Continuous subcutaneous insulin infusion versus multiple daily injection therapy in pregnant women with type 1 diabetes.

INTRODUCTION: The study aimed to compare glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus (T1DM) using multiple daily injection therapy (MDI) and continuous subcutaneous insulin infusion (CSII) and to compare outcomes of women treated with long-acting insulin or neutral protamine Hagedorn (NPH). METHODS: This multicenter prospective cohort study involved women with pregestational T1DM treated with MDI and CSII. Primary outcome was glycated hemoglobin (HbA1c) before and during pregnancy. Secondary outcomes included maternal and neonatal outcomes and quality of life. RESULTS: Of the 121 studied women, the average age was 28.48 years, and the average body mass index was 21.29 kg/m2 at conception and 26.32 kg/m2 at delivery. Of the studied women, 78.51% had planned pregnancy. Women treated with MDI and CSII had comparable HbA1c before pregnancy or in the first and second trimesters. In the third trimester, women on CSII therapy had significantly lower HbA1c (6.07 ± 0.62 vs 6.20 ± 0.88%, p = .017), higher HbA1c on-target rate (71.43% vs 64.62%, p = .030), and greater decline of HbA1c from preconception to the third trimester (-0.65 vs -0.30%, p = .047). Fewer daily insulin requirements were observed in those used CSII compared with MDI-treated women (0.60 ± 0.22 vs 0.73 ± 0.25 U/kg/day, p = .004). Newborns born of mothers treated with the CSII method were more likely to have neonatal jaundice (adjusted odds ratio [OR] 2.76, 95% confidence interval [CI] 1.16-6.57) and neonatal intensive care unit (adjusted OR 3.73, 95%CI 1.24-11.16), and women on CSII had lower scores in patient-reported quality of life (p = .045). In the MDI group, those receiving long-acting insulin had nonsignificant lower HbA1c and higher HbA1c on-target rate in the second and third trimesters, compared with those treated with NPH. CONCLUSIONS: Insulin pump users may achieve better glycemic control than multiple daily insulin injections, which did not substantially improve pregnancy outcome.

Preconception episodes of severe hypoglycemia and risk of adverse pregnancy outcomes in pregnant women with type 1 diabetes mellitus.

AIMS: To explore the relationship between preconception severe hypoglycemia (PSH) and pregnancy outcomes in pregnancies complicated with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: In this multicenter prospective cohort study, women with pregestational T1DM were stratified by episodes of severe hypoglycemia within 1 year before conception: No PSH, sporadic PSH (1-6 times/year), and recurrent PSH (>6 times/year). We analysed the predictive ability of PSH for maternal and neonatal outcomes using log-binomial regression models and receiver operating characteristic (ROC) curve. RESULTS: Of the 124 women studied, 37.1% experienced at least one episode of severe hypoglycemia preconception. In the multiple adjusted regression models, recurrent PSH was significantly associated with increased incidence of preeclampsia (RR 17.59, 95% CI: 2.89-150.62, p for trend = 0.007), preterm birth (RR 6.34, 95% CI: 1.22-40.63, p for trend = 0.027), neonatal hypoglycemia (RR 4.52, 95% CI: 1.14-17.16, p for trend = 0.017), neonatal hyperbilirubinemia (RR 4.12, 95% CI: 1.11-15.56, p for trend = 0.004), and composite neonatal outcome (RR 3.85, 95% CI: 1.01-19.61, p for trend = 0.003). In the ROC analysis, PSH predicted preeclampsia, preterm birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and composite neonatal outcome with areas under the ROC curve all ≥0.6. CONCLUSIONS: Recurrent preconception severe hypoglycemia is associated with increased risks of adverse outcomes in pregnant women with T1DM.

Clinical Significance and Immune Infiltration Analyses of a Novel Nerve-Related lncRNA Signature in Gastric Cancer.

Gastric cancer (GC) is a progressive disease with high morbidity and mortality. Accumulating evidence indicated that nervous system-cancer crosstalk can affect the occurrence and progression of GC. However, the role of nerve-related lncRNAs (NRLs) in GC remains largely unexplored. In this study, a total of 441 nerve-related genes were collected from the KEGG database, and two approaches, unsupervised clustering and WGCNA, were employed to identify NRLs. Lasso regression analysis was then used to construct the nerve-related lncRNA signature (NRLS). Based on the expression profiles of 5 lncRNAs, we developed a stable NRLS to predict survival in GC patients, and survival analyses showed significantly shorter overall survival (OS) in patients with high NRLS. In addition, the NRLS was found to be positively correlated with immune characteristics, including tumor-infiltrating immune cells, immune modulators, cytokines and chemokines. We then analyzed the role of NRLS in predicting chemotherapy and immunotherapy responses, and constructed the OS nomogram combining NRLS and other clinical features. In conclusion, we constructed a robust NRLS model to stratify GC patients and predict the outcomes of chemotherapy and immunotherapy. This study can provide a new perspective for future individualized treatment of GC.

