Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by ...dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.
Background Stem cell transplantation therapy is a potential approach for the repair of spinal cord injuries and other neurodegenerative diseases, but its effectiveness is hampered by the low rate of ...targeted migration of cells to the area of injury. The aim of this study was to investigate the effects of miR-31 on the migration of bone marrow mesenchymal stem cells (BMSCs) and the regulation of MMP-2 and CXCR4 expression in vitro and in vivo. Methods eGFP-expressing BMSCs were isolated and cultured for subsequent experiments. The experiments were divided into three groups: control group, miR-31agomir group, and miR-31antagomir group. Proliferation was analyzed using CCK-8 and flow cytometry; cell migration in vitro was analyzed using wound-healing and transwell assays. The mouse SCI model was prepared by the impact method, and cells were transplanted (3 groups, 12 per group). Relevant inflammatory factors were detected by ELISA. The BMS score was used to evaluate the functional recovery of the mouse spinal cord and the frozen section was used to analyze the cell migration ability in vivo. The in vitro and in vivo expression levels of MMP-2 and CXCR4 were evaluated by Western blot and immunohistochemical staining. Results In vitro experiments showed that cells in the miR-31agomir group exhibited enhanced cell proliferation (P<0.05, P<0.001) and migration (P<0.001) and upregulated protein expression levels of CXCR4 (P<0.01) and MMP-2 (P<0.001) compared with cells in the control group. The results of in vivo experiments showed that the expression of pro-inflammatory factors was reduced after cell transplantation treatment. Cells in the miR-31agomir group showed enhanced cell-targeted migration ability (P<0.001), improved the function of damaged tissues (P<0.001), and upregulated CXCR4 and MMP-2 expression compared to the control group (P<0.001). Conclusion Our experiment demonstrated that miR-31 could promote the migration of BMSCs and miR-31 could repair and improve the function of damaged tissues in SCI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This pilot study examined the use of early HbA1c in screening for gestational diabetes mellitus and adverse pregnancy outcomes in Singapore. One hundred and fifty-one pregnant women with a ...gestational age of under 14 weeks had an HbA1c test measured with their antenatal bloods prior to a second trimester oral glucose tolerance test. Patient characteristics and pregnancy outcome data were collected. Gestational diabetes mellitus prevalence was 11%. A receiver operating characteristic curve showed an HbA1c level of 5.2% (33 mmol/mol), had an 82% sensitivity, 72% specificity, 97% negative predictive value and 27% positive predictive value to predict gestational diabetes mellitus. Women with HbA1c of 5.2% (33 mmol/mol) or over 5.2% (33 mmol/mol) were older, had higher BMI and were less likely to be Chinese than those with HbA1c less than 5.2% (33 mmol/mol). There was no difference in pregnancy outcomes. Early HbA1c less than 5.2% (33 mmol/mol) may be useful to exclude low-risk Singaporean women from further testing, while those with HbA1c of 5.2% (33 mmol/mol) or greater would still need a oral glucose tolerance test between 24 and 28 weeks’ gestation.
Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming ...measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.
Adjusting to new or additional parenting responsibilities increases stress and affects parental well-being. Existing research has highlighted both parents' desire to receive more support. It has also ...been found that receiving sufficient social support enhances parenting outcomes. With the increasing popularity of mobile health apps, a Supportive Parenting App (SPA) intervention was developed to fulfill the support needs of parents during the perinatal period.
This study aimed to examine the effectiveness of the SPA on parental outcomes during the perinatal period.
A 2-group pretest and repeated posttest randomized controlled trial was conducted wherein 200 couples (N=400 mothers and fathers) were recruited from 2 public health care institutions in Singapore. Parents were randomly assigned to intervention (100/200, 50%) or control (100/200, 50%) groups. The SPA intervention consisted of a mobile app-based psychoeducation and peer support program to support parents from pregnancy to 6 months post partum. The outcome measures included postnatal depression, anxiety, parental bonding, parental self-efficacy, perceived social support, and parenting satisfaction. Data were collected at baseline (at >24 weeks of gestation-age of viability in Singapore) and at the first, second, fourth, sixth, ninth, and 12th month post partum. Linear mixed models were used to compare parental outcomes between the groups, and a linear mixed model for repeated measures was used to examine within-group changes.
