Prognostic value of tumor deposits and positive lymph node ratio in stage III colorectal cancer: a retrospective cohort study.

BACKGROUND: In colorectal cancer (CRC), tumor deposits (TD) have been used to guide the N staging only in node-negative patients. It remains unknown about the prognostic value of TD in combination with positive lymph node ratio (LNR) in stage III CRC. PATIENTS AND METHODS: We analyzed data from 31,139 eligible patients diagnosed with stage III CRC, including 30,230 from the Surveillance, Epidemiology, and End Results (SEER) database as a training set and 909 from two Chinese hospitals as a validation set. The associations of TD and LNR with cancer-specific survival (CSS) and overall survival (OS) were evaluated using the Kaplan-Meier method and Cox regression models. RESULTS: Both TD-positive and high LNR (value≥0.4) were associated with worse CSS in the training (multivariable hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.43-1.58 and HR, 1.74; 95% CI, 1.62-1.86, respectively) and validation sets (HR,1.90; 95%CI, 1.41-2.54 and HR,2.01; 95%CI, 1.29-3.15, respectively). Compared to patients with TD-negative and low LNR (value<0.4), those with TD-positive and high LNR had a 4.09-fold risk of CRC-specific death in the training set (HR, 4.09; 95% CI, 3.54-4.72) and 4.60-fold risk in the validation set (HR, 4.60; 95% CI, 2.88-7.35). Patients with TD-positive/H-LNR CRC on the right side had the worst prognosis (P<0.001). The combined variable of TD and LNR contributed the most to CSS prediction in the training (24.26%) and validation (32.31%) sets. A nomogram including TD and LNR showed satisfactory discriminative ability, and calibration curves indicated favorable consistency in both the training and validation sets. CONCLUSIONS: TD and LNR represent independent prognostic predictors for stage III CRC. A combination of TD and LNR could be used to identify those at high risk of CRC deaths.

Engineering of Pore Design and Oxygen Vacancy on High-Entropy Oxides by a Microenvironment Tailoring Strategy.

High-entropy oxides (HEOs) exhibit abundant structural diversity due to cationic and anionic sublattices with independence, rendering them superior in catalytic applications compared to monometallic oxides. Nevertheless, the conventional high-temperature calcination approach undermines the porosity and reduces the exposure of active sites (such as oxygen vacancies, OVs) in HEOs, leading to diminished catalytic efficiency. Herein, we fabricate a series of HEOs with a large surface area utilizing a microenvironment modulation strategy (m-NiMgCuZnCo: 86 m2/g, m-MnCuCoNiFe: 67 m2/g, and m-FeCrCoNiMn: 54 m2/g). The enhanced porosity in m-NiMgCuZnCo facilitates the presentation of numerous OVs, exhibiting an exceptional catalytic performance. This tactic creates inspiration for designing HEOs with rich porosity and active species with vast potential applications.

Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia.

OBJECTIVE: Syncytiotrophoblasts form via mononuclear cytotrophoblast fusion during placentation and play a critical role in maternal-fetal communication. Impaired syncytialization inevitably leads to pregnancy-associated complications, including preeclampsia. Endoplasmic reticulum stress (ERS) is reportedly linked with preeclampsia, but little is known about its association with syncytialization. High temperature requirement factor A4 (HtrA4), a placental-specific protease, is responsible for protein quality control and placental syncytialization. This study aimed to investigate the relationship among HtrA4, ERS, and trophoblast syncytialization in the development of early-onset preeclampsia (EO-PE). METHODS: HtrA4 expression and ERS in preeclamptic placentas and control placentas were analyzed by Western blotting and qRT-PCR. HtrA4 and ERS localization in placentas was determined by immunohistochemistry and immunofluorescence. BeWo cells were used to stimulate the effects of HtrA4 and ERS on syncytialization. RESULTS: HtrA4 expression was upregulated in EO-PE and positively correlated with ERS. HtrA4 activity was increased in preeclampsia. Under normoxia, HtrA4 overexpression in BeWo cells did not alter the ERS level. In addition, treatment with hypoxia/reoxygenation (H/R) or an ERS inducer increased HtrA4 expression. HtrA4 upregulation suppressed the levels of syncytin-2 and ß-HCG in the presence of forskolin (FSK), and this change was exaggerated after ERS activation. In addition, treatment with an ERS inhibitor markedly suppressed FSK-treated cell fusion in a manner related to downregulation of HtrA4 expression. CONCLUSION: Our results suggest that ERS enables syncytialization of placental development by upregulating HtrA4, but that excessive HtrA4 expression and preexisting ERS impair syncytialization and cause EO-PE.

In situ activation of flexible magnetoelectric membrane enhances bone defect repair.

