Search

Abstract The levels of fasting-state serum bile acids (BAs) in individuals with polycystic ovary syndrome (PCOS) differ from those of control subjects. However, there is a lack of research on the BAs profile in lean women with PCOS and whether these changes are linked to the host metabolism. Therefore, our objective was to investigate the synthesis and metabolism of serum BAs in lean women with PCOS and assess the correlation between BAs and clinical characteristics. This study employed a cross-sectional design of lean women with PCOS (n = 240) in comparison to a control group (n = 80) consisting of healthy lean women. The findings revealed significant increases in the levels of non-12-OH BAs and chenodeoxycholic acid (CDCA)% (both P

Abstract Three-dimensional Spatial Transcriptomics has revolutionized our understanding of tissue regionalization, organogenesis, and development. However, existing approaches overlook either spatial information or experiment-induced distortions, leading to significant discrepancies between reconstruction results and in vivo cell locations, causing unreliable downstream analysis. To address these challenges, we propose ST-GEARS (Spatial Transcriptomics GEospatial profile recovery system through AnchoRS). By employing innovative Distributive Constraints into the Optimization scheme, ST-GEARS retrieves anchors with exceeding precision that connect closest spots across sections in vivo. Guided by the anchors, it first rigidly aligns sections, next solves and denoises Elastic Fields to counteract distortions. Through mathematically proved Bi-sectional Fields Application, it eventually recovers the original spatial profile. Studying ST-GEARS across number of sections, sectional distances and sequencing platforms, we observed its outstanding performance on tissue, cell, and gene levels. ST-GEARS provides precise and well-explainable ‘gears’ between in vivo situations and in vitro analysis, powerfully fueling potential of biological discoveries.

Abstract Aortic root aneurysm is a potentially life‐threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single‐nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell‐type‐specific transcriptomic and cis‐regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.

Abstract A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins

Abstract Elderly hypertensive patients diagnosed with transient ischemic attack (TIA) are at a heightened risk for developing acute ischemic stroke (AIS). This underscores the critical need for effective risk prediction and identification of predictive factors. In our study, we utilized patient data from peripheral blood tests and clinical profiles within hospital information systems. These patients were followed for a three-year period to document incident AIS. Our cohort of 11,056 individuals was randomly divided into training, validation, and testing sets in a 5:2:3 ratio. We developed an XGBoost model, developed using selected indicators, provides an effective and non-invasive method for predicting the risk of AIS in elderly hypertensive patients diagnosed with TIA. Impressively, this model achieved a balanced accuracy of 0.9022, a recall of 0.8688, and a PR-AUC of 0.9315. Notably, our model effectively encapsulates essential data variations involving mixed nonlinear interactions, providing competitive performance against more complex models that incorporate a wider range of variables. Further, we conducted an in-depth analysis of the importance and sensitivity of each selected indicator and their interactions. This research equips clinicians with the necessary tools for more precise identification of high-risk individuals, thereby paving the way for more effective stroke prevention and management strategies.

Abstract Uncertainty in operating parameters during laser thermal pain treatment can yield unreliable results. To ensure reliability and effectiveness, we performed uncertainty analysis and optimization on these parameters. Firstly, we conducted univariate analysis to identify significant operational parameters. Next, an agent model using RBNN regression determined the relationship between these parameters, the constraint function, and the target function. Using interval uncertainty analysis, we obtained confidence distributions and established a nonlinear interval optimization model. Introducing RPDI transformed the model into a deterministic optimization approach. Solving this with a genetic algorithm yielded an optimal solution. The results demonstrate that this solution significantly enhances treatment efficacy while ensuring temperature control stability and reliability. Accounting for parameter uncertainties is crucial for achieving dependable and effective laser thermal pain treatment. These findings have important implications for advancing the clinical application of this treatment and enhancing patient outcomes.

Abstract The prognostic value of the left atrial function index (LAFI) in acute ST segment elevation myocardial infarction (STEMI) patients treated with percutaneous coronary intervention (PCI) is unknown. This study sought to determine whether the LAFI predicts prognosis in STEMI patients treated with PCI. Patients with newly diagnosed STEMI who were treated with PCI in Hunan Provincial People's Hospital from March 2020 to October 2020 were prospectively enrolled. All patients underwent transthoracic echocardiography at baseline and follow-up. The endpoint events included rehospitalization due to unstable angina, nonfatal myocardial infarction, rehospitalization due to heart failure and cardiovascular death. A total of 156 STEMI patients treated with PCI were studied with a median follow-up of 14 months. Forty-eight patients had endpoint events. The LAFI had the highest area under the receiver operating characteristic curve (AUC) predicting the endpoint events, with an AUC of 0.90 (95% CI 0.84–0.94). Multivariate Cox analysis demonstrated that only the LAFI (HR: 0.91, 95% CI 0.87–0.96, P 42.25 cm/cc/m2 (HR: 19.15, 95% CI 8.90–41.21, P

