Search

Abstract Background At present, the guidelines for urology recommend percutaneous nephrolithotomy (PCNL) as the preferred treatment for staghorn renal calculi (SRC). However, for complete SRC, it has been questioned by clinicians and patients due to high residual stone rate, complications, repeated hospitalizations and high treatment cost. Anatrophic nephrolithotomy (ANL) is a traditional and classic method for the treatment of SRC. Due to its high trauma and high technical requirements, it is difficult to carry out in primary hospitals, and gradually replaced by PCNL. The purpose of this study is to compare the efficacy of PCNL and ANL in the treatment of complete SRC. Methods Overall, 238 patients with complete SRC were divided into mini-PCNL in lateral supine position group, (n = 190) and ANL group (n = 94) according to treatment for a retrospective cohort study. The calculi parameters, renal function index, comorbidities of calculi, surgical complications, length and frequency of hospitalization, treatment costs, results of postoperative satisfaction survey were compared between the two groups. Results The risk of the residual stone rate after mini-PCNL in lateral supine position was 239 times (OR = 238.667, P

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

Extracellular vesicles (EVs), characterized by low immunogenicity, high biocompatibility and targeting specificity along with excellent blood-brain barrier permeability, are increasingly recognized as promising drug delivery vehicles for treating a variety of diseases, such as cancer, inflammation and viral infection. However, recent findings demonstrate that the intracellular delivery efficiency of EVs fall short of expectations due to phagocytic clearance mediated by the host mononuclear phagocyte system through Fcγ receptors, complement receptors as well as non-opsonic phagocytic receptors. In this text, we investigate a range of bacterial virulence proteins that antagonize host phagocytic machinery, aiming to explore their potential in engineering EVs to counteract phagocytosis. Special emphasis is placed on IdeS secreted by Group A Streptococcus and ImpA secreted by Pseudomonas aeruginosa, as they not only counteract phagocytosis but also bind to highly upregulated surface biomarkers αVβ3 on cancer cells or cleave the tumor growth and metastasis-promoting factor CD44, respectively. This suggests that bacterial anti-phagocytic proteins, after decorated onto EVs using pre-loading or post-loading strategies, can not only improve EV-based drug delivery efficiency by evading host phagocytosis and thus achieve better therapeutic outcomes but also further enable an innovative synergistic EV-based cancer therapy approach by integrating both phagocytosis antagonism and cancer targeting or deactivation.

ObjectiveAiming at the uncertainty of model perturbation and external interference in unmanned surface vehicles (USVs), an improved model-free adaptive control (MFAC) method suitable for the heading control of USVs is proposed. MethodsBased on the existence of non-self-balancing characteristics in the heading control subsystems of USVs, this study directly discusses the control problem of the heading control subsystems of USVs under uncertain influences using the compact form dynamic linearization-based MFAC (CFDL-MFAC). The historical input items are introduced into the standard control criteria, and a variable output CFDL-MFAC (VCFDL-MFAC) is proposed to weaken the integral effect existing in the heading control subsystems of USVs. Finally, the simulation of USV heading control using the proposed method is carried out and a field-test with regard to validity for operation on board a Dophin IB small USV is conducted.ResultsThe results show that compared to the standard CFDL-MFAC method and PID method, the heading control of the VCFDL-MFAC method is more stable.ConclusionsThis study can provide a USV heading control algorithm with good adaptability and robustness that is insensitive to environmental disturbances and model perturbations.