For bone defect repair under co-morbidity conditions, the use of biomaterials that can be non-invasively regulated is highly desirable to avoid further complications and to promote osteogenesis. However, it remains a formidable challenge in clinical applications to achieve efficient osteogenesis with stimuli-responsive materials. Here, we develop polarized CoFe2O4@BaTiO3/poly(vinylidene fluoridetrifluoroethylene) [P(VDF-TrFE)] core-shell particle-incorporated composite membranes with high magnetoelectric conversion efficiency for activating bone regeneration. An external magnetic field force conduct on the CoFe2O4 core can increase charge density on the BaTiO3 shell and strengthens the ß-phase transition in the P(VDF-TrFE) matrix. This energy conversion increases the membrane surface potential, which hence activates osteogenesis. Skull defect experiments on male rats showed that repeated magnetic field applications on the membranes enhanced bone defect repair, even when osteogenesis repression is elicited by dexamethasone or lipopolysaccharide-induced inflammation. This study provides a strategy of utilizing stimuli-responsive magnetoelectric membranes to efficiently activate osteogenesis in situ.

Electric/Magnetic Intervention for Bone Regeneration: A Systematic Review and Network Meta-Analysis.

Electric/magnetic material or field is a promising strategy for bone regeneration. The aim of this systematic review and network meta-analysis was to analyze the evidence regarding the efficacy of electric and magnetic intervention for bone regeneration and provide directions for further research. A comprehensive search was performed to identify the rats/rabbits/mice research that involved the electric/magnetic treatment with quantitative radiographic assessment of bone formation. Network meta-analyses were also conducted to assess different interventions and outcomes for osteogenesis. In total, there were 51 articles included in the systematic review and 19 articles in the network meta-analyses. The majority used microcomputerized tomography bone volume/tissue volume (BV/TV) to evaluate outcomes in rats. Results showed that placing electric/magnetic materials in situ had more prominent effects than the electric/magnetic field on bone regeneration. For all species, electrical materials with zeta potential of -53 mV proved to be the most effective in increasing BV (mean difference [MD]: 4.20 mm3, 95% confidence interval [CI]: [1.72-6.68]) and bone mineral density (MD: 312 mg/cm3, 95% CI: [172.43-451.57]). Magnetic materials with external magnetic fields topped in BV/TV (MD: 43%, 95% CI: [36.04-49.96]). It also led in trabecular number (MD: 2.00 mm-1, 95% CI: [1.45-2.55]), trabecular thickness (MD: 61.00 µm, 95% CI: [44.31- 77.69]), and trabecular separation (MD: -0.40 mm, 95% CI: [-0.56 to -0.24]) on the condition of lacking electric materials. Biomaterials implantation is the most effective method for stimulating osteogenesis in rats, especially in electrical materials with negative charge. The combination of diverse interventions shows promising effects but needs further research, so does the underlying mechanism. Impact Statement Bone defect, especially for the large defect from aging, trauma, or pathology, which cannot be completely healed, remains a clinical challenge. Mimicking physical microenvironment has emerged as a new strategy for tissue regeneration. Electric and magnetic material and field used as the physical stimulation for bone regeneration have attracted interest due to their potential and facile application in clinic. This article reviewed related animal studies and carried out a network meta-analysis to thoroughly understand how electric and magnetic interventions impacted on tissues and created an osteogenic microenvironment.

Particulate air pollution and cardiovascular disease mortality in Jiangsu Province, China: a time-series analysis between 2015 and 2021.

Introduction: Previous time-series studies have revealed a positive association between particulate matter (PM) and acute cardiovascular effects. However, the evidence mostly comes from developed countries and regions, while the majority of air-pollution-related deaths occur in developing countries. To assess the effect of short-term exposure to PM on daily cause-specific cardiovascular disease (CVD) mortality in Jiangsu Province, China, we investigated 1,417,773 CVD deaths from 2015 to 2021 in Jiangsu. Methods: The city-specific association was estimated using generalized additive models with quasi-Poisson regression, and then, random effects meta-analysis was performed to estimate the pooled provincial-average associations between acute exposure to PM2.5 and PM10 and cardiovascular disease mortality. To test the independence of PM from gaseous pollutants, we fitted two-pollutant models. Mortality data were also stratified by sex, age, and region to investigate the modification of associations. The exposure-response (E-R) curve from each city was combined using meta-analysis to drive the provincial-level E-R curve. Results: The results showed that each 10-µg/m3 increase in the PM2.5 concentration was associated with a 0.723% [95% confidence interval (CI): 0.512, 0.935] increase in daily total CVD mortality, a 0.669% (95% CI: 0.461, 0.878) increase in CHD mortality, a 0.758% (95% CI: 0.584, 0.931) increase in stroke mortality, a 0.512% (95% CI: 0.245, 0.780) increase in ICH mortality, and a 0.876% (95% CI: 0.637, 1.116) increase in CI mortality. The corresponding increases in daily mortality rates for the same increase in the PM10 concentration were 0.424% (95% CI: 0.293, 0.556), 0.415% (95% CI: 0.228, 0.602), 0.444% (95% CI: 0.330, 0.559), 0.276% (95% CI: 0.026, 0.526), and 0.510% (95% CI: 0.353, 0.667), respectively. The association between PM and total CVD mortality remained significant after adjusting for gaseous pollutants. Females, older adults and districts with lower average PM levels are more sensitive, especially for PM10. The E-R curve for PM on CVD mortality is steeper at lower concentrations and flattens out at higher concentrations. The estimates remained generally consistent in sensitivity analyses when excluding the data during the COVID-19 pandemic period. Discussion: Our time-series study provides evidence of positive associations between acute exposure to PM2.5 and PM10 and total and cause-specific cardiovascular disease mortality in developing countries.