BackgroundRupture of abdominal aortic aneurysm (rAAA) is a fatal event in the elderly. Elevated blood pressure and weakening of vessel wall strength are major risk factors for this devastating event. This present study examined whether the expression profile of mechanosensitive genes correlates with the phenotype and outcome, thus, serving as a biomarker for AAA development.MethodsIn this study, we identified mechanosensitive genes involved in AAA development using general bioinformatics methods and machine learning with six human datasets publicly available from the GEO database. Differentially expressed mechanosensitive genes (DEMGs) in AAAs were identified by differential expression analysis. Molecular biological functions of genes were explored using functional clustering, Protein-protein interaction (PPI), and weighted gene co-expression network analysis (WGCNA). According to the datasets (GSE98278, GSE205071 and GSE165470), the changes of diameter and aortic wall strength of AAA induced by DEMGs were verified by consensus clustering analysis, machine learning models, and statistical analysis. In addition, a model for identifying AAA subtypes was built using machine learning methods.Results38 DEMGs clustered in pathways regulating 'Smooth muscle cell biology' and 'Cell or Tissue connectivity'. By analyzing the GSE205071 and GSE165470 datasets, DEMGs were found to respond to differences in aneurysm diameter and vessel wall strength. Thus, in the merged datasets, we formally created subgroups of AAAs and found differences in immune characteristics between the subgroups. Finally, a model that accurately predicts the AAA subtype that is more likely to rupture was successfully developed.ConclusionWe identified 38 DEMGs that may be involved in AAA. This gene cluster is involved in regulating the maximum vessel diameter, degree of immunoinflammatory infiltration, and strength of the local vessel wall in AAA. The prognostic model we developed can accurately identify the AAA subtypes that tend to rupture.

Glioblastoma patients are treated with Aurora kinase A (AURKA) inhibitors but resistance can occur. Here, the authors show that AURKA inhibition induces metabolic reprogramming, which leads to increased mitochondrial activity and inhibition of oxidative metabolism sensitizes glioblastoma cells to AURKA inhibition.

The homography estimation of infrared and visible images, a key technique for assisting perception, is an integral element within the 6G Space–Air–Ground Integrated Network (6G SAGIN) framework. It is widely applied in the registration of these two image types, leading to enhanced environmental perception and improved efficiency in perception computation. However, the traditional estimation methods are frequently challenged by insufficient feature points and the low similarity in features when dealing with these images, which results in poor performance. Deep-learning-based methods have attempted to address these issues by leveraging strong deep feature extraction capabilities but often overlook the importance of precisely guided feature matching in regression networks. Consequently, exactly acquiring feature correlations between multi-modal images remains a complex task. In this study, we propose a feature correlation transformer method, devised to offer explicit guidance for feature matching for the task of homography estimation between infrared and visible images. First, we propose a feature patch, which is used as a basic unit for correlation computation, thus effectively coping with modal differences in infrared and visible images. Additionally, we propose a novel cross-image attention mechanism to identify correlations between varied modal images, thus transforming the multi-source images homography estimation problem into a single-source images problem by achieving source-to-target image mapping in the feature dimension. Lastly, we propose a feature correlation loss (FCL) to induce the network into learning a distinctive target feature map, further enhancing source-to-target image mapping. To validate the effectiveness of the newly proposed components, we conducted extensive experiments to demonstrate the superiority of our method compared with existing methods in both quantitative and qualitative aspects.

Soft tissue tumors (STTs) include a range of benign and malignant tumors originating from soft tissues. Transarterial and percutaneous therapies are image-guided and minimally invasive approaches for managing primary and metastatic STTs. The objective of this review is to discuss transarterial and percutaneous therapies by examining the current literature, including indications, patient selection, safety, and effectiveness. Transarterial therapies (e.g., transarterial bland embolization and transarterial chemoembolization) involve the delivery of either embolic or chemotherapeutic particles using a catheter into arteries feeding the tumor, resulting in localized tumor destruction. Percutaneous therapies (e.g., radiofrequency ablation, cryoablation, irreversible electroporation, laser ablation, and magnetic resonance-guided high-intensity focused ultrasound) involve the delivery of either hot or cold temperatures, electrical current, laser, or ultrasound to specifically target tumor cells. Both therapies have been shown to be safe and effective for reducing morbidity and local control of STTs, specifically in patients who are surgically inoperable or who are unresponsive to conventional therapies. Accurate diagnosis, staging, and histological subtype identification are crucial for treatment selection. A multidisciplinary approach, a thorough understanding of tissue anatomy and surrounding structures, as well as individualized strategies based on assessment are essential for optimal patient care.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with high mortality worldwide. Spermatogenesis-associated serine-rich 2 (SPATS2) could be a novel diagnostic and prognostic biomarker in HCC. However, the regulatory mechanism of SPATS2 in HCC requires further elucidation. Therefore, the study’s objective was to investigate this process in HCC. In this study, we found that SPATS2 is significantly upregulated in HepG2 cells to promote cell growth and migration. SPATS2 is the target transcript of lncRNA SNHG5. SPATS2 positively affects the proliferation and migration of HepG2 cells caused by the higher expression of SNHG5. Mechanistically, we identified that the elevated of SPATS2 was attributed to SNHG5 related hypomethylation of SPATS2. SNHG5 reduced the expression of DNMT3a to suppress the methylation level of SPATS2. Taken together, our results uncover a novel epigenetic regulatory mechanism of lncRNA SNHG5-DNMT3a axis-related SPATS2 expression underlying HCC progression. This may serve as a novel prognostic marker and a promising therapeutic target for the treatment of HCC.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with high mortality worldwide. Spermatogenesis-associated serine-rich 2 (SPATS2) could be a novel diagnostic and prognostic biomarker in HCC. However, the regulatory mechanism of SPATS2 in HCC requires further elucidation. Therefore, the study's objective was to investigate this process in HCC. In this study, we found that SPATS2 is significantly upregulated in HepG2 cells to promote cell growth and migration. SPATS2 is the target transcript of lncRNA SNHG5. SPATS2 positively affects the proliferation and migration of HepG2 cells caused by the higher expression of SNHG5. Mechanistically, we identified that the elevated of SPATS2 was attributed to SNHG5 related hypomethylation of SPATS2. SNHG5 reduced the expression of DNMT3a to suppress the methylation level of SPATS2. Taken together, our results uncover a novel epigenetic regulatory mechanism of lncRNA SNHG5-DNMT3a axis-related SPATS2 expression underlying HCC progression. This may serve as a novel prognostic marker and a promising therapeutic target for the treatment of HCC.

