RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway.

Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent, and acquired resistance to PI treatment emerges in most patients. Here, we performed a high-throughput screen of 1855 Food and Drug Administration (FDA)-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and resensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated retinoic acid receptor (RAR)γ and interferon-ß response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to double-stranded RNA (dsRNA) induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large datasets of patients' gene profiling showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients.

MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma.

Multiple myeloma (MM) remains largely incurable despite significant advances in biotherapy and chemotherapy. The development of drug resistance is a major problem in MM management. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and MM patients with high MIF had significantly shorter progression-free survival (PFS) and overall survival (OS). MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI)-induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and to maintain SOD1 activity. MIF inhibitor 4-iodo-6-phenylpyrimidine and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and resensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in patients with MM. This study shows that MIF plays a crucial role in MM sensitivity to PIs and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.

Transcriptional regulation and ubiquitination-dependent regulation of HnRNPK oncogenic function in prostate tumorigenesis.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein K (HnRNPK) is a nucleic acid-binding protein that regulates diverse biological events. Pathologically, HnRNPK proteins are frequently overexpressed and clinically correlated with poor prognosis in various types of human cancers and are therefore pursued as attractive therapeutic targets for select patients. However, both the transcriptional regulation and degradation of HnRNPK in prostate cancer remain poorly understood. METHODS: qRT-PCR was used to detect the expression of HnRNPK mRNA and miRNA; Immunoblots and immunohistochemical assays were used to determine the levels of HnRNPK and other proteins. Flow cytometry was used to investigate cell cycle stage. MTS and clonogenic assays were used to investigate cell proliferation. Immunoprecipitation was used to analyse the interaction between SPOP and HnRNPK. A prostate carcinoma xenograft mouse model was used to detect the in vivo effects of HnRNPK and miRNA. RESULTS: In the present study, we noted that HnRNPK emerged as an important player in the carcinogenesis process of prostate cancer. miR-206 and miR-613 suppressed HnRNPK expression by targeting its 3'-UTR in PrCa cell lines in which HnRNPK is overexpressed. To explore the potential biological function, proliferation and colony formation of PrCa cells in vitro and tumor growth in vivo were also dramatically suppressed upon reintroduction of miR-206/miR-613. We have further provided evidence that Cullin 3 SPOP is a novel upstream E3 ubiquitin ligase complex that governs HnRNPK protein stability and oncogenic functions by promoting the degradation of HnRNPK in polyubiquitination-dependent proteolysis in the prostate cancer setting. Moreover, prostate cancer-associated SPOP mutants fail to interact with and promote the destruction of HnRNPK proteins. CONCLUSION: Our findings reveal new posttranscriptional and posttranslational modification mechanisms of HnRNPK regulation via miR-206/miR-613 and SPOP, respectively. More importantly, given the critical oncogenic role of HnRNPK and the high frequency of SPOP mutations in prostate cancer, our results provide a molecular rationale for the clinical investigation of novel strategies to combat prostate cancer based on SPOP genetic status.

One-way quantum state transfer in a lossy coupled-cavity array.

Quantum state transfer plays an important role in quantum information processing, and it has been obtained many of the theoretical and experimental triumphs. But designing a dissipation-assisted scheme to transfer a quantum state is still by no means trivial. Here we put forward an easier scheme to dissipatively transfer an arbitrary quantum state from a sender to a receiver with two four-level atoms and three lasers in a lossy coupled-cavity array, and make the quantum state stable at the receiver via the photon loss of optical cavities. Owing to the assistance of the dissipation, the target state becomes the steady state of the whole process. Thus there is no requirement on external time-dependent controls. Furthermore, the atomic spontaneous emission can be significantly suppressed as the adiabatic elimination of the excited states. We also discuss the experimental feasibility of this scheme with the current experimental technologies and a high fidelity of the transferred state in the receiver can be above 98%.

Study of biodegradable occluder of atrial septal defect in a porcine model.