Suggested mesiodistal distance for multiple implant placement based on the natural tooth crown dimension with digital design.

PURPOSE: The purpose of this investigation was to identify a mesiodistal algorithm for multiple posterior implant placement based upon an ideal prosthetically restoration design. METHODS: One hundred one cases of posterior free-end edentulous arches were selected for digital crown designs and measurements. Cone bean computed tomogram and digital fabricated crown were applied. DICOM files were exported to a viewer software (BlueSkyPlan4) to generate digital crown and measurement. The mesiodistal space between roots of adjacent teeth and center of the potential implant horizontally, from both cross-section and coronal plane were measured. Comparisons were performed using t-tests. RESULTS: No significant difference was found in the distances of the maxillary and mandibular posterior implants to adjacent natural teeth (p > 0.05). For interdental/implant distances, premolars are around 4.2 mm and molars are 5.4 mm, correspondently. The second premolar interimplant distance is around 7-7.4 mm. The distance of interimplant of the first molar is about 8-8.5 mm. For the maxillary second molar, the interimplant distance is 9.26 ± 0.29 mm and the mandibular second molar interimplant distance is 9.58 ± 0.19 mm, which is significantly different. No difference was found between the two different measurement methods. CONCLUSION: A mesiodistal algorithm of 4-4.6 (implant to adjacent canine tooth), 7-7.4, 8-8.5, and 9-9.5 mm was recommended for interimplant/tooth distance from first premolar to second molar when placing implants with or without case-specific prosthetic planning prior to surgery.

Digital signal extraction approach for cardiotocography image.

BACKGROUND AND OBJECTIVE: Cardiotocography, commonly called CTG, has become an indispensable auxiliary examination in obstetrics. Generally, CTG is provided in the form of a report, so the fetal heart rate and uterine contraction signals have to be extracted from the CTG images. However, most studies focused on reading data for a single curve, and the influence of complex backgrounds was usually not considered. METHODS: An efficient signal extraction method was proposed for the binary CTG images with complex backgrounds. Firstly, the images' background grids and symbol noise were removed by templates. Then a morphological method was used to fill breakpoints of curves. Moreover, the projection map was utilized to localize the area and the starting and ending positions of curves. Subsequently, data of the curves were extracted by column scanning. Finally, the amplitude of the extracted signal was calibrated. RESULTS: This study had tested 552 CTG images simulated using the CTU-UHB database. The correlation coefficient between the extracted and original signals was 0.9991 ± 0.0030 for fetal heart rate and 0.9904 ± 0.0208 for uterine contraction, and the mean absolute error of fetal heart rate and uterine contraction were 2.4658 ± 1.8446 and 1.8025 ± 0.6155, and the root mean square error of fetal heart rate and uterine contraction were 4.2930 ± 2.9771 and 2.5214 ± 0.9640, respectively. After being validated using 293 clinical authentic CTG images, the extracted signals were remarkably similar to the original counterparts, and no significant differences were observed. CONCLUSIONS: The proposed method could effectively extract the fetal heart rate and uterine contraction signals from the binary CTG images with complex backgrounds.

The Metabolic Signatures of Surviving Cotwins in Cases of Single Intrauterine Fetal Death During Monochorionic Diamniotic Pregnancy: A Prospective Case-Control Study.

