Type 2 diabetes mellitus (T2DM) is often complicated by steatotic liver disease, cardiovascular disease (CVD), and extrahepatic cancer. We investigated whether FIB-4, an indicator of liver fibrosis, ...is associated with a higher risk of CVD and extrahepatic cancer history in T2DM.
Two hundred and nine of 244 diabetics admitted to our center in one year were included and retrospectively evaluated.
One hundred and fifty-two (72.7%) were males and 57 (27.3%) females. The mean age and FIB-4 were 64.3 ± 11 years, and 1.15 ± 0.5, respectively. One hundred and fifty patients (71.8%) had FIB-4 ≤ 1.3, and 59 (28.2%) had FIB-4 > 1.3. A history of CVD was presented in 76 (36.4%) patients, and of extrahepatic cancer in 39 (18.7%). Patients with CVD were significantly older than those without (68.4 ± 8.5 vs. 63.2 ± 11.5 years;
= 0.002), with significantly higher FIB-4 (1.26 ± 0.5 vs. 1.08 ± 0.5;
= 0.012). Patients with cancer were older, with higher FIB-4 compared to those without (68.2 ± 9.5 vs. 64.4 ± 10.9 years;
= 0.098 and 1.37 ± 0.6 vs. 1.1 ± 0.5;
= 0.004, respectively). FIB-4 > 1.3 was associated with a 2.1-fold probability for CVD (χ
= 5.810;
= 0.025) and 2.7-fold probability for cancer history (χ
= 7.603;
= 0.01).
FIB-4 ≥ 1.3 is associated with a higher probability of CVD or extrahepatic cancer history. FIB-4 could potentially discriminate patients at risk, justifying stricter surveillance.
Prenatal challenges such as maternal stress perception increase the risk and severity of asthma during childhood. However, insights into the trajectories and targets underlying the pathogenesis of ...prenatally triggered asthma are largely unknown. The developing lung and immune system may constitute such targets.
Here we have aimed to identify the differential sex-specific effects of prenatal challenges on lung function, immune response, and asthma severity in mice.
We generated bone marrow chimeric (BMC) mice harboring either prenatally stress-exposed lungs or a prenatally stress-exposed immune (hematopoietic) system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNA sequencing) of lungs and assessment of airway epithelial barrier function in ovalbumin-sensitized control and prenatally stressed offspring was also performed.
Profoundly enhanced airway hyperresponsiveness, inflammation, and fibrosis were exclusively present in female BMC mice with prenatally stress-exposed lungs. These effects were significantly perpetuated if both the lungs and the immune system had been exposed to prenatal stress. A prenatally stress-exposed immune system alone did not suffice to increase the severity of these asthma features. RNA sequencing analysis of lungs from prenatally stressed, non-BMC, ovalbumin-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling, and tight junction formation. It was also possible to independently confirm a tight junction disruption. In line with this, we identified an altered perinatal and/or postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice.
Here we have shown that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by a predisposed immune system.
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Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory ...(auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.
We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants.
Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns.
Different adjuvants induce distinct IgG+ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3– follicular helper T (TFH) cell–inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor–dependent IFN-γ+ TFH1 cells, IL-6/IL-23–dependent IL-17A+ TFH17 cells, and high ratios of TFH cells to Foxp3+ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor.
This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.
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Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural ...effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1β, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable.
