Confirmatory factor analysis including MRI-derived adipose tissues quantification improves associations of metabolic dysregulation to diastolic dysfunction

AimsTo quantify metabolic impairment via a one-factor approach with confirmatory factor analysis (CFA) including MRI-derived visceral and subcutaneous adipose tissues and to associate it with diastolic dysfunction.MethodsIn this cross-sectional analysis, 916 participants (53% female, mean age (SD): 56 (6)) underwent abdominal and cardiovascular MRI. With CFA a metabolic-load factor of metabolic-syndrome variables and visceral and subcutaneous adipose tissues was constructed. A piecewise structural equation model approach with adjustment for confounding factors was used to determine associations with left-ventricular diastolic function, cardiac morphology and hemodynamics.ResultsModel fitting excluding blood pressure and waist circumference but including visceral and subcutaneous adipose tissues, fasting glucose, HDL-c and triglycerides was used to construct the metabolic-load factor. Evaluating measurement invariance demonstrated sex-specificity. Change in mitral early/late peak filling rate ratio was ?0.12 for both males [?0.20; ?0.05, p > 0.05] and females [?0.17; ?0.07, p > 0.001] per SD of metabolic-load factor. Change in deceleration time of mitral early filling was ?11.83ms only in females [?17.38; ?6.27, p > 0.001] per SD of metabolic-load factor.ConclusionA single latent metabolic-load factor via CFA including MRI-derived adipose tissues increased sensitivity for metabolic impairment obsoleting waist circumference and is associated with a decreased left-ventricular diastolic function, more apparent in females than in males.     

Expression of Gadd45α in human early placenta and its role in trophoblast invasion

Objectives

Well-controlled trophoblast migration and invasion at the maternal–foetal interface are crucial events for normal placentation and successful pregnancy. Growing evidence has revealed that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) participates in tumour migration and invasion as a tumour suppressor. However, the expression and function of Gadd45α in trophoblasts is unknown. This study aimed to determine the Gadd45α expression and function in the human first trimester placenta and identify the underlying mechanisms.

Methods

The expression of Gadd45α in human first trimester placenta was determined using immunohistochemistry. HTR8/SVneo cell line was used to investigate the effects of Gadd45α on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP)2/9 activities, and tissue inhibitor of metalloproteinase (TIMP)1/2 expression using cell proliferation assays, flow cytometric analysis, transwell migration/invasion assays, gelatin gel zymography, and western blotting, respectively. Moreover, a placental villous explant model was employed to verify its functions in placentation.

Results

Gadd45α was strongly expressed in syncytiotrophoblasts and trophoblast columns of human placental villi, extravillous trophoblast cells and glandular epithelium within the maternal decidua. Gadd45α knockdown significantly promoted migration and invasion of HTR8/SVneo cells, whereas it did not affect cell proliferation or apoptosis. Silencing Gadd45α also enhanced trophoblast outgrowth and migration in placental explants. These effects were related to increased activities of MMP2/9 and the decreased expression of TIMP1/2.

Discussion and conclusion

Gadd45α may be involved in human trophoblast migration and invasion and may function as an important negative regulator at the foetal–maternal interface during early pregnancy by directly or indirectly regulating MMP2/9 activities.     

Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression

IntroductionPlacental development involves the variation of oxygen supply due to vascular changes and cytotrophoblast invasion. Chemokines and their receptors play an important role during placental formation. Herein, the analysis of the chemokine/receptor pair CXCL12/CXCR4 and further chemokine receptors, such as CCR1, CCR7 and CXCR6 expression in human cytotrophoblasts was conducted.MethodsHuman cytotrophoblasts were examined directly after isolation or after incubation with different oxygen tensions and a chemical HIF-stimulator for 12 h with realtime PCR, immunoblot, immunohistochemistry. Conditioned media of placental villi, decidua, and endothelial cells was used for ELISA analysis of CXL12. Cytotrophoblast migration assays were conducted applying conditioned media of endothelial cells, a CXCL12 gradient, and different oxygen level. Endometrial and decidual tissue was stained for CXCL12 expression.ResultsAn upregulation of CXCL12, CXCR4, CCR1, CCR7 and CXCR6 was observed after cytotrophoblast differentiation. Low oxygen supply upregulated CXCR4, CCR7 and CXCR6, but downregulated CXCL12 and CCR1. In contrast to the HIF associated upregulation of the aforementioned proteins, downregulation of CXCL12 and CCR1 seemed to be HIF independent. Cytotrophoblast migration was stimulated by low oxygen, the application of a CXCL12 gradient and endothelial cell conditioned media. CXCL12 was detected in endometrial vessels, glands and conditioned media of placental and decidual tissue, but not decidual vessels.Discussion/conclusionTaken together, oxygen supply and cytotrophoblast differentiation seem to be regulators of chemokine and receptor expression and function in human cytotrophoblasts. Therefore, this system seems to be involved in placental development, directed cytotrophoblast migration in the decidual compartment and a subsequent sufficient supply of the growing fetus.     