Introduction: Single intrauterine fetal death (sIUFD) in monochorionic diamniotic (MCDA) twin pregnancy may be associated with adverse clinical outcomes and possible metabolic changes in the surviving co-twin. Metabolomic profiling has not been undertaken before in these complex twin pregnancies. Methods: In this prospectively collected case-control study, three cross-cohort comparisons were made between sIUFD MCDA (n = 16), uncomplicated MCDA (n = 16, eight pairs), and uncomplicated singleton pregnancies (n = 8). To identify major sources of variation within the sIUFD MCDA cohort, a secondary comparison was conducted between spontaneous sIUFD (n = 8) and sIUFD in MCDA twins due to selective termination of a single abnormal fetus by radiofrequency ablation (RFA) (n = 8). Metabolomics analysis of placental tissue and umbilical cord plasma was performed using LC-MS profiling. The underlying metabolic networks and pathways were analyzed by web-based platforms. Associations and statistical correlations of all identified differential metabolites with neonatal birthweight and birth length were assessed by multivariable linear regression, adjusted for maternal age and gestation. Results: Across four comparisons, 131 and 111 differential metabolites were identified in placental tissue and cord plasma, respectively, with the highest variation seen between the spontaneous vs. single-induced IUFD in MCDA twins by RFA in the cord plasma. Conversely, the number of viable fetuses and the presence of sIUFD in MCDA twins had the highest impact on metabolite variation in placental tissue. Compounds correlated with fetal growth including placental acylcarnitines and gangliosides, along with specific amino acids (e.g., histidinyl-hydroxyproline), xenobiotics and biliverdin in cord plasma. Conclusion: sIUFD in MCDA twin pregnancy correlates with distinctive metabolic signatures, mostly in fatty acyls and complex lipids, in placental tissue and cord plasma of the surviving cotwin. Some metabolites are also associated with fetal growth.

Fresh vegetable and fruit consumption and carotid atherosclerosis in high-cardiovascular-risk population: a cross-sectional study in Jiangsu, China.

This study aimed to investigate the association of vegetable and fruit consumption with carotid plaque (CP) and carotid intima-media thickness (CIMT), two predictors of carotid atherosclerosis, within urban and rural adults at high risk of developing cardiovascular diseases (CVDs) in regional China. A total of 11,392 adults at high CVD risk were identified from general population of 71,511 in this cross-sectional study, conducted between November of 2015 and May of 2016 in the Jiangsu Province. Among these 11,392 high risk participants, CP prevalence was 36.7%. The independent variables, vegetable and fruit intake frequency, were assessed by a food frequency questionnaire. The outcome variables, CIMT and CP, were measured by ultrasound examination. The ANCOVA analysis showed no association between CIMT values and vegetable and fruit intake frequencies. Multivariate logistic regression models were introduced to examine the association between vegetable and fruit intake and CP. After adjustment for potential confounders, the odds ratios (ORs) for participants who occasionally and daily consumed vegetable to experience any CP were 0.67 (95%CI: 0.58-0.78) and 0.70 (95%CI: 0.62-0.79), respectively, compared with those rarely consumed vegetable. While the adjusted ORs were 0.77 (95%CI: 0.64-0.92) and 0.80 (95%CI: 0.68-0.94), separately, for occasional and daily vegetable consumers to develop single CP relative to their counterparts who rarely consumed any vegetables. However, no significant association between fruit consumption and CP was observed. Among the Chinese population at high CVD risk, consumption of fresh vegetables was negatively associated with the risk of developing carotid plaque.

The Potent Antioxidant MitoQ Protects Against Preeclampsia During Late Gestation but Increases the Risk of Preeclampsia When Administered in Early Pregnancy.

Aims: Although preeclampsia (PE) has been attributed to excessive oxidative stress (OS) in the placenta, mild antioxidants failed to prevent PE in clinical trials. As mitochondria are a major source of OS, this study assessed the potential of a potent mitochondria-targeting antioxidant MitoQ in the prevention of PE. Results: Placentas from women with PE and from reduced uterine perfusion pressure (RUPP) mice demonstrated significantly higher OS, along with increased mitochondrial damage and compromised glutathione peroxidase (GPx) activities. MitoQ administration during late gestation alleviated RUPP-induced PE; whereas early-pregnancy MitoQ treatment not only exacerbated blood pressure, fetal growth restriction, and proteinuria but also reduced the labyrinth/spongiotrophoblast ratio and blood sinuses in the labyrinth. Invasion (Matrigel transwell) and migration (wound healing assay) of trophoblasts were greatly improved by 1 µM hydrogen peroxide (H2O2), but this improvement was abolished by MitoQ or MitoTempo. Mild OS enhanced the expression of miR-29b-3p, which regulates five genes involved in viability and mobility, in HTR8-S/Vneo cells. Innovation and Conclusions: Although the potent mitochondrial-targeting antioxidant MitoQ protects against hypertension and kidney damage induced by RUPP in mice when administered in late gestation, it exacerbates the PE-like phenotype when given in early gestation by interfering with placenta formation because mild OS is required to stimulate trophoblast proliferation, invasion, and migration. Eliminating trophoblastic OS during early pregnancy may lead to compromised placentation and a risk of diseases of placental origin. Therefore, antioxidant therapy for pregnant women should be carefully considered.