IntroductionResearch indicates that individuals experiencing hemorrhagic stroke face a greater likelihood of developing lower extremity deep vein thrombosis (DVT) compared to those with ischemic stroke. This study aimed to assess the predictive capacity of the Caprini risk assessment model (RAM), D-dimer (D-D) levels, and fibrinogen (FIB) levels for lower extremity DVT in patients with spontaneous intracerebral hemorrhage (sICH).MethodologyThis study involved a retrospective analysis of medical records from all sICH patients admitted to Shanghai General Hospital between June 2020 and June 2023. Within 48 h of admission, patients underwent routine screening via color Doppler ultrasonography (CDUS). Patients were categorized into the DVT and control groups based on the occurrence of lower extremity DVT during hospitalization. Differences in Caprini RAM, D-dimer, and FIB levels between the two groups were compared. The sensitivity and specificity of combined Caprini RAM, peripheral blood D-dimer, and FIB levels in predicting lower extremity DVT in sICH patients were analyzed. Receiver operating characteristic (ROC) curves assessed the overall predictive accuracy of Caprini RAM, D-D, and FIB levels.ResultsThe study involving 842 sICH patients revealed 225 patients with DVT and 617 patients without DVT. Caprini RAM, D-D, and FIB levels were significantly higher in the DVT group compared to the control group (P < 0.05). Sensitivity values for Caprini RAM, D-D, and FIB levels in predicting lower extremity DVT in sICH patients were 0.920, 0.893, and 0.680, respectively, while specificities were 0.840, 0.680, and 0.747, respectively. The ROC curve analysis demonstrated an area under the curve (AUC) of 0.947 for combined DVT prediction, with 97.33% sensitivity and 92.00% specificity, indicating superior predictive value compared to individual applications of Caprini RAM, D-D, and FIB levels.ConclusionThe combined utilization of Caprini RAM, D-D, and FIB levels holds significant clinical relevance in predicting lower extremity DVT in sICH patients.

Radix Bupleuri (RB) is commonly used to treat depression, but it can also lead to hepatotoxicity after long-term use. In many anti-depression prescriptions, RB is often used in combination with Radix Paeoniae Alba (RPA) as an herb pair. However, whether RPA can alleviate RB-induced hepatotoxicity remain unclear. In this work, the results confirmed that RB had a dose-dependent antidepressant effect, but the optimal antidepressant dose caused hepatotoxicity. Notably, RPA effectively reversed RB-induced hepatotoxicity. Afterward, the mechanism of RB-induced hepatotoxicity was confirmed. The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase (GSS) activity in the liver, and further cause liver injury through oxidative stress and nuclear factor kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway. Furthermore, the mechanisms by which RPA attenuates RB-induced hepatotoxicity were investigated. The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity, thereby promoting the conversion of saikosaponins to saikogenins in vivo. Different from saikosaponin A and saikosaponin D, which are directly combined with GSS as an inhibitor, their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity. Based on this, RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NF-κB/NLRP3 pathway. In conclusion, the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.

In recent years, considerable achievements have been made in pediatric oncology with the innovation and development of antitumor drugs. However, compared to adults, children as a special group have not yet matured fully in terms of liver and kidney function. Moreover, pediatric patients are prone to more adverse drug reactions (ADRs) from the accumulation of antineoplastic drugs due to their smaller body size and larger body surface area. Chemotherapy-related ADRs have become a non-negligible factor that affects cancer remission. To date, studies on ADRs in pediatric cancer patients have emerged internationally, but few systematic summaries are available. Here, we reviewed the various systemic ADRs associated with antitumor drugs in children and adolescent patients, as well as the advances in strategies to cope with ADRs, which consisted of neurotoxicity, hematological toxicity, cardiotoxicity, ADRs of the respiratory system and gastrointestinal system and urinary system, ADRs of the skin and its adnexa, allergic reactions, and other ADRs. For clinicians and researchers, understanding the causes, symptoms, and coping strategies for ADRs caused by anticancer treatments will undoubtedly benefit more children.

