Evaluation of the effect of intraventricular haemorrhage on cerebral perfusion in preterm neonates using three-dimensional pseudo-continuous arterial spin labelling.

BACKGROUND: Intraventricular haemorrhage (IVH) often arises as a cerebral complication directly related to preterm birth. The impaired autoregulation of cerebral blood flow is closely associated with IVH in preterm neonates. Three-dimensional pseudo-continuous arterial spin labelling (3D-pCASL) is a noninvasive magnetic resonance imaging (MRI) technique used for evaluating cerebral perfusion. OBJECTIVE: This study aimed to compare cerebral blood flow values among three distinct groups using 3D-pCASL: preterm neonates with and without IVH and preterm neonates at term-equivalent age. MATERIALS AND METHODS: A total of 101 preterm neonates who underwent conventional MRI and 3D-pCASL were included in this study. These neonates were categorised into three groups: 12 preterm neonates with IVH, 52 preterm neonates without IVH, and 37 healthy neonates at term-equivalent age. Cerebral blood flow measurements were obtained from six brain regions of interest (ROIs)-the frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, and thalamus-in the right and left hemispheres. RESULTS: The cerebral blood flow values measured in all ROIs of preterm neonates with IVH were significantly lower than those of neonates at term-equivalent age (all P<0.05). Additionally, the cerebral blood flow in the temporal lobe was lower in preterm neonates without IVH than in neonates at term-equivalent age (16.87±5.01 vs. 19.76±5.47 ml/100 g/min, P=0.012). Furthermore, a noteworthy positive correlation was observed between post-menstrual age and cerebral blood flow in the temporal lobe (P=0.037), basal ganglia (P=0.010), and thalamus (P=0.010). CONCLUSION: The quantitative cerebral blood flow values, as measured by 3D-pCASL, highlighted that preterm neonates with IVH had decreased cerebral perfusion. This finding underscores the potential of 3D-pCASL as a technique for evaluating the developmental aspects of the brain in preterm neonates.

Global air pollution exposure and congenital anomalies: an updated systematic review and meta-analysis of epidemiological studies.

A systematic review and meta-analysis was conducted to evaluate recent epidemiological evidence on the association of air pollution with congenital anomalies (CAs). Of 11,014 records, 49 were finally included in this meta-analysis. Per 10 µg/m3 increase in air pollutant, PM10 exposure during the 1st month of pregnancy and at the first trimester (T1) was associated with increased overall CAs. Further, exposure to PM10 was associated with congenital heart disease (OR = 1.055, 95% CI: 1.035, 1.074) and patent ductus arteriosus (OR = 1.094, 95% CI: 1.020, 1.168) at T1, with chromosomal anomalies during the entire pregnancy and with nervous system anomalies when exposure occurred 3 months prior to pregnancy, during the 1st, 2nd months of pregnancy and at T1. Besides, a significant association with overall CAs was observed for a combined exposure of PM10 and SO2 during the 1st month of gestation (OR: 1.101, 95% CI: 1.023, 1.180). A combined exposure of PM10 and CO was also associated with tetralogy of Fallot during 3-8 weeks of gestation (OR: 1.016, 95% CI: 1.005, 1.027). No significant associations were observed between PM2.5, NO2, and O3 exposure and CAs.

The effect of China's birth policy changes on birth defects-A large hospital-based cross-sectional study.

A retrospective analysis of birth data hospital-based obtained from 14 monitoring areas in the Huaihe River Basin from 2009 to 2019 was conducted. Trend in the total prevalence of birth defects (BDs) and subgroups were analyzed using the Joinpoint Regression model. The incidence of BDs increased gradually from 118.87 per 10,000 in 2009 to 241.18 per 10,000 in 2019 (AAPC = 5.91, P < 0.001). Congenital heart diseases were the most common subtype of BDs. The proportion of maternal age younger than 25 decreased but the age 25-40 years increased significantly (AAPC<20=-5.58; AAPC20-24=-6.38; AAPC25-29 = 5.15; AAPC30-35 = 7.07; AAPC35-40 = 8.27; All P < 0.05). Compared with the one-child policy period, the risk of BDs was greater for groups among maternal age younger than 40 years during the partial and universal two-child policy period (P < 0.001). The incidence of BDs and the proportion of women with advanced maternal age in Huaihe River Basin is increasing. There was an interaction between changes in birth policy and the mother's age on the risk of BDs.

