Design, synthesis, biological evaluation, and in silico studies of novel pyridopyridine derivatives as anticancer candidates targeting FMS kinase.

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.

Urinary sFlt-1 and PlGF as preeclampsia predictors: sFlt-1/creatinine ratio improves the prediction value.

OBJECTIVES: To evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction. STUDY DESIGN: This case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios. RESULTS: Urine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863). CONCLUSIONS: Urinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable.

Comparison of the Effects of Pilates and Yoga Exercise on the Dynamic Balancing Ability and Functional Movement of Fencers.

This study was conducted to compare and analyze whether Pilates exercise and yoga exercise help improve the performance of female fencers and prevent injury, and the dynamic balance test (LQ-YBT) and functional movement screening (FMS) test score of the elite adult female fencers were compared and analyzed as evaluation indicators. Participants were randomly classified into Pilates (n = 10) and yoga groups (n = 10), members of which took part in 50 min of exercise (5 min of warm-up, 40 min of main exercise, and 5 min of cool-down) twice weekly for eight weeks. The results obtained from this study were analyzed via independent t-test and 2-way ANOVA. The results were as follows: LQ-YBT measures (reaching distance) increased significantly for both groups, as did FMS scores (deep squat, hurdle step, inline lunge, shoulder mobility, active straight-leg raise, trunk-stability push-up, and rotary stability). These results suggest that Pilates exercise and yoga exercise might be likely effective in improving the performance of adult female fencers and injury prevention by increasing their dynamic balance ability and functional movement.

Double synergic chitosan-coated poly (lactic-co-glycolic) acid nanospheres loaded with nucleic acids as an intranasally administered vaccine delivery system to control the infection of foot-and-mouth disease virus.

BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

Gilteritinib with or without venetoclax for relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.

Predicting Time to Delivery in Hypertensive Disorders: Assessing PlGF and sFlt-1 with the Novel Parameter 'Mtp-Multiples of a Normal Term Placenta'.

Background: Imbalanced angiogenesis is characteristic of normal placental maturation but it also signals placental dysfunction, underlying hypertensive disorders during pregnancy. This study aimed to investigate the relationship between angiogenic placental aging, measured by markers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) using the new index "Multiples of a normal term placenta" (Mtp) and the duration of pregnancy. Methods: A retrospective observational study was conducted, including singleton pregnancies diagnosed or suspected of hypertensive disorders after the 20th gestational week. Mtp measures how far a single dosage of angiogenic marker deviates from the expected value in an uncomplicated full-term pregnancy (Mpt = sFlt-1/sFlt-1 reference value or PIGF/PIGF reference value). We considered the 90th, 95th, and 97.5th centiles for sFlt-1 and the 2.5th, 5th, and 10th centiles for PlGF as references. Results: The categories with longer time to delivery, regardless of gestational age, were: Mtp PlGF 10th c ≥ 2, ≥3 and Mtp sFlt-1 90th c ≤ 0.5 (median days of 9, 11, 15 days, respectively). These two categories Mtp sFlt-1 90th c ≥ 3 and Mtp sFlt-1 97.5th c ≥ 2 allow the identification of women at risk for imminent delivery within 1 day. Women who were deemed at low/medium risk based on the sFlt-1/PIGF ratio appeared to be at high risk when considering the individual values of sFlt-1 and/or PIGF. Conclusions: This new Mtp index for sFlt-1 and PlGF could be employed to assess the degree of placental aging in women with hypertensive disorders. It represents a valid tool for evaluating the risk of imminent birth, irrespective of gestational age, surpassing the current stratification based on the sFlt-1/PIGF ratio.

Stability of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1).

Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) are biomarkers used for diagnosis and risk estimation of preeclampsia. Stability in room temperature (RT) may affect the usefulness of these analyses, as shipping at ambient temperature is the most practical and suitable way to ship samples. To date, scientific studies of such stability are lacking. We aimed to assess the stability of PlGF and sFlt-1 at RT in serum from pregnant women. In addition, a smaller study of stability at 4 °C was performed. Serum was collected from 69 pregnant women and stored at RT or at 4 °C for up to 192 h. Analytes were considered stable if the mean percent change ± 90 confidence interval of the mean was within the baseline concentration ± allowable bias. Allowable bias was calculated from data on biological variation. In addition, an instability equation was calculated to assess loss of stability, in line with recent European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recommendations. The mean percent change was <3.5% for PlGF, <1% for sFlt-1 and <4.5% for sFlt-1/PlGF ratio up to 192 h. PlGF was considered stable for 168 h, and sFlt-1 and sFlt-1/PlGF ratios were considered stable for 192 h at RT. At 4 °C, PlGF was considered stable for 120 h, sFlt-1 for 168 h and sFlt-1/PlGF ratio for 120 h. Both PlGF and sFlt-1 as well as sFlt-1/PlGF ratio show sufficient stability (minimum 168 h) for samples to be shipped at RT.

