Trophoblast giant cells (TGCs) are the first cell type to terminally differentiate during embryogenesis and are of vital importance for implantation and modulation of post-implantation placentation. TGCs are mononuclear and polyploid but are heterogenous and dynamic. At least four different subtypes of TGCs are present within the mature placenta that have distinct cell lineage origins. The development of TGCs is complex and requires transition from the mitotic to the endoreduplication cell cycle and is regulated by a wide variety of factors. During early gestation, TGCs mediate blastocyst attachment and invasion into the uterine epithelium, regulate uterus decidualization, and anatomosis with maternal blood spaces to form the transient yolk sac placenta. During later gestation, TGCs secrete a wide array of hormones and paracrine factors, including steroid hormones and Prolactin-related cytokines, to target the maternal physiological systems for proper maternal adaptations to pregnancy and the fetal-maternal interface to ensure vasculature remodeling. The large number of mouse mutants with defects in TGC development and function are giving us significant new insights into the biology of these fascinating cells.

Background: CXCR4 chemokine receptors play an important role in leukemia proliferation, extramedullary migration, infiltration, adhesion, and resistance to chemotherapy drugs.Methods: The CXCR4 expression by flow cytometry in 122 acute myeloid leukemia (AML) patients between 2010 and 2014 was analyzed.Results: The expression of CXCR4 in AML‐M4/M5 was found to be significantly higher than that of other subtypes according to both FAB subtype and WHO classification. The FLT3‐ITD mutant was significantly higher in high CXCR4 expression group (P = .0086). Our data also showed that CXCR4 expression was correlated with CD64 expression. Low CXCR4 expression on AML cells was associated with better prognosis, and the median overall survival (OS) for low CXCR4 expression patients was 318 days, compared with 206 days for patients with high CXCR4 expression (P = .045). Multivariate analysis revealed that CXCR4 expression, age, and extramedullary infiltration were independent prognostic factors.Conclusions: Our study demonstrated that CXCR4 expression in AML was an independent prognostic predictor for disease survival that could be rapidly and easily determined by flow cytometry at disease presentation.

Although 21 causative mutations have been associated with PRKAG2 syndrome, our understanding of the syndrome remains incomplete. The aim of this project is to further investigate its unique genetic background, clinical manifestations, and underlying structural changes. We recruited 885 hypertrophic cardiomyopathy (HCM) probands and their families internationally. Targeted next-generation sequencing of sudden cardiac death (SCD) genes was performed. The role of the identified variants was assessed using histological techniques and computational modeling. Twelve PRKAG2 syndrome kindreds harboring 5 distinct variants were identified. The clinical penetrance of 25 carriers was 100.0%. Twenty-two family members died of SCD or heart failure (HF). All probands developed bradycardia (HRmin, 36.3 ± 9.8 bpm) and cardiac conduction defects, and 33% had evidence of atrial fibrillation/paroxysmal supraventricular tachycardia (PSVT) and 67% had ventricular preexcitation, respectively. Some carriers presented with apical hypertrophy, hypertension, hyperlipidemia, and renal insufficiency. Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation. Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up.

Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann–Whitney U test, Fisher exact test, logistic regression, Kaplan–Meier and Cox regression analyses were used. In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.