BackgroundChronic kidney disease (CKD) is often accompanied by alterations in the metabolic profile of the body, yet the causative role of these metabolic changes in the onset of CKD remains a subject of ongoing debate. This study investigates the causative links between metabolites and CKD by leveraging the results of genomewide association study (GWAS) from 486 blood metabolites, employing bulk two-sample Mendelian randomization (MR) analyses. Building on the metabolites that exhibit a causal relationship with CKD, we delve deeper using enrichment analysis to identify the metabolic pathways that may contribute to the development and progression of CKD.MethodsIn conducting the Mendelian randomization analysis, we treated the GWAS data for 486 metabolic traits as exposure variables while using GWAS data for estimated glomerular filtration rate based on serum creatinine (eGFRcrea), microalbuminuria, and the urinary albumin-to-creatinine ratio (UACR) sourced from the CKDGen consortium as the outcome variables. Inverse-variance weighting (IVW) analysis was used to identify metabolites with a causal relationship to outcome. Using Bonferroni correction, metabolites with more robust causal relationships are screened. Additionally, the IVW-positive results were supplemented with the weighted median, MR-Egger, weighted mode, and simple mode. Furthermore, we performed sensitivity analyses using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out (LOO) test. Pathway enrichment analysis was conducted using two databases, KEGG and SMPDB, for eligible metabolites.ResultsDuring the batch Mendelian randomization (MR) analyses, upon completion of the inverse-variance weighted (IVW) approach, sensitivity analysis, and directional consistency checks, 78 metabolites were found to meet the criteria. The following four metabolites satisfy Bonferroni correction: mannose, N-acetylornithine, glycine, and bilirubin (Z, Z), and mannose is causally related to all outcomes of CKD. By pathway enrichment analysis, we identified eight metabolic pathways that contribute to CKD occurrence and progression.ConclusionBased on the present analysis, mannose met Bonferroni correction and had causal associations with CKD, eGFRcrea, microalbuminuria, and UACR. As a potential target for CKD diagnosis and treatment, mannose is believed to play an important role in the occurrence and development of CKD.

Summary: KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of β-catenin at lysine 508, which enhances the binding between β-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.

Abstract Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.

Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes.Methods: We screened all 162 “kidney transplant”–related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms—LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs—were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan–Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis.Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response–related pathways were found in the C4 group, which had poor prognosis.Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.

Résumé Contexte À l’heure actuelle, la L-carnitine (LC) et le coenzyme Q10 (CoQ10), tels qu’utilisés en clinique pour traiter l’infertilité masculine due à une asthénozoospermie (AZS), sont encore principalement administrés par voie orale, mais certains patients atteints d’AZS ne montrent pas toujours d’amélioration significative de la motilité des spermatozoïdes, ni de grossesse chez la conjointe. Prodom™ est. un dispositif utilisé pour aider à la reproduction, qui est. temporairement installé sur le pénis pour faciliter la conception en aidant la femme à injecter certains médicaments dans le vagin. Cette étude a utilisé une association CL + CoQ10 assistée par Prodom™ pour traiter des patients atteints d’AZS et a évalué l’effet de cette méthode sur la mobilité des spermatozoïdes et la grossesse clinique, dans le but de trouver une méthode confortable, peu coûteuse et efficace. Résultats Au cours de cet essai thérapeutique, 232 cas sont allés au bout de l’étude, alors que 25 se sont arrêtés. Au cours des tests in vitro, la mobilité progressive des spermatozoïdes dans le groupe LC, le groupe CoQ10, le groupe CL + CoQ10 et dans le groupe témoin de sperme, était respectivement de 24,3 ± 4,6% et 38,1 ± 5,1%, de 23,0 ± 4,8% et 36,9 ± 4,4%, de 28,4 ± 5,0% et 43,8 ± 5,4%, et de 19,7 ± 4,4% et 26,0 ± 4,9%. La mobilité progressive des spermatozoïdes était significativement différentes entre les groupes (toutes les valeurs de P

To overcome the shortcomings of traditional dairy cow feed intake assessment model and BP neural network, this paper proposes a method of optimizing BP neural network using polynomial decay learning rate, taking the cow’s body weight, lying duration, lying times, walking steps, foraging duration and concentrate-roughage ratio as input variables and taking the actual feed intake is the output variable to establish a dairy cow feed intake assessment model, and the model is trained and verified by experimental data collected on site. For the sake of comparative study, feed intake is simultaneously assessed by SVR model, KNN logistic regression model, traditional BP neural network model, and multilayer BP neural network model. The results show that the established BP model using the polynomial decay learning rate has the highest assessment accuracy, the MSPE, RMSE, MAE, MAPE and R2 are 0.043 kg2/d and 0.208 kg/d, 0.173 kg/d, 1.37% and 0.94 respectively. Compared with SVR model and KNN mode, the RMSE value reduced by 43.9% and 26.5%, it is also found that the model designed in this paper has many advantages in comparison with the BP model and multilayer BP model in terms of precision and generalization. Therefore, this method is ready to be applied for accurately evaluating the dairy cow feed intake, and it can provide theoretical guidance and technical support for the precise-feeding and can also be of high significance in the improvement of dairy precise-breeding.

