Search

Through a copper-catalyzed oxidative three-component annulation reaction, a new method for direct and syn-selective construction of cyclic ether-fused tetrahydroquinolines from readily available feedstock was demonstrated.

Background: In recent studies, tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy.Methods: We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance by using receiver operating characteristic (ROC) and calibration curves.Results: CYBA and SMPD3 were significantly related to prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC.Conclusion: Our novel prognostic model based on CYBA and SMPD3 accurately predicted the prognosis and immunotherapy outcomes of patients with EC. Our results provide a new direction to study tumourgenesis and development, as well as guidance for clinical diagnosis and therapy of EC.

Kir5.1 interacts with Kir4.2 in proximal tubule and with Kir4.1 in distal convoluted tubule (DCT), connecting tubule (CNT) and cortical collecting duct (CCD) to form basolateral-K+-channels. Kir4.2/Kir5.1 and Kir4.1/Kir5.1 play an important role in regulating Na+/HCO3--transport of the proximal tubule and Na+/K+ -transport in the DCT/CNT/CCD. The main focus of this review is to provide an overview of the recent development in the field regarding the role of Kir5.1 regulating renal electrolyte transport in the proximal tubule and DCT.Loss-of-function-mutations of KCNJ16 cause a new form of tubulopathy, characterized by hypokalaemia, Na+-wasting, acid-base-imbalance and metabolic-acidosis. Abnormal bicarbonate transport induced by loss-of-function of KCNJ16-mutants is recapitulated in Kir4.2-knockout-(Kir4.2 KO) mice. Deletion of Kir5.1 also abolishes the effect of dietary Na+ and K+-intakes on the basolateral membrane voltage and NCC expression/activity. Long-term high-salt intake or high-K+-intake causes hyperkalaemic in Kir5.1-deficient mice.Kir4.2/Kir5.1 activity in the proximal tubule plays a key role in regulating Na+, K+ and bicarbonate-transport through regulating electrogenic-Na+-bicarbonate-cotransporter-(NBCe1) and type 3-Na+/H+-exchanger-(NHE3). Kir4.1/Kir5.1 activity of the DCT plays a critical role in mediating the effect of dietary-K+ and Na+-intakes on NCC activity/expression. As NCC determines the Na+ delivery rate to the aldosterone-sensitive distal nephron (ASDN), defective regulation of NCC during high-salt and high-K+ compromises renal K+ excretion and K+ homeostasis.

In this paper, an effective solution is presented for efficient robotic object search by leveraging metric-topological map. Based on the reference of objects, we construct a novel metric-topological map that is particularly suitable for object search, where the topological nodes represent the object-related locations in the environment. To effectively determine the creation of nodes on the map, a rapid adjustment method of the robot viewing angle is introduced. Compared with traditional maps, the map built in this paper not only removes redundant nodes irrelevant to objects, but also facilitates the mobile robot to locate the target object. Besides, inspired by human search behavior, a search strategy is proposed by considering the tradeoff between the current position of the robot and the distance from the robot to the promising location of finding the target object, in order to further improve the search efficiency. The effectiveness and efficiency of our solution is verified through comparative experiments in both simulation and real-world environments. Results show that the presented approach always allows the mobile robot to find the target object efficiently and reliably, while achieving human-like search behavior.