MiR-136 contributes to pre-eclampsia through its effects on apoptosis and angiogenesis of mesenchymal stem cells

IntroductionMesenchymal stem cells (MSCs) play an important role in the pathology of preeclampsia (PE). The survival of MSCs and angiogenesis in the maternal-fetal interface are important for a successful pregnancy. MicroRNA-136 (miR-136) is highly expressed in decidua-derived MSCs (MSCs) from PE compared with healthy donors (NC). The role of the MSCs aberrant expressed miR-136 in PE development is still unclear. In the present study, we examined the impact of miR-136 on the survival of MSCs and angiogenesis in the maternal-fetal interface.MethodsMSCs were extracted and transfected with miR-136 mimic and interfering RNAs using lipofectamine-2000. Then cell apoptosis were tested using flow cytometry. HUVEC tube formation ability was tested on Matrigel co-cultured with conditioned MSCs supernatants.ResultsHigh level of miR-136 could suppress cell proliferation and promote apoptosis of MSCs through targeting BCL2. It could also impairs HUVEC capillary formation by suppressing VEGF.DiscussionMiR-136 significantly increase the apoptosis and suppress the proliferation of MSCs. It could also inhibit the capillary formation and trophoblast cell invasion. These data suggest that decidua-derived miR-136 that is increased in PE is a potential causal factor of PE.     

Clinical outcomes of unrelated cord blood transplantation in children with malignant and non‐malignant diseases: Multicenter experience in China

This multicenter retrospective study included 184 children with malignant and non‐malignant diseases who underwent UCBT between January 1998 and August 2012. The malignant disease group included 101 children with ALL, AML, CML, JMML, and MDS, and the non‐malignant disease group included 83 children with PID, β‐thalassemia, IMD BMF, and HLH. The median duration to neutrophil and platelet engraftment was 16 and 35 days in the malignant disease group vs 15 and 38 days in the non‐malignant disease group. The cumulative incidence of grade II‐IV aGVHD and cGVHD was 25.6% and 13.5% in the malignant disease group vs 19.7% and 11.1% in the non‐malignant disease group, respectively. The median duration and cumulative incidence of neutrophil and platelet engraftment, and the cumulative incidence of grade II‐IV aGVHD and cGVHD were similar between the two groups. Of the 184 pediatric patients, 114 patients survived during a median follow‐up period of 14 months (range 4‐138). The 5‐year OS and DFS were not statistically different between the two groups (56.3% and 46.1% in malignant disease group vs 68.5% and 52.8% in non‐malignant disease group). The above results indicate that UCB is a viable source for HSCT for children with malignant or non‐malignant diseases, especially in urgent cases.     

Monitoring the efficacy of infant hepatitis B vaccination and revaccination in 0- to 8-year-old children: Protective anti-HBs levels and cellular immune responses

Vaccination against hepatitis B virus (HBV) is recommended worldwide. The aim of this study was to assess the efficacy of infant hepatitis B vaccination and revaccination in 0- to 8-year-old children in the context of protective anti-HBs levels and cellular immune responses. Using a random questionnaire survey, 1695 pre-school children were recruited as research subjects during January 2015 to June 2017. Blood samples were obtained to measure HBV serological markers as well as peripheral immunocytes. The children were divided into non-, low- and hyper- responsive groups (NR, LR, and HR) based on the vaccination efficacy. Additionally, the effect of revaccination on the NR group was evaluated at 1 month after completion of the vaccination course. Among a total of 1695 children, 1591 (93.86%) were infants who were followed while undergoing their primary course of hepatitis B vaccination at the 0-1-6 month schedule, and 1249 (79.30%) of them developed antibodies against HBsAg (anti-HBs) titers greater than 10 IU/L. The results of immunocyte studies indicated that the CD8⁺ T cells, CD4⁺CD45RO⁺ T cells, CD8⁺CD45RA⁺ T cells, and T follicular helper (Tfh) cells increased significantly in NR compared with HR. However, lymphocytes, CD4⁺ T cells, and CD4⁺CD45RA⁺ T cells in NR were lower than that in HR. 96 of the non-response cases showed seroprotection after revaccination among 103 cases. Therefore, most of the preschool children who received hepatitis B vaccine in infancy achieved significant seroprotection. Seroconversion rates of individuals revaccinated after initial vaccination failure were significantly higher than those after primary vaccination. Different vaccination efficacy groups showed significant changes in circulating immunocytes, which might be a factor affecting the recombinant HBV vaccine’s immune effectiveness.     

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the management of peritoneal surface malignancies – An evidence-based review

Background: Traditionally, peritoneal surface malignancies (PSM) were considered terminal diseases because of their advanced nature, therefore, systemic chemotherapy was given with palliative intent only. As a result, very poor survival outcomes were observed. But with the introduction of complete Cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC), the scenario has changed dramatically. Methodology: An objective electronic database search was performed in Pubmed, NLM Catalog, Google scholar, Bookshelf, and Pubmed Central published in the time period from 2000 till 2020. All the randomized studies were included. In the absence of randomized studies, both prospective and retrospective studies were included. The outcomes of HIPEC were measured in terms of median survival, disease-free survival, overall survival, complications and drug toxicities. Results: CRS and HIPEC are considered the standard of care for PMP and MPM even in the absence of level 1 evidence due to lack of an effective alternative treatment. In colorectal and gastric cancer, several phase-three trials are showing overall survival benefit in selected cases while there is a prophylactic and palliative role of HIPEC in gastric cancer. Three reported phase 3 trials showed positive results in ovarian cancer. In peritoneal sarcomatosis, the role of HIPEC is yet to be proven. Conclusion: The patient selection is the key to the successful outcomes after HIPEC. HIPEC should be performed by the experienced surgeons in specialized centres with a strong critical care and intensive care support to reduce the morbidity and mortality. Ongoing trials and future directions will prove to be an indispensable arm in the oncological armamentarium.