Minghua Jiang

Objective: To investigate the association between low fetal fraction (FF) in non‐invasive prenatal testing (NIPT) and pregnancy complications or adverse pregnancy outcomes. Methods: Sixty‐four pregnant women undergoing NIPT at the Second Affiliated Hospital of Wenzhou Medical University between 13 June 2019 and 6 January 2023 had an initial NIPT failure due to low FF. Three cases were lost to follow‐up, leaving 61 cases in the failure group (Group A). Group A was subdivided into 37 cases with a valid result after redraw (Group A1) and 24 cases remaining unsuccessful after redraw (Group A2). Concurrently, 119 pregnancies with successful NIPT (normal FF, no fetal chromosomal abnormalities) were randomly selected as controls (Group C). Logistic regression and XGBoost models were established, and their area under the curve (AUC), sensitivity, and specificity were calculated and compared. Results: The incidence of pre‐eclampsia was significantly higher in Group A than in Group C ( p < 0.05). No significant difference in the incidence of pre‐eclampsia was found between Groups A1 and A2. A logistic regression model incorporating FF predicted pre‐eclampsia with an AUC of 0.750 (95% CI: 0.639–0.860), sensitivity of 0.875, and specificity of 0.727. An XGBoost model incorporating 10 factors (FF, age, weight, BMI, gestational age, systolic/diastolic blood pressure at sampling, ART history, delivery history, heparin use history) demonstrated superior performance (AUC = 0.956, 95% CI: 0.868–1.000; accuracy = 0.944). The top three important factors were systolic blood pressure, diastolic blood pressure, and FF. Conclusions: Low FF in NIPT may indicate an increased risk of pre‐eclampsia. Regardless of the success of redraw, pregnancies with initial NIPT failure due to low FF warrant vigilance for pre‐eclampsia development. The XGBoost machine learning model demonstrates good efficacy for predicting pre‐eclampsia and has potential as an adjunctive prenatal screening tool for early diagnosis.

Reshaping metabolic compartmentalization is frequently observed in cancer cells, however, the underlying mechanisms and physiological implications are less known. Here, we show that pancreatic ductal adenocarcinoma (PDAC) patients with low integral membrane protein SMIM4 expression exhibits a poor prognosis and reduces oxidative stress in tumors, which can be confirmed in cultured human PDAC cells and mice Pdx1-Cre/Kras^G12D/+/Trp53R^172H/+ (KPC) cells. Mechanistically, SMIM4 interacts with and facilitates the assembly of SLC25A1-containing complexes, enabling SLC25A1-mediated malate/citrate exchange. Depleting SMIM4 has little effect on mitochondrial respiration but impairs the assembly of SLC25A1-containing complexes, thereby reshaping of malate compartmentalization. This shift promotes NADPH generation through increased cytosolic conversion of malate to pyruvate, protecting cells from glucose deprivation-induced apoptosis. Moreover, PDAC cells with low level of SMIM4 are resistant to RSL3-induced toxicity, indicating that PDAC tumors with high SMIM4 expression are promising candidates for treatment with oxidative stress inducers.

KRAS-driven metabolic reprogramming is a known peculiarity features of pancreatic ductal adenocarcinoma (PDAC) cells. However, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed significantly elevated expression of YY1 in human PDAC tissues, which positively correlated with a poor disease progression. Furthermore, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion led to impaired mitochondrial RNA expression, which further inhibited mitochondrial oxidative phosphorylation (OXPHOS) complex assembly and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function reduced the generation of aspartate, an output of the tricarboxylic acid cycle (TCA), and resulted in the inhibition of cell proliferation owing to unavailability of aspartate-associated nucleotides. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Our findings suggest that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. Thus, targeting nucleotide biosynthesis is a promising strategy for PDAC treatment.

To identify the clinical phenotypic and molecular pathogeneses of four cases of coagulation factor XII deficiency and to deepen the cognition of this disease.Coagulation tests were performed throug...