Low potassium (K) intake has adverse health effects, including hypertension, osteoporosis, and nephrolithiasis. Dietary K restriction rapidly activates a K switch in the distal nephron to maintain homeostasis by reducing K excretion and activating the sodium chloride cotransporter (NCC). The distal convoluted tubule (DCT) is morphologically and functionally divided into DCT1 and DCT2, with each segment specialized for a different function. Here, we define the differences between DCT1 and DCT2 transcriptionally, examine their unique responses to potassium restriction, and detrimental physiological responses in mice.The K restriction effects were examined at 3 time points, overnight (acute), 4 days (short-term), and 4 weeks (chronic). Electrophysiology was used to assess effects of acute K deprivation on basolateral K channel (Kir4.1/5.1) activity. To determine effects of K restriction for 4 days, the DCT-targeted single-nucleus RNA-sequencing (snRNAseq) approach was applied. Female NCC-Cre-INTACT (PMID: 26087164) mice were provided either normal (NK) or K deficient (KD) diet for 4 days (short-term) and kidneys were snap-frozen for targeted snRNAseq (10X Chromium, NovaSeq) (3 mice per diet, 10,000 nuclei per mouse). Effects of chronic K-restriction were assessed by serum electrolytes, tissue clearing, and western blot.Acute K restriction stimulated basolateral K channel activity in DCT1, but not in DCT2, indicating that DCT1 and DCT2 respond differently. Although both DCT1 and DCT2 express NCC, snRNAseq data showed that DCT1 and DCT2 have distinct transcriptional signatures, with DCT1 expressing genes involved in magnesium reabsorption, and DCT2 expressing genes involved in calcium reabsorption and electrogenic sodium channel (ENaC). Four days of K restriction switched the DCT from a K-wasting state to K-sparing state, shown by reduction of gENaC ( Scnn1g) and Kallikrein ( Klk1) expression. Furthermore, K restriction decreased the expression of the calcium-handling genes Slc8a1, Calb and Vdr. When prolonged, K restriction led to increases in NCC, reduction in ENaC cleavage, and elongation of the DCT. It also led to calcium wasting (plasma iCa in NK, 1.38 ± 0.03, n=7; KD, 1.24 ± 0.01 mM, n=6) and reduction in calbindin D-28k protein.Our results suggest that DCT1 and DCT2 both express NCC, but have distinct transcriptomic signatures with unique roles in magnesium and calcium transport, respectively. Dietary K restriction reprograms DCT2 cells to be more like DCT1 cells, thereby maintaining K balance but contributing to calcium wasting as a complication. NIH DK51496, NIH DK054983, VA 1I01BX002228, LeDucq Fondation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The non-adiabatic geometric quantum computation (NGQC) has attracted a lot of attention for noise-resilient quantum control. However, previous implementations of NGQC require long evolution paths that make them more vulnerable to incoherent errors than their dynamical counterparts.In this work, we experimentally realize a universal short-path non-adiabatic geometric gate set (SPNGQC) with a 2-times shorter evolution path on a superconducting quantum processor. Characterizing with both quantum process tomography and randomized benchmarking methods, we report an average single-qubit gate fidelity of 99.86% and a two-qubit gate fidelity of 97.9%. Additionally, we demonstrate superior robustness of single-qubit SP-NGQC gate to Rabi frequency error in some certain parameter space by comparing their performance to those of the dynamical gates and the former NGQC gates., Comment: 15 pages, 11 figures

The aims of this work were to explore the use of weighted gene coexpression network analysis (WGCNA) for identifying the key genes in severe burns and to provide a reference for finding therapeutic targets for burn wounds. The GSE8056 dataset was selected from the gene expression database of the US National Center for Biotechnology Information for analysis, and a WGCNA network was constructed to screen differentially expressed genes (DEGs). Gene Ontology and pathway enrichment of DGEs were analyzed, and protein interaction network was constructed. A burn mouse model was constructed, and the burn tissue was taken to identify the expression levels of differentially expressed genes. The results showed that the optimal soft threshold for constructing the WGCNA network was 9. 10 coexpressed gene modules were identified, among which the green, brown, and gray modules had the largest number of burn-related genes. The DEGs were mainly related to immune cell activation, inflammatory response, and immune response, and they were enriched in PD-1/PD-L1, Toll-like receptor, p53, and nuclear factor-kappa B (NF-κB) signaling pathways. 5 DEGs were screened and identified, namely, Jun protooncogene (JUN), signal transducer and activator of transcription 1 (STAT1), BCL2 apoptosis regulator (Bcl2), matrix metallopeptidase 9 (MMP9), and Toll-like receptor 2 (TLR2). Compared with skin tissue of normal mouse, the messenger ribose nucleic acid (mRNA) and protein expression levels (PEL) of STAT1 and Bcl2 in burn tissue were greatly decreased, while those of JUN, MMP9, and TLR2 were increased obviously ( p < 0.05 ). In conclusion, STAT1, Bcl2, JUN, MMP9, and TLR2 can be potential biological targets for the treatment of severe burn wounds.

