BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial-immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial-immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.
Humans ; MicroRNAs/metabolism* ; RNA, Long Noncoding/metabolism* ; Head and Neck Neoplasms/metabolism* ; Cell Proliferation ; Squamous Cell Carcinoma of Head and Neck/genetics* ; Urokinase-Type Plasminogen Activator/genetics* ; Cell Movement ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Carcinoma, Squamous Cell/genetics* ; Neoplasm Invasiveness

Objective: To analyze mortality and its trend of chronic respiratory diseases (CRD) in China from 1990 to 2019. Methods: Based on the provincial results of China from the 2019 Global Burden of Disease (GBD) study, the average annual percent change (AAPC) of standardized mortality rates of different CRDs were analyzed by using Joinpoint 4.8.0.1, and the age-standardized mortality rate of CRD was calculated by using the GBD 2019 world standard population. Based on the comparative risk assessment theory of GBD, the attributable deaths due to 12 CRD risk factors were estimated, including smoking, indoor air pollution, occupational gas exposure, particulates and smog exposure, environmental particulate pollution, low temperature, passive smoking, ozone pollution, occupational exposure to silica, occupational asthma, high body mass index, high temperature and occupational exposure to asbestos. Results: From 1990 to 2019, the number of deaths and standardized mortality of chronic obstructive pulmonary disease (COPD) showed a downward trend (P<0.001). The number of COPD deaths decreased from 1 244 000 (912 000 - 1 395 000) in 1990 to 1 037 000 (889 000 - 1 266 000) in 2019. AAPC=-0.9% (95%CI: -1.5% - -0.3%), P<0.001; The standardized mortality rate decreased from 217.9/100 000 (163.3/100 000 - 242.0/100 000) in 1990 to 65.2/100 000 (55.5/100 000 - 80.1/100 000) in 2019. AAPC= -4.2% (95%CI:-5.2% - -3.2%), P<0.001. The number of deaths from asthma decreased from 40 000 (30 000 - 58 000) in 1990 to 25 000 (20 000 - 31 000) in 2019. AAPC=-2.0% (95%CI: -2.6% - -1.4%), P<0.001; The standardized mortality rate of asthma decreased from 6.4/100 000 (4.7/100 000 - 9.5/100 000) in 1990 to 1.5/100 000 (1.2/100 000 - 1.9/100 000) in 2019. AAPC=-5.1% (95%CI: -5.8% - -4.4%), P<0.001. The number of pneumoconiosis deaths decreased from 11 000 (8 000 - 14 000) in 1990 to 10 000 (8 000 - 14 000) in 2019, AAPC=-0.2%(95%CI:-0.4% - 0.1%), P=0.200; The standardized mortality rate of pneumoconiosis decreased from 1.4/100 000 (1.0/100 000 - 1.7/100 000) in 1990 to 0.5/100 000 (0.4/100 000 - 0.7/100 000) in 2019. AAPC=-3.1% (95%CI: -3.4% - -2.8%), P<0.001. The number of deaths from pulmonary interstitial diseases and pulmonary sarcoidosis increased from 3 000 (3 000 - 6 000) in 1990 to 8 000 (6 000 - 10 000) in 2019, AAPC=3.5% (95%CI: 2.7% - 4.2%), P<0.001; The corresponding standardized mortality rate changed little from 1990 to 2019, and AAPC was not statistically significant.The age-standardized mortality rates of different CRDs were higher in men than those in women. In 1990 and 2019, the mortality rates of COPD, asthma, pneumoconiosis and interstitial pulmonary disease and pulmonary sarcoidosis increased with age. In 2019, the population attributable fractions (PAFs) for smoking, environmental particulate pollution, occupational gas exposure, particulate and smog exposure, low temperature exposure and passive smoking were 71.1% (68.0% - 74.3%), 24.7% (20.1% - 30.0%), 19.3% (13.0% - 25.4%), 15.7% (13.6% - 18.3%) and 8.8% (4.5% - 13.1%) respectively in men, and the PAFs for environmental particulate pollution, smoking, low temperature exposure, occupational gas exposure, particulate and smog exposure, and passive smoking were 24.1% (19.6% - 29.3%), 21.9% (18.7% - 25.2%), 16.4% (14.0% - 19.2%), 15.6% (10.2% - 21.1%) and 14.7% (7.9% - 21.3%) respectively in women. Conclusions: During 1990-2019, the overall death level of CRD decreased significantly in China, but it is still at high level in the world. Active prevention and control measures should be taken to reduce the death level caused by CRD.
Asthma ; China/epidemiology* ; Female ; Global Burden of Disease ; Humans ; Male ; Mortality ; Pulmonary Disease, Chronic Obstructive ; Quality-Adjusted Life Years