Trail Formation Alleviates Excessive Adhesion and Maintains Efficient Neutrophil Migration.

Migrating neutrophils are found to leave behind subcellular trails in vivo, but the underlying mechanisms remain unclear. Here, an in vitro cell migration test plus an in vivo observation was applied to monitor neutrophil migration on intercellular cell adhesion molecule-1 (ICAM-1) presenting surfaces. Results indicated that migrating neutrophils left behind long-lasting, chemokine-containing trails. Trail formation tended to alleviate excessive cell adhesion enhanced by the trans-binding antibody and maintain efficient cell migration, which was associated with differential instantaneous edge velocity between the cell front and rear. CD11a and CD11b worked differently in inducing trail formation with polarized distributions on the cell body and uropod. Trail release at the cell rear was attributed to membrane ripping, in which ß2-integrin was disrupted from the cell membrane through myosin-mediated rear contraction and integrin-cytoskeleton dissociation, potentiating a specialized strategy of integrin loss and cell deadhesion to maintain efficient migration. Moreover, neutrophil trails left on the substrate served as immune forerunners to recruit dendritic cells. These results provided an insight in elucidating the mechanisms of neutrophil trail formation and deciphering the roles of trail formation in efficient neutrophil migration.

Neutralization heterogeneity of circulating SARS-CoV-2 variants to sera elicited by a vaccinee or convalescent.

COVID-19, which was first reported in December 2019 in China, has caused a global outbreak. Five variants of concern (VOCs) have been identified in different countries since the global pandemic, namely, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.529). Although multiple vaccines have been found to be effective, some of the amino acid changes may increase the infectivity of virus and decrease the sensitivity to antibodies. Here we characterize the VOCs and discuss their sensitivity to antibodies elicited by convalescent and vaccinee sera. In conclusion, several variants display a reduction in the susceptibility to neutralization antibodies generated by natural infection or vaccination, which threatens the containment of the epidemic.

Bioinformatic Analysis of Hepatocellular Carcinoma Cell Lines to the Efficacy of Nimotuzumab.

INTRODUCTION: Hepatocellular carcinoma (HCC) continues to be a cancer with rising incidence, high mortality, and recurrence rate. The therapeutic effects on HCC are not satisfactory currently. Epidermal growth factor receptor (EGFR) is an important factor, while anti-EGFR agencies have not shown ideal results in HCC. MATERIALS AND METHODS: We tested efficacy of nimotuzumab and EGFR expression on cell surface in six HCC cell lines (Hep 3B2.1-7, Li-7, PLC/PRF/5, SK-HEP-1, SNU-182, and SNU-387). Then, we analyzed RNA sequences of every cell line and performed a bioinformatic analysis. Differentially expressed genes (DEGs) were analyzed. The data, TCGA-LIHC from The Cancer Genome Atlas (TCGA) and GSE102079 from Gene Expression Omnibus (GEO), were used to analyse DEGs of Hoshida subclass. RESULTS: Hep 3B2.1-7 and PLC/PRF/5 were sensitive to nimotuzumab whereas Li-7, SK-HEP-1, SNU-182, and SNU-387 cell lines were resistant. Then, we compared the DEGs between sensitive and resistant group cell lines. We enriched DEGs in GO and KEGG and performed GSEA in each group. Genes in two groups did not show obvious different expressions in EGFR pathways, while Hoshida subclass of HCC seemed to associate with the efficacy of nimotuzumab in that S2 and S3 showed better therapeutic effect than S1. Therefore, we analyzed genes in human tumor samples which were from TCGA-LIHC and GSE102079. We found that COL1A1, COL1A2, COL3A1, and MMP9 were the focus DEGs of S1 and S2 & S3 related to EGFR. CONCLUSION: The efficacy of nimotuzumab in HCC did not show direct relevance with EGFR protein expression and EGFR-related pathway. However, efficacy could associate with Hoshida subclass of HCC. Three ECM genes (COL1A1, COL1A2, COL3A1) and MMP9 were paid attention, as they might play important roles in the curative effect of nimotuzumab in HCC.