Abstract XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems. Our results show that inhibition of XPO1 reduces cellular viability in glioblastoma cell cultures. Moreover, addition of ABT263 significantly enhances the efficacy of XPO1 inhibition on the reduction of cellular viability, which occurs in a synergistic manner. While selinexor inhibits the proliferation of glioblastoma cells, the combination treatment of ABT263 and selinexor results in substantial induction of cell death, which is accompanied by activation of effector- initiator caspases and cleavage of PARP. Mechanistically we find that XPO1 inhibition results in down-regulation of anti-apoptotic Mcl-1 and attenuates ABT263 driven Mcl-1 up-regulation. Consistently, siRNA mediated silencing of Mcl-1 sensitizes for ABT263 mediated cell death and partially for the combination treatment. By using a human patient-derived xenograft model of glioblastoma in mice, we demonstrate that the combination treatment of ABT263 and Selinexor reduces tumor growth significantly more than each compound alone. Collectively, these results suggest that inhibition of XPO1 and Bcl-2/Bcl-xL might be a potential strategy for the treatment of malignant glial tumors.

Abstract Recent data suggest that glioblastomas (GBM) activate the c-MET signaling pathway and display increased levels in anti-apoptotic Bcl-2 family members. Therefore, targeting these two deregulated pathways for therapy might yield synergistic treatment responses. We applied extracellular flux analysis to assess tumor metabolism. We found that combined treatment with ABT263 and Crizotinib synergistically reduces the proliferation of glioblastoma cells, which was dependent on dual inhibition of Bcl-2 and Bcl-xL. The combination treatment led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, c-MET-inhibition results in significant energy deprivation with a reduction in oxidative phosphorylation, respiratory capacity and a suppression of intracellular energy production (ATP). In turn, loss of energy levels suppresses protein synthesis, causing a decline in anti-apoptotic Mcl-1 levels. Silencing of Mcl-1 enhanced ABT263 and MET-inhibitor mediated apoptosis, but marginally the combination treatment, indicating that Mcl-1 is the central factor for the induction of cell death induced by the combination treatment. Finally, combined treatment with BH3-mimetics and c-MET inhibitors results in significantly smaller tumors than each treatment alone in a PDX model system of glioblastoma. These results suggest that c-MET inhibition causes a selective vulnerability of GBM cells to Bcl-2/Bcl-xL inhibition.

Glioblastoma (GBM) cells are often characterized by the presence of the IDH1 R132H mutation and high expression of anti-apoptotic proteins. Here, the authors show that the inhibition of Bcl-xL is synthetically lethal in IDH1-mutated GBM models and that this effect is mediated by the oncometabolite, 2-HG, which reduces Mcl-1 protein levels.

Abstract Acupuncture is a traditional Chinese medicine therapy that has been found useful for treating various diseases. The treatments involve the insertion of fine needles at acupoints along specific meridians (meridian specificity). This study aims to investigate the metabolic basis of meridian specificity using proton nuclear magnetic resonance (1H NMR)-based metabolomics. Electro-acupuncture (EA) stimulations were performed at acupoints of either Stomach Meridian of Foot-Yangming (SMFY) or Gallbladder Meridian of Foot-Shaoyang (GMFS) in healthy male Sprague Dawley (SD) rats. 1H-NMR spectra datasets of serum, urine, cortex, and stomach tissue extracts from the rats were analysed by multivariate statistical analysis to investigate metabolic perturbations due to EA treatments at different meridians. EA treatment on either the SMFY or GMFS acupoints induced significant variations in 31 metabolites, e.g., amino acids, organic acids, choline esters and glucose. Moreover, a few meridian-specific metabolic changes were found for EA stimulations on the SMFY or GMFS acupoints. Our study demonstrated significant metabolic differences in response to EA stimulations on acupoints of SMFY and GMFS meridians. These results validate the hypothesis that meridian specificity in acupuncture is detectable in the metabolome and demonstrate the feasibility and effectiveness of a metabolomics approach in understanding the mechanism of acupuncture.

