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1.
Tumor Organoid Model and Its Pharmacological Applications in Tumorigenesis Prevention.
Qiang, Y, Yao, N, Zuo, F, Qiu, S, Cao, X, Zheng, W
Current molecular pharmacology. 2023;(4):435-447
Abstract
Cancer is a leading cause of death and a severe threat to global public health. Organoid, as a novel 3D in vitro model, has been applied in various tumor related studies due to its apparent advantages. The organoid is mainly constructed by Matrigel-depended 3D culture system, Air-Liquid Interface (ALI) culture, and Microfluidic culture or Organ-on-chips platform. For the application in carcinogenesis studies, the organoid model may favor depicting initiative hallmarks and identifying potential intervening targets, investigating driver genes of carcinogenesis, and identifying known or unknown risk or protective factors. In this review, we discussed different organoid construction methods and their properties. We also noted that tumor organoids can portray initiative hallmarks and identify possible intervening targets, as well as explore carcinogenesis driver genes and uncover known or unknown risks or protective factors. Organoid systems have been used to identify tumor-preventive drugs such as oligomeric proanthocyanidins, Vitamin D, n-3 PUFAs, and pomegranate. The current evidence underscores the organoid model's potential importance in developing innovative tumorprevention techniques.
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SARS-CoV-2-specific B- and T-cell immunity in a population-based study of young Swedish adults.
Björkander, S, Du, L, Zuo, F, Ekström, S, Wang, Y, Wan, H, Sherina, N, Schoutens, L, Andréll, J, Andersson, N, et al
The Journal of allergy and clinical immunology. 2022;(1):65-75.e8
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Abstract
BACKGROUND Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear. OBJECTIVE We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults. METHODS We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 follow-up. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain-specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2-specific memory B- and T-cell responses were detected for a subpopulation (n = 108) by ELISpot and FluoroSpot. RESULTS A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARS-CoV-2 specific B- and T-cell responses, respectively. B- and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects. CONCLUSIONS Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued.
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Exenatide improves hepatocyte insulin resistance induced by different regional adipose tissue.
Bai, C, Wang, Y, Niu, Z, Guan, Y, Huang, J, Nian, X, Zuo, F, Zhao, J, Kazumi, T, Wu, B
Frontiers in endocrinology. 2022;:1012904
Abstract
Obesity is resulted from energy surplus and is characterized by abnormal adipose tissue accumulation and/or distribution. Adipokines secreted by different regional adipose tissue can induce changes in key proteins of the insulin signaling pathway in hepatocytes and result in impaired hepatic glucose metabolism. This study aimed to investigate whether exenatide affects key proteins of IRS2/PI3K/Akt2 signaling pathway in hepatocytes altered by the different regional fat depots. Six non-obese patients without endocrine diseases were selected as the research subjects. Their subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)were co-cultured with HepG2 cells in the transwell chamber. In the presence or absence of exenatide, adipokines content in the supernatant of each experimental group was detected by ELISA. In addition, HepG2 cells in each co-culture group with and without insulin were collected, and the expression of key proteins IRS2, p-IRS2(S731), PI3K-p85, Akt2, and p-Akt2(S473) was detected by western blotting (WB). The results showed that the adipokines IL-8, MCP-1, VEGF, and sTNFR2 in the supernatant of HepG2 cells induced by different regional adipose tissue were significantly higher than those in the HepG2 group, and VAT released more adipokines than SAT. Furthermore, these adipokines were significantly inhibited by exenatide. Importantly, the different regional fat depot affects the IRS2/PI3K/Akt2 insulin signaling pathway of hepatocytes. Exenatide can up-regulate the expression of hepatocyte proteins IRS2, PI3K-p85, p-Akt2(S731) inhibited by adipose tissue, and down-regulate the expression of hepatocyte proteins p-IRS2(S731) promoted by adipose tissue. The effect of VAT on the expression of these key proteins in hepatocytes is more significant than that of SAT. But there was no statistical difference in the expression of Akt2 protein among each experimental group, suggesting that exenatide has no influence on the expression of Akt2 protein in hepatocytes. In conclusion, exenatide may improve hepatic insulin resistance (IR) by inhibiting adipokines and regulating the expression of key proteins in the IRS2/PI3K/Akt2 pathway.
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Single-Cell Metabolomics in Hematopoiesis and Hematological Malignancies.