Résumé Introduction Le muscle Ischiocavernosus (MIC) est une paire de muscles courts attachés à l’anneau pelvien. Elle commence à la tubérosité ischiale et se termine au crus du pénis tout en couvrant la surface de ce dernier. Selon la vision traditionnelle, la contraction du MIC joue un rôle auxiliaire dans l’érection pénienne. Cependant, nos travaux précédents ont montré qu’il joue un rôle important dans l’érection pénienne par une méthode indirecte de diagnostic de la dysfonction érectile (DE) induite par une blessure du MIC en observant l’infertilité des rats femelles appariés. Comme la pression intracaverneuse (PIC) est actuellement l’étalon de référence pour le diagnostic, cette étude visait à amputer unilatéralement/bilatéralement l’ICM pour établir un modèle de DE par détection de l’ICP, par détection de l’infertilité de rats femelles appariés, et par comparaison des deux méthodes. Résultats Quarante rats mâles adultes sexuellement matures ont été sélectionnés et répartis aléatoirement dansquatre groupes groupe témoin (n = 10), groupe d’opération simulée (n = 10), groupe d’amputation unilatérale du MIC (Uni-MIC) (n = 10), et groupe d’amputation bilatérale du MIC (Bi-MIC) (n = 10). Quatre-vingts rats femelles en période de reproduction ont été réparties de façon aléatoire dans chacun des groupes mentionnés ci-dessus, selon un rapport de 2:1. Nous avons évalué le temps avant la conception des rats femelles appariés et les effets de l’amputation Uni /Bi-MIC sur la fonction érectile. Les résultats ont montré que la pression de base et la PIC maximale dans le groupe témoin, le groupe d’opération simulée, le groupe Uni-MIC et le groupe Bi-MIC étaient respectivement de 17.44 ± 2.50 mmHg et 93.51 ± 10.78 mmHg, 17.81 ± 2.81 mmHg et 95.07 ± 10.40 mmHg, 16.73 ± 2.11 mmHg et 83.49 ± 12.38 mmHg, et 14.78 ± 2.78 mmHg et 33.57 ± 6.72 mmHg, immédiatement après l’opération. La PIC maximale dans le groupe Bi-MIC était inférieure à celles des trois autres groupes (tous P < 0.05). Les taux de grossesse étaient de 90% dans le groupe Uni-MIC et de 0% dans le groupe Bi-MIC. Le taux de grossesse dans le groupe Bi-MIC était significativement plus faible que dans les autres groupes (tous P < 0.05). Le temps de conception a été d’environ 7 à 10 jours plus tard dans le groupe Uni-MIC que dans le groupe témoin et le groupe d’opération simulée (tous P < 0.05). Conclusions Les rats mâles subissant une amputation Bi-MIC peuvent développer une DE permanente qui affecte leur fertilité. En revanche, ceux qui subissent une amputation Uni-MIC peuvent connaître des troubles érectiles transitoires.

Human antigen R (HuR), also known as ELAVL1, is a widely expressed RNA-binding protein (RBP) that has a significant impact on the development and advancement of tumors. Our previous study found that 5-fluorouracil (5-FU) may impede the proliferation and increase apoptosis in gastric cancer cells by reducing the nucleocytoplasmic shuttling of HuR. However, how posttranscriptional regulation influences HuR functions in gastric cancer remains to be elucidated. Here, we demonstrated that miR-325-3p has the potential to regulate the expression level of HuR by directly binding to its 3′UTR, which in turn led to a significant reduction in proliferation and an increase in apoptosis in gastric cancer cells. In addition, xenograft experiment showed that knockdown of HuR or overexpression of miR-325-3p group exhibited smaller tumor sizes after transplant of gastric cancer cells into zebrafish larvae. Thus, our findings offer new insights into the pathogenesis of gastric cancer and may potentially assist in identifying novel targets for drug therapy.