Abstract Endogenous cyclic GMP-AMP (cGAMP) binds and activates STING to induce type I interferons. However, whether cGAMP plays any roles in regulating metabolic homeostasis remains unknown. Here we show that exogenous cGAMP ameliorates obesity-associated metabolic dysregulation and uniquely alters proinflammatory responses. In obese mice, treatment with cGAMP significantly decreases diet-induced proinflammatory responses in liver and adipose tissues and ameliorates metabolic dysregulation. Strikingly, cGAMP exerts cell-type-specific anti-inflammatory effects on macrophages, hepatocytes, and adipocytes, which is distinct from the effect of STING activation by DMXAA on enhancing proinflammatory responses. While enhancing insulin-stimulated Akt phosphorylation in hepatocytes and adipocytes, cGAMP weakens the effects of glucagon on stimulating hepatocyte gluconeogenic enzyme expression and glucose output and blunts palmitate-induced hepatocyte fat deposition in an Akt-dependent manner. Taken together, these results suggest an essential role for cGAMP in linking innate immunity and metabolic homeostasis, indicating potential applications of cGAMP in treating obesity-associated inflammatory and metabolic diseases.

BackgroundStenoses of internal pudendal arteries (IPAs) appear to be related to erectile dysfunction (ED). Nevertheless, the correlation between the severity of ED and stenosis of the IPAs is not well established.ObjectivesTo evaluate angiographic findings of IPAs in patients with suspected coronary artery disease (CAD) and to assess the correlation between the severity of ED and IPA stenosis.Materials and methodsNinety-one patients who were scheduled for cardiac angiogram (CAG) because of suspected CAD participated. ED was assessed using the International Index of Erectile Function (IIEF) questionnaire. Erectile function (EF) domain scoring was used to assess the severity of ED: severe (EF score = 1-10); moderate (11-16); mild-moderate (17-21); mild (22-25); and no ED (26-30). Angiography was performed in bilateral common, internal iliac, and IPAs and the location and extent of stenoses were measured. We divided patients according to those with maximum stenosis of less than 50% (Group I) and those with more than 50% (Group II), regardless of direction.ResultsWe diagnosed 88 patients (88/91, 96.70%) with ED. There was no correlation between increasing age and severity of ED (r = - 0.063, p = 0.555). There were 72 patients in Group I and 19 in Group II. In Group I, 62 patients were diagnosed with ED even though there was no stenosis. There was no significant correlation between the severity of ED and the extent of stenosis in IPAs (r = -0.118, p = 0.265).ConclusionsThere was no significant correlation between the severity of ED and the extent of stenosis of IPAs. We believe that this is because the progression of ED is induced by endothelial cell dysfunction, not by mechanical obstruction leading to blood flow reduction.

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20–50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The in vitro drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against Candida albicans. The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.

Based on the lattice Boltzmann method (LBM), the lattice Boltzmann flux solver (LBFS), which combines the advantages of conventional Navier–Stokes solvers and lattice Boltzmann solvers, was proposed recently. Specifically, LBFS applies the finite volume method to solve the macroscopic governing equations which provide solutions for macroscopic flow variables at cell centers. In the meantime, numerical fluxes at each cell interface are evaluated by local reconstruction of LBM solution. In other words, in LBFS, LBM is only locally applied at the cell interface for one streaming step. This is quite different from the conventional LBM, which is globally applied in the whole flow domain. This paper shows three different versions of LBFS respectively for isothermal, thermal and compressible flows and their relationships with the standard LBM. In particular, the performance of isothermal LBFS in terms of accuracy, efficiency and stability is investigated by comparing it with the standard LBM. The thermal LBFS is simplified by using the D2Q4 lattice velocity model and its performance is examined by its application to simulate natural convection with high Rayleigh numbers. It is demonstrated that the compressible LBFS can be effectively used to simulate both inviscid and viscous flows by incorporating non-equilibrium effects into the process for inviscid flux reconstruction. Several numerical examples, including lid-driven cavity flow, natural convection in a square cavity at Rayleigh numbers of 107 and 108 and transonic flow around a staggered-biplane configuration, are tested on structured or unstructured grids to examine the performance of three LBFS versions. Good agreements have been achieved with the published data, which validates the capability of LBFS in simulating a variety of flow problems.

RNA-induced silencing complex (RISC) is composed of miRNAs and AGO proteins. AGOs use miRNAs as guides to slice target mRNAs to produce truncated 5' and 3' RNA fragments. The 5' cleaved RNA fragments are marked with uridylation for degradation. Here, we identified novel cofactors of Arabidopsis AGOs, named RICE1 and RICE2. RICE proteins specifically degraded single-strand (ss) RNAs in vitro; but neither miRNAs nor miRNA*s in vivo. RICE1 exhibited a DnaQ-like exonuclease fold and formed a homohexamer with the active sites located at the interfaces between RICE1 subunits. Notably, ectopic expression of catalytically-inactive RICE1 not only significantly reduced miRNA levels; but also increased 5' cleavage RISC fragments with extended uridine tails. We conclude that RICEs act to degrade uridylated 5’ products of AGO cleavage to maintain functional RISC. Our study also suggests a possible link between decay of cleaved target mRNAs and miRNA stability in RISC.