Ambient fine particulate matter and pregnancy outcomes: An umbrella review.

The available evidence on the effects of ambient fine particulate matter (PM2.5) and pregnancy outcomes (birth outcomes and pregnancy complications) has increased substantially. The purpose of this umbrella review is to refine the evidence of the association between birth outcome (birth defects) and PM2.5; and summarize the credibility of existing research on the association between pregnancy complications and PM2.5. We searched PubMed, Web of Science, Embase, and Cochrane databases for relevant systematic reviews and meta-analyses up to March 16, 2022 in accordance with PRISMA guidelines. Two independent investigators conducted data extraction. AMSTAR 2 and GRADE assessment criteria were used to evaluate the methodological and evidence quality. We performed subgroup analyses by trimesters of pregnancy. The review protocol for this study has been registered in PROSPERO (CRD42022325550). This umbrella review identified a total of 41 systematic reviews, including 28 articles evaluating the influence of PM2.5 on birth outcomes and 13 on pregnancy complications. Positive associations between perinatal PM2.5 exposure and adverse birth outcomes were found, including low birth weight, preterm birth, stillbirth, small for gestational age, and birth defects. Pregnant women exposed to PM2.5 had a significantly higher risk of developing hypertensive disorder of pregnancy, gestational diabetes mellitus, gestational hypertension, and preeclampsia. The findings of subgroup analysis demonstrated that the effects of ambient PM2.5 exposure on pregnancy outcomes varied by trimesters. The findings of this extensive umbrella review provide convincing proof that exposure to ambient PM2.5 raises the risks of unfavorable birth outcomes and pregnancy complications. Some associations show considerable disparity between trimesters. These findings have implications for strengthen perinatal health care on air pollution and improving intergenerational equity.

Quantitative Relaxometry Assessment of Brain Microstructural Abnormality of Preschool Children With Autism Spectrum Disorder With Synthetic Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to perform an assessment of brain microstructure in children with autism aged 2 to 5 years using relaxation times acquired by synthetic magnetic resonance imaging. MATERIALS AND METHODS: Thirty-four children with autism spectrum disorder (ASD) (ASD group) and 17 children with global developmental delay (GDD) (GDD group) were enrolled, and synthetic magnetic resonance imaging was performed to obtain T1 and T2 relaxation times. The differences in brain relaxation times between the 2 groups of children were compared, and the correlation between significantly changed T1/T2 and clinical neuropsychological scores in the ASD group was analyzed. RESULTS: Compared with the GDD group, shortened T1 relaxation times in the ASD group were distributed in the genu of corpus callosum (GCC) ( P = 0.003), splenium of corpus callosum ( P = 0.002), and right thalamus (TH) ( P = 0.014), whereas shortened T2 relaxation times in the ASD group were distributed in GCC ( P = 0.011), left parietal white matter ( P = 0.035), and bilateral TH (right, P = 0.014; left, P = 0.016). In the ASD group, the T2 of the left parietal white matter is positively correlated with gross motor (developmental quotient [DQ] 2) and personal-social behavior (DQ5), respectively ( r = 0.377, P = 0.028; r = 0.392, P = 0.022); the T2 of the GCC was positively correlated with DQ5 ( r = 0.404, P = 0.018); and the T2 of the left TH is positively correlated with DQ2 and DQ5, respectively ( r = 0.433, P = 0.009; r = 0.377, P = 0.028). All significantly changed relaxation values were not significantly correlated with Childhood Autism Rating Scale scores. CONCLUSIONS: The shortened relaxometry times in the brain of children with ASD may be associated with the increased myelin content and decreased water content in the brain of children with ASD in comparison with GDD, contributing the understanding of the pathophysiology of ASD. Therefore, the T1 and T2 relaxometry may be used as promising imaging markers for ASD diagnosis.

The spread of antibiotic resistance to humans and potential protection strategies.