Fresh vegetable and fruit consumption and carotid atherosclerosis in high-cardiovascular-risk population: a cross-sectional study in Jiangsu, China / Consumo de frutas e verduras frescas e aterosclerose carotídea em uma população de alto risco cardiovascular: um estudo transversal em Jiangsu, China / Consumo de verduras frescas y fruta y la aterosclerosis carotídea en una población con alto riesgo cardiovascular: un estudio trasversal en Jiangsu, China

This study aimed to investigate the association of vegetable and fruit consumption with carotid plaque (CP) and carotid intima-media thickness (CIMT), two predictors of carotid atherosclerosis, within urban and rural adults at high risk of developing cardiovascular diseases (CVDs) in regional China. A total of 11,392 adults at high CVD risk were identified from general population of 71,511 in this cross-sectional study, conducted between November of 2015 and May of 2016 in the Jiangsu Province. Among these 11,392 high risk participants, CP prevalence was 36.7%. The independent variables, vegetable and fruit intake frequency, were assessed by a food frequency questionnaire. The outcome variables, CIMT and CP, were measured by ultrasound examination. The ANCOVA analysis showed no association between CIMT values and vegetable and fruit intake frequencies. Multivariate logistic regression models were introduced to examine the association between vegetable and fruit intake and CP. After adjustment for potential confounders, the odds ratios (ORs) for participants who occasionally and daily consumed vegetable to experience any CP were 0.67 (95%CI: 0.58-0.78) and 0.70 (95%CI: 0.62-0.79), respectively, compared with those rarely consumed vegetable. While the adjusted ORs were 0.77 (95%CI: 0.64-0.92) and 0.80 (95%CI: 0.68-0.94), separately, for occasional and daily vegetable consumers to develop single CP relative to their counterparts who rarely consumed any vegetables. However, no significant association between fruit consumption and CP was observed. Among the Chinese population at high CVD risk, consumption of fresh vegetables was negatively associated with the risk of developing carotid plaque.

O estudo buscou investigar a associação entre consumo de frutas e verduras e placa carotídea (PC) e espessura íntima-média carotídea (EIMC), dois preditores de aterosclerose entre adultos das áreas urbana e rural com alto risco de desenvolver doenças cardiovasculares (DCVs) em uma região da China. Foram identificados 11.392 adultos com alto risco de DCV, entre 71.511 indivíduos da população geral, em um estudo transversal entre novembro de 2015 e maio de 2016 na Província de Jiangsu. Entre esses 11.392 participantes de alto risco, a prevalência de PC foi de 36,7%. As variáveis independentes, ou seja, frequências de consumo de frutas e verduras, foram avaliadas através de um questionário de frequência alimentar. As variáveis de desfecho, EIMC e PC, foram medidas por ultrassom. A análise ANCOVA não mostrou associação entre valores de EIMC e frequências de consumo de frutas e verduras. Foram introduzidos modelos de regressão logística multivariada para examinar a associação entre consumo de frutas e verduras e PC. Depois de ajustar para potenciais fatores de confusão, as ORs para participantes com consumo eventual e diário de verduras para qualquer PC foram 0,67 (IC95%: 0,58-0,78) e 0,70 (IC95%: 0,62-0,79), respectivamente, comparado com aqueles com consumo raro de verduras. Enquanto isso, as ORs ajustados foram 0,77 (IC95%: 0,64-0,92) e 0,80 (IC95%: 0,68-0,94), separadamente, para adultos com consumo eventual e diário de verduras para desenvolver uma PC única, comparado aos que relatavam consumo raro de verduras. Entretanto, não foi observada uma associação significativa entre consumo de frutas e PC. Entre a população chinesa com alto risco de DCV, o consumo de verduras frescas mostrou associação negativa com o risco de desenvolvimento de placa carotídea.