Low-dose irradiation (LDI) has been used in clinics to treat human diseases, including chronic inflammation. This study assessed the effects of LDI on the inflammatory response of activated mouse primary peritoneal macrophages, and the underlying signal pathways. Primary peritoneal macrophages were isolated from mice and then incubated with lipopolysaccharide (LPS)-coated Ti microparticles (Ti-positive control) with or without brief exposure to LDI (X-ray, 0.5 Gy) 1 h later (Ti-LDI group) or left untreated in culture medium (Ti-negative control). The macrophages were then subjected to qRT-PCR, Western blot, cell viability CCK-8 assay, and ELISA. qRT-PCR analysis revealed the Ti-LDI group expressed significantly lower levels of IL-1β, IL-6, and TNF-α mRNA than those of the Ti-positive control group, while the ELISA data showed that Ti-LDI group had significantly lower secretion of IL-1β, IL-6, and TNF-α proteins. The most significant reduction associated with LDI was the secretion TNF-α protein, which barely increased from 13 to 25 h after treatment. Western blot data demonstrated that phosphorylation of p65 and ERK was much lower in the Ti-LDI group than in the controls. The data from the current study suggests that LDI of activated mouse macrophages was associated with significantly lower inflammation responses, compared with non-exposed activated macrophages, which was possibly through inhibition of the NF-κB and ERK pathways.

Breast cancer is recognized as a major public health problem in developing countries; however, there is very little evidence of behavioral factors associated with breast cancer risk. This study was conducted to identify lifestyles as risk factors for breast cancer among Central African women. A case-control study was conducted with 174 cases confirmed histologically by the pathology unit of the National Laboratory and 348 age-matched controls. Data collection tools included a questionnaire with interviews and medical records of patients. Data were analyzed using SPSS software version 20. Odd ratio (OR) and 95% confidence intervals (95% CI) were obtained by unconditional logistic regression. In total, 522 women were studied with a mean age of 45.8 (SD = 13.4) years. By unconditional logistic regression model, women with breast cancer were more likely to have attained illiterate and elementary education level [11.23 (95% CI, 4.65-27.14) and 2.40 (95% CI, 1.15-4.99)], married [2.09 (95% CI, 1.18-3.71)], positive family history [2.31 (95% CI, 1.36-3.91)], radiation exposure [8.21 (95% CI, 5.04-13.38)], consumption charcuterie [10.82 (95% CI, 2.39-48.90)], fresh fish consumption [4.26 (95% CI, 1.56-11.65)], groundnut consumption [6.46 (95% CI, 2.57-16.27)], soybean consumption [16.74 (95% CI, 8.03-39.84)], alcohol [2.53 (95% CI, 1.39-4.60)], habit of keeping money in bras[3.57 (95% CI, 2.24-5.69)], overweight [5.36 (95% CI, 4.46-24.57)] and obesity [3.11(95% CI, 2.39-20.42)]. However, decreased risk of breast cancer was associated with being employed [0.32 (95% CI, 0.19-0.56)], urban residence [0.16 (95% CI, 0.07-0.37)], groundnut oil consumption [0.05 (95% CI, 0.02-0.14)], wine consumption [0.16 (95% CI, 0.09-0.26)], non habit of keeping cell phone in bras [0.56 (95% CI, 0.35-0.89)] and physical activity [0.71(95% CI, 0.14-0.84)]. The study showed that little or no education, marriage, positive family history of cancer, radiation exposure, charcuterie, fresh fish, groundnut, soybean, alcohol, habit of keeping money in bras, overweight and obesity were associated with breast cancer risk among Central African women living in Bangui. Women living in Bangui should be more cautious on the behavioral risk associated with breast cancer.