Effects of Nontraditional Division III Lacrosse Participation on Movement Pattern Quality and Dynamic Postural Control.

Background/Purpose: No studies have observed the effects of a collegiate lacrosse season on movement pattern quality, dynamic postural control, or the accuracy of athletes' perceived movement pattern quality. The purpose was to examine the effects of a nontraditional fall season on movement pattern quality, perceived movement pattern quality, and dynamic postural control in collegiate lacrosse athletes. Design: Cross-sectional laboratory study. Methods: Fifty men's (age=19.38±1.24 years, height=182.63±6.16 cm, mass=82.37±8.46 kg) and 22 women's (age=19.68±1.17 years, height=165.10±6.88 cm, mass=64.09±8.72 kg) lacrosse players were recruited. Outcome measures included individual Functional Movement Screen™ (FMS™) scores, self-reported perceived movement pattern quality scores, lower and upper extremity Y-Balance Test (YBT) measurements, and active dorsiflexion range of motion (ROM) before the start and again at the end of the fall lacrosse season. Pre- and post-season measurements were assessed using paired t-tests and chi-squared analyses. Results: FMS™ composite scores did not significantly change from preseason to postseason for males (p=0.74) or females (p=0.07). Male perceived movement pattern quality was significantly higher than measured for 10 of 12 movements (p<0.05). Female perceived movement pattern quality was significantly higher than measured for four of 12 movements (p<0.05). Asymmetry frequency significantly increased in males in the hurdle step from two individuals to nine (χ21=25.52, p<0.01), inline lunge from 10 to 20 (χ21=12.50, p<0.01), and shoulder mobility from 4 to 21 (χ21=78.53, p<0.01). Asymmetries in male athletes significantly decreased in the active straight leg raise from 26 to 8 (χ21=25.96, p<0.01). YBT composite scores increased in males for the right leg (p=0.001) and left leg (p<0.03). Right dorsiflexion ROM (p<0.001) and left dorsiflexion ROM (p<0.001) significantly decreased in males from preseason to postseason. YBT scores for the right leg significantly increased in females from preseason to postseason (p=0.01). YBT scores for females for the right arm significantly increased from preseason to postseason (p=0.045). Conclusions: A 5-week season may not change overall movement pattern quality of men's or women's lacrosse players, but some individual movement scores diminished. Athletes may overestimate self-reported movement pattern quality and are therefore unlikely to individually address movement deficits. Male dynamic postural control may change throughout a season, resulting in a potential increased risk of injury later in the season due to compensatory patterns or changes in mobility, proprioception, or balance. Level of Evidence: 3b.

Impact and Implementation of an Early Years Fundamental Motor Skills Intervention for Children 4-5 Years.

Fundamental motor skills (FMS) are the cornerstone of a child's motor development, but concerns remain on the current level of FMS competencies, and intervention is required. This evaluation investigated if a targeted Early Years FMS intervention, delivered by a specialist physical education (PE) provider, improved the FMS of 4-5-year-old children across multiple sites. METHODS: The Early Years FMS intervention ran for 18 weeks, 1 h/week, using a standardised programme of activities to develop FMS competencies across 219 children from 15 schools in the Midlands, UK. An adapted assessment was employed as a measure of FMS, assessing locomotor, object control, and stability skills at weeks 1, 9, and 18. The FMS were each rated as green = competent, amber = working towards, or red = not meeting the standards of the skill. A description of key programme implementation characteristics was described. FINDINGS: Statistically significant increases in FMS competencies were achieved for 80% of participants at 18 weeks. Key implementation characteristics for the intervention included consistent staffing, a standardised programme, and a variety of pedagogical approaches delivered by specialist PE staff. CONCLUSION: This evaluation provided important insights into the effectiveness and implementation of the Early Years FMS intervention to improve FMS competencies in children aged 4-5 years.

A Second Trimester Prediction Algorithm for Early-Onset Hypertensive Disorders of Pregnancy Occurrence and Severity Based on Soluble fms-like Tyrosine Kinase 1 (sFlt-1)/Placental Growth Factor (PlGF) Ratio and Uterine Doppler Ultrasound in Women at Risk.

