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Yangyang Hui,1,&ast; Han Wang,2,&ast; Gaoyue Guo,1,&ast; Wanting Yang,1 Xuqian Zhang,3 Jie Yang,1 Fang Yang,4 Xiaoyu Wang,1 Xiaofei Fan,1 Binxin Cui,5 Xin Chen,1 Huanli Jiao,2 Chao Sun1,5 1Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Health Management, Tianjin Hospital, Tianjin, People’s Republic of China; 3Department of Gastroenterology and Hepatology, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, People’s Republic of China; 4Department of Digestive System, Baodi Clinical College of Tianjin Medical University, Tianjin, People’s Republic of China; 5Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin Airport Economic Area, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huanli Jiao; Chao Sun, Tel +8613642060733 ; +8613820846027, Fax +86-022-27813550, Email jiaohuanli@163.com; chaosun@tmu.edu.cnPurpose: The utility of the EuroQol Group 5 Dimension (EQ-5D) measuring health-related quality of life (HRQoL) has been verified; however, knowledge gaps remain concerning predictive performance in cirrhosis. We aimed to identify the optimal threshold for risk stratification and the pronounced domain in the EQ-5D linked to inferior outcomes.Patients and Methods: The X-tile project was used to obtain a threshold, considering the composite outcome of 1-year all-cause mortality or readmission. A restricted cubic spline (RCS) was performed to test the non-linear relationship between the EQ-5D utility value and the primary outcome. Six multivariate Cox regression models incorporating EQ-5D utility value and each of the five domains were constructed.Setting/Participants: Totally, 420 patients with cirrhosis were recruited.Results: The median utility value of the study population was 0.77 and 59.8% reported impairment in minimal one EQ-5D domain. RCS indicated a linear relationship between the utility value and composite inferior outcome. X-tile pinpointed a utility value of 0.59 stratifying populations into high- and low-risk groups based on the outcome. Inpatients with cirrhosis and deteriorated HRQoL (utility value ≤ 0.59) were at higher risk of death or readmission (adjusted HR: 2.18, P < 0.001). Furthermore, mobility and usual activities were the most pronounced domains associated with composite inferior outcome.Conclusion: A utility value ≤ 0.59 can identify cirrhotic inpatients exhibiting compromised HRQoL and mortality/readmission risk. It is tempting to reverse the decreased HRQoL by applying longitudinal measurements and keeping surveillance on utility value, while interventions appear to mainly focus on improving mobility and usual activities.Keywords: EQ-5D, liver cirrhosis, mortality, readmission, disability-adjusted life year

Yan Fu, Xue Liu, Beichen Cui, Cong Wang, Zhiwei Liu, Bin Zhao Emergency Department, Beijing Jishuitan Hospital, Beijing, People’s Republic of ChinaCorrespondence: Bin ZhaoEmergency Department, Beijing Jishuitan Hospital, No. 31, Xinjiekou East Street, Xicheng District, Beijing, 100035, People’s Republic of ChinaTel +86-10-5851-6417Email zhaobin60@aliyun.comObjective: The objective of this retrospective study was to evaluate the clinical characteristics of diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) patients with acute pancreatitis (AP) in a cohort from China and to identify simple laboratory parameters to discriminate high-risk patients.Methods: Patients diagnosed with AP and T2DM from January 2015 to December 2020 were retrospectively enrolled. They were divided into DKA group and non-DKA group. We calculated etiologies of AP, compared demographic and clinical features, laboratory findings on admission and clinical course. The receiver operating characteristic (ROC) curve was used to explore the ability of clinical parameters to identify high-risk patients.Results: A total of 136 patients were enrolled, of which 19.9% (27 patients) concomitant with DKA. Compared with patients without DKA, patients with DKA were younger and more obese with higher levels of serum triglycerides (TGs), blood glucose and hemoglobin A1c (HbA1C). There was a significant difference in etiology between the two groups. Compared with the non-DKA group, the DKA group showed higher rate of HTG, lower rates of gallstones and alcohol abuse. And patients in the DKA group were more likely to be admitted to intensive care unit (ICU) and have longer hospital stays. ROC analyses showed that blood glucose concentration at a cutoff value of 21.75 mmol/L resulted in the highest Youden index with sensitivity and specificity at 81.5% and 94.5%, respectively, for identifying concomitant DKA (AUC = 0.949).Conclusion: The prevalence of concomitant DKA in T2DM patients with AP was 19.9%, concomitant DKA patients tend to be younger, more obese and have higher blood glucose and TGs levels on admission. We found that blood glucose > 21.75mmol/L could potentially be used as a simple laboratory parameter to identify high-risk patients.Keywords: type 2 diabetes mellitus, acute pancreatitis, diabetic ketoacidosis

