[Screening and validation of therapeutic targets for chronic sinusitis with nasal polyps based on proteomics].

Objective: To identify potential therapeutic targets of chronic sinusitis with nasal polyps (CRSwNP) through proteomics screening of and verify its effectiveness experimentally. Methods: The nasal tissue samples were collected from patients undergoing surgical treatment in the Department of Otorhinolaryngology, Head and Neck Surgery in Yuhuangding Hospital of Yantai from June 2010 to December 2021, including 69 patients with CRSwNP and 39 patients in the control group. Tissue samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-independent acquisition (DIA) mode to find differentially expressed proteins. Bioinformatics tools were employed to analyze the functions of differentially expressed proteins. The expression of hematopoietic cell kinase (HCK) in nasal tissues of patients with CRSwNP was further confirmed by qPCR and western blot. The mouse model of CRSwNP was established and treated with HCK inhibitor. The levels of inflammatory factors IgE, IL-4 and IL-5 in serum of CRSwNP mice, both treated and untreated with HCK inhibitors, were detected by enzyme-linked immunosorbent assay (ELISA) across different experimental groups. The experimental data were analyzed by Graphpad Prism 9 software. Results: DIA analysis identified 1 850 differential proteins, including 760 up-regulated proteins and 1 090 down-regulated proteins. Weighted correlation network analysis (WGCNA) correlation analysis of phenotypic data such as cell count and CT score with the results of genomics indemnified 575 proteins of MEBrown module which intersected with 35 kinases further screened from 1 850 differential proteins, yielding eight protein kinases: HCK, SYK, PDK2, FGR, PRKCB, ROR1, CAMK1 and GRK6. qPCR showed that the expression of HCK in CRSwNP was significantly higher than that in the control group (P<0.05). Further experiments in mice confirmed that the secretion of IgE, IL-4 and IL-5 in the serum of CRSwNP group was significantly higher than the control group (all P<0.05), indicating successful model establishment. The intervention of HCK significantly decreased the secretion of IgE, IL-4 and IL-5 in serum of mice (all P<0.05). Conclusion: The HCK inhibitor can reduce the inflammatory index of mice with CRSwNP, and HCK is a potential therapeutic target of CRSwNP.

Comparison of Efficacy and Safety of Different Second-line Therapies for Patients With Advanced Thymic Carcinoma.

AIMS: Thymic carcinoma (TC) is a rare form of highly invasive tumors. Currently, the standard first-line therapy involves paclitaxel plus carboplatin treatment, while the recommended regimen for second-line therapy remains uncertain. The purpose of this study is to explore the second-line mode of TC patients. MATERIALS AND METHODS: We evaluated the outcome of subjects with advanced TC between 2009 and 2023 in three medical centers, retrospectively. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Kaplan-Meier was used for calculating Progression-free survival (PFS) and overall survival (OS). The factors affecting survival in the real world were evaluated by Cox analysis. RESULTS: Totally 136 patients were included in this study, the median PFS (mPFS) for all subjects was 5.97 months, and the median OS (mOS) was 25.03 months. According to patient's treatment modes, they are divided into monotherapy (n = 95) and combination therapy (n = 41), PFS manifested the difference between two groups (5.17 vs. 9.00 months, P = 0.043). OS also indicated a significant distinction (22.50 vs. 38.00 months, P = 0.017). Furthermore, there was a significant difference in PFS between patients using immunotherapy combined with chemotherapy and those with antivascular therapy (8.57 vs. 13.10 months, P = 0.047). CONCLUSION: In the second-line therapy for advanced TC, the efficacy of combination therapy was better than monotherapy, especially for immunotherapy combined with antivascular therapy.

[Sensitivity of colorectal cancer organoids to hyperthermic intraperitoneal chemotherapy with lobaplatin].