Hypertensive disorders of pregnancy (HDPs) represent a significant source of severe maternal and fetal morbidity. Screening strategies relying on traditional medical history and clinical risk factors have traditionally shown relatively modest performance, mainly in the prediction of preeclampsia, displaying a sensitivity of 37% for the early-onset form and 29% for the late-onset form. The development of more accurate predictive and diagnostic models of preeclampsia in the early stages of pregnancy represents a matter of high priority. The aim of the present paper is to create an effective second trimester prediction algorithm of early-onset HDP occurrence and severity, by combining the following two biochemical markers: a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio and uterine artery Doppler ultrasound parameters, namely the pulsatility index (PI) and the resistivity index (RI), in a population of high-risk pregnant women, initially assessed through traditional risk factors. A prospective single-center observational longitudinal study was conducted, in which 100 women with singleton pregnancy and traditional clinical and medical history risk factors for preeclampsia were enrolled at 24 weeks of gestation. Shortly after study enrollment, all women had their sFlt-1 and PlGF levels and mean uterine artery PI and RI determined. All pregnancies were followed up until delivery. Receiver operating characteristic (ROC) analysis established algorithms based on cutoffs for the prediction of the later development of preeclampsia: PI 1.25 (96.15% sensitivity, 86.49% specificity), RI 0.62 (84.6% sensitivity, 89.2% specificity) and sFlt-1/PlGF ratio 59.55 (100% sensitivity, 89.2% specificity). The sFlt-1/PlGF ratio was the best predictor for preeclampsia, as it displayed the highest area under the curve (AUC) of 0.973. The prediction algorithm for the severe form of preeclampsia, complicated by fetal growth restriction leading to preterm birth, antepartum fetal demise or acute fetal distress with a cerebro-placental ratio of

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

[FLT3-ITD mutation-positive acute myeloid leukemia undergoing clonal transition with PTPN11 mutation at relapse].

A 28-year-old man was diagnosed with acute myelomonocytic leukemia. He achieved complete remission (CR) after two cycles of induction therapy. However, after consolidation therapy, bone marrow aspiration performed to prepare for allogeneic hematopoietic stem cell transplantation revealed disease relapse. Companion diagnostics confirmed the presence of the FLT3-ITD mutation. The patient received gilteritinib monotherapy and achieved CR. Subsequently, he underwent unrelated allogeneic bone marrow transplantation. One year after transplantation, the patient relapsed, and gilteritinib was resumed. However, the leukemia progressed, and panel sequencing using a next-generation sequencer showed that the FLT3-ITD mutation disappeared. A mutation in PTPN11, which regulates the RAS/MAPK signaling pathway, was also detected. Gilteritinib was discontinued, and the patient achieved CR with salvage chemotherapy. He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.

Angiogenic and vasoactive proteins in the maternal-fetal interface in healthy pregnancies and preeclampsia.

BACKGROUND: Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels. OBJECTIVE: We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1-3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations. STUDY DESIGN: Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins. RESULTS: The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower. CONCLUSION: An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins' involvement in the pathophysiology and as treatment targets is warranted.

Prediction of preterm birth in women with fetal growth restriction - Is the weekly change in sFlt-1/PlGF ratio or PlGF levels useful?

INTRODUCTION: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. MATERIAL AND METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68). CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.

The Role of Fundamental Movement Skills and Spatial Abilities in the Relationship between Physical Activity and Mathematics Achievement in Primary School Children.

Research has demonstrated positive relationships between fundamental movement skills (FMS) and mathematics achievement in children, and this relationship may be mediated by spatial ability. Engaging in physical activity (PA) may also have positive outcomes on mathematics achievement; however, no study has investigated this network of relationships together. This study aimed to examine the relationship between PA and mathematics achievement, and the mediating effects of FMS and spatial abilities, in primary school children. Using a cross-sectional design, data were collected from 182 children (aged 7 to 8 years old) across four schools in England. Objective moderate-to-vigorous PA (MVPA) levels and subjective parental reports of their children's PA participation were collected. Children's FMS were assessed, along with their performance on four spatial ability tasks and a mathematics test. Mediation analyses revealed no significant mediation effects of FMS and spatial abilities on the positive significant relationship between MVPA and mathematics achievement; however, spatial ability partially mediated the relationship between FMS and mathematics achievement. These results suggest that FMS and spatial ability may not be related to MVPA in this network of relationships, but children with more mature FMS perform better in mathematics due to them performing better on specific spatial ability tasks.