Asthenozoospermia is a common form of abnormal sperm quality in idiopathic male infertility. While most sperm-mediated causes have been investigated in detail, the significance of seminal plasma has been neglected. Herein, we aimed to investigate the possible pathogenic factors leading to decreased sperm motility based on seminal plasma. Semen was collected from normo- (NOR, n = 70 ), idiopathic oligo- (OLI, n = 57 ), and idiopathic asthenozoospermic (AST, n = 53 ) patients. Using attenuated total reflection-Fourier transform infrared coupled with chemometrics, distinct differences in the biochemical compositions of nucleic acids, protein structure (amides I, II, and III), lipids, and carbohydrates in seminal plasma of AST were observed when compared to NOR and OLI. Compared with NOR and OLI, the levels of peptide aggregation, protein phosphorylation, unsaturated fatty acid, and lipid to protein ratio were significantly increased in AST; however, the level of lipid saturation was significantly decreased in seminal plasma of AST. Compared with NOR, the levels of ROS, MDA, 8-iso-prostaglandin F2α (8-isoPGF2α), and the ratio of phospho-AMPKα/AMPKα1 were significantly increased in AST; however, the levels of SOD, glutathione S-transferase (GSTs), protein carbonyl derivative (PC), and the ratio of phospho-Rictor/Rictor were significantly decreased in seminal plasma of AST. Changes of the AMPK/mTORC2 signaling in the seminal microenvironment possibly induce abnormal glucose and lipid metabolism, which impairs energy production. Oxidative stress potentially damages seminal plasma lipids and proteins, which in turn leads to impaired sperm structure and function. These findings provide evidence that the changes in seminal plasma compositions, oxidative stress, and activation of the AMPK/mTORC2 signaling contribute to the development of asthenozoospermia.

Objective. This study was aimed at developing a model for predicting postoperative biochemical recurrence of prostate cancer (PCa) using clinical data-CEUS-MRI radiomics and at verifying its clinical effectiveness. Methods. The clinical imaging data of 159 patients pathologically confirmed with PCa and who underwent radical prostatectomy in Xiangyang No. 1 People’s Hospital and Jiangsu Hospital of Chinese Medicine from March 2016 to December 2020 were retrospectively analyzed. According to the 2-5-year follow-up results, the patients were divided into the biochemical recurrence (BCR) group ( n = 59 ) and the control group ( n = 100 ). The training set and test set were established in the proportion of 7/3; 4 prediction models were established based on the clinical imaging data. In training set, the area under the curve (AUC) and decision curve analysis (DCA) by R was conducted to compare the efficiency of 4 prediction models, and then, external validation was performed using the test set. Finally, a nomogram tool for predicting BCR was developed. Results. Univariate regression analysis confirmed that the SmallAreaHighGrayLevelEmphasis, RunVariance, Contrast, tumor diameter, clinical T stage, lymph node metastasis, distant metastasis, Gleason score, preoperative PSA, treatment method, CEUS-peak intensity (PI), time to peak (TTP), arrival time (AT), and elastography grade were the influencing factors for predicting BCR. In the training set, the AUC of combinatorial model demonstrated the highest efficiency in predicting BCR [AUC: 0.914 (OR 0.0305, 95% CI: 0.854-0.974)] vs. the general clinical data model, the CEUS model, and the MRI radiomics model. The DCA confirmed the largest net benefits of the combinatorial model. The test set validation gave consistent results. The nomogram tool has been well applied clinically. Conclusion. The previous clinical and imaging data alone did not perform well for predicting BCR. Our combinatorial model firstly using clinical data-CEUS-MRI radiomics provided an opportunity for clinical screening of BCR and help improve its prognosis.

Objective. This study aimed to investigate the risk factors of reversible posterior leukoencephalopathy syndrome (RPLS) in pregnant women with severe preeclampsia or eclampsia (SPE/E) based on a predicting model and to analyze the perinatal outcomes. Methods. From January 2015 to March 2020, 78 pregnant women data diagnosed with severe preeclampsia or eclampsia with cranial magnetic resonance imaging (MRI) and transcranial Doppler (TCD) screening in Xiangyang No. 1 People’s Hospital and Jiangsu Province Hospital of Chinese Medicine were analyzed retrospectively. They were divided into the RPLS group (n = 33) and non-RPLS group (n = 45) based on the MRI results. The general clinical data (blood pressure, BMI, symptoms, and so forth), laboratory examination, TCD results, and perinatal outcomes in the two groups were compared. The risk factors of severe preeclampsia or eclampsia complicated with RPLS were analyzed by multivariate logistic regression. The prediction model and decision curve (DCA) were established according to the clinical-imaging data. Results. The univariate analysis showed that poor placental perfusion, hypertension emergency, use of two or more oral antihypertensive drugs, headache, white blood cell (WBC) count, platelet (PLT) count, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), uric acid (UA), serum albumin (ALB), average flow velocity, and resistance index of the posterior cerebral and basilar arteries were significantly different in the RPLS group compared with the non-RPLS group (all P < 0.05 ). The multivariate logistic regression analysis showed that hypertensive emergency, headache, WBC, PLT, ALT, and average flow velocity of the basilar artery (BAAFV) were the risk factors in the RPLS group. The aforementioned clinical-imaging data modeling (general data model, laboratory examination model, TCD model, and combined model) showed that the combined model predicted RPLS better. DCA also confirmed that the net benefit of the combined model was higher. In addition, the incidence of postpartum hemorrhage, stillbirth, and preterm infants was higher in the RPLS group than in the non-RPLS group (all P < 0.05 ). Conclusions. More postpartum complications were detected in pregnant women with severe preeclampsia or eclampsia complicated with RPLS. Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV were the important risk factors for RPLS. The combined model had a better effect in predicting RPLS.