Objective: To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy. Method: Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022. Organoids were cultured and tumor tissue were passaged. In vitro hyperthermic perfusion experiments were performed on organoids with good viability. Firstly, 10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations: 1 000, 250, 62.5, 15.6, 3.9, and 0.98 µmol/L. The organoids were exposed to oxaliplatin at 42℃ for 30 minutes and to lobaplatin at 42℃ for 60 minutes. Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated. Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids. This testing revealed oxaliplatin was effective at 579 µmol/L at a hyperthermic perfusion temperature of 42℃ for 30 min and lobaplatin was effective at 240 µmol/L at a hyperthermic perfusion temperature of 42℃ for 60 minutes. Result: Thirty-two tumor organoids were cultured from samples of colorectal cancer. The median concentration required for oxaliplatin to eliminate 50% of tumor cells (IC50) was 577.45 µmol/L (IQR: 1846.09 µmol/L). The median IC50 for lobaplatin was 85.04 µmol/L (IQR: 305.01 µmol/L).The difference between the two groups was not statistically significant (Z=1.784, P=0.084). In seven of 10 organoids, lobaplatin showed a greater IC50 after in vitro hyperthermic perfusion than did oxaliplatin. Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6% (95%CI: 32.1%‒47.0%), whereas the average rate of inhibition for lobaplatin was 89.7% (95%CI: 87.0%‒92.3%): this difference is statistically significant (t=‒15.282, P<0.001). Conclusion: The rate of inhibition achieved by hyperthermic perfusion of lobaplatin in vitro is better than that achieved by hyperthermic perfusion with oxaliplatin. Lobaplatin is more effective than oxaliplatin when administered by hyperthermic intraperitoneal perfusion and therefore has the potential to replace oxaliplatin in this setting.

[Interpretation of specification for service of cancer screening for workers].

As the backbone force of China's social and economic construction, the health status of workers is closely related to the nation's productivity and social development. Currently, cancers have become one of the major diseases threatening the health of workers. However, there are still many shortcomings in the cancer screening services for the workers. To standardize cancer screening services for workers, ensure the quality of screening services, and improve the overall screening effectiveness, 19 institutions, including Peking Union Medical College Hospital of the Chinese Academy of Medical Sciences, have jointly formulated the Group Standard "Specification for service of cancer screening for workers (T/CHAA 023-2023)". This standard follows the principles of "legality, scientific rigor, advancement, and feasibility" and combines the frontier scientific advances in cancer screening. It clarifies the relevant requirements for service principles, service design, service delivery, service management, service evaluation, and improving worker cancer screening. Implementing this group standard will help connect the common screening needs of workers, employers, and cancer screening service providers, standardize the screening process, improve screening quality, and ultimately increase the early diagnosis rate and survival rate of cancer patients. Consequently, this group standard will help safeguard workers' health rights and interests, ensure the labor force resources, promote the comprehensive coordinated and sustainable development of society, and contribute to realizing the "Healthy China 2030" strategic policy.

[Use of the ETV6/RUNX1 probe to verify the performance of the fluorescence in situ hybridization probe before clinical detection].

Objective: To explore the standardized performance of a FISH probe before clinical detection. Methods: The probe sensitivity and specificity of ETV6/RUNX1 were analyzed via interphase and metaphase FISH in 20 discarded healthy bone marrow samples. The threshold system of the probe was established using an inverse beta distribution, and an interpretation standard was established. Finally, a parallel-controlled polymerase chain reaction detection study was conducted on 286 bone marrow samples from patients at our hospital. The clinical sensitivity, specificity, and diagnostic coincidence rate of ETV6/RUNX1 FISH detection were analyzed, and the diagnostic consistency of the two methods was analyzed by the kappa test. Results: The probe sensitivity and specificity of the ETV6/RUNX1 probe were 98.47% and 100%, respectively. When 50, 100, and 200 cells were counted, the typical positive signal pattern cutoffs were 5.81%, 2.95%, and 1.49%, respectively, and the atypical positive signal pattern cutoffs were 13.98%, 9.75%, and 6.26%, respectively. The clinical sensitivity of FISH was 96.1%, clinical specificity was 99.6%, diagnostic coincidence rate was 99.00%, diagnostic consistency test kappa value was 0.964, and P value was <0.001. Conclusion: For FISH probes without a national medical device registration certificate, standardized performance verification and methodology performance verification can be performed using laboratory developed test verification standards to ensure a reliable and accurate reference basis for clinical diagnosis and treatment.

[Gemcitabine long-term maintenance chemotherapy benefits patients with survival: a multicenter, real-world study of advanced breast cancer treatment in China].