Abstract PD-L1(CD274) is a well-known immunosuppressive molecule, which confers immunoescape features to cancer cells and has become one of the major targets in cancer immunotherapies. Understanding the regulatory mechanisms that control PD-L1 protein expression is important for guiding immune checkpoint blockade therapy. Here, we showed that ubiquitin specific peptidase 5 (USP5) was a novel PD-L1 deubiquitinase in non-small cell lung cancer (NSCLC) cells. USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability. Meanwhile, USP5 protein levels were highly elevated and positively correlated to PD-L1 levels in NSCLC tissues, and were closely correlated with poor prognosis of these patients. In addition, knockdown of USP5 retarded tumor growth in the Lewis lung carcinoma mouse model. Thus, we identified that USP5 was a new regulator of PD-L1 and targeting USP5 is a promising strategy for cancer therapy.

Caverns are generally formed by a combination of regional geological action and groundwater, and their improper treatment will inevitably lead to dangerous conditions in underground works. To detect the specific failure mechanism of tunnel-surrounding rock induced by invisible caverns, a true triaxial compression test is conducted, accompanied by acoustic emission technology and an internal borehole camera, for monitoring the acoustic response and visible secondary cracks, and a corresponding DEM simulation is carried out to reveal the meso-mechanism. The results indicate the following: (1) The invisible cavern demonstrates a negative influence on the stability of the tunnel and leads to a 25.82% reduction in the peak z-axis load of the specimens. (2) The acoustic emission results show that the relatively severe dominant failures mainly occur near the peak stress in all types of specimens, and the speed and intensity of the cavern-existing specimen is significantly greater than that of the cavern-free specimen. (3) The cavity-free tunnel shows mirror-symmetric splitting failure on the left and right sidewalls, while the secondary cracks appear earlier and show asymmetrical distribution in the cavern-existing specimen, and the volume of broken rock blocks near the free surface is larger. (4) The cavern directly changes the failure process of the tunnel-surrounding rock (intermediate rock failure occurs earlier than splitting failure), the distribution of principal stress, and the corresponding mechanism of secondary failures. (5) Application of the displacement and velocity trend fields helped to reveal accurate failure procedures in the true triaxial test.

Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.

Abstract Background Early-stage non-small lung cancer patients may survive long enough to develop second primary lung cancers. However, few studies have accurately described the therapeutic method, evaluation or prognostic factors for long-term survival in this complex clinical scenario. Methods Patients who had first and second primary non-small lung cancer in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were evaluated. Patients were included when their tumors were pathologically diagnosed as non-small lung cancer and in the early-stage (less than 3 cm and with no lymph node metastasis). Therapeutic methods were categorized as lobectomy, sublobectomy or no surgery. The influence of different therapeutic methods on the overall survival rate was compared. Results For the first primary tumor, patients who underwent lobectomy achieved superior survival benefits compared with patients who underwent sublobectomy. For the second primary tumor, long-term survival was similar in patients who underwent lobectomy and those who underwent sublobectomy treatment. The multivariate analysis indicated that age, disease-free time interval, sex, and first and second types of surgery were independent prognostic factors for long-term survival. Our results showed that the 5-year overall survival rate was 91.9% when the disease-free interval exceeded 24 months. Conclusion Lobectomy for the first primary tumor followed by sublobectomy for the second primary tumor may be a beneficial therapeutic method for patients. If the disease-free interval exceeds 24 months, the second primary tumor will have no influence on the natural course for patients diagnosed with a first primary non-small lung cancer.