Ruolin Mao,1,&ast; Zilong Liu,1,&ast; Yunfeng Zhao,2,&ast; Chunlin Du,3,&ast; Jintao Zhou,4,&ast; Qian Wang,5,&ast; Jinchang Lu,3 Lei Gao,1 Bo Cui,1 Yuan Ma,1 Tieying Sun,6 Lei Zhu,1,7 Zhihong Chen1 1Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University. Shanghai Institute of Respiratory Disease, Shanghai, People’s Republic of China; 2Department of Respiratory Disease, Punan Hospital, Pudong New Area, Shanghai, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Taicang Hospital Affiliated with Soochow University, Taicang, Jiangsu, People’s Republic of China; 5Department of Respiratory Medicine, Jing’an District Zhabei Central Hospital, Shanghai, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Beijing Tsinghua Changgung Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihong Chen;Tieying Sun Tel +86-21-64041990-2445; +86-10-85132266Fax +86-21-64187165; +86-10-65132969Email chen.zhihong@zs-hospital.sh.cn; suntieying@126.comBackground: Early diagnosis and proper management of a large number of chronic obstructive pulmonary disease (COPD) patients are great challenges for the Chinese health care system. Although tiered medical services have been promoted by the Chinese government since 2015, they have not been ideally implemented for COPD diagnosis and management.Patients and Methods: We designed a cross-sectional study. Eligible COPD patients (n = 648) and physicians (n = 161) were consecutively recruited from 8 hospitals in different tiers in China. COPD characteristics and treatments were compared among hospitals in different tiers. Multivariate logistic regression was performed to identify risk factors associated with airflow limitation, symptoms and acute exacerbation.Results: The PFT rate at first diagnosis was 99%, 69.4% and 29.9% in teaching, second-tier and community hospitals (P < 0.001). Only approximately 10.9%, 1.7% and 9.6% and 21.8%, 6.9% and 32% of COPD patients received influenza or pneumococcal vaccines (P < 0.001). The proportion of patients who did not use inhaled drugs or had irregular inhalation was 2%, 24.6% and 78.8% (P < 0.001). Education level (RR-1 = − 41.26%, P = 0.007), FEV1%pred (RR-1 = − 2.76%, P < 0.001), and influenza vaccination in the last year (RR-1 = − 64.53%, P = 0.006) were all negatively correlated with COPD acute exacerbation (AE). COPD duration (RR-1 = 131.73%, P = 0.009), AE (RR-1 = 151.39%, P < 0.001), and COPD Assessment Test (CAT) scores (RR-1 = 3.82%, P = 0.019) were all positively correlated with COPD airflow limitation severity.Conclusion: Differences exist in the diagnosis, treatment and management of COPD among different tiers of hospitals in China. Teaching hospitals can manage COPD patients relatively well. There are still some gaps compared with developed countries.Keywords: stable chronic obstructive pulmonary disease, tiered medical system, airflow limitation, symptoms, acute exacerbation

