Overweight/obesity in women of childbearing age is a serious public-health problem. In China, the incidence of maternal overweight/obesity has been increasing. However, there is not a meta-analysis ...to determine if pre-pregnancy body mass index (BMI) is related to infant birth weight (BW) and offspring overweight/obesity.
Three electronic bibliographic databases (MEDLINE, EMBASE and CINAHL) were searched systematically from January 1970 to November 2012. The dichotomous data on pre-pregnancy overweight/obesity and BW or offspring overweight/obesity were extracted. Summary statistics (odds ratios, ORs) were used by Review Manager, version 5.1.7.
After screening 665 citations from three electronic databases, we included 45 studies (most of high or medium quality). Compared with normal-weight mothers, pre-pregnancy underweight increased the risk of small for gestational age (SGA) (odds ratios OR, 1.81; 95% confidence interval CI, 1.76-1.87); low BW (OR, 1.47; 95% CI, 1.27-1.71). Pre-pregnancy overweight/obesity increased the risk of being large for gestational age (LGA) (OR, 1.53; 95% CI, 1.44-1.63; and OR, 2.08; 95% CI; 1.95-2.23), high BW (OR, 1.53; 95% CI, 1.44-1.63; and OR, 2.00; 95% CI; 1.84-2.18), macrosomia (OR, 1.67; 95% CI, 1.42-1.97; and OR, 3.23; 95% CI, 2.39-4.37), and subsequent offspring overweight/obesity (OR, 1.95; 95% CI, 1.77-2.13; and OR, 3.06; 95% CI, 2.68-3.49), respectively. Sensitivity analyses revealed that sample size, study method, quality grade of study, source of pre-pregnancy BMI or BW had a strong impact on the association between pre-pregnancy obesity and LGA. No significant evidence of publication bias was observed.
Pre-pregnancy underweight increases the risk of SGA and LBW; pre-pregnancy overweight/obesity increases the risk of LGA, HBW, macrosomia, and subsequent offspring overweight/obesity. A potential effect modification by maternal age, ethnicity, gestational weight gain, as well as the role of gestational diseases should be addressed in future studies.
Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa ...protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis
and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.
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•Analysis of different inversion sequences on hydraulic tomography results.•Prior information use enhances inversion accuracy in hydraulic tomography.•Verifying hydraulic tomography's efficacy in ...identifying preferential flow paths.
Water inrush accident in the mining area is a potential hazard in the coal mining industry. Detailed detection of the inrush flow paths remains a challenge for the industry. In this study, taking the Panbei coal mine as an example, a new strategy of hydraulic tomography (HT) inversion is proposed. In order to improve the accuracy of inversion, the geological information of the site is brought into the HT inversion as a boundary condition. Then, we analyze the effect of different inversion sequences and prior information on the inversion results of HT. Finally, we use the results of HT compared with tracer test results and groundwater level contour map to determine the preferential flow paths of the study area. The results showed that: (1) The inversion sequence will not significantly impact the HT results because the distribution of K and S.S. obtained by inversion does not have a significant deviation. (2) The sequential inversion with prior information has higher accuracy than the traditional continuous inversion. HT an identify the location of fault zones. (3) Combined with the tracer test results, it can be determined that the DF1 (fault zone) has strong conductivity, while the F70 (fault zone) and WF1 (fault zone) are weakly permeable. Then, combined with the contour map of the groundwater level, it can be inferred that the preferential flow paths of groundwater in the study area. From the C3I formation outcrop, water was supplied by the Panji anticline. Groundwater mainly flows from northwest to southeast; most groundwater flow paths are along the development direction of the fault zone. The results of this paper verify that HT is a promising technology for exploring the groundwater preferential flow paths in the coal mine area.
Induction of nonapoptotic cell death could be an approach to eliminate apoptosis-resistant tumors. We investigated necroptosis-based therapies in mouse models of pancreatic ductal adenocarcinoma ...cancer (PDAC).
