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The two species previously included in the genus Hayesiana Fletcher, 1982 were studied. The life history of the sole currently included species, Hayesiana triopus (Westwood, 1847) is illustrated in colour for the first time. Field records of Hayesiana triopus and Dahira farintaenia (Zhu & Wang, 1997) (previously Hayesiana farintaenia) are given, with the first description of the female genitalia of the latter. The diagnostic features and DNA barcoding data of Hayesiana triopus and Dahira farintaenia are also discussed.

Purpose The aero-engine array electrostatic monitoring technology (AEMT) can provide more and more accurate information about the direct product of the fault, and it is a novel condition monitoring technology that is expected to solve the problem of high false alarm rate of traditional electrostatic monitoring technology. However, aliasing of the array electrostatic signals often occurs, which will greatly affect the accuracy of the information identified by using the electrostatic sensor array. The purpose of this paper is to propose special solutions to the above problems. Design/methodology/approach In this paper, a method for de-aliasing of array electrostatic signals based on compressive sensing principle is proposed by taking advantage of the sparsity of the distribution of multiple pulse signals that originally constitute aliased signals in the time domain. Findings The proposed method is verified by finite element simulation experiments. The simulation experiments show that the proposed method can recover the original pulse signal with an accuracy of 96.0%; when the number of pulse signals does not exceed 5, the proposed method can recover the pulse peak with an average absolute error of less than 5.5%; and the recovered aliased signal time-domain waveform is very similar to the original aliased signal time-domain waveform, indicating that the proposed method is accurate. Originality/value The proposed method is one of the key technologies of AEMT.

The real-world clinical and economic burden of graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation has not been comprehensively studied in France. Clinical outcomes, healthcare resource utilization and costs associated with acute GVHD (aGVHD), chronic GVHD (cGVHD), acute plus chronic GVHD (a + cGVHD) versus no GVHD were compared using French administrative claims data. After propensity score matching, 1 934, 408, and 1 268 matched pairs were retained for the aGVHD, cGVHD, and a + cGVHD cohorts, respectively. Compared with patients with no GVHD, odds of developing severe infection was greater in patients with aGVHD (odds ratio (OR): 1.7, [95% confidence interval: 1.4, 2.1]). Compared with patients with no GVHD, mortality rates were higher in patients with aGVHD (rate ratio (RR): 1.6 [1.4, 1.7]) and in patients with a + cGVHD (RR: 1.1 [1.0, 1.2]) but similar in patients with cGVHD (RR: 0.9 [0.7, 1.1]). Mean overnight hospital admission rates per patient-year were significantly higher in patients with aGVHD and a + cGVHD compared with no GHVD. Total direct costs were 1.2, 1.5, and 1.9 times higher for patients with aGVHD, cGVHD, and a + cGVHD, respectively, versus patients with no GVHD. These results highlight the significant unmet need for effective treatments of patients who experience GVHD.

The role of protein members containing the WD40 repeat domain in many diseases, including cancer, is well documented. However, the role of WD repeat domain 48 (WDR48) in hepatocellular carcinoma (HCC) and its molecular basis remain to be further investigated. In the present study, we report that WDR48 is downregulated in clinical HCC samples and evaluate the relationship between its expression and clinical features of HCC. In vitro experiments showed that WDR48 positively regulated the proliferation, invasion and metastasis of HCC cells and in vivo experiments showed that downregulation of WDR48 significantly inhibited the tumorigenicity of HCC cells. Mechanistically, WDR48 binds to the proto-oncogene transcriptional regulator c-Myc and stabilizes c-Myc expression by mediating its deubiquitination, thereby enhancing cell proliferation and EMT signalling. Our study demonstrates the oncogenic role of WDR48 and suggests that WDR48 can be an important target in HCC.

