum of infections in humans. The lack of effective bactericidal drugs and the formation of biofilm make its clinical treatment very difficult. The FDA-approved drug library containing 3048 marketed and pharmacopeial drugs or compounds was screened at 20 µM against M. abscessus type strain 19977 in 7H9 medium, and 62 hits with potential antimicrobial activity against M. abscessus were identified. Among them, bithionol, a clinically approved antiparasitic agent, showed excellent antibacterial activity and inhibited the growth of three different subtypes of M. abscessus from 0.625 µM to 2.5 µM. We confirmed the bactericidal activity of bithionol by the MBC/MIC ratio being ≤4 and the time-kill curve study and also electron microscopy study. Interestingly, it was found that at 128 µg/mL, bithionol could completely eliminate biofilms after 48h, demonstrating an outstanding antibiofilm capability compared to commonly used antibiotics. Additionally, bithionol could eliminate 99.9% of biofilm bacteria at 64 µg/mL, 99% at 32 µg/mL, and 90% at 16 µg/mL. Therefore, bithionol may be a potential candidate for the treatment of M. abscessus infections due to its significant antimicrobial and antibiofilm activities.
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Psoriasis is a common skin disease with a high recurrence rate. Aberrant keratinocyte proliferation is a significant pathogenic characteristic of psoriatic lesions, and studies have revealed that the development of psoriasis is significantly influenced by pro-inflammatory cytokines, such as IL-17A and TNF-α. Biologics targeting these cytokines have been widely used in psoriasis treatment and achieve remarkable effects, however, the underlying mechanism of how IL-17A and TNF-α specifically regulate keratinocyte proliferation has not been fully elucidated. Dectin-1 is an essential membrane protein that is directly related to the immune microenvironment and the proliferation of multiple cell types. To elucidate how IL-17A and TNF-α may promote keratinocyte proliferation in psoriatic lesions and whether Dectin-1 is involved. The expression of Dectin-1 in keratinocytes from psoriatic lesions was detected by real-time PCR, western blot and immunofluorescence. Correlation analysis and cytological experiments were then performed to determine the relationship between Dectin-1 and IL-17A/TNF-α in psoriatic lesions. Finally, we investigated the signalling pathway through which Dectin-1 may promote keratinocyte proliferation. Dectin-1 was significantly increased in keratinocytes from psoriatic lesions. Moreover, IL-17A and TNF-α effectively induced the expression of Dectin-1 in HaCaT cells, which was shown to activate the Syk/NF-κB signalling pathway and promote the proliferation of keratinocytes. IL-17A and TNF-α may promote the proliferation of keratinocytes in psoriatic lesions through induction of Dectin-1, indicating that Dectin-1 could be a potential therapeutic target for the treatment of psoriasis.
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Proliferación Celular , Interleucina-17 , Queratinocitos , Lectinas Tipo C , Psoriasis , Transducción de Señal , Factor de Necrosis Tumoral alfa , Adulto , Femenino , Humanos , Masculino , Células Cultivadas , Interleucina-17/metabolismo , Queratinocitos/metabolismo , Lectinas Tipo C/metabolismo , FN-kappa B/metabolismo , Psoriasis/metabolismo , Psoriasis/patología , Quinasa Syk/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Bisphenols and phthalates are two classes of endocrine-disrupting chemicals (EDCs) thought to influence weight and adiposity. Limited research has investigated their influence on maternal weight changes, and no prior work has examined maternal fat mass. We examined the associations between exposure to these chemicals during pregnancy and multiple maternal weight and fat mass outcomes. METHODS: This study included a sample of 318 women enrolled in a Canadian prospective pregnancy cohort. Second trimester urinary concentrations of 2 bisphenols and 12 phthalate metabolites were quantified. Self-reported and measured maternal weights and measured skinfold thicknesses were used to calculate gestational weight gain, 3-months and 3- to 5-years postpartum weight retention, late pregnancy fat mass gain, total postpartum fat mass loss, and late postpartum fat mass retention. Adjusted robust regressions examined associations between chemicals and outcomes in the entire study population and sub-groups stratified by pre-pregnancy body mass index (BMI). Bayesian kernel machine regression examined chemical mixture effects. RESULTS: Among women with underweight or normal pre-pregnancy BMIs, MBzP was negatively associated with weight retention at 3- to 5-years postpartum (B = -0.04, 95%CI: -0.07, -0.01). Among women with overweight or obese pre-pregnancy BMIs, MEHP and MMP were positively associated with weight retention at 3-months and 3- to 5-years postpartum, respectively (B's = 0.12 to 0.63, 95%CIs: 0.02, 1.07). DEHP metabolites and MCNP were positively associated with late pregnancy fat mass gain and late postpartum fat mass retention (B's = 0.04 to 0.18, 95%CIs: 0.001, 0.32). Further, the mixture of EDCs was positively associated with late pregnancy fat mass gain. CONCLUSION: In this cohort, pre-pregnancy BMI was a key determinant of the associations between second trimester exposure to bisphenols and phthalates and maternal weight changes and fat accumulation. Investigations of underlying physiological mechanisms, windows of susceptibility, and impacts on maternal and infant health are needed.