Antibiotic resistance is currently one of the greatest threats to human health. Widespread use and residues of antibiotics in humans, animals, and the environment can exert selective pressure on antibiotic resistance bacteria (ARB) and antibiotic resistance gene (ARG), accelerating the flow of antibiotic resistance. As ARG spreads to the population, the burden of antibiotic resistance in humans increases, which may have potential health effects on people. Therefore, it is critical to mitigate the spread of antibiotic resistance to humans and reduce the load of antibiotic resistance in humans. This review briefly described the information of global antibiotic consumption information and national action plans (NAPs) to combat antibiotic resistance and provided a set of feasible control strategies for the transmission of ARB and ARG to humans in three areas including (a) Reducing the colonization capacity of exogenous ARB, (b) Enhancing human colonization resistance and mitigating the horizontal gene transfer (HGT) of ARG, (c) Reversing ARB antibiotic resistance. With the hope of achieving interdisciplinary one-health prevention and control of bacterial resistance.

Ambient particulate matter, maternal thyroid function, and birth weight: A mediation analysis.

BACKGROUND: Birth weight (BW) is an indicator of fetal growth and development. Previous studies showed inconsistent results on the association of ambient particulate matter (PM) exposure with BW, and the role of maternal thyroid function has not been clarified. METHODS: We recruited 1711 gravidas between 2017 and 2019 in Henan, China. All participants were followed up until delivery. Daily concentrations of PM, including PM2.5 and PM10, were evaluated by using the spatial-temporal model. Maternal thyroid hormone (TH) levels were quantified by electrochemiluminescent microparticle immunoassay. Linear regression models were employed to examine the association among PM, BW, and maternal TH. Mediating effects of maternal TH interrelated with PM exposure on BW were investigated by causal mediation analyses. RESULTS: A total of 1049 gravidas were identified. We found that per 10 µg/m3 increase in PM2.5 and PM10 were associated with a decreased BW of 9.941 g, and 7.758 g (PM2.5: 95 %CI: -18.184, -1.698; PM10: 95 %CI: -14.436, -1.080). An inverse correlation of maternal FT4 levels with BW was found, with the pooled ß of -319.983 g (95 %CI: -483.216, -156.750). We found a prominent positive correlation between gestational FT4 and PM exposure (PM2.5: ß = 0.004, 95 %CI: 0.001, 0.007; PM10: ß = 0.003, 95 %CI: 0.000, 0.006). Mediation analysis found that FT4 levels mediated the relationship between maternal PM exposure and BW, ranging from 5.55 % to 15.86 %. CONCLUSIONS: Maternal PM exposure may induce a reduction in newborn BW by affecting the maternal TH concentrations.

Green space, air pollution and gestational diabetes mellitus: A retrospective cohort study in central China.

Emerging evidence suggests residential surrounding green space is beneficial for human health. The association between green space and GDM showed inconsistent results, and potential effect modification of green space with air pollution is still unclear. This study aims to evaluate the association between green space and GDM, and further explore potential interaction and medication effects. Participants were recruited from a retrospective cohort study between 2015 and 2020 in Henan, China. Residential green space based on normalized difference vegetation index (NDVI) and air pollution exposure were estimated using spatial-statistical models. Multivariate logistic regression was applied to evaluate the association between per 0.1 unit increase in NDVI with 4 buffer sizes (250 m, 500 m, 1000 m, 2000 m) and GDM. We examined potential interaction of green space and air pollutants on GDM. Mediating effects of air pollution associated with green space exposure on GDM were also investigated by causal mediation analyses. A total of 46,665 eligible pregnant women were identified. There were 4092 (8.8 %) women diagnosed with GDM according to the IADPSG criteria. We found that per 0.1-unit increment in NDVI250 m, NDVI500 m, NDVI1000 m and NDVI2000 m in second trimester were associated with the decreased risk of GDM, with adjusted OR of 0.921(95 %CI: 0.890-0.953), 0.922 (95 %CI: 0.891-0.953), 0.921 (95 %CI: 0.892-0.952) and 0.921 (95 %CI: 0.892-0.951), respectively. We identified significant interactions between second trimester PM2.5 and O3 exposure and NDVI for GDM (Pinteraction < 0.001). The causal mediation analysis showed that PM2.5 mediated approximately 2.5-5.5 % of the association between green space and GDM, while the estimated mediating effect of O3 was approximately 30.1-38.5 %. In conclusion, our study indicates that residential green space was associated with a reduced risk of GDM, particularly second trimester. Green space may benefit to GDM partly mediated by a reduction in PM2.5 and O3.