Intraoperative O-arm navigation systems improve the accuracy of spinal instrumentation placement. However, deviation of the pedicle screw from the guide line might occur. The aim of the present study was to explore the causes of and countermeasures for the drift phenomenon during pedicle screw implantation with the aid of an O-arm three-dimensional navigation system in spinal deformity surgery.This was a retrospective analysis of 341 patients with spinal deformity who underwent O-arm navigation system-assisted pedicle screw placement from July 2015 to June 2019. The patient's general condition, Cobb angle, apical vertebra position, softness index, spinal release status, fixed reference frame position, and distance between the navigation vertebral body and the reference frame were collected and compared by independent-samples t test or Pearson's chi-square analysis. The potential risk factors for the drift phenomenon were identified using binary logistic regression analysis.The drift phenomenon occurred in 57 patients during the first navigation-assisted pedicle screw placement, for an incidence of 16.7% (57/341). There were significant differences in factors such as the apical vertebra position, softness index, spinal release status, and distance between the vertebral body and the reference frame when the drift phenomenon occurred (P 0.05). Binary logistic regression analysis showed that the softness index, spinal release status, and distance between the vertebral body and the reference frame when drifting occurred were independent risk factors for the drift phenomenon during O-arm navigation-assisted pedicle screw placement.During the use of an O-arm navigation system to assist with pedicle screw placement, pedicle screws should not be placed away from the reference frame, and spinal osteotomy and release should be performed after pedicle screw placement. In addition, the accuracy of O-arm navigation-assisted pedicle screw placement will be affected more in those with larger softness indices.

The spatial smoothing-based and matrix reconstruction-based decorrelation algorithms are widely used to realize the accurate direction-of-arrival (DOA) estimation with the coexistence of both uncorrelated and coherent sources. However, these methods apply only to the traditional uniform linear array (ULA), of which the manifold matrix is a Vandermonde structure. In this paper, to achieve the DOA estimation of mixed signals on coprime array, the coprime array is decomposed into two independent sub-ULAs, and the received data is processed, respectively. An improved spatial differencing technique is exploited to estimate the uncorrelated and coherent sources separately, and the lost degree of freedom (DOF) caused by array decomposition is recovered. The final high-precision DOA estimation is obtained by conducting an ambiguity resolution method to the estimation results of the decomposed subarrays. Furthermore, double-phase partial spectral search scheme is introduced to diminish the computational complexity. The feasibility and superiority of the proposed algorithm are validated through detailed experimental simulations.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.

Background: Turnover among general practitioners (GPs) has become a significant public health concern worldwide. Aims: This study aimed to investigate the interrelationships between job satisfaction, professional identity, burnout, and turnover intention among GPs in China and to assess the mediating effect of job satisfaction on the association between burnout and turnover intention and the moderating effect of professional identity on the association between burnout and job satisfaction. Method: A cross-sectional study was conducted to collect data from 3,236 GPs in eastern, central, and western China between October 2017 and February 2018 using a self-administered questionnaire. Pearson’s correlation analysis and hierarchical regression were used to identify the relationships between job satisfaction, professional identity, burnout, and turnover intention among Chinese GPs. Results: Among these respondents, 65.02% reported a medium or high level of emotional exhaustion (EE), 35.38% reported a moderate or high level of depersonalization (DP), and 62.05% reported reduced personal achievement (PA). Overall, 71.08% of GPs expressed a relatively high intention to seek another position (turnover intention). We found all 3 dimensions of burnout contributed to job dissatisfaction while turnover intention arising from burnout was associated with EE and DP. Job satisfaction had a direct negative impact on turnover intention and partially mediated the impact of EE and DP on turnover intention. Professional identity played a partial moderated role between EE and job satisfaction. Conclusions: The prevalence of burnout and turnover intention among GPs is high in China. The effect of EE and DP on turnover intention is mediated by job satisfaction, and the effect of EE on job satisfaction is moderated by professional identity.