Objective: To compare clinical efficacy between laparoscopic radical proximal gastrectomy with double-tract reconstruction (LPG-DTR) and laparoscopic radical total gastrectomy with Roux-en-Y reconstruction (LTG-RY) in patients with early upper gastric cancer, and to provide a reference for the selection of surgical methods in early upper gastric cancer. Methods: A retrospective cohort study method was carried out. Clinical data of 80 patients with early upper gastric cancer who underwent LPG-DTR or LTG-RY by the same surgical team at the Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from January 2018 to January 2021 were retrospectively analyzed. Patients were divided into the DTR group (32 cases) and R-Y group (48 cases) according to surgical procedures and digestive tract reconstruction methods. Surgical and pathological characteristics, postoperative complications (short-term complications within 30 days after surgery and long-term complications after postoperative 30 days), survival time and nutritinal status were compared between the two groups. For nutritional status, reduction rate was used to represent the changes in total protein, albumin, total cholesterol, body mass, hemoglobin and vitamin B12 levels at postoperative 1-year and 2-year. Non-normally distributed continuous data were presented as median (interquartile range), and the Mann-Whitney U test was used for comparison between groups. The χ(2) test or Fisher's exact test was used for comparison of data between groups. The Mann-Whitney U test was used to compare the ranked data between groups. The survival rate was calculated by Kaplan-Meier method categorical, and compared by using the log-rank test. Results: There were no statistically significant differences in baseline data betweeen the two groups, except that patients in the R-Y group were oldere and had larger tumor. Patients of both groups successfully completed the operation without conversion to laparotomy, combined organ resection, or perioperative death. There were no significant differences in the distance from proximal resection margin to superior margin of tumor, postoperative hospital stay, time to flatus and food-taking, hospitalization cost, short- and long-term complications between the two groups (all P>0.05). Compared with the R-Y group, the DTR group had shorter distal margins [(3.2±0.5) cm vs. (11.7±2.0) cm, t=-23.033, P<0.001], longer surgery time [232.5 (63.7) minutes vs. 185.0 (63.0) minutes, Z=-3.238, P=0.001], longer anastomosis time [62.5 (17.5) minutes vs. 40.0 (10.0) minutes, Z=-6.321, P<0.001], less intraoperative blood loss [(138.1±51.6) ml vs. (184.3±62.1) ml, t=-3.477, P=0.001], with significant differences (all P<0.05). The median follow-up of the whole group was 18 months, and the 2-year cancer-specific survival rate was 97.5%, with 100% in the DTR group and 95.8% in the R-Y group (P=0.373). Compared with R-Y group at postoperative 1 year, the reduction rate of weight, hemoglobin and vitamin B12 were lower in DTR group with significant differences (all P<0.05); at postoperative 2-year, the reduction rate of vitamin B12 was still lower with significant differences (P<0.001), but the reduction rates of total protein, albumin, total cholesterol, body weight and hemoglobin were similar between the two groups (all P>0.05). Conclusions: LPG-DTR is safe and feasible in the treatment of early upper gastric cancer. The short-term postoperative nutritional status and long-term vitamin B12 levels of patients undergoing LPG-DTR are superior to those undergoing LTG-RY.
Albumins ; Anastomosis, Roux-en-Y/adverse effects* ; Cholesterol ; Gastrectomy/methods* ; Hemoglobins ; Humans ; Laparoscopy/methods* ; Postoperative Complications/etiology* ; Retrospective Studies ; Stomach Neoplasms/pathology* ; Treatment Outcome ; Vitamin B 12