The ages of Zn-Pb deposits are exceptionally challenging to determine owing to the lack of suitable mineral chronometers and techniques. Here we present the first result for in situ LA-ICP-MS U-Pb dating of carbonates and barite from a Mississippi Valley– type (MVT) Zn-Pb deposit in South China. Hydrothermal dolomite in close textural and paragenetic association with Zn-Pb sulfides, and calcite and barite cement from the breccia ores, yield ages of 473.4 ± 2.7 Ma and 368.7 ± 3.1 Ma, respectively. Together with new in situ S-Pb-Sr isotope values, these data reveal an epigenetic Zn-Pb mineralization history, agreeing well with a model involving basinal brine accumulation and MVT Zn-Pb sulfide precipitation. Because carbonate is a common mineral in Zn-Pb deposits worldwide, and other minerals in such deposits suitable for isotope dating are generally absent, in situ U-Pb dating of gangue carbonates opens a new window for better defining the ore genesis of this globally important Zn-Pb deposit type and for tracking hydrothermal fluid flow in sedimentary basins.

To cope with the problem caused by inadequate training data, many person re-identification (re-id) methods exploit generative adversarial networks (GAN) for data augmentation, where the training of GAN is typically independent of that of the re-id model. The coupling relation between them that probably brings in a performance gain of re-id is thus ignored. In this work, we propose a general framework, namely JoT-GAN, to jointly train GAN and the re-id model. It can simultaneously achieve the optima of both the generator and the re-id model, where the training is guided by each other through a discriminator. The re-id model is boosted for two reasons: (1) the adversarial training encourages it to fool the discriminator, and (2) the generated samples augment the training data. Extensive results on benchmark datasets show that for the re-id model trained with the identification loss as well as the triplet loss, the proposed joint training framework outperforms existing methods with separate training and achieves state-of-the-art re-id performance.

The key challenges of scene recognition for service robots in various family environments are the view shortage of holistic scenes and poor adaptation. To address these problems, a family scene recognition mechanism for the service robot is proposed in this paper. A comprehensive application of fish-eye, pinhole, and depth cameras is provided to guarantee the sufficient view of robot. A selective CNN features fusion for the recognition of fish-eye scene images is designed to improve the training efficiency and the recognition accuracy. The mechanism is deployed in a designed hybrid cloud including public and private clouds. The proposed family scene recognition model is trained by large-scale datasets in the public cloud and runs in the private cloud. Besides, the recognition skill can be reinforced and increased by matching human guidance and CNN features to help the robot learn new scenes and improve the adaptation in different family environments. Extensive experiments are implemented to evaluate the proposed method using real scene images from six families. The experiment results show the validity and good performance of our method for the service robot scene recognition in various family environments.

Effective path planning (PP) is the basis of autonomous navigation for mobile robots. Since the PP is an NP-hard problem, intelligent optimization algorithms have become a popular option to solve this problem. As a classic evolutionary algorithm, the artificial bee colony (ABC) algorithm has been applied to solve numerous realistic optimization problems. In this study, we propose an improved artificial bee colony algorithm (IMO-ABC) to deal with the multi-objective PP problem for a mobile robot. Path length and path safety were optimized as two objectives. Considering the complexity of the multi-objective PP problem, a well-environment model and a path encoding method are designed to make solutions feasible. In addition, a hybrid initialization strategy is applied to generate efficient feasible solutions. Subsequently, path-shortening and path-crossing operators are developed and embedded in the IMO-ABC algorithm. Meanwhile, a variable neighborhood local search strategy and a global search strategy, which could enhance exploitation and exploration, respectively, are proposed. Finally, representative maps including a real environment map are employed for simulation tests. The effectiveness of the proposed strategies is verified through numerous comparisons and statistical analyses. Simulation results show that the proposed IMO-ABC yields better solutions with respect to hypervolume and set coverage metrics for the later decision-maker.