The aims of this study are to identify the most important predictors of total diagnosed and undiagnosed diabetes and estimate the mean change in the predicted probability among aged 45+ adults in China. We used baseline data collected from 2011 wave of the China Health and Retirement Longitudinal Study (CHARLS) (n = 9,513). First, we estimated the prevalence of diagnosed, measured, total diagnosed, and undiagnosed diabetes. Second, we used probit models to determine whether individual attributes, socioeconomic characteristics and behavioral health factors, including smoking, alcohol consumption, obesity, central obesity, are associated with total diagnosed and undiagnosed diabetes. We also consider other factors, including contact with medical system, hypertension and urban/rural settings. Third, we estimated average marginal effects of variables in probit models. Among Chinese people aged 45+, the prevalence of diagnosed, measured, total diagnosed and undiagnosed diabetes were 5.8% (95%CI, 5.3%-6.3%), 14.7% (95%CI, 14.0%-15.4%), 17.0% (95%CI, 16.3%-17.7%), 11.3% (95%CI, 10.6%-12.0%), respectively. The probability of total diagnosed diabetes is 3.3% (95% CI, 1.2%-5.3%) and 10.2% (95% CI, 7.0%-13.5%) higher for overweight and obesity than normal BMI, 5.0% (95% CI, 3.0%-7.1%) higher for central obesity than normal waist circumference, 5.4% (95% CI, 3.7%-7.0%) higher for hypertensive than normotensive and 1.8% (95% CI, 0.8%- 2.7%) higher in urban areas than in rural areas, respectively. The probability of undiagnosed diabetes is 2.7% (95% CI, 1.2%-4.2%) and 7.2% (95% CI, 4.7%-9.6%) higher for overweight and obesity than normal BMI, 2.6% (95% CI, 0.9%-4.4%) higher for central obesity than normal waist circumference and 2.6% (95% CI, 1.2%-4.0%) higher for hypertensive than normotensive, respectively, and -1.5% (95% CI, -2.5% to -0.5%) lower for individuals who were in contact with the medical system. Greater focus on prevention of diabetes is necessary for obesity, central obesity, hypertensive and in urban areas for middle-aged and older in China.

This study aims to understand the level of contraceptive knowledge and attitudes towards contraception, and then to explore the association between the contraceptive behavior and unintended pregnancy in unmarried female university students in China. A cross-sectional study was conducted of university students in 49 universities across 7 cities in China from September 2007 to January 2008. We distributed 74,800 questionnaires, of which 69,842 were returned. In this paper, the data from 35,383 unmarried female university students were analyzed. The prevalence of sexual intercourse in unmarried female university students was 10.2%. The prevalence of unintended pregnancy in those sexually active female university students, was 31.8%. Among students with pregnancy, 53.5% experienced two or more pregnancies. 28.3% of the students with sexual intercourse reported that they always adopted contraceptive methods, and of those 82.9% chose to use male condoms. The majority (83.9%) of students with unintended pregnancy chose to terminate the latest pregnancy by surgical abortion or medical abortion. The contraceptive knowledge level of students who experienced unintended pregnancy was lower than those who did not. In China, about one third of unmarried female students with sexual intercourse experience unintended pregnancy. A variety of contraceptive methods are adopted, but the frequency of contraceptive use is low. Most of unmarried female students who experienced unintended pregnancy would choose to terminate the pregnancy with surgical or medical abortion. University students, especially the ones who have experienced unintended pregnancy, lack contraceptive and reproductive health knowledge.

Preeclampsia is a multi-system disorder involved in pregnancy without an effective treatment except delivery. The precise pathogenesis of this complicated disorder is still not completely understood. The objective of this study is to evaluate the alterations of protein expression and phosphorylations that are important in regulating placental cell function in preterm and term preeclampsia. Using the Protein Pathway Array, 38 proteins in placental tissues were found to be differentially expressed between preterm preeclampsia and gestational age matched control, while 25 proteins were found to be expressed differentially between term preeclampsia and matched controls. Among these proteins, 16 proteins and their associated signaling pathways overlapped between preterm and term preeclampsia, suggesting the common pathogenesis of two subsets of disease. On the other hand, many proteins are uniquely altered in either preterm or term preeclampsia and correlated with severity of clinical symptoms and outcomes, therefore, providing molecular basis for these two subsets of preeclampsia. Furthermore, the expression levels of some of these proteins correlated with neonatal small for gestational age (PAI-1 and PAPP-A) and adverse outcomes (Flt-1) in women with preterm preeclampsia. These proteins could potentially be used as candidate biomarkers for predicting outcomes of preeclampsia.

BACKGROUND: Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation. METHODOLOGY/PRINCIPAL FINDINGS: Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.ΔZ) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (VT) by VRI and EIT, absolute values were normalized to the VT obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled VT by VEA and rel.ΔZ was R(2) = 0.96. Bland-Altman analysis showed a bias of -1.07±24.71 ml and limits of agreement of -49.05 to +47.36 ml. Within the different ROIs, correlations of VT-distribution by EIT and VRI ranged between R(2) values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of VT between VRI and EIT. CONCLUSIONS/SIGNIFICANCE: Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT.

Dendritic cells (DCs) and tumor cell-derived exosomes have been used to develop antitumor vaccines. However, the biological properties and antileukemic effects of leukemia cell-derived exosomes (LEXs) are not well described. In this study, the biological properties and induction of antileukemic immunity of LEXs were investigated using transmission electron microscopy, western blot analysis, cytotoxicity assays, and animal studies. Similar to other tumor cells, leukemia cells release exosomes. Exosomes derived from K562 leukemia cells (LEXK562) are membrane-bound vesicles with diameters of approximately 50-100 μm and harbor adhesion molecules (e.g., intercellular adhesion molecule-1) and immunologically associated molecules (e.g., heat shock protein 70). In cytotoxicity assays and animal studies, LEXs-pulsed DCs induced an antileukemic cytotoxic T-lymphocyte immune response and antileukemic immunity more effectively than did LEXs and non-pulsed DCs (P