OBJECTIVE: To evaluate the safety and feasibility of a modified poly(l-lactic acid) (PLLA) atrial septal defect (ASD) occluder. METHODS: Forty-five piglets were divided into two groups: an experimental group (n = 27) and a control group (n = 18). The experimental group underwent percutaneous implantation of a modified PLLA ASD device while the control group underwent percutaneous implantation of a widely used metal ASD device. X-ray imaging, transthoracic echocardiography (TTE), electrocardiogram (ECG), histopathology and electron microscopic examination were performed at 7 days, 1, 3, 6, and 12 months after implantation. RESULTS: Twenty-seven experimental piglets and 18 control piglets were all successfully implanted with modified biodegradable and metal ASD devices, respectively. While both devices exhibited very good occluding effects, the modified PLLA ASD devices were completely endothelialized at 3 months after implantation, and the endothelialization appeared to be more complete compared to the control group. Degradation of the PLLA devices was noted at 12 months follow-up with no loss of integrity at the atrial septum. CONCLUSION: This animal model with implanting of the occluders was effective and not associated with complications. The modified PLLA ASD devices are more controllable and practical than our previous devices. The implanted devices demonstrated good endothelialization and degradability in short and moderate term follow-up. Long-term studies are now underway to further evaluate the biodegradability of this novel device.

Bortezomib sensitizes human osteosarcoma cells to adriamycin-induced apoptosis through ROS-dependent activation of p-eIF2α/ATF4/CHOP axis.

Osteosarcoma is the most common bone cancer, and chemotherapy is currently indispensable for its treatment. Adriamycin has been claimed to be the most effective agent for osteosarcoma, however, the outcome of adriamycin chemotherapy remains unsatisfactory. Here, we reported a potent combination therapy that bortezomib, a proteasome inhibitor, enhances adriamycin-induced apoptosis to eliminate osteosarcoma cells and we revealed that the activation of p-eIF2α/ATF4/CHOP axis is the underlying associated mechanisms. First, we observed that bortezomib enhances adriamycin-mediated inhibition of cell proliferation and enhances the apoptosis in osteosarcoma cell lines. Moreover, this drug combination produced more potent tumor-growth inhibitory effects in human osteosarcoma cell line KHOS/NP xenografts. Our study showed that reactive oxygen species (ROS) plays an important role in apoptosis induced by adriamycin plus bortezomib, whereas ROS scavenger NAC could almost completely block the apoptosis induced by the combination treatment. Meanwhile, p-eIF2α is remarkably elevated in the combination group. As a result, ATF4 exhibits strong activation which consequently induces the activation of CHOP and leads to the cell death. Finally, 13 primary osteosarcoma cells demonstrated potent response to the combination treatment. In a human osteosarcoma patient-derived xenograft (PDX) model, our finding suggests that when combined with bortezomib, a relatively low dose of adriamycin produced more potent tumor-growth inhibitory effects without increased toxicity. Thus, our findings not only provide a promising combination strategy to overcome osteosarcoma but also shed new light on the strategy of combining increased ROS and inhibited proteasome to open up new opportunities for the clinical development of chemotherapy regimens.

A Novel-Design Poly-L-Lactic Acid Biodegradable Device for Closure of Atrial Septal Defect: Long-Term Results in Swine.

OBJECTIVES: The aim of this study is to evaluate the long-term effectiveness and safety of a self-expandable, double-disk biodegradable device made of poly-L-lactic acid (PLLA) for closure of atrial septal defects (ASDs) in swine. METHODS: ASDs were created by transseptal needle puncture followed by balloon dilatation in 20 piglets. The experimental group comprised 18 animals, while the remaining 2 animals were used as controls. Effectiveness and safety were evaluated by rectal temperature, leukocyte count, chest radiography, electrocardiogram, transthoracic echocardiography (TTE), intracardiac echocardiography (ICE), and histologic studies. Animals were followed up at 1, 3, 6, and 12 months. RESULTS: An ASD model was successfully created in 19 animals; 1 piglet died during the procedure. The ASD diameters that were created ranged from 5 to 6.4 mm. Devices were successfully implanted in 17 animals. No animal died during the follow-up studies. Rectal temperatures and electrocardiograms were normal at follow-up, while leukocyte counts transiently increased from 1 to 6 months. Radiography, TTE, ICE, and macroscopic studies demonstrated that PLLA occluders were positioned well, with no shifting, mural thrombus formation, or atrioventricular valve insufficiency. Histologic evaluations showed that PLLA devices were partially degraded in the follow-up study. CONCLUSIONS: ASD closure with the novel PLLA biodegradable device is safe and effective. Longer-term studies are needed to evaluate long-term biodegradability.

Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers.

BACKGROUND: Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development of mAbs with improved cytotoxicity, targeting new and known tumor-associated antigens, therefore continues to be an active research area. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo. METHODS: The specificity and antibody-binding capacity of DKK1-A2 mAbs were determined using indirect ELISA, confocal imaging, QIFIKIT antibody-binding capacity and cell surface binding assays. The affinity of mAbs was determined using a surface plasmon resonance biosensor. A flow cytometry-based cell death was performed to detect tumor cell apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays were used to evaluate the ability of DKK1-A2 mAbs to mediate ADCC and CDC activities against tumor cells in vitro. Flow cytometry data were collected with an FACSymphony A3 cell analyzer and analyzed with FlowJo V.10.1 software. Human cancer xenograft mouse models were used to determine the in vivo therapeutic efficacy and the potential safety and toxicity of DKK1-A2 mAbs. In situ TUNEL assay was performed to detect apoptosis in tumors and mouse organs. RESULTS: We generated novel DKK1-A2 mAbs that recognize the DKK1 P20 peptide presented by human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+ cancer cells. These mAbs directly induced apoptosis in HLA-A2+DKK1+ hematologic and solid cancer cells by activating the caspase-9 cascade, effectively lysed the cancer cells in vitro by mediating CDC and ADCC and were therapeutic against established cancers in their xenograft mouse models. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs neither bound to or killed HLA-A2+ blood cells in vitro nor caused tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice. CONCLUSION: Our study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers.

Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis.

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake. Loss of LILRB1 impairs cholesterol uptake but activates the de novo cholesterol synthesis pathway to maintain cellular cholesterol homeostasis, leading to the decrease of anti-ferroptotic metabolite squalene. Our study uncovers the function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis, implicating LILRB1 as a promising therapeutic target for MM patients.

Lipid peroxidation of immune cells in cancer.

Growing evidence indicates that cellular metabolism is a critical determinant of immune cell viability and function in antitumor immunity and lipid metabolism is important for immune cell activation and adaptation to the tumor microenvironment (TME). Lipid peroxidation is a process in which oxidants attack lipid-containing carbon-carbon double bonds and is an important part of lipid metabolism. In the past decades, studies have shown that lipid peroxidation participates in signal transduction to control cell proliferation, differentiation, and cell death, which is essential for cell function execution and human health. More importantly, recent studies have shown that lipid peroxidation affects immune cell function to modulate tumor immunity and antitumor ability. In this review, we briefly overview the effect of lipid peroxidation on the adaptive and innate immune cell activation and function in TME and discuss the effectiveness and sensitivity of the antitumor ability of immune cells by regulating lipid peroxidation.

Additional diagnostic value of the monocyte to red blood cell count ratio and the product of lymphocyte count and albumin concentration in lung cancer management.