Objective To explore the association between depression and semen quality and the mediating role of oxidative stress. Design Cross-sectional study with repeated measures of semen quality. Setting Human Sperm Bank of Hubei Province, People’s Republic of China. Patient(s) From April 2017 to July 2018, we recruited 1,000 potential sperm donors who completed the Beck Depression Inventory questionnaire and had measures of oxidative stress biomarkers. Intervention(s) None. Main Outcome Measure(s) Severity of depression was evaluated by the Beck Depression Inventory scores (0–4, no depression; 5–13, mild depression; 14–20, moderate depression; and 21 or greater, severe depression). The urinary concentrations of 8-hydroxy-2-deoxyguanosine, 4-hydroxy-2-nonenal-mercapturic acid, and 8-iso-prostaglandin F2α (8-isoPGF2α) were measured to reflect oxidative stress status. Repeated semen quality parameters (n = 5,880) were examined by trained professional technicians according to the World Health Organization laboratory manual. Associations between depression, oxidative stress, and repeated measures of semen quality parameters were evaluated using linear or mixed-effects models with adjustment for potential confounders. Mediation analysis was performed to test the potential mediating role of oxidative stress. Result(s) A total of 391 (39.1%) men were classified as mild depression, 67 (6.7%) as moderate depression, and 19 (1.9%) as severe depression. Inverse dose–response relationships between severity of depression and semen quality parameters were found. Compared with men without depression (n = 523), those with severe depression had a 25.26% (95% confidence interval, −38.65%, −8.93%) lower semen volume, 37.04% (−55.37%, −11.20%) lower total sperm count, 13.57% (−23.17%, −2.78%) lower total motility, and 15.08% (−25.09%, −3.72%) lower progressive motility; men with moderate depression also had a 12.28% (−21.16%, −2.40%) lower semen volume and 23.56% (−36.50%, −7.97%) lower total sperm count. We found a positive dose–response relationship between severity of depression and urinary 8-isoPGF2α concentrations. However, we found no evidence that the associations between depression status and semen quality were mediated by oxidative stress markers. Conclusion(s) In the study of Chinese male sperm donors, men with depression had worse semen quality parameters, including semen volume, sperm concentration, total sperm count, total motility, and progressive motility. Although depression was positively associated with urinary 8-isoPGF2α concentrations, depression–semen quality associations were not mediated by oxidative stress.

Alkali metal K in exhaust gas has a deactivation effect on NH3-SCR catalysts. In this work, it is discovered that the addition of Ho on CeTi catalyst can remarkably strengthen its K tolerance. The conclusions of Brunauer–Emmett–Teller (BET) , X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), NH3 temperature programmed desorption (NH3-TPD) and H2 temperature programmed reduction (H2-TPR) analyses demonstrate that the enhancement of K resistance mainly originates from its stronger surface acidity and redox capability, the higher concentration of Ce3+ species and surface chemisorbed oxygen. In situ DRIFT analysis reveals that the introduction of Ho on CeTi can remarkably improve the adsorption of NH3 and NOx species on catalyst surface, accompanied by the intensified reactivity of ad-NH3 species, which should also administer to improve the K resistance.

Convolutional neural networks (CNN) has been widely used in biomedical image segmentation (BIS) tasks for its remarkable feature representation capability, and most of existing CNN-based segmentation networks leverage a down-sampling operation to achieve larger acceptance domain. However, down-sampling operations could inevitably loss the detailed information of images which is very important for the BIS task. In this paper, we propose a full-resolution biomedical image segmentation network(FRNet) that could maintain the integrated detailed information of image while keeping sufficient semantic information and large receptive field. Specifically, the basic semantic feature and non-destructive feature are employed to represent the semantic and detailed information of images, respectively. A backbone network and a new full-feature extraction branch are conducted to extract those two kinds of complementary features. Furthermore, a novel feature fusion module is designed to integrate those complementary features to achieve non-destructive description of images. Finally, in order to further improve the description ability of the integrated feature, a Densely connected Atrous Spatial Pyramid Pooling(DenseASPP) module is arranged at the end of our proposed FRNet to extract the multiscale information of images. Thorough experimental results on several available databases demonstrate the effectiveness and advancement of FRNet.