Chen Chen, Yanlong Liu, Peng Han, Binbin Cui Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Binbin CuiDepartment of Colorectal Surgery, Harbin Medical University Cancer Hospital, No. 150 Raod Haping, Nangang District, Harbin, 150081, Heilongjiang Province, People’s Republic of ChinaTel +13351112888Email cbbhrb@163.comAbstract: Research has confirmed that plasma albumin (Alb), prealbumin (PA) and fibrinogen (Fib) are involved in regulating the occurrence and development of various tumors. Their levels in peripheral blood are related to the survival outcome and treatment response of patients, but the accuracy and specificity of single application have yet to be fully realized. A growing amount of evidence indicates that predictors such as preoperative fibrinogen to prealbumin ratio (FPR), fibrinogen to albumin ratio (FAR) or albumin to fibrinogen ratio (AFR) are emerging as comprehensive indicators. Indeed, their components play a key regulatory role in the progression of colorectal cancer (CRC). Preoperative FPR, FAR or AFR levels, therefore, are expected to become new biomarkers for prognosis evaluation and curative effect prediction for CRC patients and are significant in the guidance they could provide for the development of individualized treatment strategies.Keywords: colorectal cancer, FPR, FAR or AFR, prognosis, efficacy

Huifeng Bi,1,2 Zhenhua Shang,1 Chunsong Jia,1 Jiangtao Wu,1 Bo Cui,1 Qi Wang,1 Tongwen Ou1 1Department of Urology, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China; 2Department of Urology, Jincheng General Hospital, Jincheng, Shanxi Province, People’s Republic of ChinaCorrespondence: Tongwen OuXuanwu Hospital Capital Medical University, No. 45 Changchun Street, Xicheng District, Beijing 100053, People’s Republic of ChinaTel +86 135 0106 5134Fax +86 010 8319 8388Email outongwen1967@126.comPurpose: This study aimed to investigate the associations between the preoperative prognostic nutritional index (PNI), systemic immune-inflammation index (SII) and overall survival (OS) and cancer-specific survival (CSS) in high-risk non-muscle-invasive bladder cancer (NMIBC) patients who received intravesical instillation of Bacillus Calmette-Guerin (BCG) after transurethral resection of bladder tumour (TURBT).Patients and Methods: We retrospectively collected data from 387 high-risk NMIBC patients between January 2004 and December 2014. PNI was calculated as total lymphocyte count (109/L)× 5+albumin concentration (g/L). SII was calculated as neutrophil count (109/L)×platelet count (109/L)/lymphocyte count (109/L). The cutoff values of PNI and SII were determined through receiver operating characteristic (ROC) analysis. OS and CSS were estimated by Kaplan–Meier analysis. The Log rank test was used to compare differences between the groups. Univariate and multivariate Cox regression analyses were performed to assess the predictive values of PNI and SII for OS and CSS. Additionally, highest-risk NMIBC patients were also divided into low or high groups according to PNI and SII. The OS and CSS of highest-risk NMIBC patients were estimated using Kaplan-Meier analysis with the Log rank test.Results: The patients were divided into two groups according to the cutoff values of PNI (< 50.17 vs ≥ 50.17) and SII (< 467.76 vs ≥ 467.76). Kaplan–Meier analysis revealed that low PNI and high SII were associated with poorer OS and CSS in high-risk NMIBC patients. Univariate and multivariate Cox regression analyses revealed that PNI and SII were independent predictive factors for OS and CSS. Kaplan–Meier analysis also revealed that low PNI and high SII were related to poorer OS and CSS in highest-risk NMIBC patients.Conclusion: These results suggest that preoperative PNI and SII, based on standard laboratory measurements, may be useful noninvasive, inexpensive and simple tools for predicting the long-term survival of high-risk NMIBC patients who received intravesical instillation of BCG after TURBT.Keywords: prognostic nutritional index, systemic immune-inflammation index, non-muscle-invasive bladder cancer, Bacillus Calmette-Guerin, overall survival, cancer-specific survival