The present study aimed to evaluate the potential of the monocyte to red blood cell count ratio (MRR), the neutrophil to red blood cell count ratio (NRR), the lymphocyte to red blood cell count ratio (LRR) and the product of lymphocyte count and albumin concentration (LA) for the diagnosis of lung cancer. The cases of 216 patients with newly diagnosed lung cancer and 184 healthy volunteers were retrospectively analysed. The MRR and NRR were found to be higher in patients with lung cancer compared with those in healthy controls, while the LRR and LA were lower. The receiver operating characteristic curve analysis revealed that of the four markers, the MRR and LA yielded a higher area under the curve (AUC) (MRR: AUC, 0.810; 95% CI, 0.768-0.847; and LA: AUC, 0.721; 95% CI, 0.674-0.764). The combination of MRR, LA, carcinoembryonic antigen (CEA) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) achieved the highest diagnostic value when compared with other single or combined markers (AUC, 0.882; 95% CI, 0.846-0.912; sensitivity, 81.9%; specificity, 81.0%). As the disease progressed, the MRR tended to increase, while LA exhibited a decreasing trend. Binary logistic regression analysis revealed an increase in the MRR, as well as in CEA and CYFRA21-1 concentrations, and a decrease in the LA, which could all be possible risk factors for lung cancer. Differences in the MRR and LA between patients with early stage (IA-IIIA) lung cancer and healthy controls were observed. Further analysis revealed that the MRR also exhibited the potential to detect early stage (IA-IIIA) lung cancer in the model. The present findings demonstrated that the MRR and LA may be used as auxiliary biomarkers for the diagnosis of lung cancer and could partly indicate disease progression.

Application of Monocyte-to-Albumin Ratio and Neutrophil Percentage-to-Hemoglobin Ratio on Distinguishing Non-Small Cell Lung Cancer Patients from Healthy Subjects.

Objective: This study aims at assessing the potential benefits of observation of monocyte-to-albumin ratio (MAR) and neutrophil percentage-to-hemoglobin ratio (NPHR) in the detection of non-small cell lung cancer (NSCLC). Methods: This study retrospectively involved 195 NSCLC patients and 204 healthy volunteers. The correlations between the clinicopathological characteristics of NSCLC and the two ratios including MAR and NPHR were assessed. The diagnostic efficiency of NSCLC patients by MAR and NPHR, alone or in combination with carcinoembryonic antigen (CEA), was assessed by receiver operating characteristic (ROC) curve. The risk factors for NSCLC were analyzed with binary logistic regression. Results: Compared to healthy controls, the levels of MAR and NPHR in NSCLC patients were elevated. MAR and NPHR were related to clinicopathologic characteristics and increased significantly along with the progression of NSCLC. The area under the curve (AUC) for 95% confidence interval (95% CI) of MAR and NPHR in the diagnosis of NSCLC was 0.812 (0.769-0.854) and 0.724 (0.675-0.774), respectively. The combination of MAR, NPHR, and CEA achieved the highest diagnostic utility compared to each individually or combined markers (AUC, 0.86; 95% CI, 0.824-0.896; sensitivity, 72.8%; specificity, 87.3%). Further analysis showed that MAR combined with NPHR presented the potential to detect early-stage (IA-IIB) NSCLC (AUC, 0.794; 95% CI, 0.743-0.845; sensitivity, 55.1%; specificity, 87.7%). The result indicated that MAR and NPHR might be risk factors for NSCLC. Conclusion: MAR and NPHR could be novel and effective auxiliary indexes in the detection of NSCLC, especially when combined with CEA.

Research on the Relationship Between Informational Team Faultline and Team Resilience-Team Leader Member Exchange and Team Member Exchange as Mechanism.

Background: This study aims to investigate how a team can be resilient in the face of crisis and adversity. Methods: This empirical study adopted a quantitative research method. The data were collected by questionnaire survey, and the stats analysis package in R language and AMOS 23 were used for empirical analysis of 98 teams. Based on complex adaptive system theory and conservation of resources theory, this study was constructed the theoretical framework of "environmental influence - team exchange - team resilience" with informational team faultline (ITF) as independent variable, team leader member exchange (TLMX) and team member exchange (TMX) as mediating and moderating variables, and team resilience as dependent variable in the context of Chinese culture. Results: We found that the ITF had a significant negative effect on the team resilience. TLMX and TMX played partial mediating role between ITF and team resilience. In addition, TLMX and TMX played moderating role between ITF and team resilience, that is, weakening the negative influence of ITF on team resilience. Conclusion: This study contributes to clarify the mechanism of the influence of ITF on team resilience, and provide reference for team leaders to improve team resilience in the face of adversity.

Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy.