Background: Platelets occupy a prominent place in tumor proliferation and metastasis, and platelet count is relevant to the prognosis of tumor patients. But preoperative platelet counts cannot be standardized and individualized due to the variability among individuals, instruments, and regions, and the connection between postoperative platelet count and prognosis remains unknown. A standardized indicator of platelet count was designed to forecast the prognosis of colorectal cancer (CRC).Methods: Five hundred and eighty six patients who suffered radical resection of CRC between 2013 and 2019 were collected. A development‐validation cohort of standardized and individualized platelet counts for prognostic assessment of CRC was designed. We first determined the ability of PPR and other peripheral blood count‐related indicators to predict the mortality of patients with CRC and validated them in a separate cohort. Kaplan–Meier analysis was executed to evaluate the survival and univariate and multivariate analyses were executed to explore the relevance. Time‐dependent ROC was measured to estimate the predictive usefulness. Decision curve analysis was used to verify the clinical net benefit.Results: Important baseline variables showed a similar distribution in two independent queues. In the development cohort, postoperative platelet count and postoperative/preoperative platelets ratio (PPR) were independent predictors of prognosis in CRC patients. PPR showed the largest area under the curve (AUC) in evaluating 1‐year and 5‐year OS (AUC: 0.702 and 0.620) compared to others. In the validation cohort, platelet/lymphocyte ratio and PPR were validated to be independently concerned about OS of CRC patients and PPR showed the largest AUC in evaluating 1‐year and 3‐year OS (AUC: 0.663 and 0.673). PPR and joint index of platelet count and PPR showed better predictive value and clinical net benefit.Conclusions: PPR has been identified and validated to be independently concerned about OS of patients with CRC and was a reliable and economic indicator to evaluate the prognosis.

To analyze the phenotype and genotype of two Chinese family with inherited dysfibrinogenemia and the molecular pathogenic mechanism. In the probands and their family members, coagulation routine, fibrinogen activity (Fg: A) and fibrinogen antigen (Fg: Ag) were detected. To find the mutation and exclude single nucleotide polymorphisms, all the exons and exons-intron boundaries of fibrinogen genes (FGA, FGB and FGG) were amplified by Ploymerase Chain Reaction (PCR), then sequenced. Bioinformatics prediction softwares were used to predict and score the change of function caused by the variant. PyMol were used to analyze the structure of protein caused by the variant. Clustal X software was used to analyze the conservation of the mutant amino acids. The thrombin time (TT) of the two was slightly prolonged and could not be corrected by protamine sulfate, and the fibrinogen activity was significantly reduced (1.25 g/L and 1.17 g/L), but the fibrinogen antigen content was normal, respectively (3.50 g /L and 3.81 g/L). Genetic analysis showed that both probands were heterozygous missense variants (FGB exon 7 c.1115T>A (p.Val372Glu)), both of which originated from the paternal line. The prediction results of the four bioinformatics softwares indicate that this variant could be disease causing. Clustal X software showed that Val372 is highly conserved among homologous species. Based on the guidelines of the American College of Medical Genetics and Genomics, c.1115T>A was predicted to be likely pathgenic (PM2+PP1+PP2+PP3+PP4). PyMol showed that the secondary structure and three-dimensional structure of fibrinogen protein were changed by p.Val372Glu variant. Inherited dysfibrinogenemia of the probands maybe caused by variant of FGB c.1115 T>A (p.Val372Glu), and the variant was firstly reported.

Objective: Sepsis remains a major cause of neonatal death. To better characterize the inflammatory response during neonatal sepsis, we compared the differences in serum cytokines and chemokines between full-term neonates with sepsis and without infection. Methods: We enrolled 40 full-term neonates with sepsis and 26 full-term neonates without infection as controls between October 2016 and June 2018. Forty cytokines /chemokines in serum were analyzed using the Luminex Bead Immunoassay System. Results: Our results showed that serum IL-6, IL-8, TNF-α, IL-1β, MIF, CXCL13, CXCL1, CXCL2, CXCL5, CXCL6, CXCL16, CCL27, CCL2, CCL8, CCL3, CCL20, CCL23, and CX3CL1 levels were significantly increased in neonates with sepsis compared to those in the control group (all p< 0.05). The levels of serum CCL20, and IL-17 were higher in late-onset sepsis (LOS) than those in early-onset sepsis (EOS) (all p< 0.05). Conversely, serum CXCL16 was lower in LOS than that in EOS (p< 0.05). Conclusion: Our findings revealed that excessive pro-inflammatory cytokines might be involved in neonatal sepsis. In addition, chemokines significantly increased the recruitment of immune cells after infection to participate in the anti-infection defense of neonates, but this could lead to damage.