Group A streptococcus (GAS, Streptococcus pyogenes) is a strict human pathogen that causes severe, invasive diseases. GAS does not produce catalase, but has an ability to resist killing by reactive oxygen species (ROS) through novel mechanisms. The peroxide response regulator (PerR), a member of ferric uptake regulator (Fur) family, plays a key role for GAS to cope with oxidative stress by regulating the expression of multiple genes. Our previous studies have found that expression of an iron-binding protein, Dpr, is under the direct control of PerR. To elucidate the molecular interactions of PerR with its cognate promoter, we have carried out structural studies on PerR and PerR-DNA complex. By combining crystallography and small-angle X-ray scattering (SAXS), we confirmed that the determined PerR crystal structure reflects its conformation in solution. Through mutagenesis and biochemical analysis, we have identified DNA-binding residues suggesting that PerR binds to the dpr promoter at the per box through a winged-helix motif. Furthermore, we have performed SAXS analysis and resolved the molecular architecture of PerR-DNA complex, in which two 30 bp DNA fragments wrap around two PerR homodimers by interacting with the adjacent positively-charged winged-helix motifs. Overall, we provide structural insights into molecular recognition of DNA by PerR and define the hollow structural arrangement of PerR-30bpDNA complex, which displays a unique topology distinct from currently proposed DNA-binding models for Fur family regulators.

Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo.The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model.The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone.PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM.

Great controversy exists regarding the biologic responses of osteoblasts to X-ray irradiation, and the mechanisms are poorly understood. In this study, the biological effects of low-dose radiation on stimulating osteoblast proliferation, differentiation and fracture healing were identified using in vitro cell culture and in vivo animal studies. First, low-dose (0.5 Gy) X-ray irradiation induced the cell viability and proliferation of MC3T3-E1 cells. However, high-dose (5 Gy) X-ray irradiation inhibited the viability and proliferation of osteoblasts. In addition, dynamic variations in osteoblast differentiation markers, including type I collagen, alkaline phosphatase, Runx2, Osterix and osteocalcin, were observed after both low-dose and high-dose irradiation by Western blot analysis. Second, fracture healing was evaluated via histology and gene expression after single-dose X-ray irradiation, and low-dose X-ray irradiation accelerates fracture healing of closed femoral fractures in rats. In low-dose X-ray irradiated fractures, an increase in proliferating cell nuclear antigen (PCNA)-positive cells, cartilage formation and fracture calluses was observed. In addition, we observed more rapid completion of endochondral and intramembranous ossification, which was accompanied by altered expression of genes involved in bone remodeling and fracture callus mineralization. Although the expression level of several osteoblast differentiation genes was increased in the fracture calluses of high-dose irradiated rats, the callus formation and fracture union were delayed compared with the control and low-dose irradiated fractures. These results reveal beneficial effects of low-dose irradiation, including the stimulation of osteoblast proliferation, differentiation and fracture healing, and highlight its potential translational application in novel therapies against bone-related diseases.

OBJECTIVES: The purpose of this study was to assess image quality and radiation dose of lower extremity CT angiography (CTA) with 70 kVp, high pitch acquisition and sinogram-affirmed iterative reconstruction (SAFIRE). METHODS: Lower extremity CTAs were performed on 44 patients: 22 patients were examined using protocol A (120 kVp, pitch of 0.85 and 120 ml of contrast agent on a first-generation dual-source CT) (120 kVp group) and 22 patients were evaluated with protocol B (70 kVp, pitch of 2.2 and 80 ml of contrast agent on a second-generation dual-source CT) (70 kVp group). Images from the 120 kVp group were reconstructed with filtered back projection (FBP) and images from the 70 kVp group with SAFIRE. The attenuation, image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Two radiologists subjectively assessed image quality of lower extremity arteries, plantar arterial enhancement and venous contamination of all patients. Radiation dose was compared between the two groups. RESULTS: Higher mean intravascular attenuation was obtained in the 70 kVp group (70 vs. 120 kVp group, 555.4 ± 83.4 HU vs. 300.9 ± 81.4 HU, P0.05). The venous contamination score was 1.5 ± 0.8 for 120 kVp group while no venous contamination was found in 70 kVp group. The inter-observer agreement was moderate to good for both groups (0.515∼1, P

We propose a new method for family-based tests of association and linkage called transmission/disequilibrium tests incorporating unaffected offspring (TDTU). This new approach, constructed based on transmission/disequilibrium tests for quantitative traits (QTDT), provides a natural extension of the transmission/disequilibrium test (TDT) to utilize transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. TDTU can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. When the study sample contains only case-parent trios, the TDTU is equivalent to TDT. Informative-transmission disequilibrium test (i-TDT) and generalized disequilibrium test(GDT) are another two methods that can use information of both unaffected offspring and affected offspring. In contract to i-TDT and GDT, the test statistic of TDTU is simpler and more explicit, and can be implemented more easily. Through computer simulations, we demonstrate that power of the TDTU is slightly higher compared to i-TDT and GDT. All the three methods are more powerful than method that uses affected offspring only, suggesting that unaffected siblings also provide information about linkage and association.