Tumor development relies on a complex and aberrant tissue environment in which cancer cells receive the necessary nutrients for growth, survive through immune escape, and acquire mesenchymal properties that mediate invasion and metastasis. Stromal cells and soluble mediators in the tumor microenvironment (TME) exhibit characteristic anti-inflammatory and protumorigenic activities. Ubiquitination, which is an essential and reversible posttranscriptional modification, plays a vital role in modulating the stability, activity and localization of modified proteins through an enzymatic cascade. This review was motivated by accumulating evidence that a series of E3 ligases and deubiquitinases (DUBs) finely target multiple signaling pathways, transcription factors and key enzymes to govern the functions of almost all components of the TME. In this review, we systematically summarize the key substrate proteins involved in the formation of the TME and the E3 ligases and DUBs that recognize these proteins. In addition, several promising techniques for targeted protein degradation by hijacking the intracellular E3 ubiquitin-ligase machinery are introduced.

IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.

CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro-polarized, transferred IL-9-secreting CD8+ Tc9 (cytotoxic T lymphocyte subset 9) cells exert greater persistence and antitumor efficacy than Tc1 cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell-derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistance to tumor- or ROS-induced ferroptosis in the tumor microenvironment. IL-9 signaling deficiency, inhibiting STAT3, or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also exhibited lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL9 and higher lipid peroxidation- and ferroptosis-related genes than circulating CD8+ T cells in patients with melanoma. This study indicates that lipid peroxidation regulates Tc9 cell longevity and antitumor effects via the IL-9/STAT3/fatty acid oxidation pathway and regulating T cell lipid peroxidation can be used to enhance T cell-based immunotherapy in human cancer.

A novel role of lysophosphatidic acid (LPA) in human myeloma resistance to proteasome inhibitors.

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that regulates cell proliferation, survival, and migration. However, its role on human multiple myeloma (MM) cells is largely unknown. In this study, we show that LPA, which is highly elevated in MM patients, plays an important role in protecting human MM cells against proteasome inhibitor (PI)-induced apoptosis. LPA bound to its receptor LPAR2 activated its downstream MEK1/2-ERK1/2 signaling pathway and enhanced oxidative phosphorylation (OXPHOS) in mitochondria in MM cells. Increased OXPHOS activity produced more NAD+ and ATP, reduced proteasome activity, and enhanced protein folding and refolding in endoplasmic reticulum (ER), leading to induction of MM resistance to PIs. Importantly, inhibiting LPAR2 activity or knocking out LPAR2 in MM cells significantly enhanced MM sensitivity to PI-induced apoptosis in vitro and in vivo. Interestingly, primary MM cells from LPA-high patients were more resistant to PI-induced apoptosis than MM cells from LPA-low patients. Thus, our study indicates that LPA-LPAR2-mediated signaling pathways play an important role in MM sensitivity to PIs and targeting LPA or LPAR2 may potentially be used to (re)sensitize patients to PI-based therapy.

Novel insights into the SPOP E3 ubiquitin ligase: From the regulation of molecular mechanisms to tumorigenesis.

Ubiquitin-mediated protein degradation is the primary biological process by which protein abundance is regulated and protein homeostasis is maintained in eukaryotic cells. Speckle-type pox virus and zinc finger (POZ) protein (SPOP) is a typical substrate adaptor of the Cullin 3-RING ligase (CRL3) family; it serves as a bridge between the Cullin 3 (Cul3) scaffold protein and its substrates. In recent years, SPOP has received increasing attention because of its versatility in its regulatory pathways and the diversity of tumor types involved. Mechanistically, SPOP substrates are involved in a wide range of biological processes, and abnormalities in SPOP function perturb downstream biological processes and promote tumorigenesis. Additionally, liquid-liquid phase separation (LLPS), a potential mechanism of membraneless organelle formation, was recently found to mediate the self-triggered colocalization of substrates with higher-order oligomers of SPOP. Herein, we summarize the structure of SPOP and the specific mechanisms by which it mediates the efficient ubiquitination of substrates. Additionally, we review the biological functions of SPOP, the regulation of SPOP expression, the role of SPOP in tumorigenesis and its therapeutic value.

[Determination of metal elements in paper sludges by ICP-AES].