Zuo, F, Yu, J, He, X
Frontiers in oncology. 2022;:931393
Abstract
Aberrant metabolism contributes to tumor initiation, progression, metastasis, and drug resistance. Metabolic dysregulation has emerged as a hallmark of several hematologic malignancies. Decoding the molecular mechanism underlying metabolic rewiring in hematological malignancies would provide promising avenues for novel therapeutic interventions. Single-cell metabolic analysis can directly offer a meaningful readout of the cellular phenotype, allowing us to comprehensively dissect cellular states and access biological information unobtainable from bulk analysis. In this review, we first highlight the unique metabolic properties of hematologic malignancies and underscore potential metabolic vulnerabilities. We then emphasize the emerging single-cell metabolomics techniques, aiming to provide a guide to interrogating metabolism at single-cell resolution. Furthermore, we summarize recent studies demonstrating the power of single-cell metabolomics to uncover the roles of metabolic rewiring in tumor biology, cellular heterogeneity, immunometabolism, and therapeutic resistance. Meanwhile, we describe a practical view of the potential applications of single-cell metabolomics in hematopoiesis and hematological malignancies. Finally, we present the challenges and perspectives of single-cell metabolomics development.
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Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease.
Mason, T, Coelho-Filho, OR, Verma, S, Chowdhury, B, Zuo, F, Quan, A, Thorpe, KE, Bonneau, C, Teoh, H, Gilbert, RE, et al
JACC. Cardiovascular imaging. 2021;(6):1164-1173
Abstract
OBJECTIVES This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). BACKGROUND Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown. METHODS This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2. RESULTS Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m2; 95% CI: -2.6 to -0.5 ml/m2; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m2; 95% CI: -3.8 to 0.3 ml/m2; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2. CONCLUSIONS In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).
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Randomized Trial of Oral Iron and Diet Advice versus Diet Advice Alone in Young Children with Nonanemic Iron Deficiency.
Parkin, PC, Borkhoff, CM, Macarthur, C, Abdullah, K, Birken, CS, Fehlings, D, Koroshegyi, C, Maguire, JL, Mamak, E, Mamdani, M, et al
The Journal of pediatrics. 2021;:233-240.e1
Abstract
OBJECTIVE To compare the effects of 2 treatment options on neurodevelopmental and laboratory outcomes in young children with nonanemic iron deficiency. STUDY DESIGN A blinded, placebo-controlled, randomized trial of children 1-3 years with nonanemic iron deficiency (hemoglobin ≥110 g/L, serum ferritin <14 μg/L) was conducted in 8 primary care practices in Toronto, Canada. Interventions included ferrous sulfate or placebo for 4 months; all parents received diet advice. The primary outcome was the Early Learning Composite (ELC) using the Mullen Scales of Early Learning (mean 100, SD 15). Secondary outcomes included serum ferritin. Measurements were obtained at baseline and 4 and 12 months. Sample size was calculated to detect a between-group difference of 6-7 points in ELC. RESULTS At enrollment (n = 60), mean age was 24.2 (SD 7.4) months and mean serum ferritin was 10.0 (SD 2.4) μg/L. For ELC, the mean between-group difference at 4 months was 1.1 (95% CI -4.2 to 6.5) and at 12 months was 4.1 (95% CI -1.9 to 10.1). For serum ferritin, at 4 months, the mean between-group difference was 16.9 μg/L (95% CI 6.5 to 27.2), and no child randomized to ferrous sulfate had a serum ferritin <14 μg/L (0% vs 31%, P = .003). CONCLUSIONS For young children with nonanemic iron deficiency, treatment options include oral iron and/or diet advice. We remain uncertain about which option is superior with respect to cognitive outcomes; however, adding ferrous sulfate to diet advice resulted in superior serum ferritin outcomes after 4 months. Shared decision-making between practitioners and parents may be considered when selecting either option. TRIAL REGISTRATION Clinicaltrials.gov: NCT01481766.
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Advancing mechanistic understanding and bioengineering of probiotic lactobacilli and bifidobacteria by genome editing.
Zuo, F, Marcotte, H
Current opinion in biotechnology. 2021;:75-82
Abstract
Typical traditional probiotics lactobacilli and bifidobacteria are gaining great interest to be developed as living diagnostics and therapeutics for improving human health. However, the mechanistic basis underlying their inherent health beneficial property remain incompletely understood which can slow down the translational pipeline in the functional food and pharmaceutical field. Efficient genome editing will advance the understanding of the molecular mechanism of the probiotics' physiological properties and their interaction with the host and the host microbiota, thereby further promote the development of next-generation designer probiotics with improved robustness and tailored functionalities. With the expansion of genome editing strategies such as CRISPR-Cas-based tools and IPSD assisted genome engineering as well as other synthetic biology technologies, the research and application of these health-promoting bacteria for the food and pharmaceutical industry will be further enhanced.