BACKGROUND: Colorectal cancer (CRC) is the fourth cause of cancer death in China. We aimed to provide national and subnational estimates and changes of CRC premature mortality burden during 2005-2020. METHODS: Data from multi-source on the basis of the national surveillance mortality system were used to estimate mortality and years of life lost (YLL) of CRC in the Chinese population during 2005-2020. Estimates were generated and compared for 31 provincial-level administrative divisions in China. RESULTS: Estimated CRC deaths increased from 111.41 thousand in 2005 to 178.02 thousand in 2020; age-standardized mortality rate decreased from 10.01 per 100,000 in 2005 to 9.68 per 100,000 in 2020. Substantial reduction in CRC premature mortality burden, as measured by age-standardized YLL rate, was observed with a reduction of 10.20% nationwide. Marked differences were observed in the geographical patterns of provincial units, and they appeared to be obvious in areas with higher economic development. Population aging was the dominant driver which contributed to the increase in CRC deaths, followed by population growth and age-specific mortality change. CONCLUSIONS Substantial discrepancies were observed in the premature mortality burden of CRC across China. Targeted considerations were needed to promote a healthy lifestyle, expand cost-effective CRC early screening and diagnosis, and improve medical treatment to reduce CRC mortality among high-risk populations and regions with inadequate healthcare resources.
China/epidemiology* ; Colorectal Neoplasms ; Humans

OBJECTIVE: To evaluate the clinical efficacy and safety of Congrong Shujing Granules ( , CSGs) in treating patients with Parkinson's disease (PD) and Chinese medicine (CM) syndrome of Shen (Kidney) essence deficiency, and to investigate the potential mechanism involving efficacy through a transcriptome sequencing approach. METHODS: Eligible PD patients with syndrome of Shen essence defificiency were randomly assigned to a treatment group or a control group by a random number table, and were treated with CSGs combined with Western medicine (WM), or placebo combined with WM, respectively. Both courses of treatment lasted for 12 weeks. The Unifified Parkinson's Disease Rating Scale (UPDRS) score, the PD Question-39 (PDQ-39) score, CM Syndrome Scale score, and drug usage of all patients were evaluated before and after treatment. Safety was evaluated by clinical laboratory tests and electrocardiographs. Blood samples from 6 patients in each group were collected before and after the trial and used for transcriptomic analysis by gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Differentially expressed genes were validated using reverse transcription-polymerase chain reaction. RESULTS: A total of 86 PD patients were selected from the Third Affifiliated People's Hospital of Fujian University of Traditional Chinese Medicine between January 2017 and December 2017. Finally, 72 patients completed the trial, including 35 in the treatment group and 37 in the control group. When compared with the control group after treatment, patients in the treatment group showed signifificant decreases in UPDRS sub-II score, PDQ-39 score, CM syndrome score, and Levodopa equivalent dose (P<0.05). During the treatment course, no signifificant changes were observed in safety indicators between the two groups (P>0.05). A possible mechanism of clinical effificacy was proposed that involved regulating cell metabolism-related processes and ribosome-related pathways. Treatment with CSGs had shown to affect relevant gene loci for PD, including AIDA, ANKRD36BP2, BCL2A1, BCL2L11, FTH1P2, GCH1, HPRT1, NFE2L2, RMRP, RPS7, TGFBR1, WIPF2, and COX7B. CONCLUSIONS CSGs combined with WM can be used to treat PD patients with CM syndrome of Shen essence defificiency with a good safety. The possible mechanism of action and relevant gene loci were proposed. (Registration No. ChiCTR-IOR-16008394).

Animals ; Embryo, Nonmammalian ; drug effects ; metabolism ; Ethanol ; toxicity ; RNA, Messenger ; metabolism ; Resveratrol ; pharmacology ; Zebrafish ; Zebrafish Proteins ; metabolism

A two-dimensional liquid chromatography method was developed for the analysis of rice leaves proteomics based on the coupling of hydrophilic interaction liquid chromatography-reversed-phase liquid chromatography with online tandem mass spectrometry. The influence of pH value of chromatographic mobile phase on the orthogonality of the hydrophilic interaction-reversed-phase two-dimensional liquid chromatography was evaluated by the changes of standard peptide retention. The results indicated that the better orthogonality (R2=0.34113) was achieved from the system with hydrophilic interaction columns(pH 9.3) in the first and C18columns(pH 3.3) in the second LC dimension. Coupled with multiple fraction concatenation strategy,the orthogonality of two-dimensional liquid chromatography was further evaluated in the analysis of complex rice leaf proteins. The results showed that more than 50% of the total peptides were identified less than two times, and the peptides obtained from first-dimension were well distributed across the elution window,indicating that the method showed significant orthogonality in the identification of complex rice leaf proteins. Based on the proteome discoverer software,207345 peptides belonged to 2930 protein clusters were identified.