Abstract O-GalNAc glycans (or mucin O-glycans) play pivotal roles in diverse biological and pathological processes, including tumor growth and progression. Structurally defined O-GalNAc glycans are essential for functional studies but synthetic challenges and their inherent structural diversity and complexity have limited access to these compounds. Herein, we report an efficient and robust chemoenzymatic modular assembly (CEMA) strategy to construct structurally diverse O-GalNAc glycans. The key to this strategy is the convergent assembly of O-GalNAc cores 1–4 and 6 from three chemical building blocks, followed by enzymatic diversification of the cores by 13 well-tailored enzyme modules. A total of 83 O-GalNAc glycans presenting various natural glycan epitopes are obtained and used to generate a unique synthetic mucin O-glycan microarray. Binding specificities of glycan-binding proteins (GBPs) including plant lectins and selected anti-glycan antibodies towards these O-GalNAc glycans are revealed by this microarray, promoting their applicability in functional O-glycomics. Serum samples from colorectal cancer patients and healthy controls are assayed using the array reveal higher bindings towards less common cores 3, 4, and 6 than abundant cores 1 and 2, providing insights into O-GalNAc glycan structure-activity relationships.

Abstract Introduction The experiment was undertaken to estimate the effect of BMSC seeding in different scaffold incorporation with HBO on the repair of a seawater-immersed bone defect. And future compared n-HA/PLGA with β-TCP/PLGA as a scaffold in treatment effect of the seawater-immersed bone defect. Methods Sixty New Zealand White rabbits with standard seawater defect in radius were randomly divided into group A (implant with nothing), group B (implanted with autogenous bone), group C (implanted with n-HA/PLGA/BMSCs), and group D (implanted with β-TCP/PLGA/BMSCs). After the implant, each rabbit receives HBO treatment at 2.4 ATA 100% oxygen for 120 min/day for 2 weeks. Radiograph, histological, and biomechanical examinations were used to analyze osteogenesis. Result X-ray analysis shows that n-HA/PLGA/BMSCs and β-TCP/PLGA/BMSCs could accelerate the new bone formation, and the new bone formation in group C was larger than that in group D or group A and close to group B (P < 0.05). After 12 weeks, in group A, the defect without scaffold shows a loose connect tissue filled in the areas. The medullary canal in group B was recanalized. Defects in groups C and D show a larger number of woven bone formation. The new woven bone formation in defect areas in group C was larger than that in group D. The mechanical examination revealed ultimate strength at 12 weeks was group D > group C > group B > group A (P < 0.05). Conclusion Scaffolds of n-HA/PLGA and β-TCP/PLGA incorporation with HBO and BMSCs were effective to treat seawater-immersed bone defect, and n-HA/PLGA was more excellent than β-TCP/PLGA.

High-pressure fluctuation and flow ripple may cause unexpected vibration and noise when the piston pump works under severe conditions, and eventually lead to hydraulic transmission failure. The geometry of the valve plate has a great influence on the pressure fluctuation of the piston chamber. In order to optimize the structure of the valve plate, a mathematical model considering the slot geometry and the flow leakage of the lubricating interfaces was established in this paper. The model was used to investigate the pressure of the piston chamber, and then the accuracy of the model was validated by comparing simulation and experimental results. Further simulation results show that the pressure fluctuation in the piston chamber can be effectively suppressed by optimizing the triangular slots parameter of the valve plate, and a good design of the slot geometry could reduce the undershoot and overshoot of the pressure in piston chamber at the starting moment.

Investigating starch properties of different adzuki beans provides an important theoretical basis for its application. A comparative study was conducted to evaluate the starch content, processing, digestion, and structural quality of 12 adzuki bean varieties. The variation ranges of the 12 adzuki bean varieties with specific analyzed parameters, including the amylose/amylopectin (AM/AP) ratio, bean paste rate, water separation rate, solubility, swelling power and resistant starch (RS) content level, were 5.52–39.05%, 44.7–68.2%, 45.56–54.29%, 6.79–12.07%, 11.83–15.39%, and 2.02–14.634%, respectively. The crystallinity varied from 20.92 to 37.38%, belonging to type BC(The starch crystal type is mainly type C, supplemented by type B). In correlation analysis, red and blue represent positive and negative correlation, respectively. Correlation analysis indicated that the termination temperature of adzuki bean starch was positively correlated with AM/AP ratio. Therefore, the higher the melting temperature, the better the freeze–thaw stability. The 12 varieties were divided into Class I, Class II, and Class III by cluster analysis, based on application field. Class I was unsuitable for the diabetics’ diet; Class II was suitable for a stabilizer; and Class III was suitable for bean paste, mixtures, and thickeners. The present study could provide a theoretical basis for their application in the nutritional and nutraceutical field.