Parents in the intervention group mostly showed better outcomes compared with those in the control group. Parents in the intervention group had higher perceived social support than those in the control group at the first (effect size=1.59, 95% CI 0.38-2.80; Cohen standardized effect size=1.31; P=.01), second (effect size=1.98, 95% CI 1.09-2.88; Cohen standardized effect size=2.21; P=.003), and fourth (effect size=2.57, 95% CI 1.62-3.51; Cohen standardized effect size=2.72; P=.048) months post partum. However, parents in the intervention group showed significantly poorer parental bonding (effect size=1.67, 95% CI 0.24-3.11; Cohen standardized effect size=1.16; P=.02). The other parental outcomes did not differ significantly between groups. The scores of mothers and fathers also differed significantly for all outcomes except parental self-efficacy.
Parents in the intervention group generally fared better, especially regarding perceived social support. However, the lack of statistical significance in most outcomes showed the limited effectiveness of the SPA intervention, which may be because of the COVID-19 pandemic. Parental differences in outcome scores suggest that mothers and fathers have different support needs; therefore, interventions should be tailored accordingly. Further improvements and evaluations are needed to examine the effectiveness of the SPA intervention in enhancing parental outcomes. Despite statistically insignificant results, limitations should be considered to further improve mobile health app-based interventions such as SPA, as they could serve as reliable and convenient sources of support for parents.
Clinicaltrails.gov NCT4706442; https://clinicaltrials.gov/ct2/show/NCT04706442.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Saturated fatty acids (SFAs) during pregnancy are associated with disrupted metabolic programming among offspring at birth and later growth. We examined plasma phospholipid SFAs in early pregnancy ...and fetal growth throughout pregnancy. We enrolled 321 pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort at gestational weeks 8-13. Ultrasonogram schedules were randomly assigned to capture weekly fetal growth. We measured plasma phospholipid SFAs at early pregnancy using blood samples and modeled fetal growth trajectories across tertiles of SFAs with cubic splines using linear mixed models after full adjustment. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each SFA using the Wald test. We found that even-chain and very long even-chain SFAs were inversely associated, whereas odd-chain SFAs were positively associated with fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) had a greater fetal weight and size, starting from week 13 until late pregnancy (at week 39: 3429.89 vs. 3269.08 g for estimated fetal weight; 328.14 vs. 323.00 mm for head circumference). Our findings could inspire future interventions using an alternative high-fat diet rich in odd-chain SFAs for optimal fetal growth.
Apoptosis is a highly conservative energy demand program for non-inflammatory cell death, which is extremely significant in normal physiology and disease. There are many techniques used for studying ...apoptosis. MicroRNA (miRNA) is closely related to cell apoptosis, and especially microRNA-31 (miR-31) is involved in apoptosis by regulating a large number of target genes and signaling pathways. In many neurological diseases, cell apoptosis or programmed cell death plays an important role in the reduction of cell number, including the reduction of neurons in spinal cord injuries. In recent years, the phosphoinositol 3-kinase/AKT (PI3K/AKT) signal pathway, as a signal pathway involved in a variety of cell functions, has been studied in spinal cord injury diseases. The PI3K/AKT pathway directly or indirectly affects whether apoptosis occurs in a cell, thereby affecting a significant intracellular event sequence. This paper reviewed the interactions of miR-31 target sites in the PI3K/AKT signaling pathway, and explored new ways to prevent and treat spinal cord injury by regulating the effect of miR-31 on apoptosis.
ABSTRACT
Aims
microRNA may be a new therapeutic direction for diabetes. As a typical tumor marker, miR‐31 is involved in a variety of metabolic diseases, but the specific role is still unclear. This ...study aimed to investigate the effect of miR‐31 on type 2 diabetes mellitus and its accompanying vascular injury, as well as on the effects of hypoxia‐inducible factor‐1α inhibitor (HIF1AN), hypoxia‐inducible factor (HIF)‐1α, and vascular endothelial growth factor (VEGF)‐A expression in vitro and in vivo.