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Compuestos de Bencidrilo , Índice de Masa Corporal , Fenoles , Ácidos Ftálicos , Humanos , Femenino , Fenoles/orina , Fenoles/efectos adversos , Ácidos Ftálicos/orina , Embarazo , Adulto , Compuestos de Bencidrilo/orina , Compuestos de Bencidrilo/efectos adversos , Estudios Prospectivos , Exposición Materna/efectos adversos , Contaminantes Ambientales/orina , Disruptores Endocrinos/orina , Adulto Joven , Adiposidad/efectos de los fármacos , CanadáRESUMEN
Variants of coronavirus porcine epidemic diarrhea virus (PEDV) frequently emerge, causing an incomplete match between the vaccine and variant strains, which affects vaccine efficacy. Designing vaccines with rapidly replaceable antigens and high efficacy is a promising strategy for the prevention of infection with PEDV variant strains. In our study, three different types of self-assembled nanoparticles (nps) targeting receptor-binding N-terminal domain (NTD) and C-terminal domain (CTD) of S1 protein, named NTDnps, CTDnps, and NTD/CTDnps, were constructed and evaluated as vaccine candidates against PEDV. NTDnps and CTDnps vaccines mediated significantly higher neutralizing antibody (NAb) titers than NTD and CTD recombinant proteins in mice. The NTD/CTDnps in varying ratios elicited significantly higher NAb titers when compared with NTDnps and CTDnps alone. The NTD/CTDnps (3:1) elicited NAb with titers up to 92.92% of those induced by the commercial vaccine. Piglets immunized with NTD/CTDnps (3:1) achieved a passive immune protection rate of 83.33% of that induced by the commercial vaccine. NTD/CTDnps (3:1) enhanced the capacity of mononuclear macrophages and dendritic cells to take up and present antigens by activating major histocompatibility complex I and II molecules to stimulate humoral and cellular immunity. These data reveal that a combination of S1-NTD and S1-CTD antigens targeting double receptor-binding domains strengthens the protective immunity of nanoparticle vaccines against PEDV. Our findings will provide a promising vaccine candidate against PEDV.
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Nanopartículas , Virus de la Diarrea Epidémica Porcina , Vacunas Virales , Virus de la Diarrea Epidémica Porcina/inmunología , Animales , Nanopartículas/química , Porcinos , Ratones , Vacunas Virales/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/inmunología , Ratones Endogámicos BALB C , Antígenos Virales/inmunología , Antígenos Virales/química , Anticuerpos Neutralizantes/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Dominios Proteicos/inmunología , Femenino , NanovacunasRESUMEN
pH-mediated drug-drug interactions (DDI) is a prevalent DDI in drug development, especially for weak base compounds with highly pH-dependent solubility. FDA has released a guidance on the evaluation of pH-mediated DDI assessments using in vitro testing and clinical studies. Currently, there is no common practice of ways of testing across the academia and industry. The development of biopredictive method and physiologically-based biopharmaceutics modeling (PBBM) approaches to assess acid-reducing agent (ARA)-DDI have been proven with accurate prediction and could decrease drug development burden, inform clinical design and potentially waive clinical studies. Formulation strategies and careful clinical design could help mitigate the pH-mediated DDI to avoid more clinical studies and label restrictions, ultimately benefiting the patient. In this review paper, a detailed introduction on biorelevant dissolution testing, preclinical and clinical study requirement and PBPK modeling approaches to assess ARA-DDI are described. An improved decision tree for pH-mediated DDI is proposed. Potential mitigations including clinical or formulation strategies are discussed.
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BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.
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Antígeno B7-H1 , Membrana Celular , Glucógeno Sintasa Quinasa 3 beta , Inhibidores de la Bomba de Protones , Inhibidores de la Bomba de Protones/farmacología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fosforilación , Humanos , Ratones , Membrana Celular/metabolismo , Ratones Endogámicos C57BL , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
We often rely on descriptive norm perceptions as a mental shortcut for decision making. However, less is known about how such perceptions are shaped and modified by our experiences in day-to-day life. The interactive nature of the current media environment offers opportunities for individuals to access others' health behavior choices through online user-generated content. Within a setting of online comment boards, the current study examined the descriptive norm perception modification process toward vaping with a large-scale experiment that systematically varied levels of exposure to online commenters' vaping behavior choice indications. Findings revealed a significant positive effect of behavior prevalence on descriptive norm perceptions, which in turn were positively associated with vaping intention. This set of results was observed only when a sufficient total amount of comment exposures was ensured. The study provided empirical evidence for the underlying mechanism of the "quasi-statistical sense," which helps people draw conclusions about behavior prevalence and may influence their behavioral decision making. Theoretical and practical implications are discussed.