Chitooligosaccharide is a kind of functional food, which is the degradation product of chitosan (COS) catalyzed by the endo-chitosanase (COSE) enzyme. A COSE with a molecular weight of 34 kDa was purified and characterized from a newly isolated Mitsuaria sp. C4 (C4), and a 38.46% recovery rate and 4.79-fold purification were achieved. The purified C4 COSE exhibited optimum activity at 40°C and pH 7.2 and was significantly inhibited in the presence of Cu2+ and Fe3+. The Km and Vmin of the COSE toward COS were 2.449 g/L and 0.042 g/min/L, respectively. The highest COSE activity reached 8.344 U/ml after optimizing, which represented a 1.34-fold of increase. Additionally, chitooligosaccharide obtained by COSE hydrolysis of COS was verified by using thin-layer chromatography and high-performance liquid chromatography analysis. Whole-genome sequencing demonstrated that the C4 strain contains 211 carbohydrate enzymes, our purified COSE belonging to GHs-46 involved in carbohydrate degradation. Phylogenetic analysis showed that the novel COSE obtained from the C4 strain was clustered into the degree of polymerization = two to three groups, which can perform catalysis in a similar manner to produce (GlcN)2 and (GlcN)3. This work indicates that the C4 strain could be a good resource for enhancing carbohydrate degradation and might represent a useful tool for chitooligosaccharide production in the functional food industry.

Simultaneous localization and mapping (SLAM) is an active localization method for Autonomous Underwater Vehicle (AUV), and it can mainly be used in unknown and complex areas such as coastal water, harbors, and wharfs. This paper presents a practical occupancy grid-based method based on forward-looking sonar for AUV. The algorithm uses an extended Kalman filter (EKF) to estimate the AUV motion states. First, the SLAM method fuses the data coming from the navigation sensors to predict the motion states. Subsequently, a novel particle swarm optimization genetic algorithm (PSO-GA) scan matching method is employed for matching the sonar scan data and grid map, and the matching pose would be used to correct the prediction states. Lastly, the estimated motion states and sonar scan data would be used to update the grid map. The experimental results based on the field data have validated that the proposed SLAM algorithm is adaptable to underwater conditions, and accurate enough to use for ocean engineering practical applications.

Siglecs are sialic acid–binding immunoglobulin-like lectins that play vital roles in immune cell signaling. Siglecs help the immune system distinguish between self and nonself through the recognition of glycan ligands. While the primary binding specificities of Siglecs are known to be divergent, their specificities for complex glycans remain unclear. Herein, we determined N-glycan binding profiles of a set of Siglecs by using a complex asymmetric N-glycan microarray. Our results showed that Siglecs had unique terminal epitope-dependent branch preference when recognizing asymmetric N-glycans. Specifically, human Siglec-3, -9, and -10 prefer the α1-3 branch when Siaα2-6Galβ1-4GlcNAc terminal epitope serves as the binding ligand but prefer the opposite α1-6 branch when Siaα2-3Galβ1-4GlcNAc epitope serves as the ligand. Interestingly, Siglec-10 exhibited dramatic binding divergence toward a pair of Neu5Ac-containing asymmetric N-glycan isomers, as well as their Neu5Gc-containing counterparts. This new information on complex glycan recognition by Siglecs provides insights into their biological roles and applications.