El objetivo de este estudio fue investigar la asociación del consumo de frutas y verduras con la placa carotídea (PC) y el grosor íntima-media carotídeo (GIMC), dos predictores de la aterosclerosis carotídea en adultos urbanos y rurales, con alto riesgo de desarrollar enfermedades cardiovasculares (ECV) en una región de China. Se identificaron, en este estudio transversal, a 11.392 adultos con alto riesgo de ECV dentro de una población general de 71.511, realizado entre noviembre de 2015 y mayo de 2016 en la provincia de Jiangsu. De estos 11.392 participantes en alto riesgo, la prevalencia de PC fue de un 36,7%. Las variables independientes, así como la frecuencia de consumo de verduras y fruta, se evaluaron mediante un cuestionario de frecuencia de comidas. Las variables de resultado, GIMC y PC, se midieron por un examen de ultrasonido. El análisis ANCOVA mostró que no existía asociación entre los valores GIMC y la frecuencia en el consumo de verduras y frutas. Los modelos de regresión logística multivariantes se introdujeron para examinar la asociación entre el consumo de verduras y frutas y la PC. Tras el ajuste para los factores potenciales de confusión, las ORs de haber tenido alguna PC para los participantes que ocasionalmente y diariamente consumían verduras fueron 0,67 (IC95%: 0,58-0,78) y 0,70 (IC95%: 0,62-0,79), respectivamente, comparadas con quienes raramente consumían verduras. Mientras que las ORs ajustadas fueron 0,77 (IC95%: 0,64-0,92) y 0,80 (IC95%: 0,68-0,94), separadamente, para los consumidores ocasionales y los consumidores diarios de verduras de desarrollar una única PC, en relación con sus contrapartes que raramente consumían verduras. No obstante, no se observó una asociación significativa entre el consumo de frutas y la PC. Entre la población con alto riesgo de ECV, el consumo de verdura fresca estuvo negativamente asociado con el riesgo de desarrollar PC.

Effects of hypertension on cerebral cortical thickness alterations in patients with type 2 diabetes.

AIMS: Although hypertension (HTN) is the high comorbidity of Type 2 diabetes mellitus (T2DM) and known to be a vascular risk factor for brain damage, the effects of HTN on brain function in T2DM patients are not well understood. Present study was performed to investigate whether HTN might accelerate the Cerebral cortical thickness (CT) alterations in patients with T2DM. METHODS: We enrolled 35 participants with only T2DM, 25 T2DM patients with HTN (HT2DM) and 28 healthy controls (HCs). The cognitive function was assessed and brain image data was collected then the CT was calculated for each participant. Partial correlations between the CT of each brain region and standard laboratory testing data and neuropsychological scale scores were also analyzed. Multivariable regression analysis was performed to evaluated the vascular risk factors and brain regions with different CT in HT2DM patients. RESULTS: Cognitive impairment is associated with thinning of the cerebral cortical thickness reduction in T2DM patients. CT thinning in the left inferior parietal lobe, left posterior cingulate and right precuneus were observed in HT2DM group relative to only T2DM group. Furthermore, the CT decreasing in the right precuneus was negatively correlated with duration of HTN. CONCLUSION: The current study revealed that coexistent HTN may accelerate the CT reduction in T2DM patients.

The Small-Port Effect and the Small-Triangle Manipulation in Laparoendoscopic Single-Site Surgery: Concept from a Training Model to the Clinic.

Objectives: A small port could possibly minimize the collision of instruments and increase operability in laparoendoscopic single-site surgery (LESS) through the realization of small-triangle manipulation. In this study, we attempted to verify the small-port effect in an in vitro suture model and in vivo LESS hysterectomy with different-sized ports. Subjects and Methods: Two different-sized homemade glove ports were used and assessed in both in vitro and in vivo studies. The trocar head of port 1 was 36 mm in diameter and that of port 2 was 25 mm. Thirty sutures under LESS were conducted in a laparoscopic training box with each port. In LESS hysterectomy, 40 patients were recruited, of whom 20 underwent surgery under port 1 and the remaining 20 under port 2. One surgeon with experience in LESS conducted all sutures. The suture time of each stitch in the training box and for closing the vaginal cuff was videotaped and compared. Results: In the training model, the mean time for each suture with port 1 and port 2 was 18.6 ± 0.5 and 12.5 ± 0.3 seconds, respectively. In LESS hysterectomy, the mean suture time of the vaginal cuff with port 1 and port 2 was 15.2 ± 3.1 and 12.4 ± 2.6 minutes, respectively. Suture with port 2 was less time consuming than that with port 1 in both in vivo and in vitro studies, and the difference was statistically significant. Conclusions: A small port could save time in the suture process both in a training model and in operating room as a result of decrease in instrument collision and realization of small-triangle manipulation.

The Regulation of Trophoblastic p53 Homeostasis by the p38-Wip1 Feedback Loop is Disturbed in Placentas from Pregnancies Complicated by Preeclampsia.