The purpose of this study was to compare the traditional 2-rod correction technique with the sectional correction technique in terms of radiographic results and clinical outcomes for patients with dystrophic scoliosis caused by neurofibromatosis type 1 (NF1).From May 2015 to April 2018, 53 patients with dystrophic scoliosis caused by NF1 underwent 1-stage posterior corrective surgery. Patients were separated into 2 groups based on technique: the sectional correction technique (SC group) and the traditional 2-rod technique (TT group). Before surgery and at the final follow-up, the demographic information, radiographic parameters, and clinical outcomes were compared between the groups using independent-sample t tests.The SC group consisted of 24 patients, while the TT group consisted of 29 patients. Patients in the SC group showed a higher coronal balance distance after the operation (8.3 ± 8.2 mm vs. 16.2 ± 8.8 mm, P = 0.002) and at the final follow-up (9.5 ± 9.3 mm vs. 19.3 ± 10.1 mm, P0.0001). At the last follow-up, the loss of correction in the SC group was 2.2 ± 0.9 and 2.1 ± 0.7 in the coronal and sagittal planes, respectively, and these values were significantly lower than those in the TT group (5.3 ± 1.6 in the coronal plane and 4.5 ± 1.9 in the sagittal plane, both P 0.05). The SC group had better improvement based on appearance and satisfaction score at the final follow-up.The sectional correction technique using a concave domino connector can restore coronal imbalance and reduce the risk of implant failure.

Auxiliary Power Unit (APU) is an indispensable component utilized in modern aircraft, which provides electrical and pneumatic power to the aircraft independently. What’s more, APU can help the main engines restart in case of main engine failure during flight. Thus there exists the need of APU monitoring. However, APU has not received sufficient attention in maintenance due to its relatively low cost and safety requirements compared to main engines. Line maintenance shows that APU is likely to fail in the start stage. Based on the Quick Access Recorder data supported by the airline, a fault detection method for APU is proposed in this paper. In order to improve the accuracy of fault detection, feature selection is carried out firstly to determine the optimal subset of monitoring parameters by Recursive Feature Elimination. Then fault detection is carried out by Support Vector Machine. Results show that Exhaust Gas Temperature is the most effective index among all monitoring parameters, and feature selection has a significant improvement on the accuracy of fault detection, which means higher accuracy with less monitoring cost. The method proposed in this paper also disposes that some monitoring parameters should be paid more attention in terms of the condition monitoring of APU.

Emotion dysregulation is a crucial component of substance use disorders in predisposition, maintenance, and relapse. Emotional regulation strategies are an important factor in emotion dysregulation. However, studies on heroin use disorder (HUD) patients' ability to use emotion regulation strategies are scarce.Time-frequency-based analyses were used to compare the power of 33 patients with HUD and 28 healthy controls to elucidate whether patients with HUD have abnormal neural oscillations during passive viewing and emotion regulation strategies. Using the standardized low-resolution brain electromagnetic tomography algorithm (sLORETA), we estimated the possible sources of the anomalous band power.Compared to patients with HUD, healthy controls showed a stronger decrease in the power of the delta/theta band across all task conditions. The effect peaked at approximately 1300-1900 ms after stimulus onset and varied by task condition. The estimation of sLORETA suggested the frontal, parietal, and limbic lobes as possible generators.We cannot exclude the potential influence of additional factors, such as sex, depression and anxiety levels, and polysubstance use, on the results.Patients with HUD have blunted arousal and impaired ability to use emotion regulation strategies. The abnormal patterns described above may be the underlying neurophysiological basis for this dysfunction. Future studies could combine different approaches to improve emotion dysregulation in patients with HUD to promote treatment outcomes.

Purpose. To assess the association between intestinal venous blood (IVB) circulating tumor cells (CTCs) and clinicopathological parameters in stage I-III colorectal cancer (CRC) patients. Methods. Participants were retrospectively retrieved, who were admitted to our hospital or took annual physical exams between December 1, 2015 and December 31, 2018. A negative enrichment-immunofluorescence in situ hybridization (NE-imFISH) technique was used to isolate and identify CTCs. Receiver operating characteristic (ROC) curves and Youden index values were used to determine the critical CTC cutoff value for the diagnosis of CRC. Kaplan-Meier and log-rank methods were used to conduct survival analyses, and multivariate Cox regression analyses were employed for multivariate corrections to comprehensively evaluate the value of CTCs in the diagnosis of CRC. Relationships between IVB CTCs, clinicopathological parameters, and prognosis were then analyzed based upon patient postoperative follow-up data. Results. In total, we retrieved 282 patients including 48 healthy controls, 72 patients with benign colorectal tumors, and 162 CRC patients. CRC patients exhibited significantly higher numbers of CTCs relative to control patients or those with benign disease. CTC numbers in CRC patient peripheral blood (PB) and IVB were closely associated with tumor node metastasis (TNM) staging (P