Radix Bupleuri-Radix Paeoniae Alba (RB-RPA) is a classic herb pair, which is commonly used to treat depression by soothing “liver qi stagnation” in the clinic. However, little is yet known concerning the combination mechanism of Radix Bupleuri (RB) and Radix Paeoniae Alba (RPA), their bioactive forms in vivo and the regulatory effects on the organism. The present study aimed to elucidate the changes in multi-component pharmacokinetics (PK) behavior after the combination of RB and RPA by a high-resolution full-scan mode of UPLC-HRMS method (a total of 38 components PK profiles were obtained, of which 23 components come from RB and 15 components come from RPA). Moreover, the metabolomics approach was used to analyze the dynamic response of endogenous metabolites intervened by RB-RPA, and the correlation between concentration-time curves of 38 components from RB-RPA and the dynamic response profiles of endogenous metabolites was characterized by Pearson correlation analysis. The results demonstrated that the combination of RB and RPA could significantly improve the bioavailability of five components in RB, and six components in RPA. Besides, metabolomics results indicated that a total of 21 endogenous metabolites exhibited time-dependent changes in response to the RB-RPA administration, of which 12 endogenous metabolites were significantly increased, and nine endogenous metabolites were significantly decreased. Furthermore, correlation analysis results indicated that the components with significantly improved bioavailability after combination such as saikogenin F, saikogenin G, albiflorin, methyl gallate, paeonimetabolin II were significantly positively correlated with picolinic acid, a metabolite with neuroprotective effect; saikogenin F, saikogenin G were significantly positively correlated with itaconic acid, a endogenous metabolite with anti-inflammatory activity; and albiflorin, paeonimetabolin II were significantly positively correlated with α-linolenic acid, a metabolite with strong protective actions on brain functions. These results indicated that the combination of RB and RPA can enhance each other’s neuroprotective and anti-inflammatory activities. In this study, A novel and efficient strategy has been developed to analyze the influence of the combination of RB and RPA in vivo behaviors by combining multi-component pharmacokinetics with metabolomics, which was contributed to clarifying the scientific connotation of herb–herb compatibility.

Angelicae Sinensis Radix (AS), a well-known herb in traditional Chinese medicine (TCM), has been wildly used for replenishing the blood and promoting circulation, in Asia for thousands of years. It has been confirmed that AS also possesses the pharmacological activity of anti-depression. At the same time, recent studies suggested that depression is associated with anemia, and depression could be ameliorated via modulating the blood system. However, it is still unknown whether the anti-depression effect of AS is related to its pharmacological activity of modulating the blood system. In the current study, hematological examination and metabonomic techniques were performed to explore potential anti-depression mechanisms of AS, related to the function of modulating the blood system in a chronic unpredictable mild stress (CUMS) model. The results demonstrated that AS could significantly improve CUMS-induced depressive symptom, hematological anomalies, and hypoxia symptoms. The analysis of metabonomics demonstrated that 26 potential biomarkers in depression could be regulated by the administration of AS. Among them, eight biomarkers participate in the metabolic pathways of amino acid and sphingolipid, and energy metabolism could also be regulated in an anemia model through the administration of AS, as reported in previous literatures. Further results proved that AS modulated energy metabolism in depression through the inhibition of the expression of pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK-1) and lactate dehydrogenase A (LDHA). These results suggested that the modulation of the blood system was involved in the anti-depression effect of AS. The mechanism may be associated with the promotion of the body’s energy metabolism, the stabilization of cell membranes, the promotion of serum protein synthesis, and the enhancement of immunity.

[This corrects the article DOI: 10.1371/journal.pone.0156145.].

Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that androgen signaling sensitizes mitochondria to apoptotic signaling, thus rendering HPr-1AR more vulnerable to cell death signals. Our study offers insight into AR-mediated regulation of prostate epithelial cell death signaling.

The androgen receptor (AR) mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT). However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR), and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK) complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.

Area coverage is one of the key issues for wireless sensor networks. It aims at selecting a minimum number of sensor nodes to cover the whole sensing region and maximizing the lifetime of the network. In this paper, we discuss the energy-efficient area coverage problem considering boundary effects in a new perspective, that is, transforming the area coverage problem to the target coverage problem and then achieving full area coverage by covering all the targets in the converted target coverage problem. Thus, the coverage of every point in the sensing region is transformed to the coverage of a fraction of targets. Two schemes for the converted target coverage are proposed, which can generate cover sets covering all the targets. The network constructed by sensor nodes in the cover set is proved to be connected. Compared with the previous algorithms, simulation results show that the proposed algorithm can prolong the lifetime of the network.