Bin Cui,1 Zhaohui Dong,2 Mengmeng Zhao,3 Shanshan Li,4 Hua Xiao,4 Zhitao Liu,4 Xiaowei Yan5 1School of Public Health, Peking University, Beijing 100191, People’s Republic of China; 2Human Resources and Social Security, Chinese Academy of Labour and Social Security, Beijing, 100029, People’s Republic of China; 3School of Pharmaceutical Science and Technology, School of Pharmacy, Tianjin University, Tianjin, 300072, People’s Republic of China; 4Medical Affairs, Bayer Healthcare Company Limited (China), Beijing, 100020, People’s Republic of China; 5Department of Cardiology, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of ChinaCorrespondence: Xiaowei YanPeking Union Medical College Hospital, Beijing 100730, People’s Republic of ChinaEmail yanxiaowei2019@gmail.comObjective: To analyze the adherence to antihypertensive drugs in Chinese patients with hypertension and the factors associated with the drug adherence.Methods: The data for this analysis were obtained from the 2014 China Health Insurance Association (CHIRA) database. The study included 64,576 patients aged ≥ 18 years who were prescribed one of the seven antihypertensive drugs included in the study in their first prescription in 2014 and were observed for ≥ 180 days. The medicine possession ratio (MPR) was calculated and taken as the measure of treatment adherence. MPR values < 0.3, 0.3 to < 0.5, 0.5 to < 0.8, and ≥ 0.8 were considered treatment adherence very low, low, intermediate, and high, respectively. Descriptive statistics were used to present baseline data and treatment adherence rate. Multiple regression models were used to determine independent factors which can affect the treatment adherence rate. P-value < 0.05 was considered significant.Results: Among the study antihypertensive drugs, amlodipine (33.98%), metoprolol (25.04%), and nifedipine (17.15%) were the frequently prescribed drugs. Nifedipine controlled release tablet had the highest MPR (0.61), followed by valsartan (0.53), valsartan/amlodipine fixed-dose combination (0.50), indapamide (0.40), and amlodipine (0.39), whereas benazepril (0.27) and metoprolol (0.19) had the lowest MPR. Higher reimbursement ratio, regular tertiary hospitals visits, lower age, and lower daily medical cost positively affected treatment adherence, whereas longer duration of illness and higher daily average cost affected treatment adherence negatively.Conclusion: Our study assessed that prescribing more cost-effective, long-acting antihypertensive drugs, and raising the reimbursement ratio were associated with a better treatment adherence in Chinese patients with hypertension.Keywords: treatment adherence, medicine possession ratio, hypertension, antihypertensive treatment

Jun Jiao,1 Xinlin Jiao,1 Qingqing Liu,1 Wenjie Qu,1 Daoxin Ma,2 Youzhong Zhang,1 Baoxia Cui1 1Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China; 2Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of ChinaCorrespondence: Baoxia Cui Tel +8618560081862Email cuibaoxia@sdu.edu.cnPurpose: Accumulating evidence indicates that circular RNAs (circRNAs) are closely involved in canceration and cancer progression. However, the role of circRNAs in cervical cancer (CC) is largely unknown. Here, we characterized the role of circRNA_101308 in CC.Materials and Methods: The expression of circRNA_101308 in CC tissues was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, circRNA_101308 was overexpressed in CC cells to detect its function by proliferation and apoptosis assays, Transwell assays and animal experiments. The potential mechanism of circRNA_101308 in CC was explored by RNA pull-down, Gene Ontology (GO) and pathway analyses.Results: CircRNA_101308 was significantly downregulated in CC tissues. The level of circRNA_101308 was much lower in CC patients with lymph node metastasis or deep myometrial invasion compared to those patients without lymph node metastasis and superficial myometrial invasion. CircRNA_101308 overexpression inhibited CC cell proliferation, invasion and migration. MiR-26a-5p, miR-196a-5p, miR-196b-5p, miR-335-3p, and miR-1307-3p were found to be sponged by circRNA_101308 in CC cells. Further, GO and pathway analyses predicted the potential functional processes and pathways of circRNA_101308 in CC.Conclusion: CircRNA_101308 is downregulated and acts as a tumor suppressor in CC. CircRNA_101308 can participate in many different processes by sponging different miRNAs in CC cells. This exploration of circRNA_101308 provides new directions for research on cancer development and the clinical treatment of CC.Keywords: circular RNA, cervical cancer, circRNA_101308, microRNA