We screened 273 commercially available kinase inhibitors for cytotoxicity against a human PDAC cell line (PANC1). We evaluated the ability of the aurora kinase inhibitor CCT137690 to stimulate necroptosis in PDAC cell lines (PANC1, PANC2.03, CFPAC1, MiaPaCa2, BxPc3, and PANC02) and the HEK293 cell line, measuring loss of plasma membrane integrity, gain in cell volume, swollen organelles, and cytoplasmic vacuoles. We tested the effects of CCT137690 in colon formation assays, and the effects of the necroptosis (necrostatin-1 and necrosulfonamide), apoptosis, autophagy, and ferroptosis inhibitors. We derived cells from tumors that developed in Pdx1-Cre;K-RasG12D/+;p53R172H/+ (KPC) mice. Genes encoding proteins in cell death pathways were knocked out, knocked down, or expressed from transgenes in PDAC cell lines. Athymic nude or B6 mice were given subcutaneous injections of PDAC cells or tail-vein injections of KPC tumor cells. Mice were given CCT137690 (80 mg/kg) or vehicle and tumor growth was monitored; tumor tissues were collected and analyzed by immunohistochemistry. We compared gene expression levels between human pancreatic cancer tissues (n = 130) with patient survival times using the online R2 genomics analysis and visualization platform.
CCT137690 induced necrosis-like death in PDAC cell lines and reduced colony formation; these effects required RIPK1, RIPK3, and MLKL, as well as inhibition of aurora kinase A (AURKA). AURKA interacted directly with RIPK1 and RIPK3 to reduce necrosome activation. AURKA-mediated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine 9 inhibited activation of the RIPK3 and MLKL necrosome. Mutations in AURKA (D274A) or GSK3β (S9A), or pharmacologic inhibitors of RIPK1 signaling via RIPK3 and MLKL, reduced the cytotoxic activity of CCT137690 in PDAC cells. Oral administration of CCT137690 induced necroptosis and immunogenic cell death in subcutaneous and orthotopic tumors in mice, and reduced tumor growth and tumor cell phosphorylation of AURKA and GSK3β. CCT137690 increased survival times of mice with orthotopic KPC PDACs and reduced tumor growth, stroma, and metastasis. Increased expression of AURKA and GSK3β mRNAs associated with shorter survival times of patients with pancreatic cancer.
We identified the aurora kinase inhibitor CCT137690 as an agent that induces necrosis-like death in PDAC cells, via RIPK1, RIPK3, and MLKL. CCT137690 slowed growth of orthotopic tumors from PDAC cells in mice, and expression of AURKA and GSK3β associate with patient survival times. AURKA might be targeted for treatment of pancreatic cancer.
•High-permeability and water-rich zones were identified by the hydraulic tomography.•Strong groundwater runoff paths were inferred for the water source area.•The hydraulic tomography was improved ...with various prior information.•THT can better reveal larger-scale heterogeneity of aquifers compared to SSHT.•Hydraulic tomography holds valuable applications in groundwater exploitation plans.
Determining the spatial hydraulic parameters of aquifers is of paramount importance for the development and utilization of groundwater in water source areas. However, most methods are unable to accurately characterize the heterogeneity of aquifers because of the influences of complex geology, hydrogeology, structure and insufficient information. Hydraulic tomography (HT) is an effective and robust method for hydraulic parameter inversion to characterize heterogeneity. In this study, a two-dimensional HT model was established to simulate hydraulic parameter fields for a fractured karst aquifer in the Zhangji water source area (Xuzhou city, China). Steady-state hydraulic tomography (SSHT) and transient hydraulic tomography (THT) with different prior information conditions were applied to determine the high-permeability area and water-rich zones, and to infer possible locations of karst conduits and strong runoff paths in the water source area. The results indicate that: (1) THT can better reveal larger-scale heterogeneous characteristics of hydraulic properties compared to SSHT. The hydraulic conductivity distribution estimated by THT correlates well with the geological conditions of the area, especially in identifying water-rich zones formed by faults and other formations. (2) When combined with geological conditions, HT possesses the ability to identify strong runoff paths in fractured karst aquifers. (3) Accurate prior information, which is more relevant to the head response information, is conducive to obtaining more acceptable HT results. (4) THT can simultaneously identify high-permeability and high-storage zones, and the analysis of the overlap of these two regions has the potential to predict underground water reservoirs, which is of the utmost importance for the development and utilization of groundwater resources in water source areas.