BACKGROUND/AIMS: Excessive apoptosis of trophoblasts, induced by sustained hypoxia, leads to abnormal placentation and is strongly linked to pregnancy complications such as preeclampsia (PE). Wild-type p53-induced phosphatase (Wip1) positively regulates cellular survival in tumor cells through the p38 and p53 pathways, but its expression pattern and effects in trophoblasts have yet to be reported. This study clarified the effect of Wip1 on the regulatory mechanism of p53-dependent apoptosis in trophoblasts, and thus increases understanding of the etiology of PE. METHODS: In normal and PE placentas, Wip1 mRNA and protein levels were determined by RT-qPCR and Western blotting respectively, while localization of Wip1 in placental tissues and in HTR8/SVneo cells was determined by immunohistochemistry and immunofluorescence. Two in vitro trophoblastic PE models were established by subjecting HTR8/SVneo cells to either hypoxia intervention in incubator (HII) or simulated ischemic buffer (SIB). Wip1 was suppressed in the aforementioned PE models by specific inhibitor or shRNA, and apoptosis was then assessed by flow cytometry, while further validation was done by measurement of cleaved-caspase 9 expression by Western blotting. The p38 inhibitor SB202190, Mdm2 inhibitor NVP-CGM097, and proteasome inhibitor MG-132 were administered in PE models, either in combination or alone, to determine the regulatory order of the component signal molecules of the feedback loop. The impact of Wip1 on p53-Mdm2 interaction was examined by coimmunoprecipitation. Lastly, the upregulation of the p38-Wip1 loop was confirmed in human placentas from pregnancies complicated by PE, using Western blotting. RESULTS: Wip1 expression was significantly elevated in human PE placentas and in vitro trophoblastic PE models; this is opposite to the pattern observed in tumor cells. Inhibition of Wip1 rescued hypoxia-induced p38 activation, cleavage of caspase 9 and apoptosis but significantly compromised p53-Mdm2 binding, while p-p53Ser15 was increased. Inhibition of Mdm2 degradation resulted in p53 destabilization and p38-Wip1 loop down-regulation, while degradation of the p53-Mdm2 complex resulted in p53 accumulation and p38-Wip1 loop hyperactivation. However, the p53-Mdm2 interaction was found to be more important in the regulation of the p38-Wip1 loop than Mdm2 stability. CONCLUSION: Trophoblastic p53 homeostasis is maintained by the p38-Wip1 feedback regulatory loop in response to hypoxic stress, which is dysregulated in the placentas of pregnancies complicated by PE, and thereby leads to excessive apoptosis.

QSOX1 regulates trophoblastic apoptosis in preeclampsia through hydrogen peroxide production.

Objective: Oxidative stress plays a significant role in the pathogenesis of preeclampsia (PE), by inducing trophoblast cell death and consequent placental dysfunction. Quiescin sulfhydryl oxidase 1 (QSOX1) is upregulated in many types of cancer cells; it promotes disulfide bond formation as well as hydrogen peroxide (H2O2) production. The aims of present study are to investigate the expression pattern of QSOX1 in placentae of pregnancies complicated by PE and the role of QSOX1 in the regulation of trophoblastic function, thus providing in-depth understanding of the putative involvement of QSOX1 in the development of PE. Methods: Human term placenta from normal pregnancies and from pregnancies complicated by PE was collected to measure QSOX1 expression and H2O2 levels. Down-regulation of QSOX1 in HTR-8/SVneo cells was achieved by siRNA interference. An in vitro cellular PE model was generated by hypoxic incubation. Protein expression levels were assessed by Western blotting, and H2O2 levels were determined in the cell culture medium as well as in the cell lysate. Trophoblast apoptosis was evaluated by TUNEL staining. Results: QSOX1 was overexpressed in the PE placenta. Inhibition of QSOX1 expression in HTR-8/SVneo cells attenuated cell apoptosis and intracellular H2O2 levels. Hypoxia-induced QSOX1 expression in HTR-8/SVneo cells and led to apoptosis of HTR-8/SVneo cells, and knock-down of QSOX1 rescued hypoxia-induced trophoblast apoptosis. Conclusions: Hypoxia-induced upregulation of QSOX1 and a consequent elevation in intracellular H2O2 increased apoptosis in placentae of pregnancies complicated by PE.

Wall shear stress promotes intimal hyperplasia through the paracrine H2O2-mediated NOX-AKT-SVV axis.

AIMS: Oscillatory wall shear stress (WSS)-linked oxidative stress promotes intimal hyperplasia (IH) development, but the underlying mechanisms are not completely understood. MATERIALS AND METHODS: We used an in vivo rabbit carotid arterial stenosis model representing different levels of WSS and found that WSS was increased at 1 month with 50% stenosis and was accompanied by VSMCs proliferation and interstitial collagen accumulation. Increased WSS promoted the expression of NOX, AKT, and survivin (SVV) and the proliferation/migration of VSMCs and reduced apoptosis. KEY FINDINGS: Our in vitro study suggested that H2O2 promoted proliferation and migration while suppressing apoptosis in cultured human umbilical vascular endothelial cells. SIGNIFICANCE: We demonstrated that the elevation of WSS promotes VSMC proliferation and migration through the H2O2-mediated NOX-AKT-SVV axis, thereby accelerating IH development.