Binding of intercellular adhesion molecule 1 to ß2-integrin regulates distinct cell adhesion processes on hepatic and cerebral endothelium.

Flowing polymorphonuclear neutrophils (PMNs) are forced to recruit toward inflamed tissue and adhere to vascular endothelial cells, which is primarily mediated by the binding of ß2-integrins to ICAM-1. This process is distinct among different organs such as liver and brain; however, the underlying kinetic and mechanical mechanisms regulating tissue-specific recruitment of PMNs remain unclear. Here, binding kinetics measurement showed that ICAM-1 on murine hepatic sinusoidal endothelial cells (LSECs) bound to lymphocyte function-associated antigen-1 (LFA-1) with higher on- and off-rates but lower effective affinity compared with macrophage-1 antigen (Mac-1), whereas ICAM-1 on cerebral endothelial cells (BMECs or bEnd.3 cells) bound to LFA-1 with higher on-rates, similar off-rates, and higher effective affinity compared with Mac-1. Physiologically, free crawling tests of PMN onto LSEC, BMEC, or bEnd.3 monolayers were consistent with those kinetics differences between two ß2-integrins interacting with hepatic sinusoid or cerebral endothelium. Numerical calculations and Monte Carlo simulations validated tissue-specific contributions of ß2-integrin-ICAM-1 kinetics to PMN crawling on hepatic sinusoid or cerebral endothelium. Thus, this work first quantified the biophysical regulation of PMN adhesion in hepatic sinusoids compared with cerebral endothelium.

Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip.

Physiologically, four major types of hepatic cells - the liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes - reside inside liver sinusoids and interact with flowing peripheral cells under blood flow. It is hard to mimic an in vivo liver sinusoid due to its complex multiple cell-cell interactions, spatiotemporal construction, and mechanical microenvironment. Here we developed an in vitro liver sinusoid chip by integrating the four types of primary murine hepatic cells into two adjacent fluid channels separated by a porous permeable membrane, replicating liver's key structures and configurations. Each type of cells was identified with its respective markers, and the assembled chip presented the liver-specific unique morphology of fenestration. The flow field in the liver chip was quantitatively analyzed by computational fluid dynamics simulations and particle tracking visualization tests. Intriguingly, co-culture and shear flow enhance albumin secretion independently or cooperatively, while shear flow alone enhances HGF production and CYP450 metabolism. Under lipopolysaccharide (LPS) stimulations, the hepatic cell co-culture facilitated neutrophil recruitment in the liver chip. Thus, this 3D-configured in vitro liver chip integrates the two key factors of shear flow and the four types of primary hepatic cells to replicate key structures, hepatic functions, and primary immune responses and provides a new in vitro model to investigate the short-duration hepatic cellular interactions under a microenvironment mimicking the physiology of a liver.

Dynamic contributions of P- and E-selectins to ß2-integrin-induced neutrophil transmigration.

Leukocyte transendothelial migration is a key step in their recruitment to sites of inflammation. However, synergic regulation of endothelium-expressed selectins on leukocyte transmigration remains unclear. In this study, an in vitro model was developed to investigate the dynamic contributions of P- and E-selectin to polymorphonuclear neutrophil (PMN) transmigration under static conditions. Human umbilical vein endothelial cells (HUVECs) were treated with LPS for 4 or 12 h to induce different expression of selectins and intercellular adhesion molecule (ICAM)-1. PMN transmigration was increased significantly by LPS stimulation, which was higher on 4-h than on 12-h LPS-treated HUVECs. Blocking and competitive tests indicated that P-selectin engages PSGL-1 to activate ß2-integrin and initiate PMN transmigration within the first 15 min, whereas E-selectin engages CD44 to influence PMN transmigration after 15 min. P- and E-selectin-induced ß2-integrin activation is likely conducted through the spleen tyrosine kinase signaling pathway. Complicated complementary and competitive mechanisms are involved in the interaction of P-/E-selectins and their ligands to promote PMN transmigration. These results provide direct evidence of the distinct and dynamic contribution of P- and E-selectins in mediating PMN transmigration and give new insight into PMN interaction with the vessel wall.-Gong, Y., Zhang, Y., Feng, S., Liu, X., Lü, S., Long, M. Dynamic contributions of P- and E-selectins to ß2-integrin-induced neutrophil transmigration.