High FLT3 expression increases immune-cell infiltration in the tumor microenvironment and correlates with prolonged disease-free survival in patients with non-small cell lung cancer.

Most of the currently used cancer immunotherapies inhibit the programmed cell death protein 1 (PD1)-programmed cell death 1 ligand 1 (PDL1) axis of T-cells. However, dendritic cells (DCs) controlled by natural killer (NK) cells via the FMS-related tyrosine kinase 3 (FLT3) axis are necessary for activation of T-cells. The aim of the study was to evaluate FLT3 as a prognostic factor and determine its role in immune infiltration (with emphasis on NK cells and DCs). Using The Cancer Genome Atlas (TCGA) database, we performed bioinformatic analysis of the gene expression datasets of 501 lung squamous cell carcinoma (LUSC) and 515 lung adenocarcinoma (LUAD) patient who had corresponding clinical data [analysis was performed in R (version 4.2.0)]. Disease-free survival (DFS) differed between the FLT3-low and FLT3-high expression groups, respectively, in LUSC (61.0 vs 71.3 months P = 0.075) and LUAD (32.7 vs 47.5 months P = 0.045). A tumor microenvironment (TME) with high immune infiltration and rich in T-cell exhaustion markers was observed in the FLT3-high group. We showed overexpression of NK cell and DC gene signatures in the FLT3-high expression group as well as overexpression of key effector genes of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes protein (STING) pathway, which is crucial in response to radiotherapy. High expression of FLT3 in the TME was associated with immune cell infiltration (especially of NK cells and DCs), increased expression of T-cell exhaustion markers and expression of effector genes of the cGAS-STING pathway, which may consequently increase susceptibility to immunotherapy and radiotherapy. High FLT3 expression correlated with prolonged DFS in the LUSC and LUAD cohorts.

Maternal cardiovascular function at mid-gestation is related to placental angiogenesis.

OBJECTIVE: To investigate whether placental function, reflected in the levels of angiogenic factors, is associated with maternal cardiac function and hemodynamic responses at 19 to 24 weeks' gestation after adjustment for maternal risk factors and pregnancy complications. METHODS: Prospective study on women with singleton pregnancies attending Kings' College Hospital, London, UK for a routine hospital visit at 19-24 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, maternal heart rate, serum placental growth factor and soluble fms-like tyrosine kinase 1 (sFLT-1). We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. RESULTS: Our cohort included 4006 women. Lower placental growth factor (PlGF) values were significantly associated with higher mean arterial pressure (MAP) (p<0.001), lower maternal heart rate (p<0.001), lower mitral valve s' velocity (p= 0.027) and higher left atrial volume (p=0.022) after adjustment for maternal characteristics and pregnancy complications. sFLT-1 was positively related to relative wall thickness (p= 0.012), whereas sFLT-1/ PlGF ratio was negatively associated with mitral valve A (p= 0.006) and positively associated with left atrial volume (p= 0.015) and MAP (p= 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors from their obstetric and medical history. CONCLUSION: A continuous link of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present at mid-gestation, independently of preexisting maternal risk factors and pregnancy complications. Impaired placental function appears to be related to a mild systolic and diastolic dysfunction and cardiac remodeling. This article is protected by copyright. All rights reserved.

Effects of functional correction training on movement patterns and physical fitness in male college students.

The objective of this study is to investigate the effects of functional corrective training and static stretching on the quality of movement patterns and physical fitness in college students. The study was conducted with 30 male college students from a university in Guangzhou, China. The participants were randomly assigned to either the functional corrective training group (FCT, n = 15, age = 20.93 ± 0.85, BMI = 22.07 ± 2.33) or the static stretching group (SS, n = 13, age = 20.85 ± 0.86, BMI = 21.98 ± 1.80). Two participants from the SS group dropped out due to personal reasons, leaving 13 subjects in that group. Both groups underwent a 6-week training intervention, with sessions held twice a week. The FCT group participated in flexibility training, and/or static motor control training, and/or dynamic motor control training for 10-15 min. The SS group performed static stretching exercises targeting five specific muscles, with 30 s per side and two sets. The Functional Movement Screen (FMS), body composition, sit-and-reach, standing long jump, and pull-ups were assessed before and after the intervention. Differences in FMS outcomes were analyzed using two samples of the Mann-Whitney U test. Physical fitness outcomes were analyzed using a repeated measures analysis of variance (ANOVA) with a 2 (group) × 2 (time) design. After 6 weeks of intervention, the FCT group showed statistically significant improvements in the hurdle step (Z = -2.449, p = 0.014), inline lunge (Z = -2.000, p = 0.046), rotary stability (Z = -2.309, p = 0.021), and composite scores (Z = -3.316, p = 0.001). Comparisons between groups indicated that BMI (FCT, ES = 0.04; SS, ES = -0.11), 30-m sprint (FCT, ES = 0.12; SS, ES = 0.28), body fat percentage (BF%) (FCT, ES = -0.25; SS, ES = -0.07), and sit-and-reach (FCT, ES = 0.17; SS, ES = 0.06) were not statistically significant in both the pre- and post-tests. The effect sizes of all physical fitness indicators were greater in the FCT group than in the SS group. The FCT, consisting of two sessions per week for 6 weeks, has been proven to be effective in improving the quality of movement patterns by improved stability and advanced movements. However, the improvements in physical fitness did not reach statistical significance. FMS and FCT are generally affordable and accessible for college students. College students have the opportunity to employ the FMS tool to assess potential injury risks and address them, thereby reducing the risk of injuries.