Materials and Methods
In vitro, a model of high‐fat and high‐glucose‐induced human aortic endothelial cell (HAEC) injury was established to simulate diabetes mellitus (DM). Cell functions were compared between the control group, the DM damage group, and the group transfected with miR‐31 after DM damage. In vivo, overexpressing miR‐31 FVB mice and FVB mice were divided into the control and induced type 2 diabetes mellitus groups. Type 2 diabetes mellitus models were induced by a high‐fat diet combined with streptozotocin. The lipid metabolism levels, viscera, and vascular damage were compared between the control and type 2 diabetes mellitus groups.
Results
In vitro, miR‐31 improved the proliferation ability of damaged cells by targeting HIF1AN and up‐regulating the expression of HIF‐1α and VEGF‐A. In vivo, miR‐31 ameliorated the development of type 2 diabetes mellitus, disturbance of glucose and lipid metabolism, and damage to some organs. Meanwhile, miR‐31 had a protective effect on vascular damage complicated by type 2 diabetes mellitus by increasing the levels of HIF‐1α and VEGF‐A.
Conclusion
Our experiments show that miR‐31 can delay the progression of type 2 diabetes mellitus and ameliorate diabetic vascular injury.
In vitro, miR‐31 improved the proliferation ability of damaged cells by targeting HIF1AN and up‐regulating the expression of HIF‐1a and VEGF‐A. In vivo, miR‐31 ameliorated the development of type 2 diabetes mellitus by increasing the levels of HIF‐1a and VEGF‐A. Our experiments show that miR‐31 can delay the progression of type 2 diabetes mellitus and ameliorate diabetic vascular injury.
Background:
Postpartum depression (PPD) is highly prevalent and plagues a significant proportion of parents. Postpartum depression also exerts various negative consequences on infant development and ...parent-infant relationships. Social support is identified as an important factor influencing many parental predictors, and may affect the development of PPD.
Objective:
This study aimed to investigate how perceived social support can indirectly influence PPD symptoms in parents at 6 months postpartum by influencing postpartum anxiety, parental satisfaction, and parental self-efficacy (PSE).
Methods:
A secondary analysis of data from a randomized controlled trial was used with a cross-sectional exploratory design. A total of 400 Singaporean parents (200 couples) were included, and structural equation modeling was used to analyze the relationships between PPD and potential predictors.
Results:
Findings revealed a less adequate fit between the hypothesized model and the data collected. Social support was found to be a significant predictor of postpartum anxiety, PSE, and parental satisfaction. Postpartum anxiety was a significant predictor of PPD, but PSE and parental satisfaction were not.
Conclusion:
This study provides an overview of how different parental predictors may be associated with PPD among Asian parents. Postpartum anxiety significantly predicted PPD, but social support had negative effects on postpartum anxiety, parenting satisfaction, and PSE. The findings provide further insight into how parents at risk of PPD can be identified and demonstrated how social support might negatively impact parental outcomes. More qualitative research with Asian parents is needed to further explain these findings and inform the development of future interventions.
The prevention, treatment, and rehabilitation of spinal cord injury (SCI) have always posed significant medical challenges. After mechanical injury, disturbances in microcirculation, edema formation, ...and the generation of free radicals lead to additional damage, impeding effective repair processes and potentially exacerbating further dysfunction. In this context, inflammatory responses, especially the activation of macrophages, play a pivotal role. Different phenotypes of macrophages have distinct effects on inflammation. Activation of classical macrophage cells (M1) promotes inflammation, while activation of alternative macrophage cells (M2) inhibits inflammation. The polarization of macrophages is crucial for disease healing. A non-coding RNA, known as microRNA (miRNA), governs the polarization of macrophages, thereby reducing inflammation following SCI and facilitating functional recovery. This study elucidates the inflammatory response to SCI, focusing on the infiltration of immune cells, specifically macrophages. It examines their phenotype and provides an explanation of their polarization mechanisms. Finally, this paper introduces several well-known miRNAs that contribute to macrophage polarization following SCI, including miR-155, miR-130a, and miR-27 for M1 polarization, as well as miR-22, miR-146a, miR-21, miR-124, miR-223, miR-93, miR-132, and miR-34a for M2 polarization. The emphasis is placed on their potential therapeutic role in SCI by modulating macrophage polarization, as well as the present developments and obstacles of miRNA clinical therapy.
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