Metal elements, especially the heavy metal element, need to be considered for resource utilization of paper sludge. Seventeen kinds of metal elements were determined by ICP-AES method, which were form two kinds of paper sludge from Anhui Shanying paper mill, one kind of paper sludge from Fujian Qingshan paper mill, and one kind of paper sludge from Fujian Zhongzhu paper mill. The results show that there are different amounts of metal elements in the 4 kinds of paper sludge including poisonous metal elements, such as Cr, etc, metal element which is poisonous when excessive, such as Fe, etc, and P and K which are beneficial for plant growth Al and Ca contents are maximal. The recovery ratio for Fujian Zhongzhu paper mill obtained by standard addition method is 94.4%-107.3%. Heavy metal elements content lower than the national standard GB/4284-84 "Control standards for pollutions in sludge form agricultural use". The order of heavy metal elements content is paper sludge from Fujian Zhongzhu paper mill

Prediction of casing wear depth and residual strength in highly-deviated wells based on modeling and simulation.

Casing wear is a serious problem in highly-deviated wells because serious wear will lead to casing deformation, drilling tool sticking and failure of subsequent operations. The purpose of this paper is to predict casing wear depth and evaluate its effect on casing strength degradation in highly-deviated well drilling operation. Special attention has been given to the algorithm to achieve the prediction and evaluation. The effect of tool joint on contact force distribution is considered in contact force model. Then a wear depth prediction model and its solution method are proposed based on crescent-shaped wear morphology and wear-efficiency model. Besides, strength degradation of worn casing is analyzed in bipolar coordinate system and the model is verified by finite element method. Therefore, the technology of casing wear prediction and residual strength evaluation is completed systematically. Then, to apply casing wear prediction and residual strength evaluation technologies to an actual highly-deviated well, casing wear experiment and friction coefficient experiment are carried out to obtain wear coefficient and friction coefficient. Finally, based on the established models as well as experimental results, the distribution of casing wear is predicted and residual strength is evaluated. The method presented in this paper will contribute greatly to casing wear prediction and evaluation in highly-deviated wells.

Preexisting chronic conditions for fatal outcome among SFTS patients: An observational Cohort Study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is caused by a novel bunyavirus SFTSV. Currently our knowledge of the host-related factors that influence the pathogenesis of disease is inadequate to allow prediction of fatal outcome. Here we conducted a prospective study of the largest database on the SFTS patients, to identify the presence of comorbidities in SFTS, and estimate their effect on the fatal outcome. Among 2096 patients eligible for inclusion, we identified nine kinds of comorbidities, from which hyperlipidemia (12.2%; 95% CI: 10.8%-13.6%), hypertension (11.0%; 95% CI: 9.6%-12.3%), chronic viral hepatitis (CVH) (9.3%; 95% CI: 8.1%-10.5%), and diabetes mellitus (DM) (6.8%; 95% CI: 5.7%-7.9%) were prevalent. Higher risk of death was found in patients with DM (adjusted OR = 2.304; 95% CI: 1.520-3.492; P<0.001), CVH (adjusted OR = 1.551; 95% CI: 1.053-2.285; P = 0.026) and chronic obstructive pulmonary diseases (COPD) (adjusted OR = 2.170; 95% CI: 1.215-3.872; P = 0.009) after adjusting for age, sex, delay from disease onset to admission and treatment regimens. When analyzing the comorbidities separately, we found that the high serum glucose could augment diseases severity. Compared to the group with max glucose < 7.0 mmol/L, patients with glucose between 7.0-11.1 mmol/L and glucose ≥11.1 mmol/L conferred higher death risk, with the adjusted OR to be 1.467 (95% CI: 1.081-1.989; P = 0.014) and 3.443 (95% CI: 2.427-4.884; P<0.001). Insulin therapy could effectively reduce the risk of severe outcome in DM patients with the adjusted OR 0.146 (95% CI: 0.058-0.365; P<0.001). For CVH patients, severe damage of liver and prolongation of blood coagulation time, as well as high prevalence of bleeding phenotype were observed. These data supported the provocative hypothesis that treating SFTS related complications can attain potentially beneficial effects on SFTS.