Drawing on a study of the range and magnitude of harms that alcohol caused to specific others in Australia, and on social and health agency statistics for collective costs, this article produces an analysis of the economic cost of alcohol's harm to others (AHTO) in Australia.This study used a general population survey and routinely collected social response agencies' data to quantify different costs of AHTO, using methods consistent with International Guidelines for Estimating the Costs of Substance Abuse. This approach estimates costs for health care and social services, crime costs, costs of productivity loss, quality of life-year loss and other expenses, including both tangible costs (direct and indirect) and intangible costs of loss of quality of life (respondents' self-reported loss of health-related quality of life).The cost of AHTO in Australia was AUD$19.81 billion (95% CI [11.99, 28.34]), with tangible costs accounting for 58% of total costs ($11.45 billion, which is 0.68% of gross domestic product in 2016) and intangible costs of $8.36 billion. The costs to private individuals or households ($18.1 billion and 89% of total costs of AHTO) are greater than the costs to the government or society because of others' drinking in Australia.This study presents an estimation of the economic cost of harm from others' drinking. The economic costs from others' drinking are large and of much the same magnitude as the costs that drinkers impose on themselves, as found in previous studies. Preventing harm to others from drinking is important as a public health goal for both economic and humane reasons.

The features of lumbar curves in patients with lumbar spondylolisthesis (LS) are unclear. The aim of this retrospective study was to present the clinical and radiologic characteristics of scoliosis due to LS and LS concurrent with main thoracolumbar/lumbar adolescent idiopathic scoliosis (AIS).This study was conducted as a single-center retrospective comparative study on 56 pediatric spondylolisthesis patients with main thoracolumbar/lumbar curves. Cases were divided into 2 groups according to the course of scoliosis after spinal surgery of LS. Sagittal spinopelvic parameters and scoliotic characteristics were compared between the 2 groups.The prevalence of scoliosis was 15.3% in pediatric LS patients in our study population. Lumbar lordosis (LL), Cobb angle, apical rotation, and coronal deformity angular ratio (C-DAR) were higher in the LS concurrent with AIS group than in the LS with functional scoliosis group (P0.05), while curve span, apical vertebral translation, and central sacral vertical line to C7 plumb line were lower (P0.05). Logistic regression analyses and receiver operating characteristic curves showed that LL and C-DAR were significant risk factors of unresolved lumbar curves after spinal surgery for LS, with a cutoff value of 51.5°and 3.5, respectively.Lumbar scoliosis may develop due to LS, or a concurrent condition to LS. LL and C-DAR are the features that differentiate AIS from functional scoliosis in patients with LS.

Chemically pretreating lignocellulose has been widely used in the production of clean energy. An energy grass called hybrid Pennisetum was pretreated with different H2SO4 and NaOH concentrations to analyse the effects of an acid and alkali pretreatment on the degradation of hybrid Pennisetum lignocellulose. The chemical composition, hydrolyzed sugar yield, and microstructure were determined. The results showed that a NaOH pretreatment retained more cellulose and removed more lignins, while a H2SO4 pretreatment significantly inhibited the removal of lignins and increased hemicellulose degradation. X-ray diffraction analysis indicated that increasing the concentration of NaOH or H2SO4 could intensify the cellulose polymerization; this effect was stronger with NaOH compared to H2SO4. Scanning electron microscopy images showed that the cellulose bundles pretreated with H2SO4 were arranged tightly, while the cellulose bundles pretreated with NaOH were loose. Fourier transform infrared spectroscopy exhibited that the ether/ester bond between lignins and carbohydrates was broken by the H2SO4 pretreatment. The NaOH pretreatment increased the number of carbonyl and hydroxyl groups, resulting in more hydrophilic lignins, enabling greater facile degradation. Although the two methods are different in terms of destroying the structure of lignocellulose, the NaOH pretreatment can retain more cellulose, which is beneficial to subsequent ethanol production.