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Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease.
Mazer, CD, Hare, GMT, Connelly, PW, Gilbert, RE, Shehata, N, Quan, A, Teoh, H, Leiter, LA, Zinman, B, Jüni, P, et al
Circulation. 2020;(8):704-707
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Vision-Related Functioning in Patients Undergoing Pneumatic Retinopexy vs Vitrectomy for Primary Rhegmatogenous Retinal Detachment: A Post Hoc Exploratory Analysis of the PIVOT Randomized Clinical Trial.
Muni, RH, Francisconi, CLM, Felfeli, T, Mak, MYK, Berger, AR, Wong, DT, Altomare, F, Giavedoni, LR, Kohly, RP, Kertes, PJ, et al
JAMA ophthalmology. 2020;(8):826-833
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Abstract
IMPORTANCE Although rhegmatogenous retinal detachment (RRD) repair techniques have high anatomical reattachment rates, there may be differences in various aspects of postoperative vision-related quality of life (VRQoL). OBJECTIVE To explore the differences in various aspects of VRQoL between pneumatic retinopexy (PnR) and pars plana vitrectomy (PPV) following RRD repair. DESIGN, SETTING, AND PARTICIPANTS Post hoc exploratory analysis of the the Pneumatic Retinopexy vs Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes randomized clinical trial conducted between August 2012 and May 2017 at St Michael's Hospital, Toronto, Ontario, Canada. Patients with RRD with a single break or multiple breaks within 1 clock hour of detached retina in the superior 8 clock hours of the retina with any number, location, and size of retinal breaks or lattice degeneration in attached retina. MAIN OUTCOMES AND MEASURES Differences in the 25-Item National Eye Institute Visual Function Questionnaire 12 subscale scores between the PnR and PPV groups at 6 months following RRD repair. RESULTS A total of 160 patients were included in this analysis, with 81 patients (92%) and 79 patients (90%) in the PnR and PPV groups, respectively. The PnR group consisted of 32% women with a mean (SD) age of 60.9 (9.3) years, while the PPV group consisted of 38% women with a mean (SD) age of 60.3 (7.6) years. For the 152 patients with 6-month follow-up (75 patients in PnR [85%] and 77 patients in PPV [88%]), there was evidence for an association of PnR with superior vision-related functioning compared with PPV for several subscales. There were no differences between groups at 1 year. After adjusting for age, sex, baseline macular status, visual acuity in the nonstudy eye, and lens status, patients who underwent PnR had higher scores for distance activities (mean [SD] PnR, 88.7 [13.4]; PPV, 82.8 [17.1]; adjusted difference, 6.5; 95% CI, 1.6-11.4; P = .01), mental health (mean [SD] PnR, 84.3 [17.4]; PPV, 78.7 [21.1]; adjusted difference, 6.7; 95% CI, 0.4-13; P = .04), dependency (mean [SD] PnR, 96.1 [10.1]; PPV, 91.1 [18.6]; adjusted difference, 5.7; 95% CI, 0.6-10.8; P = .03), and peripheral vision (mean [SD] PnR, 91.6 [16.2]; PPV, 81.2 [24.4]; adjusted difference, 10.8; 95% CI, 4.3-17.4; P = .001) at 6 months. CONCLUSIONS AND RELEVANCE These findings demonstrate that patients undergoing PnR for RRD report higher mental health scores and superior vision-related functioning scores in several subscales of the 25-Item National Eye Institute Visual Function Questionnaire during the first 6 months postoperatively compared with PPV. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01639209.
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Engineer probiotic bifidobacteria for food and biomedical applications - Current status and future prospective.
Zuo, F, Chen, S, Marcotte, H
Biotechnology advances. 2020;:107654
Abstract
Bifidobacteria are members of the human gut microbiota and have shown to exert beneficial effects on their host. Certain strains have a long history of safe and effective use as probiotics. Due to the lack of efficient genetic tools, however, little is known about the molecular mechanisms on which these health-promoting properties are based, thus limiting the synthetic biology applications in bifidobacteria. Here, we discuss the recent development of genetic tools and their engagement in engineering bifidobacteria for food and biomedical applications, from eliminating antibiotic resistance mobile elements and improving robustness to preventing pathogen infections and delivering therapeutics for cancer treatment. In addition, we highlight the application of emerging genome engineering techniques for manipulating the bifidobacterial genome. Finally, we provide our perspective on the future development of synthetic biology techniques and programmed probiotic bifidobacteria with enhanced robustness and designer functionalities.