Gestational exposure to ambient particulate matter and preterm birth: An updated systematic review and meta-analysis.

Previous studies on gestational particulate matter (PM) exposure and preterm birth (PTB) showed inconsistent results, and no study systematically examined the short-term effect of PM exposure on PTB subtypes. To investigate both long- and short-term effects of the evidence to date in general population, we searched for epidemiological studies on PM exposure and PTB that published in PubMed, Web of Science, Embase and Cochrane Library up to March 31, 2022. The protocol for this review was registered with PROSPERO (CRD42021265202). Heterogeneity was assessed by Cochran's Q test and I2 statistic. Publication bias was evaluated using funnel plots and Egger's tests. Subgroup analysis, meta-regression and sensitivity analysis were performed. Of 16,801 records, 84 eligible studies were finally included. The meta-analysis of long-term effect showed that per 10 µg/m3 increase in PM2.5 and PM10 during entire pregnancy were associated with PTB, the pooled odds ratios (ORs) were 1.084 (95% CI: 1.055-1.113) and 1.034 (95% CI: 1.018-1.049). Positive associations were found between PM2.5 in second trimester and PTB subtypes. For the short-term exposure, we observed that PTB was positively associated with a 10 µg/m3 increment in PM2.5 on lag day 2 and 3, the pooled ORs and 95% CIs were 1.003 (1.001-1.004) and 1.003 (1.001-1.005), with I2 of 65.30% and 76.60%. PM10 exposure on ave day 1 increased the risk of PTB, the pooled OR was 1.001 (95% CI: 1.000, 1.001). We also found that PM10 exposure in 2 weeks prior to birth increased PTB risk. Our results support the hypothesis of both long- and short-term PM2.5 exposure increase the risk of PTB. Further well-designed longitudinal studies and investigations into potential biological mechanisms are warranted.

Maternal exposure to air pollution and congenital heart diseases in Henan, China: A register-based case-control study.

BACKGROUND: Association between ambient air pollution and congenital heart diseases (CHDs) remains inconclusive, and the critical exposure windows has not been well studied. OBJECTIVES: This case-control study aimed to assess the effect of ambient air pollution exposure on the risk of CHDs and the subtypes in Henan, China, and further to explore potential susceptible windows. METHODS: Daily average particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) and ≤10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) were collected by Chinese Air Quality Reanalysis datasets. Binary logistic regression was used to examine trimester-specific associations between per 10 µg/m3 increase in air pollutants and CHDs as well as the major subtypes. Distributed lag models incorporating logistic regression were applied to explore weekly-specific associations. RESULTS: A total of 196,069 singleton live births were included during 2013-2018, 643 CHDs were identified (3.3‰). We found that first and second trimester CO exposure increased overall CHDs risk, the adjusted odds ratio (aOR) and 95% confidence interval (CI) were 1.066 (1.010-1.125) and 1.065 (1.012-1.122). For CHDs subtypes, we observed that NO2 and CO in first trimester, PM2.5 and PM10 in the second trimester exposure were associated with the risk of atrial septal defect (ASD), the susceptible windows of air pollutants and ASD mainly occurred in the 1st- 6th gestational weeks. No positive association was observed for air pollution and tetralogy of Fallot. CONCLUSION: Our findings suggest that ambient air pollution exposure is associated with the risk of CHDs especially for ASD, and the susceptible windows generally occurred in first trimester. Further well-designed longitudinal studies are warranted to confirm our findings.

miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling.

BACKGROUND: Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke. METHODS: Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia. RESULTS: We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice. CONCLUSIONS: These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.

Pathogenic variants identified by whole-exome sequencing in 43 patients with epilepsy.