OBJECTIVE:The aim of this study was to confirm the association of RHOB and FAM167A-BLK gene polymorphisms with susceptibility to systemic sclerosis (SSc) in a Chinese Han population. METHODS:A total of 248 SSc patients and 251 healthy controls of Chinese Han ethnicity, which visited the department of dermatology of Peking Union Medical College Hospital, were included in the study. Six selected single nucleotide polymorphisms (SNPs) in the RHOB and FAM167A-BLK regions were selected as markers and were genotyped using a MassARRAY system, which is based on the matrix-assisted laser desorption/ionization time of flight mass spectrometry technique. RESULTS:Three SNPs in the coding regions of the RHOB and FAM167A-BLK genes displayed an association with SSc: (1) rs1062292T, which is a newly discovered SNP in the RHOB gene (P = 0.03, odds ratio [OR] = 1.62, 95% confidence interval (CI) = 1.05-2.50), (2) rs2736340T (P = 0.03, OR = 1.39, 95%CI = 1.03-1.85), and (3) rs13277113A (P = 0.04, OR = 1.34, 95%CI = 1.01-1.76), both in the FAM167A-BLK gene. Our results support previous findings that vaiants in the RHOB and FAM167A-BLK genes may be associated with susceptibility to SSc. However, the loci of the SNPs in RHOB region that displayed an association with SSc are quite different from the loci which were identified in studies of Caucasian populations. CONCLUSION:Our results confirm that RHOB and FAM167A-BLK polymorphisms exist in Chinese Han SSc patients. Therefore, variants of the RHOB and FAM167A-BLK genes are promising genetic markers for SSc.

The STING (stimulator of interferon genes) protein can bind cyclic dinucleotides to activate the production of type I interferons and inflammatory cytokines. The cyclic dinucleotides can be bacterial second messengers c-di-GMP and c-di-AMP, 3'5'-3'5' cyclic GMP-AMP (3'3' cGAMP) produced by Vibrio cholerae and metazoan second messenger 2'5'-3'5' Cyclic GMP-AMP (2'3' cGAMP). Analysis of single nucleotide polymorphism (SNP) data from the 1000 Genome Project revealed that R71H-G230A-R293Q (HAQ) occurs in 20.4%, R232H in 13.7%, G230A-R293Q (AQ) in 5.2%, and R293Q in 1.5% of human population. In the absence of exogenous ligands, the R232H, R293Q and AQ SNPs had only modest effect on the stimulation of IFN-β and NF-κB promoter activities in HEK293T cells, while HAQ had significantly lower intrinsic activity. The decrease was primarily due to the R71H substitution. The SNPs also affected the response to the cyclic dinucleotides. In the presence of c-di-GMP, the R232H variant partially decreased the ability to activate IFN-βsignaling, while it was defective for the response to c-di-AMP and 3'3' cGAMP. The R293Q dramatically decreased the stimulatory response to all bacterial ligands. Surprisingly, the AQ and HAQ variants maintained partial abilities to activate the IFN-β signaling in the presence of ligands due primarily to the G230A substitution. Biochemical analysis revealed that the recombinant G230A protein could affect the conformation of the C-terminal domain of STING and the binding to c-di-GMP. Comparison of G230A structure with that of WT revealed that the conformation of the lid region that clamps onto the c-di-GMP was significantly altered. These results suggest that hSTING variation can affect innate immune signaling and that the common HAQ haplotype expresses a STING protein with reduced intrinsic signaling activity but retained the ability to response to bacterial cyclic dinucleotides.

Pericardial patches are commonly used in vascular surgery to close arteriotomies. The mechanism of early healing after patch implantation is still not well defined. We used a rat aortic patch model to assess pericardial patch healing and examined Ephrin-B2, a marker of arterial identity, expression within the post-implantation patch. We also determined whether endothelial progenitor cells (EPC) are associated with early patch healing in the arterial environment.Wistar rats (200-250 grams) underwent infrarenal aortic arteriotomy and then closure via bovine or porcine pericardial patch angioplasty. Control groups included subcutaneously implanted patches. Patches were harvested at 0-30 days and analyzed by histology, immunohistochemistry, immunofluorescence and Western blot as well as quantitative PCR.Prior to implantation, pericardial patches are largely composed of collagen and are acellular. Following arterial implantation, increasing numbers of CD68-positive cells as well as Ephrin-B2 and CD34 dual-positive cells are found within both bovine and porcine pericardial patches, whereas the infiltrating cells are negative for vWF and α-actin. Porcine patches have a luminal monolayer of cells at day 7, compared to bovine patches that have fewer luminal cells. Subcutaneously implanted patches do not attract Ephrin-B2/CD34-positive cells. By day 30, both bovine and porcine pericardial patches develop a neointima that contains Ephrin-B2, CD34, and VEGFR2-positive cells.Both CD68-positive and Ephrin-B2 and CD34 dual-positive cells infiltrate the pericardial patch early after implantation. Arteriotomy closure via pericardial patch angioplasty shows patch adaptation to the arterial environment that may involve a foreign body response as well as localization of EPC. Arterial remodeling of pericardial patches support endothelialization and may represent a paradigm of healing of scaffolds used for tissue engineering.