A semi-supervised learning based EEG signal detection method was studied in this paper. The feature engineering system of this paper was established, which contains novel AutoEncoders mapping features. The optimal channel combination for all subjects was determined to improve recognition accuracy by ReliefF algorithm and recursive feature elimination. What’s more, the semi-supervised learning method based on pseudo-labelling was introduced to the character recognition method, in which the training samples were dynamically reorganized and updated, so that the proposed method could complete the symbol recognition with limited number of training samples. Based on the features extacted and the optimal channel combination, the recognition accuracy of the character recognition method can reach up to 100%. &nbsp

Owing to the exorbitant overpotential and serious carrier recombination of graphitic carbon nitride (g-C3N4), noble metal (NM) is usually served as the H2 evolution co-catalyst. Although the NM (such as Pt) nanoparticles can reduce the H2 evolution overpotential, the weak Van der Waals interaction between Pt and g-C3N4 makes against the charge transfer. Herein, the solvothermal method is developed to achieve semi-chemical interaction between Pt and g-C3N4 nanotube (Pt-CNNT) for fast charge transfer. Moreover, the generated in-plane homojunction of CNNT can accelerate charge separation and restrain recombination. Meanwhile, the metallic Pt is an excellent H2 evolution co-catalyst. Photo/electrochemical tests verify that the semi-chemical interaction can improve photogenerated charge separation and transferability of CNNT. As a result, the photocatalytic H2 evolution turnover frequency (TOF) of Pt-CNNT under visible light irradiation reaches up to 918 h−1, which is one of the highest in the g-C3N4-based photocatalysts. This work provides a new idea to improve the charge transfer for efficient photocatalytic H2 evolution.

Backgroud: Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. Methods Gene expression pattern and immune cell infiltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence, ELISA, and orthotopic xenograft model were performed to validate our database-derived results. Results The overall expression of TGs (designated as TG score) is significantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types. Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification reveals that higher TGM2 expression is linked with worse patient survival, increased IC50 value of gemcitabine, and abundant tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage infiltration with tumor microenvironment. Conclusions These results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the significance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

Concrete structures in marine environments often face durability problems owing to the coupled action of external loads and chloride-ion erosion. Therefore, in this study, we conducted chloride ion tests on damaged concrete at four tensile stress levels and three varying number of load cycles. The test results indicate that an increase in the tensile stress and number of load cycles results in a gradual increase in the concrete damage coefficient. At fewer cycles, 50% tensile stress was the critical threshold point of damage; the damage was evident beyond this range. As the number of cycles increased, the damage increased gradually up to the critical threshold and thereafter increased rapidly. With an increase in the tensile stress level, the diffusion coefficient of chloride ions increased gradually; the loading degree improved the permeability of chloride ions. In addition, based on the theory of linear fatigue cumulative damage to concrete, a mathematical model of the relationship between the load factor and concrete damage coefficient was established. Using this model, a prediction model for the chloride ion diffusion coefficient was proposed considering the tensile stress level, load cycle number, and other load factors.

The wilting process is required for the preparation of traditional low-moisture silage, which is not only subject to the interference of rainfall during the harvest season in many areas, but also increases labor, economic, and time costs. Therefore, in this experiment, newly harvested alfalfa was supplemented with a complex additive consisting of lactic acid bacteria (LAB), sucrose, and corn flour, and then ensiled directly in order to explore a suitable high-moisture silage processing method. There were four groups: control (CK), 0.01 g/kg LAB plus 2% sugar (S), 0.01 g/kg LAB plus 5% corn flour (C5), and 0.01 g/kg LAB plus 5% corn flour (C10). The results show that all four types of silage had significantly reduced acid detergent fiber, acetic acid content, and ammonia/total nitrogen (p < 0.05). The relative abundance of Lactobacillus spp. was significantly higher (p < 0.05), and that of Weissella, Clostridium sensu stricto 12, and Pantoea genera was significantly lower (p < 0.05) in all four treatments. Group S had significantly increased crude protein content, and groups C5 and C10 had significantly reduced neutral detergent fiber. Overall, group C10 had the highest LA concentration, the highest relative abundance of Lactobacillus spp., and the lowest pH, ammonia/total nitrogen, neutral detergent fiber, and acid detergent fiber. Silage with a complex additive consisting of LAB + 10% corn flour is recommended to achieve good fermentation with high nutritional quality.