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The increasing global prevalence of gestational diabetes mellitus (GDM) has been hypothesized to be associated with maternal exposure to environmental chemicals. Here, among 420 women participating in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study, we examined associations between GDM and second trimester blood or urine concentrations of endocrine disrupting chemicals (EDCs): bisphenol-A (BPA), bisphenol-S (BPS), twelve phthalate metabolites, eight perfluoroalkyl acids (PFAAs), and eleven trace elements. Fifteen (3.57%) of the women were diagnosed with GDM, and associations between the environmental chemical exposures and GDM diagnosis were examined using multiple logistic and LASSO regression analyses in single- and multi-chemical exposure models, respectively. In single chemical exposure models, BPA and mercury were associated with increased odds of GDM, while a significant inverse association was observed for zinc. Double-LASSO regression analysis selected mercury (AOR: 1.51, CI: 1.12-2.02), zinc (AOR: 0.017, CI: 0.0005-0.56), and perfluoroundecanoic acid (PFUnA), a PFAAs, (AOR: 0.43, CI: 0.19-0.94) as the best predictors of GDM. The combined data for this Canadian cohort suggest that second trimester blood mercury was a robust predictor of GDM diagnosis, whereas blood zinc and PFUnA were protective factors. Research into mechanisms that underlie the associations between mercury, zinc, PFUnA, and the development of GDM is needed.
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Compuestos de Bencidrilo , Diabetes Gestacional , Disruptores Endocrinos , Contaminantes Ambientales , Fluorocarburos , Exposición Materna , Fenoles , Ácidos Ftálicos , Femenino , Humanos , Embarazo , Fluorocarburos/sangre , Diabetes Gestacional/epidemiología , Diabetes Gestacional/sangre , Fenoles/sangre , Fenoles/orina , Adulto , Compuestos de Bencidrilo/sangre , Compuestos de Bencidrilo/orina , Ácidos Ftálicos/orina , Ácidos Ftálicos/sangre , Disruptores Endocrinos/sangre , Disruptores Endocrinos/orina , Exposición Materna/efectos adversos , Contaminantes Ambientales/sangre , Estudios de Cohortes , Oligoelementos/sangre , Oligoelementos/orina , Ácidos Alcanesulfónicos/sangre , Adulto Joven , SulfonasRESUMEN
The diagnosis of primary lung adenocarcinomas with intestinal or mucinous differentiation (PAIM) remains challenging due to the overlapping histomorphological, immunohistochemical (IHC), and genetic characteristics with lung metastatic colorectal cancer (lmCRC). This study aimed to explore the protein biomarkers that could distinguish between PAIM and lmCRC. To uncover differences between the two diseases, we used tandem mass tagging-based shotgun proteomics to characterize proteomes of formalin-fixed, paraffin-embedded tumor samples of PAIM (n = 22) and lmCRC (n = 17).Then three machine learning algorithms, namely support vector machine (SVM), random forest, and the Least Absolute Shrinkage and Selection Operator, were utilized to select protein features with diagnostic significance. These candidate proteins were further validated in an independent cohort (PAIM, n = 11; lmCRC, n = 19) by IHC to confirm their diagnostic performance. In total, 105 proteins out of 7871 proteins were significantly dysregulated between PAIM and lmCRC samples and well-separated two groups by Uniform Manifold Approximation and Projection. The upregulated proteins in PAIM were involved in actin cytoskeleton organization, platelet degranulation, and regulation of leukocyte chemotaxis, while downregulated ones were involved in mitochondrial transmembrane transport, vasculature development, and stem cell proliferation. A set of ten candidate proteins (high-level expression in lmCRC: CDH17, ATP1B3, GLB1, OXNAD1, LYST, FABP1; high-level expression in PAIM: CK7 (an established marker), NARR, MLPH, S100A14) was ultimately selected to distinguish PAIM from lmCRC by machine learning algorithms. We further confirmed using IHC that the five protein biomarkers including CDH17, CK7, MLPH, FABP1 and NARR were effective biomarkers for distinguishing PAIM from lmCRC. Our study depicts PAIM-specific proteomic characteristics and demonstrates the potential utility of new protein biomarkers for the differential diagnosis of PAIM and lmCRC. These findings may contribute to improving the diagnostic accuracy and guide appropriate treatments for these patients.