It is a challenging task to produce recipes from images, due to the difficulty in bridging the gap from intuitive, static images to sequential, dynamic recipes. In this paper, we propose a novel recipe generation system for producing effective recipes from images. As medium steps, ingredient generation is introduced to guide recipe generation in our system. With potential information in ingredient lists, ingredient selection and ingredient sequence, the system is taught to generate effective recipes. For information representation, a hierarchical attention mechanism is designed to extract effective features for ingredient production and recipe generation. In order to guarantee the comprehensiveness and logic in recipes, a specific and explicit criterion around ingredients is designed under the framework of reinforcement learning. In ingredient generation, the system is required to generate ingredients with correct sequence in cooking procedures. And in recipe generation, ingredients in recipes are required to be consistent with produced ingredients. In experiments, the proposed method is compared with state-of-the-art methods to evaluate the feasibility. The results indicate that the proposed system achieves a better performance than other methods on both aspects of producing proper ingredients and effective recipes.

Hepatocellular carcinoma (HCC) is defined as a universal malignancy while radiation therapy is the effective treatment for it. This study validated the mechanism of long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed gene (CRNDE) in radiation resistance in HCC. LncRNA CRNDE upregulation was detected in HCC cells. The radiation-resistant cell strains Huh7R and SNU-387R were established. After silencing lncRNA CRNDE, the cell colony formation ability, cell activity, apoptosis, cell cycles, and γ-H2AX positive rate in Huh7R and SNU-387R were detected. Silencing lncRNA CRNDE decreased the cell activity, colony formation ability, and cell number in the G2 phase and facilitated DNA damage and apoptosis. The binding relations of specificity protein 1 (SP1) with lncRNA CRNDE and 3-phosphoinositide dependent protein kinase 1 (PDK1) were verified. LncRNA CRNDE regulated PDK1 transcription by binding to transcription factor SP1. PDK1 overexpression partially reversed the inhibition of silencing lncRNA CRNDE on radiation resistance in HCC cells. The transplanted tumor mouse model was established and showed that silencing lncRNA CRNDE decreased tumor volume and weight and Ki67-positive cells in HCC mice in vivo. Collectively, lncRNA CRNDE was upregulated in HCC cells and promoted PDK1 transcription by binding to SP1, thus enhancing radiation resistance in HCC cells.

Invasion assay of ARCaPM-TBX2 and ARCaPM-Neo cells

Legend to Supplementary Figures

Plot showing relative protein expression of TBX2 and WNT3A in human PCa cell lines

Invasion assay of PC3 (TBX2DN+WNT3A, TBX2DN, and Neo)cells with the addition of SFRP-2

Supplementary Materials and Methods

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC.Significance:MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.

Schematic depiction of WNT3A gene promoter, and ChIP analysis of LNCaP-TBX2 and LNCaP-Neo cells to assess the binding of TBX2 on WNT3A promoter

Supplementary Fig S2. (A) Expression of miR-409-3p and miR-154* assayed by qRT- PCR in ARCaPM-C control PCa cells and ARCaPM-cluster inhibitor transduced cells. Data is normalized to RNU6B. (B) Morphological changes in ARCaPM-cluster inhibitor compared to ARCaPM-C control PCa cells. (C) E-cadherin and N-cadherin mRNA assayed in ARCaPM-C control PCa cells and ARCaPM cluster inhibitor expressing PCa cells by qRT-PCR, normalized to 18s RNA. (D) Invasion assay of in ARCaPM-C and ARCaPM-cluster inhibitor expressing PCa cells. *: p

This file include 11 Supplementary Figures, Supplementary Materials and Methods, and Supplementary References.

