Background and Objectives: Tcfs and Lef1 are DNA-binding transcriptional factors in the canonical Wnt signaling pathway. In the absence of β-catenin, Tcfs and Lef1 generally act as transcriptional repressors with co-repressor proteins such as Groucho, CtBP, and HIC-5. However, Tcfs and Lef1 turn into transcriptional activators during the interaction with β-catenin. Therefore, the activity of Tcfs and Lef1 is regulated by β-catenin. However, the intrinsic role of Tcfs and Lef1 has yet to be examined. The purpose of this study was to determine whether Tcfs and Lef1 play differential roles in the regulation of self-renewal and differentiation of mouse ES cells. Methods: and Results: Interestingly, the expression of Tcfs and Lef1 was dynamically altered under various differentiation conditions, such as removal of LIF, EB formation and neuronal differentiation in N2B27 media, suggesting that the function of each Tcf and Lef1 may vary in ES cells. Ectopic expression of Tcf1 or the dominant negative form of Lef1 (Lef1-DN) contributes to ES cells to self-renew in the absence of leukemia inhibitory factor (LIF), whereas ectopic expression of Tcf3, Lef1 or Tcf1-DN did not support ES cells to self-renew. Ectopic expression of either Lef1 or Lef1-DN blocked neuronal differentiation, suggesting that the transient induction of Lef1 was necessary for the initiation and progress of differentiation. ChIP analysis shows that Tcf1 bound to Nanog promoter and ectopic expression of Tcf1 enhanced the transcription of Nanog. Conclusions The overall data suggest that Tcf1 plays a critical role in the maintenance of stemness whereas Lef1 is involved in the initiation of differentiation.

INTRODUCTION: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore. METHODS: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission. RESULTS: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia; one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days; one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive >11 weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal samples taken at birth were negative; placenta and cord histology showed non-specific inflammation; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5). CONCLUSION The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection; this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta.
Abortion, Spontaneous/epidemiology* ; Adult ; COVID-19/transmission* ; COVID-19 Nucleic Acid Testing ; COVID-19 Serological Testing ; Cohort Studies ; Disease Transmission, Infectious/statistics & numerical data* ; Female ; Fetal Blood/immunology* ; Humans ; Infectious Disease Transmission, Vertical/statistics & numerical data* ; Live Birth/epidemiology* ; Maternal Age ; Milk, Human/virology* ; Obesity, Maternal/epidemiology* ; Placenta/pathology* ; Pregnancy ; Pregnancy Complications, Infectious/physiopathology* ; Pregnancy Outcome/epidemiology* ; Pregnancy Trimester, First ; Pregnancy Trimester, Second ; Prospective Studies ; RNA, Viral/analysis* ; Risk Factors ; SARS-CoV-2 ; Severity of Illness Index ; Singapore/epidemiology* ; Umbilical Cord/pathology* ; Young Adult

Background: and Purpose Mechanical thrombectomy (MT) is an effective treatment for patients with basilar artery occlusion (BAO) acute ischemic stroke. It remains unclear whether bridging intravenous thrombolysis (IVT) prior to MT confers any benefit. This study compared the outcomes of acute BAO patients who were treated with direct MT versus combined IVT plus MT. Methods: This multicenter retrospective cohort study included patients who were treated for acute BAO from eight comprehensive stroke centers between January 2015 and December 2019. Patients received direct MT or combined bridging IVT plus MT. Primary outcome was favorable functional outcome defined as modified Rankin Scale 0–3 measured at 90 days. Secondary outcome measures included mortality and symptomatic intracranial hemorrhage (sICH). Results: Among 322 patients, 127 (39.4%) patients underwent bridging IVT followed by MT and 195 (60.6%) underwent direct MT. The mean±standard deviation age was 67.5±14.1 years, 64.0% were male and median National Institutes of Health Stroke Scale was 16 (interquartile range, 8 to 25). At 90-day, the rate of favorable functional outcome was similar between the bridging IVT and direct MT groups (39.4% vs. 34.4%, P=0.361). On multivariable analyses, bridging IVT was not asComorbidisociated with favorable functional outcome, mortality or sICH. In subgroup analyses, patients with underlying atherosclerosis treated with bridging IVT compared to direct MT had a higher rate of favorable functional outcome at 90 days (37.2% vs. 15.5%, P=0.013). Conclusions Functional outcomes were similar in BAO patients treated with bridging IVT versus direct MT. In the subgroup of patients with underlying large-artery atherosclerosis stroke mechanism, bridging IVT may potentially confer benefit and this warrants further investigation.

BACKGROUND: We previously showed that the expression of follistatin-like protein 1 (FSTL1) was significantly down-regulated in metastatic clear-cell renal cell carcinoma (ccRCC). In this study, we aimed to characterize the role of FSTL1 in the development of ccRCC. METHODS: The effects of FSTL1 on cell activity and cell cycle were investigated in ccRCC cell lines with altered FSTL1 expression. Gene expression microarray assays were performed to identify the major signaling pathways affected by FSTL1 knockdown. The expression of FSTL1 in ccRCC and its effect on postoperative prognosis were estimated in a cohort with 89 patients. RESULTS: FSTL1 knockdown promoted anchorage-independent growth, migration, invasion, and cell cycle of ccRCC cell lines, whereas FSTL1 overexpression attenuated cell migration. FSTL1 knockdown up-regulated nuclear factor-κB (NF-κB) and hypoxia-inducible factor (HIF) signaling pathways, increased epithelial-to-mesenchymal transition, up-regulated interleukin-6 expression, and promoted tumor necrosis factor-α-induced degradation of NF-κB inhibitor (IκBα) in ccRCC cell lines. FSTL1 immunostaining was selectively positive in epithelial cytoplasm in the loop of Henle, and positive rate of FSTL1 was significantly lower in ccRCC tissues than in adjacent renal tissues (P < 0.001). The multivariate Cox regression analysis showed that the intratumoral FSTL1 expression conferred a favorable independent prognosis with a hazard ratio of 0.325 (95% confidence interval 0.118-0.894). HIF-2α expression was negatively correlated with FSTL1 expression in ccRCC specimens (r = - 0.229, P = 0.044). Intratumoral expression of HIF-2α, rather than HIF-1α, significantly predicted an unfavorable prognosis in ccRCC (log-rank, P = 0.038). CONCLUSIONS FSTL1 plays a tumor suppression role possibly via repressing the NF-κB and HIF-2α signaling pathways. To increase FSTL1 expression might be a candidate therapeutic strategy for metastatic ccRCC.
Adult ; Aged ; Aged, 80 and over ; Basic Helix-Loop-Helix Transcription Factors ; genetics ; Carcinoma, Renal Cell ; genetics ; pathology ; Cell Line, Tumor ; Cell Movement ; genetics ; Disease-Free Survival ; Epithelial-Mesenchymal Transition ; genetics ; Female ; Follistatin-Related Proteins ; genetics ; Gene Expression Regulation, Neoplastic ; genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; Male ; Middle Aged ; NF-kappa B ; genetics ; Neoplasm Metastasis ; Signal Transduction ; genetics ; Tumor Suppressor Proteins ; genetics