BACKGROUND: Epilepsy is a group of neurological disorders characterized by recurrent epileptic seizures. Epilepsy is affected by many factors, approximately 20-30% of cases are caused by acquired conditions, but in the remaining cases, genetic factors play an important role. Early establishment of a specific diagnosis is important to treat and manage this disease. METHODS: In this study, we have recruited 43 epileptic encephalopathy patients and the molecular genetic analysis of those children was performed by whole-exome sequencing (WES). RESULTS: Fourteen patients (32.6%, 14/43) had positive genetic diagnoses, including fifteen mutations in fourteen genes. The overall diagnostic yield was 32.6%. A total of 9 patients were diagnosed as pathogenic mutations, including 4 variants had been reported as pathogenic previously and 6 novel variants that had not been reported previously. Therefore, WES heralds promise as a tool for clinical diagnosis of patients with genetic disease. CONCLUSION: Early establishment of a specific diagnosis, on the one hand, is necessary for providing an accurate prognosis and recurrence risk as well as optimizing management and treatment options. On the other hand, to unveil the genetic architecture of epilepsy, it is of vital importance to investigate the phenotypic and genetic complexity of epilepsy.

Cranial irradiation alters neuroinflammation and neural proliferation in the pituitary gland and induces late-onset hormone deficiency.

Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6 Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.

A Slug-dependent mechanism is responsible for tumor suppression of p53-stabilizing compound CP-31398 in p53-mutated endometrial carcinoma.

Mutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP-31398, a p53-stabilizing compound, has been indicated to possess the ability to alter the expression of non-p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP-31398. A p53-mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 µM CP-31398. A p53-independent mechanism of CP-31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR-1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt-specific activators (LiCl) or inhibitors (XAV-939) followed by CP-31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP-31398 could promote the apoptosis of p53-mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP-31398 increased the GSK-3ß, p-Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp-53, Slug, Bcl-2, and Ki-67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP-31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP-31398-regulated Slug downregulation represses the p53-mutated EC via the p53/Wnt/Puma pathway.

Brain Development in Infants of Mothers With Gestational Diabetes Mellitus: A Diffusion Tensor Imaging Study.

OBJECTIVE: The objective of this study was to investigate clinical neurocognitive performance and microstructural white matter (WM) alterations in infants of mothers with gestational diabetes mellitus (GDM) using diffusion tensor imaging. MATERIALS AND METHODS: Infants (corrected gestational age, 33.42-36.00 weeks) of mothers with GDM (n = 31) and gestational age- and sex-matched unexposed controls (n = 31) accomplished 3-T diffusion tensor imaging scans and neurocognitive tests. Diffusion tensor imaging measures, mainly referring to fractional anisotropy (FA) values, were compared between 2 groups, and within-group analysis of correlation between FA values and neurocognitive testing outcomes in GDM-exposed infants was conducted subsequently. RESULTS: Fractional anisotropy was significantly decreased in the splenium of corpus callosum, posterior limb of internal capsule, thalamus in infants of mothers with GDM when compared with controls (P < 0.05), reflecting microstructural WM abnormalities in the GDM group. Decreased FA was associated with worse neurocognitive performance in the exposed group (P < 0.05). CONCLUSIONS: Individuals of mothers with GDM showed microstructural WM abnormalities in different brain regions, which were significantly related to worse neurocognitive performance. This might reveal that GDM directly insults the brain development of the offspring.

Effects of shRNA-mediated silencing of PSMA7 on cell proliferation and vascular endothelial growth factor expression via the ubiquitin-proteasome pathway in cervical cancer.