Micro-CT images of mouse tibiae injected with ARCaPM-TBX2 and ARCaPM-Neo cells

Identification of factors that mediate visceral and bone metastatic spread and subsequent bone remodeling events is highly relevant to successful therapeutic intervention in advanced human prostate cancer. TBX2, a T-box family transcription factor that negatively regulates cell-cycle inhibitor p21, plays critical roles during embryonic development, and recent studies have highlighted its role in cancer. Here, we report that TBX2 is overexpressed in human prostate cancer specimens and bone metastases from xenograft mouse models of human prostate cancer. Blocking endogenous TBX2 expression in PC3 and ARCaPM prostate cancer cell models using a dominant-negative construct resulted in decreased tumor cell proliferation, colony formation, and invasion in vitro. Blocking endogenous TBX2 in human prostate cancer mouse xenografts decreased invasion and abrogation of bone and soft tissue metastasis. Furthermore, blocking endogenous TBX2 in prostate cancer cells dramatically reduced bone-colonizing capability through reduced tumor cell growth and bone remodeling in an intratibial mouse model. TBX2 acted in trans by promoting transcription of the canonical WNT (WNT3A) promoter. Genetically rescuing WNT3A levels in prostate cancer cells with endogenously blocked TBX2 partially restored the TBX2-induced prostate cancer metastatic capability in mice. Conversely, WNT3A-neutralizing antibodies or WNT antagonist SFRP-2 blocked TBX2-induced invasion. Our findings highlight TBX2 as a novel therapeutic target upstream of WNT3A, where WNT3A antagonists could be novel agents for the treatment of metastasis and for skeletal complications in prostate cancer patients. Cancer Res; 77(6); 1331–44. ©2017 AACR.

Quantitative Real-Time RT-PCR and Invasion assay of LNCaP-TBX2 and LNCaP-Neo cells

Cancer Outlier Profile Analysis (COPA) in Oncomine 4.4 showing TBX2 over-expression in PCa microarray data sets

Supplementary Fig S1. miR-154* staining of human tissues was performed as described in the Methods section. Values are represented as intensity counts/cell, (n=1, duplicate samples from the same patient tumor tissues were stained).

Purpose: MicroRNAs in the delta-like 1 homolog–deiodinase, iodothyronine 3 (DLK1-DIO3) cluster have been shown to be critical for embryonic development and epithelial to mesenchymal transition (EMT). DLK1-DIO3 cluster miRNAs are elevated in the serum of patients with metastatic cancer. However, the biologic functions of these miRNAs in the EMT and metastasis of cancer cells are poorly understood. We previously demonstrated the oncogenic and metastatic role of miR-409-3p/5p, a member of this cluster, in prostate cancer. In this study, we defined the role of miR-154* and miR-379, two key members of this cluster, in prostate cancer progression and bone metastasis in both cell line models and clinical specimens.Experimental Design: Genetic manipulation of miR-154* and miR-379 was performed to determine their role in tumor growth, EMT, and bone metastasis in mouse models. We determined the expression of miR-154* in prostate cancer clinical samples and bone metastasis samples using in situ hybridization and quantum dot labeling.Results: Elevated expression of miR-154* and miR-379 was observed in bone metastatic prostate cancer cell lines and tissues, and miR-379 expression correlated with progression-free survival of patients with prostate cancer. Intracardiac inoculation (to mimic systemic dissemination) of miR-154* inhibitor-treated bone metastatic ARCaPM prostate cancer cells in mice led to decreased bone metastasis and increased survival.Conclusion: miR-154* and miR-379 play important roles in prostate cancer biology by facilitating tumor growth, EMT, and bone metastasis. This finding has particular translational importance because miRNAs in the DLK1-DIO3 cluster can be attractive biomarkers and possible therapeutic targets to treat bone metastatic prostate cancer. Clin Cancer Res; 20(24); 6559–69. ©2014 AACR.

Purpose Low levels of Free Triiodothyronine (FT3) are associated with poor survival in chronic kidney disease, and the aim of this study was to further assess the relationship between changes in FT3 levels and renal damage in patients with type 2 diabetes based on glomerular and tubular markers. Methods We retrospectively studied 452 type 2 diabetic patients, measured glomerular damage markers (UACR, eGFR) and tubular damage markers (NAG/Cr,β2-MG), analyzed the relationship between FT3 and renal damage by logistic regression models, and plotted restrictive cubic splines. Results 41.6% of subjects had diabetic kidney disease (DKD), and the prevalence of DKD decreased progressively with increasing FT3 levels in the third quartile. Spearman correlation analysis showed that FT3 was negatively associated with UACR, NAG/Cr and β2-MG, while eGFR was positively associated with FT3. Multifactorial analysis, after adjusting for relevant confounders, revealed that compared with the lowest quartile of FT3, the highest quartile reduced the risk of developing urinary albumin (OR = 0.499,95% CI:0.289–0.856), moderate to severe impairment of glomerular filtration rate (OR = 0.106,95% CI:0.032–0.354), renal tubular marker β2 -MG positive (OR = 0.516,95% CI:0.299 to 0.883) and the risk of DKD occurrence (OR = 0.450,95% CI:0.260 to 0.774). In the sample model, FT3 levels below 4.39 pmol/L were associated with an increased risk of glomerular tubule injury and DKD occurrence. Conclusion FT3 is closely associated with glomerular tubular injury and is a protective factor. As FT3 levels (