Lithium-sulfur all-solid-state batteries using inorganic solid-state electrolytes are considered promising electrochemical energy storage technologies. However, developing positive electrodes with high sulfur content, adequate sulfur utilization, and high mass loading is challenging. Here, to address these concerns, we propose using a liquid-phase-synthesized Li3PS4-2LiBH4 glass-ceramic solid electrolyte with a low density (1.491 g cm−3), small primary particle size (~500 nm) and bulk ionic conductivity of 6.0 mS cm−1 at 25 °C for fabricating lithium-sulfur all-solid-state batteries. When tested in a Swagelok cell configuration with a Li-In negative electrode and a 60 wt% S positive electrode applying an average stack pressure of ~55 MPa, the all-solid-state battery delivered a high discharge capacity of about 1144.6 mAh g−1 at 167.5 mA g−1 and 60 °C. We further demonstrate that the use of the low-density solid electrolyte increases the electrolyte volume ratio in the cathode, reduces inactive bulky sulfur, and improves the content uniformity of the sulfur-based positive electrode, thus providing sufficient ion conduction pathways for battery performance improvement.

Nadia Quignot,1 Heng Jiang,1 Indraraj Umesh Doobaree,2 Jan Lehmann,3 Ola Ghatnekar4 1Evidence & Access, Certara France, Paris, France; 2Evidence & Access, Certara UK, Sheffield, UK; 3Department of Urology, Städtisches Krankenhaus, Kiel, Germany; 4Ferring Pharmaceuticals, Kastrup, DenmarkCorrespondence: Nadia Quignot, Certara France, 54 Rue de Londres, Paris, 75008, France, Tel +3 318 514 2683, Email nadia.quignot@certara.comBackground: Intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection of the bladder tumour (TURBT) followed by intravesical Bacillus Calmette–Guérin (BCG) immunotherapy; however, NMIBC patients can become refractory or unresponsive to BCG treatment, and/or progress to muscle-invasive bladder cancer (MIBC). Healthcare resource utilization (HCRU) and costs in these patient populations are high.Methods: A retrospective longitudinal cohort design of adult (≥ 18 years) patients with bladder cancer and BCG treatment (01/01/2012– 31/12/2017) was conducted using data from a representative subset of the German statutory health insurance database. During the follow-up period after last BCG, patients were categorized into subgroups of No further NMIBC treatment, Continuous treatment for NMIBC, or MIBC evidence; HCRU and costs were tabulated for each subgroup and for the entire cohort.Results: A total of 1049 patients met the study inclusion criteria (mean age, 70.9 years; 84.8% male). Across the different subgroups, patients showing MIBC evidence had more than two times higher hospitalization rates compared to the other subgroups. Overall, the entire BCG-treated cohort’s total direct medical cost including hospitalizations, outpatient care and drugs was € 33.9 million and € 9250 per patient-year. Cost for patients with MIBC evidence was much higher, at € 17,983 per patient-year, than patients with No further NMIBC treatment (€ 6617) and patients with Continuous treatment for NMIBC (€ 7786). Across the subgroups, hospitalization was the largest driver of cost and contributed the most to cost for those with MIBC evidence.Conclusion: The overall cost burden of this BCG-treated cohort of 1049 patients is high (€ 38 million whereof 4.1 million are indirect costs) over a mean follow-up of 3.9 years; economic burden is especially substantial for patients who fail BCG treatment and those who progress.Keywords: urinary bladder neoplasm, retrospective study, healthcare cost, intravesical instillation, healthcare resource

Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg. Cancer Res; 78(9); 2305–17. ©2018 AACR.