This study aims to evaluate the effects of PSMA7 silencing on cervical cancer (CC) cell proliferation and vascular endothelial growth factor (VEGF) expression through the ubiquitin-proteasome pathway. CC tissues (n = 43) and normal tissues (n = 27) were first collected from patients. Human CC cell line (SiHa) and human normal cervical epithelial cells (H8) were obtained and classified into the normal, blank, negative control (NC), PSMA7-shRNA1, and PSMA7-shRNA2 groups, respectively. In situ hybridization was used to detect the expressions of wild-type and mutant p53 proteins. Immunofluorescence assay was carried out to test the activity of 20S proteasomes. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were both performed to determine the expressions of PSMA7, ubiquitin, P27, P53, and VEGF in sample tissues and cells. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to analyze cell proliferation rates, and flow cytometry was used to analyze the cell cycle and the apoptotic rate. Compared with normal tissues, CC tissues showed increased expression levels of PSMA7, ubiquitin, p53, VEGF as well as increased activity of 20S proteasomes but exhibited a decrease in p27 expression. Compared with the blank and NC groups, the PSMA7-shRNA1 and PSMA7-shRNA2 groups all had decreased expression levels of PSMA7, ubiquitin, p53, and VEGF as well as decreased cell proliferation, 20S proteasomes activity, and cell number in the S phase, increased p27 expression, cell apoptosis and cell number in the G0/G1 phase. Our study demonstrated that PSMA7 silencing can suppress CC cell proliferation and VEGF expression in addition to promoting cell apoptosis through inhibiting the UPP signaling pathway.

CP-31398 inhibits the progression of cervical cancer through reversing the epithelial mesenchymal transition via the downregulation of PAX2s.

CP-31398, a styrylquinazoline, emerges from a screen for therapeutic agents that restore the wild-type DNA-binding conformation of mutant p53 to suppress tumors in vivo, but its effects on cervical cancer (CC) remain unknown. Hence, this study aimed to explore the effects CP-31398 has on the CC cells and to investigate whether it is associated with paired box 2 (PAX2) expression. CC cells were treated with different concentrations of CP-31398 (1, 2, 4, 6, 8, and 10 µg/ml) to determine the optimum concentration using fluorometric microculture cytotoxicity assay. After constructing the sh-PAX2 vector, CC cells were transfected with sh-PAX2 or treated with CP-31398. The effects of CP-31398 or PAX2 silencing on CC cell proliferation, apoptosis, invasion, and migration were evaluated. Epithelial mesenchymal transition (EMT)-related genes such as E-cadherin, vimentin, N-cadherin, snail, and twist in CC cells were detected. Tumor formation experiment in nude mice was performed to observe tumor growth. The optimum concentration of CP-31398 was 2 µg/ml. PAX2 was overexpressed in CC cells. CC cells treated with CP-31398 or treated with sh-PAX2 inhibited proliferation, invasion, and migration but promoted apoptosis with decreased PAX2 expression. The EMT process in CC cells was also reversed after treatment with CP-31398 or sh-PAX2. Moreover, the tumor formation experiment in nude mice revealed the inhibitory activity of CP-31398 in CC tumor in nude mice by suppressing PAX2. Our results provide evidence that CP-31398 could inhibit EMT and promote apoptosis of CC cells to curb CC tumor growth by downregulating PAX2.

Mapping tissue pH in an experimental model of acute stroke - Determination of graded regional tissue pH changes with non-invasive quantitative amide proton transfer MRI.

pH-weighted amide proton transfer (APT) MRI is sensitive to tissue pH change during acute ischemia, complementing conventional perfusion and diffusion stroke imaging. However, the currently used pH-weighted magnetization transfer (MT) ratio asymmetry (MTRasym) analysis is of limited pH specificity. To overcome this, MT and relaxation normalized APT (MRAPT) analysis has been developed that to homogenize the background signal, thus providing highly pH conspicuous measurement. Our study aimed to calibrate MRAPT MRI toward absolute tissue pH mapping and determine regional pH changes during acute stroke. Using middle cerebral artery occlusion (MCAO) rats, we performed lactate MR spectroscopy and multi-parametric MRI. MRAPT MRI was calibrated against a region of interest (ROI)-based pH spectroscopy measurement (R2 = 0.70, P < 0.001), showing noticeably higher correlation coefficient than the simplistic MTRasym index. Capitalizing on this, we mapped brain tissue pH and semi-automatically segmented pH lesion, in addition to routine perfusion and diffusion lesions. Tissue pH from regions of the contralateral normal, perfusion/diffusion lesion mismatch and diffusion lesion was found to be 7.03 ±â€¯0.04, 6.84 ±â€¯0.10, 6.52 ±â€¯0.19, respectively. Most importantly, we delineated the heterogeneous perfusion/diffusion lesion mismatch into perfusion/pH and pH/diffusion lesion mismatches, with their pH being 7.01 ±â€¯0.04 and 6.71 ±â€¯0.12, respectively (P < 0.05). To summarize, our study calibrated pH-sensitive MRAPT MRI toward absolute tissue pH mapping, semi-automatically segmented and determined graded tissue pH changes in ischemic tissue and demonstrated its feasibility for refined demarcation of heterogeneous metabolic disruption following acute stroke.