Maternal serum soluble fms-like tyrosine kinase-1-to-placental growth factor ratio distinguishes growth-restricted from non-growth-restricted small-for-gestational-age fetuses.

BACKGROUND: Fetal growth restriction secondary to chronic placental insufficiency is a major cause of perinatal morbidity and mortality. A significant proportion of fetuses with fetal growth restriction are small for gestational age, defined as a birthweight of ≤10th percentile. However, not all small-for-gestational-age fetuses are growth restricted. Some are constitutionally small and otherwise healthy. It is important to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction to ensure appropriate interventions in small-for-gestational-age fetuses with fetal growth restriction and to minimize unnecessary interventions in healthy small-for-gestational-age fetuses. The maternal serum ratio of soluble fms-like tyrosine kinase-1 and placental growth factor is an indicator of placental insufficiency in the latter half of pregnancy. As such, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio may be a clinically useful tool to distinguish between small-for-gestational-age fetuses with and without fetal growth restriction. OBJECTIVE: This study aimed to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio can distinguish between small-for-gestational-age fetuses with and without fetal growth restriction with a birthweight of ≤10th percentile. STUDY DESIGN: A retrospective audit of 233 singleton pregnancies delivering an infant with a birthweight of ≤10th percentile corrected for gestational age with an antenatal maternal serum soluble fms-like tyrosine kinase-1-to-placental growth factor result was performed. Fetal growth restriction was defined as a birthweight of ≤10th percentile with an umbilical artery pulsatility index of >95th percentile, fetal middle cerebral artery pulsatility index of <5th percentile, amniotic fluid index of <6 cm, and/or cerebroplacental ratio of <1st percentile. The soluble fms-like tyrosine kinase-1-to-placental growth factor ratios before delivery between fetuses with and without fetal growth restriction (121 [fetal growth restriction] vs 112 [no fetal growth restriction]) were compared. The Student t test and Fisher exact test were used to compare cases and controls. The Mann-Whitney U test, linear regression analysis, and Spearman correlation coefficient (Rho) were used to examine associations between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and fetal outcomes to determine whether the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio served as a prognostic marker of fetal growth restriction severity. RESULTS: The mean soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was increased in fetal growth restriction cases compared with non-fetal growth restriction controls (234.3±25.0 vs 67.4±7.7, respectively; P<.0001). When controlling for preeclampsia, which is associated with placental insufficiency, fetal growth restriction cases still demonstrated an independent increase in the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (effect size, 0.865; 95% confidence interval, 0.509-1.220; P<.001). The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with birthweight percentiles in pregnancies delivering an infant with a birthweight of ≤10th percentile (r=-0.3565; P<.0001). This association was maintained for fetuses with fetal growth restriction (r=-0.2309; P<.05), whereas fetuses without fetal growth restriction had no significant correlation between the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio and neonatal birthweight percentiles. CONCLUSION: The soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was significantly higher in small-for-gestational-age fetuses with fetal growth restriction than small-for-gestational-age fetuses without fetal growth restriction, independent of preeclampsia. Furthermore, the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio was negatively correlated with fetal growth restriction birthweight percentiles, suggesting that it may be a clinical measure of fetal growth restriction severity. Therefore, the ratio may usefully delineate fetal growth restriction from constitutionally small but otherwise healthy fetuses antenatally, allowing for timely interventions in small-for-gestational-age cases with fetal growth restriction and unnecessary interventions to be minimized in small-for-gestational-age cases without fetal growth restriction.