Ying Wang,1,2,* Sai Han,1,* Xuewu You,1 Xuejiao Shi,3 Lu Liu,1 Yu Sun,1 Yana Ma,1 Qiuhong Qian,1 Hongli Liu,1 Baoxia Cui,1 Youzhong Zhang11Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People’s Republic of China; 2Department of Obstetrics and Gynecology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, People’s Republic of China; 3Department of Rheumatism and Immunology, Weihai Municipal Hospital, Weihai, Shandong 264200, People’s Republic of ChinaCorrespondence: Youzhong ZhangDepartment of Obstetrics and Gynecology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, People’s Republic of ChinaEmail zhangyouzhong@sdu.edu.cn*These authors contributed equally to this workBackground: It is unclear whether low density lipoprotein receptor-related protein 11 (LRP11), a newly found lipoprotein receptor regulatory protein, has the carcinogenic effects in cervical cancer.Methods: Bioinformatics analysis, immunohistochemical (IHC) staining and evaluation, cell proliferation assay, flow cytometry, transwell migration and invasion assays, Western blotting, growth of LRP11-silenced cells in athymic nude mice were performed in this research.Results: We found that LRP11 expression was higher in high-grade squamous intraepithelial lesions (HSIL) and cervical cancer tissue than in normal cervix, and high expression of LRP11 was associated with differentiation degree (P=0.0266), indicating poor prognosis (P=0.0210). The silencing of LRP11 in SiHa and CaSki cell lines inhibited cell proliferation, reduced migration and invasion and suppressed cell growth in nude mice, which possibly related to cell cycle protein regulation of CDK 2/4, cyclin D1/E1, MMP-2/9, and VEGF. Furthermore, LRP11 showed substantial positive correlation with P16 in vivo and in vitro.Conclusion: LRP11 plays important roles in proliferation, migration and invasion, with the potential to be a useful prognostic marker and therapeutic target for patients with HSIL and cervical cancer.Keywords: HPV, cervical cancer, LRP11, P16, cell cycle

Bo Zhang,1,* Bomiao Cui,1,* Jintao Du,2 Xin Shen,1 Kun Wang,1 Jiao Chen,1 Liying Xiao,1 Chongkui Sun,1 Yan Li1 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; 2Department of Otorhinolaryngology–Head and Neck Surgery, West China Hospital, Chengdu 610041, Sichuan, China *These authors contributed equally to this work Purpose: Epstein–Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC) and increases the chemotherapy resistance of tumor cells. Although the mechanism by which EBV manipulates ataxia telangiectasia mutation (ATM)-mediated DNA damage response in NPC has been extensively studied, the relationship between ATR (ATM and Rad-3 related) and EBV infection is largely unexplored, and also the role of ATR in chemotherapy resistance in EBV-positive NPC has not been specifically reported.Materials and methods: Levels of γ-H2AX, latent membrane protein 1 (LMP1), and EBV-encoded RNA in clinical NPC and nasopharyngeal inflammation (NPI) specimens were examined using immunohistochemistry and in situ hybridization. The effects of EBV infection, chemotherapy drugs cisplatin (CDDP) and 5-fluorouracil (5-FU) treatment, and ATR silencing were assessed in NPC cells in vitro using immunofluorescence, Western blot, and flow cytometry.Results: A notable increase of γ-H2AX expression was examined in the EBV-positive NPC clinical specimens. Additionally, we observed that the phosphorylation of ATR/checkpoint kinase 1 (CHK1) pathway protein was gradually activated along with the duration of EBV exposure in NPC cell lines, which was obviously inhibited after ATR depletion. Moreover, EBV infection promoted the resistance of NPC cells to CDDP and 5-FU, whereas the chemosensitivity of cells was significantly enhanced following ATR knockdown. Furthermore, ATR depletion caused both S-phase cell arrest and apoptosis, enhanced p53 phosphorylation, and impaired the formation of Rad51.Conclusion: Our data suggest that EBV activation of ATR-mediated DNA damage response might result in chemotherapy resistance to CDDP and 5-FU in NPC. Accordingly, ATR knockdown may serve as an effective treatment strategy for chemotherapy-resistant, EBV-positive NPC. Keywords: ATR, EBV, NPC, chemotherapy resistance, cisplatin, 5-fluorouracil, ATRi, CNE1, Rad51, p53