[Arginase inhibitor nor-NOHA induces apoptosis and inhibits invasion and migration of HepG2 cells].

Objective To investigate the cell inhibitory effect of arginase inhibitor nor-NOHA on HepG2 hepatocellular carcinoma cells and related mechanism. Methods CCK-8 assay was used to detect the cell proliferation and flow cytometry to detect the apoptosis of HepG2 cells treated with (0, 0.5, 1.0, 2.0, 3.0) ng/µL nor-NOHA. The protein levels of arginase 1 (Arg1), P53, matrix metalloproteinase-2 (MMP-2), E-cadherin (ECD) were determined by Western blotting. Real time quantitative PCR was employed to examine the changes in the mRNA level of inducible nitric oxide synthase (iNOS). Griess assay was used to measure the concentration of nitric oxide (NO) in HepG2 cells. TranswellTM assay and wound-healing assay were performed to evaluate the changes of the cell invasion and migration ability, respectively. Results nor-NOHA inhibited the proliferation and induced the apoptosis of HepG2 cells. It also decreased the expression levels of Arg1 and MMP-2, increased the expression levels of P53 and ECD as well as the production of NO; in addition, nor-NOHA inhibited the invasion and migration of HepG2 cells. Conclusion Nor-NOHA can induce cell apoptosis and inhibit the ability of invasion and migration of HepG2 cells by inhibiting Arg1, which is related with the increase of iNOS expression and the high concentration of NO.

Pleiotropic effects of survivin in vascular endothelial cells.

OBJECTIVE: To assess the effects of survivin (SVV)in vascular endothelial cells. METHODS: In this study, we applied a gain-of-function approach and ectopically expressed SVV in rat aortic endothelial cells (RAECs) using a SVV-expressing adenovirus. The resulting SVV expression on the steady-state mRNA and protein level in RAECs was determined by reverse transcription quantitative PCR and Western blot, respectively. Cell viability, apoptosis, and migration were assessed in vitro by CCK-8 assay, flow cytometry, and transwell assay, respectively. The effect of SVV on in vivo angiogenesis was evaluated by immunohistochemistry in nude mice. Non-infected RAECs and those infected with GFP-expressing control adenovirus were used as controls. RESULTS: Compared to non-infected or control adenovirus-infected RAECs in vitro, SVV-expressing cells had increased viability and migratory capability, but reduced apoptosis. In vivo, SVV-expressing RAECs were associated with a higher level of angiogenesis. CONCLUSION: SVV is a positive regulator of endothelial cell survival and migration, and thus, stabilizes endothelial cells and stimulates angiogenesis.

Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma.

Alternatively activated macrophages (M2) can secrete chemokines, such as chemokine ligand 17 (CCL17), and are associated with promoting tumorigenesis of hepatocellular carcinoma (HCC). This study aimed at investigating the potential role of M2 and CCL17 in progression of HCC. The levels of CCL17 expression in 90 HCC samples were characterized by tissue microarray and stratified for the postsurgical survival. MHCC97L cells were co-cultured with classically activated M1, M2 or CCL17-silencing M2(ccl17mute) or treated with conditional medium (CM) from these cells or CCL17 in vitro. The wound healing, invasion, viability and apoptosis of MHCC97L cells in vitro and tumor growth in vivo were determined. The stemness of MHCC97L cells was examined by sphere formation, flow cytometry and Western blot. The relative expression levels of epithelial-mesenchymal transition (EMT) factors and the Wnt/ß-catenin signaling were determined. Higher levels of intratumoral CCL17 expression were significantly associated with clinical pathological characteristics of HCC and with poorer overall survival rates in HCC patients (P < 0.05). High levels of CCR4 were detected in MHCC97L cells. Treatment with the CM from M2 or with CCL17 significantly enhanced the wound healing process, invasion and proliferation of MHCC97L cells in vitro. Co-implantation MHCC97L cells with M2 significantly promoted the growth of MHCC97L tumors in vivo. Co-culture with M2 or treatment with CCL17 enhanced the stemness, EMT process, the TGF-ß1 and Wnt/ß-catenin signaling in MHCC97L cells. CCL17 promotes the tumorigenesis of HCC and may be a potential biomarker and target for HCC prognosis and therapy.