Variant pulmonary vein anatomy (PVA) has been reported to influence the recurrence of atrial fibrillation (AF) after radiofrequency ablation.However,the effects of PVA on AF in patients undergoing cryoballoon ablation (CBA) remain unknown.The present study aimed to examine the impact of PVA on the long-term outcome of CBA for AF.A total of 78 patients (mean age 60.7±10.9 years,64.1％ males) with symptomatic and drug-refractory paroxysmal AF were enrolled in the study.Left atrium (LA) and PVA acquired at computed tomography angiography (CTA) were reconstructed with CARTO(R) 3 SYSTEM.Patients were routinely evaluated by 24-hour Holter monitoring following CBA.Cox regression was used to detect the predictors of AF recurrence after CBA.The results showed abnormal PVA in 30 patients (38.5％) and 18 patients (23.1％) had left common PV (LCPV).Electrical pulmonary vein isolation was achieved in all patients.After a mean follow-up of 689.5±103.8 days,it was found that patients with abnormal PVA had similar AF recurrence rate to those with normal PVA (26.7％ vs.25.0％,P=0.54),and there was no significant difference in AF recurrence rate between LCPV patients and non-LCPV patients (33.7％ vs.23.3％,P=0.29).Cox regression analysis showed that AF duration (72.9±9.0 vs.42.3±43.2 months,HR 1.001;95％CI 1.003-1.014;P＜0.001) and cryo-applications of right-side PVs (3.0±1.6 vs.4.7±1.7,HR 0.661;95％ CI 0.473-0.925;P=0.016) were independent predictors of freedom from AF,but PVA was not identified as a predictor of long-term success.In conclusion,the variant PVA cannot significantly influence the long-term outcome of AF patients undergoing CBA;longer AF duration and less cryo-applications of right-side PVs are associated with higher AF recurrent rate.

BACKGROUNDPatients on hemodialysis have a high-mortality risk. This study analyzed factors associated with death in patients on maintenance hemodialysis (MHD). While some studies used baseline data of MHD patients, this study used the most recent data obtained from patients just prior to either a primary endpoint or the end of the study period to find the characteristics of patients preceding death.

METHODSParticipants were selected from 16 blood purification centers in China from January 2012 to December 2014. Patients' data were collected retrospectively. Based on survival status, the participants were divided into two groups: survival group and the death group. Logistic regression analysis was performed to determine factors associated with all-cause mortality.

RESULTSIn total, 4104 patients (57.58% male, median age 59 years) were included. Compared with the survival group, the death group had more men and more patients with diabetic nephropathy (DN) and hypertensive nephropathy. The patients preceding death also had lower levels of diastolic blood pressure, hemoglobin, serum albumin, serum calcium, serum phosphate, Kt/V, and higher age. Multivariate analysis revealed that male sex (odd ratio [OR]: 1.437, 95% confidence interval [CI]: 1.094-1.886), age (OR: 1.046, 95% CI: 1.036-1.057), and presence of DN (OR: 1.837, 95% CI: 1.322-2.552) were the risk factors associated with mortality. High serum calcium (OR: 0.585, 95% CI: 0.346-0.989), hemoglobin (OR: 0.974, 95% CI: 0.967-0.981), albumin (OR: 0.939, 95% CI: 0.915-0.963) levels, and dialysis with noncuffed catheter (OR: 0.165, 95% CI: 0.070-0.386) were protective factors based on a multivariate analysis.

CONCLUSIONSHemodialysis patients preceding death had lower hemoglobin, albumin, and serum calcium levels. Multivariate analysis showed that male sex, age, DN, low hemoglobin, low albumin, and low serum calcium were associated with death in hemodialysis patients.

Adult ; Aged ; China ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Renal Dialysis ; adverse effects ; mortality ; Retrospective Studies ; Risk Factors