Zhenhua Shang, Jukun Wang, Xu Wang, Hao Yan, Bo Cui, Chunsong Jia, Qi Wang, Xin Cui, Jin Li, Tongwen Ou Department of Urology, Xuanwu Hospital Capital Medical University, Beijing, People’s Republic of China Introduction: The aim of this study was to elucidate the association between apolipoprotein A-I (Apo A-I) and overall survival (OS) as well as cancer-specific survival (CSS) in non-muscle-invasive bladder cancer (NMIBC) patients undergoing transurethral resection of bladder tumor (TURBT). Patients and methods: We retrospectively collected data of 470 eligible patients diagnosed with NMIBC and who received TURBT between January 2004 and December 2011. Pretreatment blood indexes were examined. The association of Apo A-I with clinicopathological characteristics was further analyzed by dichotomizing our sample into those with Apo A-I ≤ 1.19 g/L (low Apo A-I group) and those with Apo A-I > 1.19 g/L (high Apo A-I group). OS and CSS were estimated by Kaplan–Meier analysis and the log-rank test was used to compare differences between groups. Univariate and multivariate Cox regression analyses were plotted to assess the prognostic value of Apo A-I in NMIBC patients. In addition, subgroup analyses were performed according to the risk classification of the International Bladder Cancer Group. Results: In the overall population, patients in the high Apo A-I group had greater 5-year OS and 5-year CSS rates as compared to those in the low Apo A-I group. Kaplan–Meier survival analysis revealed that higher albumin, Apo A-I, and hemoglobin levels were associated with greater OS and CSS while elevated neutrophil–lymphocyte ratio was associated with worse OS and CSS in the overall and high-risk population rather than low- and intermediate-risk population. Furthermore, Apo A-I was shown to be an independent predictor in the overall population (for OS, hazard ratio [HR], 0.364, 95% confidence interval [CI], 0.221–0.598, p < 0.001; for CSS, HR, 0.328, 95% CI, 0.185–0.583, p < 0.001) and high-risk patients (for OS, HR, 0.232, 95% CI 0.121–0.443, p < 0.001; for CSS, HR, 0.269, 95% CI, 0.133–0.541, p < 0.001). Conclusion: These results suggest that Apo A-I level could potentially serve as a useful prognostic indicator for therapeutic decision making in NMIBC patients. Keywords: apolipoprotein A-I, NMIBC, TURBT, prognosis, overall survival, cancer-specific survival