Objective: To compare the risk of osteoporotic fractures between the urban and urban-rural fringe populations in southern China and to explore the effect of bone turnover markers on fracture risk.Methods: Epidemiological investigations were conducted in the urban and urban-rural fringe areas of southern China in June 2018. Residents aged 40 years and over who signed informed consent forms were included. Physical examination and questionnaire collection were completed. Bone turnover markers (BTMs) including osteocalcin (OC) and beta cross-linked C-telopeptide of type 1 collagen (β-CTX) were tested. Bone mineral density (BMD) of the femoral neck and lumbar vertebrae 1–4 were measured using dual energy X-ray absorptiometry. Fracture risk assessment tool (FRAX) values were calculated to show the probability of major osteoporotic fracture (PMOF) and probability of hip fracture (PHF) over the next 10 years.Results: A total of 1,051 participants were included in this study, including 553 in the urban areas and 498 in the urban-rural fringe areas. The average PMOF and PHF were 3.4 (2.3–5.4) % and .6 (.3–1.5) %, respectively. Compared with that in the urban populations, the femoral neck BMD in the urban-rural fringe populations was lower and FRAX values were generally higher, especially for women. FRAX values in various populations were mainly negatively correlated with lumbar and femoral neck BMD and were positively correlated with β-CTX; meanwhile, only PHF was negatively correlated with OC. After adjusting for sex, elevated β-CTX levels significantly increased the risk of high PMOF in various populations and increased the risk of high PHF in the urban-rural fringe populations. In particular, the risks of increased PMOF and PHF could increase by as much as 33 times and 19.5 times, respectively, in the urban-rural fringe areas.Conclusion: The urban-rural fringe populations in Southern China may be at risk of osteoporotic fracture. In addition to being related to BMD, the FRAX value also correlates with some BTMs. Combining FRAX with BMD, and BTMs may better predict the fracture risk.

BackgroundTumor mutation burden (TMB) is a promising biomarker positively associated with the benefit of immunotherapy and that might predict the outcome of chemotherapy. We described the prognostic value of TMB in advanced gastric cancer and explored the underlying mechanism.MethodsWe enrolled 155 TMB-evaluated advanced gastric cancer patients and analyzed the relationship between clinicopathological characteristics and both overall survival (OS) and progression-free survival (PFS) among 40 patients treated with first-line chemotherapy. We further verified the distribution of TMB and analyzed the potential mechanism underlying the prognosis based on The Cancer Genome Atlas (TCGA) database.ResultsAmong the 155 patients, 29 (18.7%) were TMB-high (TMB ≥ 10), roughly the same as the proportion in the TCGA data. Of the 40 patients receiving first-line chemotherapy, the median OS (7.9 vs. 12.1 months; HR 3.18; p = 0.0056) and PFS (4.4 vs. 6.2 months; HR 2.94; p = 0.0099) of the tissue-tested TMB (tTMB)-high patients were inferior to those of the tTMB-low patients. Similarly, unfavorable median OS (9.9 vs. 12.1 months; HR 2.11; p = 0.028) and PFS (5.3 vs. 6.5 months; HR 2.49; p = 0.0054) were shown in the blood-tested TMB (bTMB)-high than in the bTMB-low patients. The Cox analysis demonstrated that both tTMB-high and bTMB-high were significant independent predictors of dreadful OS and PFS. The differentially expressed genes (DEGs) according to TMB status were most significantly enriched in the downregulated metabolic pathway among the TMB-high patients.ConclusionsTMB-high advanced gastric cancer patients accounted for around one-sixth and had a poorer prognosis than TMB-low patients when treated with first-line chemotherapy. The potential mechanism might be the downregulated metabolic activity in TMB-high patients.