BackgroundIncreasing infiltration of CD8+ T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols ...use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8+ T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases.MethodsCombination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6−/− mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6+CD8+ T cells. Transgenic Cxcr6−/− OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response.ResultsWe identified that CXCR6 was exclusively expressed on intratumoral CD8+ T cell. CXCR6+CD8+ T cells were more immunocompetent, and chimeras with specific deficiency on CD8+ T cells showed weaker antitumor activity. In addition, Cxcr6−/− mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6+CD8+ T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression.ConclusionsThis study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8+ T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.
The Gaussian vertical backscatter (GVB) model has a pivotal role in describing the forest vertical structure more accurately, which is reflected by P-band polarimetric interferometric synthetic ...aperture radar (Pol-InSAR) with strong penetrability. The model uses a three-dimensional parameter space (forest height, Gaussian mean representing the strongest backscattered power elevation, and the corresponding standard deviation) to interpret the forest vertical structure. This paper establishes a two-dimensional GVB model by simplifying the three-dimensional one. Specifically, the two-dimensional GVB model includes the following three cases: the Gaussian mean is located at the bottom of the canopy, the Gaussian mean is located at the top of the canopy, as well as a constant volume profile. In the first two cases, only the forest height and the Gaussian standard deviation are variable. The above approximation operation generates a two-dimensional volume only coherence solution space on the complex plane. Based on the established two-dimensional GVB model, the three-baseline inversion is achieved without the null ground-to-volume ratio assumption. The proposed method improves the performance by 18.62% compared to the three-baseline Random Volume over Ground (RVoG) model inversion. In particular, in the area where the radar incidence angle is less than 0.6 rad, the proposed method improves the inversion accuracy by 34.71%. It suggests that the two-dimensional GVB model reduces the GVB model complexity while maintaining a strong description ability.
Ground moving targets with slow velocity and low radar cross-section (RCS) are usually embedded in the clutter Doppler spectrum. To achieve the detection and estimation of such targets, a novel ...method operating in the range-Doppler domain is developed for airborne multichannel radar systems. The interferometric phases that are sensitive to moving targets are obtained by coherent difference processing (CDP) for target detection. Moreover, the amplitude is utilized as complementary information to improve the detection performance. Then, a matched filter bank is designed and applied to the CDP processed data to complete the parameter estimation. The proposed method provides the benefits of high efficiency and robustness, since it does not involve matrix inversion, and it does not require homogeneous clutter assumption unlike adaptive algorithms. Experiments on real data acquired by an airborne X-band four-channel radar system demonstrate its effectiveness.
The post-Doppler adaptive matched filter (PD-AMF) with constant false alarm rate (CFAR) property was developed for adaptive detection of moving targets, which is a standardized version of the ...post-Doppler space–time adaptive processing (PD-STAP) in practical applications. However, its detection performance is severely constrained by the training data, especially in a dense signal environment. Improper training data and contamination of moving target signals remarkably degrade the performance of disturbance suppression and result in target cancellation by self-whitening. To address these issues, a novel post-Doppler parametric adaptive matched filter (PD-PAMF) detector is proposed in the range-Doppler domain. Specifically, the detector is introduced via the post-Doppler matched filter (PD-MF) and the lower-diagonal-upper (LDU) decomposition of the disturbance covariance matrix, and the disturbance signals of the spatial sequence are modelled as an auto-regressive (AR) process for filtering. The purpose of detecting ground moving targets as well as for estimating their geographical positions and line-of-sight velocities is achieved when the disturbance is suppressed. The PD-PAMF is able to reach higher performances by using only a smaller training data size. More importantly, it is tolerant to moving target signals contained in the training data. The PD-PAMF also has a lower computational complexity. Numerical results are presented to demonstrate the effectiveness of the proposed detector.
BackgroundThe loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research ...on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.MethodsThe antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated.ResultsWe found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids.ConclusionOur data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.
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