Tingjie Yin,* Lihui Dong,* Bei Cui, Lei Wang, Lifang Yin, Jianping Zhou, Meirong Huo State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Clinically, paclitaxel (PTX) is one of most commonly prescribed therapies against a wide range of solid neoplasms. Despite its success, the clinical applicability of PTX (Taxol®) is severely hampered by systemic toxicities induced by Cremophor EL. While attempts to bypass the need for Cremophor EL have been developed through platforms such as Abraxane™, nab™ relies heavily on the use of organic solvents, namely, chloroform. The toxicity introduced by residual chloroform poses a potential risk to patient health. To mitigate the toxicities of toxic organic solvent-based manufacture methods, we have designed a method for the formulation of PTX nanosuspensions (PTX-PEG [polyethylene glycol]-HSA [human serum albumin]) that eliminates the dependence on toxic organic solvents. Coined the solid-dispersion technology, this technique permits the dispersion of PTX into PEG skeleton without the use of organic solvents or Cremophor EL as a solubilizer. Once the PTX-PEG dispersion is complete, the dispersion can be formulated with HSA into nanosuspensions suitable for intravenous administration. Additionally, the incorporation of PEG permits the prolonged circulation through the steric stabilization effect. Finally, HSA-mediated targeting permits active receptor-mediated endocytosis for enhanced tumor uptake and reduced side effects. By eliminating the need for both Cremophor EL and organic solvents while simultaneously increasing antitumor efficacy, this method provides a superior alternative to currently accepted methods for PTX delivery. Keywords: human serum albumin, nanosuspension, paclitaxel, polyethylene glycol, solid-dispersion technology

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies.

River deltas contain some of the most densely populated areas in the world and are characterized by a rich biodiversity and highly productive ecosystems. Although previous studies have revealed that sediment grain size plays a key role in determining delta morphology, its subsequent effects on deltaic vegetation distribution patterns remain elusive. We used a theoretical templet to facilitate our study by conducting numerical experiments to simulate deltaic morphological evolution in response to various sediment grain sizes and explored the vegetation distribution determined by the elevation profile of a typical river-dominated delta. Our results showed that a fine-grained, cohesive delta would develop vegetation patterns transitioning from high- to low-elevation adapted vegetation species with increasing distance, whereas the same vegetation transformation trend could occur with decreasing distance to the center of a large-grained, noncohesive delta. The modeled vegetation distribution pattern of fine-grained, cohesive and large-grained, noncohesive deltas could be well demonstrated in the natural deltas. In addition, vegetation distribution patterns are related to the grain size-driven morphological processes of deltas, and the leading role of cohesive and noncohesive sediments on constructed delta is critical in determining the resulting vegetation distribution pattern. The dominance of each vegetation type would gradually become stable as delta matures. The interspecies competitions could influence distribution patterns of each vegetation type by enhancing the fragmentation of mid-elevation adapted vegetation. The effects of sediment grain size on the deltaic vegetation patterns associated with a delta's morphological processes have potential implications for the conservation and restoration of deltaic habitats. [ABSTRACT FROM AUTHOR]

The hydraulic turbine has been used extensively in the field of energy conservation. For turbines that have low heads and large discharge, improving recovery efficiency and stability is crucial due to their significant hydraulic impact. This paper provides a detailed analysis of the correlation between the influence of radial guide vanes on the stability of low-head, large-discharge turbines focusing on hydraulic performance and energy dissipation before and after the implementation of guide vanes. Moreover, in this paper, two types of turbines, with and without guide vanes, were designed considering the desulfurization scenario. Hydraulic efficiency, radial force, and internal flow field mechanics were numerically studied, and validated through experiments. The results reveal that the working range of the hydraulic turbine could be widened and the energy recovery efficiency improved by a maximum of 3.11% in the small flow rate under the action of guide vanes. Furthermore, it results in a substantial reduction in the radial force of the impeller. Subsequently, the variation in entropy production of different components under full flow rate conditions was compared between the models with and without guide vanes. The total energy consumption decreases sharply under overall working conditions due to the flow control ability of guide vanes affecting the flow state. The entropy production rate of the impeller remains the largest regardless of the presence of a guide vane in the turbine. The vortices inside the guide vanes increase obviously with the flow rate increase. [ABSTRACT FROM AUTHOR]