Determination of multipool contributions to endogenous amide proton transfer effects in global ischemia with high spectral resolution in vivo chemical exchange saturation transfer MRI.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI has been used for quantitative assessment of dilute metabolites and/or pH in disorders such as acute stroke and tumor. However, routine asymmetry analysis (MTRasym ) may be confounded by concomitant effects such as semisolid macromolecular magnetization transfer (MT) and nuclear Overhauser enhancement. Resolving multiple contributions is essential for elucidating the origins of in vivo CEST contrast. METHODS: Here we used a newly proposed image downsampling expedited adaptive least-squares fitting on densely sampled Z-spectrum to quantify multipool contribution from water, nuclear Overhauser enhancement, MT, guanidinium, amine, and amide protons in adult male Wistar rats before and after global ischemia. RESULTS: Our results revealed the major contributors to in vivo T1 -normalized MTRasym (3.5 ppm) contrast between white and gray matter (WM/GM) in normal brain (-1.96%/second) are pH-insensitive macromolecular MT (-0.89%/second) and nuclear Overhauser enhancement (-1.04%/second). Additionally, global ischemia resulted in significant changes of MTRasym , being -2.05%/second and -1.56%/second in WM and GM, which are dominated by changes in amide (-1.05%/second, -1.14%/second) and MT (-0.88%/second, -0.62%/second). Notably, the pH-sensitive amine and amide effects account for nearly 60% and 80% of the MTRasym changes seen in WM and GM, respectively, after global ischemia, indicating that MTRasym is predominantly pH-sensitive. CONCLUSION: Combined amide and amine effects dominated the MTRasym changes after global ischemia, indicating that MTRasym is predominantly pH-sensitive and suitable for detecting tissue acidosis following acute stroke.

Performance of p16/Ki67 immunostaining, HPV E6/E7 mRNA testing, and HPV DNA assay to detect high-grade cervical dysplasia in women with ASCUS.

BACKGROUND: Atypical squamous cell of undetermined significance (ASCUS) is a common cervical cytological diagnosis. At present, HPV DNA assay is used to triage these patients, but its lower specificity brings a series of problems. The purpose of this study was to evaluated the value of p16/Ki67 immunostaining, HPV E6/E7 mRNA testing in triaging women with ASCUS by comparing HPV DNA assay. METHODS: Liquid based cytology specimens were collected from 300 patients. P16/Ki67 immunocytochemistry using the CINtec® Plus Kit and HPV E6/E7 mRNA testing by QuantiVirus®HPV E6/E7 mRNA assay used the same cytology sample. Detection rates of each test were evaluated against histopathology. RESULTS: All assays yielded a high sensitivity for the detection of CIN3+ (100% (86.7-100) for HPV DNA assay, 88.0% (70.0-95.8) for HPV E6/E7 mRNA testing and 100% (86.7-100) for p16/Ki67 immunocytochemistry) and CIN2+ (98.2% (90.2-99.7) for HPV DNA assay, 87.0% (75.6-93.6) for HPV E6/E7 mRNA testing, 98.2% (90.2-99.7) for p16/Ki67 immunocytochemistry). The specificity to detect high grade dysplasia was highest for p16/Ki67 immunocytochemistry (74.2% (68.7-79.0) in CIN3+ and 82.5% (77.3-86.8) in CIN2+), followed by HPV E6/E7 mRNA testing (39.6% (34.0-45.5) in CIN3+ and 42.7% (36.7-48.9) in CIN2+) and HPV DNA assay (16.0% (12.1-20.8) in CIN3+ and 17.5% (13.2-22.7) in CIN2+). CONCLUSIONS: p16/Ki67 immunostaining and HPV E6/E7 mRNA testing, especially the former, may be promising tools in triage of ASCUS.