Supplymentary data figure 1-8 and table 1-2

Purpose:Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP–P2RY2 axis could be a potential therapeutic approach for PDAC treatment.Experimental Design:Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression.Results:P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT–mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice.Conclusions:These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

Supplementary figures of expression of SPON2, integrin subunit, LATS1 and YAP, effect of SPON2 on M2-like TAM infiltration, co-location of SPON2 and integrin α4/α5, influence of RhoA T19N/Q63L and Rac1 T17N mutants on active RhoA and Rac1, effect of chemokines on primed THP-1 cell migration

Supplementary materials and methods of isolation of hMC, immunohistochemical and H&E staining, 3D spheroid analysis, PLA, q-PCR, lentivirus production and cell transduction, siRNA, production of rSPON2, ELISA assay and chemokine assay

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3)-mediated intestinal calcium (Ca) absorption supplies Ca for proper bone mineralization during growth. We tested whether vitamin D receptor (VDR)-mediated 1,25(OH)2D3 signaling is critical for adult Ca absorption and bone by using mice with inducible Vdr gene knockout in the whole intestine (villin-CreERT2+/− × Vdrf/f, WIK) or in the large intestine (Cdx2-CreERT2+/− ×Vdrf/f, LIK). At 4-month-old, Vdr alleles were recombined (0.05 mg tamoxifen/g BW, intraperitoneally [i.p.], 5 days) and mice were fed diets with either 0.5% (adequate) or 0.2% (low) Ca. Ca absorption was examined after 2 weeks while serum 1,25(OH)2D3, bone mass, and bone microarchitecture were examined after 16 weeks. Intestinal and renal gene expression was measured at both time points (n = 12/genotype/diet/time point). On the 0.5% Ca diet, all phenotypes in WIK and LIK mice were similar to the controls. Control mice adapted to the 0.2% low-Ca diet by increasing renal Cyp27b1 mRNA (3-fold), serum 1,25(OH)2D3 level (1.9-fold), and Ca absorption in the duodenum (Dd, + 131%) and proximal colon (PCo, + 28.9%), which prevented bone loss. In WIK mice, low-Ca diet increased serum 1,25(OH)2D3 (4.4-fold) but Ca absorption remained unaltered in the Dd and PCo. Consequently, significant bone loss occurred in WIK mice (e.g., cortical thickness, Ct.Th, −33.7%). LIK mice adapted to the low-Ca diet in the Dd but not the PCo, and the effect on bone phenotypes was milder (e.g., Ct.Th, −13.1%). Our data suggest intestinal VDR in adult mice prevents bone loss under low Ca intake but is dispensable under adequate calcium intake.

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

Subarachnoid hemorrhage (SAH) is a rare complication secondary to cerebrospinal fluid (CSF) leakage during spinal surgery, but the specific cause of bleeding is still unclear. In this retrospective single-center study, we studied cases of acute SAH after spinal surgery to identify the related risk factors for bleeding.A total of 441 patients with CSF leakage who underwent spinal surgery from 2011 to 2020 were retrospectively analyzed. According to whether postoperative SAH occurred, the patients were divided into the SAH group and the control group. By comparing the demographic data, past history, imaging data, intraoperative findings, perioperative complications, and treatment conditions in the 2 groups to identify the risk factors for SAH, we aimed to provide guidance for the prevention of SAH after spinal surgery.In our study, the incidence of CSF during spinal surgery is 3.04%, and the rate for SAH associated with spine operation is 0.16%. In the SAH group, 17 patients (73.9%) had preoperative hypertension, and 3 patients (13.0%) had diabetes. The intraoperative CSF leakage was approximately 118.4 ± 56.9 mL. The mean postoperative drainage was 15.4 ± 5.8 mL/hour. Compared with the SAH group, the control group had 123 patients (29.4%) with hypertension before the operation and 40 patients (9.6%) with diabetes. The intraoperative CSF leakage was approximately 76.3 ± 23.0 mL, and the mean postoperative continuous drainage was 9.7 ± 2.1 mL/hour. Binary logistic regression analysis showed that hypertension, intraoperative CSF leakage, and postoperative CSF continuous drainage speed were related to SAH.The rapid leakage of CSF caused by rupture of the dural sac during surgery and the rapid drainage of CSF after surgery were closely related to the occurrence of SAH. In addition, hypertension was a factor related to SAH during spinal surgery.