The current microbiological regulatory criteria in the European Union specify a maximum Listeria monocytogenes population of 100 CFU/g allowable in ready-to-eat foods provided the product will not ...exceed this limit throughout its shelf life. The aim of this study was to validate the manufacturing method for traditional Greek Graviera cheese produced from thermized milk. Initial challenge experiments evaluated the fate of inoculated L. monocytogenes (ca. 4 log CFU/ml, three-strain cocktail) in thermized Graviera cheese milk (TGCM; 63°C for 30 s) in the presence and absence of a product-specific starter culture (SC) in vitro. Milk samples were incubated for 6 h at 37°C and then for 66 h at 18°C. Experiments were conducted to evaluate the fate of a cocktail of three nonpathogenic L. monocytogenes and L. innocua indicator strains inoculated (ca. 3 log CFU/g) in Graviera cheeses commercially manufactured from TGCM+SC. Cheeses were brined, ripened at 18°C and 90% relative humidity for 20 days, and stored at 4°C for up to day 60 under vacuum. In TGCM, L. monocytogenes increased by ca. 2 log units, whereas in TGCM+SC L. monocytogenes growth was retarded (P < 0.05) after a ca. 1-log increase within 6 h at 37°C. Populations of Listeria indicator strains did not grow in TGCM+SC cheeses at any stage; they declined 10-fold in fresh cheeses within 5 days and then survived with little death thereafter. Thus, growth inhibition but not inactivation of potent natural Listeria contaminants at levels below 100 CFU/g occurs in the core of traditional Greek Graviera cheese during fermentation, ripening, and storage.
BACKGROUND: Effector functions of IgG antibodies (Abs) are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the ...severity of inflammatory (auto)immune disorders and have also been linked to the protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.OBJECTIVE: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction upon immunization of mice with a foreign protein antigen and different adjuvants.METHODS: Mice were analyzed for GC T, B cell and plasma cell responses as well as antigen-specific serum IgG subclass titers and Fc glycosylation patterns.RESULTS: Different adjuvants induce distinct IgG+ GC B cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the T follicular helper (TFH) cell-inducing cytokine IL-6, especially induced by water-in-oil adjuvants and Mycobacterium tuberculosis (Mtb). Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27R-dependent IFNγ+ TFH1 cells, IL-6/IL-23-dependent IL-17A+ TFH17 cells and high TFH/T follicular regulatory (TFR) cell ratios. The two latter were here dependent on Mtb and its cord factor.CONCLUSION: These findings on adjuvant-dependent GC responses and IgG glycosylation programming may aid the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns.
Growth of Listeria monocytogenes during processing of traditional Greek Graviera cheese is inhibited, but the pathogen may survive ripening. Therefore, this study used Lactococcus lactis subsp. ...cremoris M104, a nisin A‐producing (NisA+) raw milk isolate, to enhance inactivation of a nonpathogenic Listeria cocktail contaminated in model Graviera mini cheeses. Cheeses were manufactured from thermized milk with a commercial starter culture (CSC) or the CSC plus strain M104 (CSC + M104), ripened at 18 °C and 90% RH for 20 days and stored at 4 °C in vacuum for 60 days. Listeria populations declined 10‐fold in all fermenting cheeses but then survived with little death during ripening and storage. NisA+ M104 colonies were prevalent and the nisA gene was detected, but nisin activity was weak to undetectable, in all CSC + M104 cheeses. Thus, Graviera cheese processing should be optimized to ensure nisA gene expression by strain M104 at levels sufficient to increase inactivation of L. monocytogenes.
Practical applications
This study provided important preliminary evidence that the in situ NisA+ antilisterial activity of L. lactis subsp. cremoris M104 during Graviera cheese fermentation increased by reducing the curd cooking temperature from 48 °C to 42 °C. This indicated the feasibility to increase nisin production and activity by suitably modifying selected technological factors during traditional cooked hard cheese processing. Apart from its bioprotective potential, this NisA+ L. lactis subsp. cremoris genotype (represented by the indigenous strains M104 and M78) possesses desirable sugar fermentation capabilities and enzymatic activities similar to those of the best performing industrial L. lactis or L. cremoris strains in commercial starters (Parapouli et al., ). Since 2015 this novel lactococcal genotype has been applied as hand‐made, costarter culture for the production of commercial Greek Graviera cheeses characterized by specific flavor characteristics and improved textural properties than counterpart cheeses produced with CSCs only (Pappas Bros. collaborating cheese plant, Epirus; private communication).
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