Objective: This study collected a real-world data on survival and efficacy of gemcitabine-containing therapy in advanced breast cancer. Aimed to find the main reasons of affecting the duration of gemcitabine-base therapy in advanced breast cancer patients. Methods: Advanced breast cancer patients who received gemcitabine-base therapy from January 2017 to January 2019 were enrolled(10 hospitals). The clinicopathological data, the number of chemotherapy cycles and the reasons for treatment termination were collected and analyzed. To identify the reasons related with continuous treatment for advanced breast cancer and the factors which affect the survival and efficacy. Results: A total of 224 patients with advanced breast cancer were enrolled in this study, with a median age of 52 years (26-77 years), 55.4%(124/224) was postmenopausal. Luminal type were 83 cases, TNBC were 97 cases, and human epidermal growth factor receptor 2 (HER's-2) overexpression were 44. At the analysis, 224 patients who received the gemcitabine-based regimens were evaluated, included 5 complete reponse (CR), 77 partial response (PR), 112 stable disease (SD) and 27 progressive disease (PD). The objective response rate (ORR) was 36.6%(82/224). Seventy patients had serious adverse diseases, including leukopenia (9), neutrophilia (49), thrombocytopenia (15), and elevated transaminase (2). The median follow-up time was 41 months (26~61 months), and the median PFS was 5.6 months. The reasons of termination treatment were listed: disease progression were 90 patients; personal reasons were 51 patients; adverse drug reactions were 18 patients; completed treatment were 65 patients. It was found that progression-free survival (PFS) was significantly longer in patients receiving >6 cycles than that in patients with ≤6 cycles (8.2 months vs 5.4 months, HR=2.474, 95% CI: 1.730-3.538, P＜0.001). Conclusions: Gemcitabine-based regimen is generally well tolerated in the Chinese population and has relatively ideal clinical efficacy in the real world. The median PFS is significantly prolonged when the number of treatment cycles are appropriately increased.

Early-life risk factors, accelerated biological aging and the late-life risk of mortality and morbidity.

BACKGROUND: Early-life exposure increases health risks throughout an individual's lifetime. Biological aging is influenced by early-life risks as a key process of disease development, but whether early-life risks could accelerate biological aging and elevate late-life mortality and morbidity risks remains unknown. Knowledge is also limited on the potential moderating role of healthy lifestyle. METHODS: We investigate associations of three early-life risks around birth, breastfeeding, maternal smoking and birth weight, with biological aging of 202 580 UK Biobank participants (54.9 ± 8.1 years old). Biological aging was quantified as KDM-BA, PhenoAge and frailty. Moderate alcohol intake, no current smoking, healthy diet, BMI <30 kg/m2 and regular physical activity were considered as healthy lifestyles. Mortality and morbidity data were retrieved from health records. RESULTS: Individual early-life risk factors were robustly associated with accelerated biological aging. A one-unit increase in the 'early-life risk score' integrating the three factors was associated with 0.060 (SE=0.0019) and 0.036-unit (SE = 0.0027) increase in z-scored KDM-BA acceleration and PhenoAge acceleration, respectively, and with 22.3% higher odds (95% CI: 1.185-1.262) of frailty. Increased chronological age and healthy lifestyles could mitigate the accelerations of KDM-BA and PhenoAge, respectively. Associations of early-life risk score with late-life mortality and morbidity were mediated by biological aging (proportions: 5.66-43.12%). KDM-BA and PhenoAge accelerations could significantly mediate the impact on most outcomes except anxiety, and frailty could not mediate the impact on T2D. CONCLUSION: Biological aging could capture and mediate the late-life health risks stemming from the early-life risks, and could be potentially targeted for healthy longevity promotion.

Causal relationship between cigarette smoking behaviors and the risk of hernias: a Mendelian randomization study.

PURPOSE: As the global population continues to age, there is a noticeable yearly rise in the incidence of hernias. Simultaneously, smoking, a widespread addictive behavior and a significant contributor to mortality, has evolved into a pervasive public health concern. Existing literature has already established a connection between smoking and an increased risk of postoperative recurrence and postoperative infections following hernia surgery. However, there remains a dearth of research exploring the association between smoking and hernia morbidity. In this study, our objective is to systematically evaluate the causal relationship between cigarette smoking behaviors and hernia morbidity using a Mendelian randomization (MR) approach. METHODS: Hernia-related data were sourced from the FinnGen Biobank database, while cigarette smoking behavior data were gathered from the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. To assess the causal relationship, we employed five methods: the weighted median, the weighted mode the inverse variance weighted (IVW), MR-Egger, and the simple mode. Sensitivity analysis was conducted, incorporating Cochran's Q test, the MR-Egger intercept test, leave-one-out analysis, and funnel plot. The presentation of the causal relationship is expressed as an odds ratio (OR) along with their corresponding 95% confidence intervals (CI). RESULTS: Employing the IVW method as the reference standard, we found that smoking intensity is associated with an increased risk of diaphragmatic hernia (OR = 1.21, 95% CI 1.00-1.46, P = 0.047). These consistent findings were further corroborated by the weighted median and weighted mode methods (OR = 1.26, 95% CI 1.03-1.54, P = 0.026; OR = 1.25, 95% CI 1.02-1.52, P = 0.045). Conversely, when applying the IVW method, we identified no statistically significant causal relationship between smoking age, smoking initiation status, smoking cessation status, and the incidence of hernia. CONCLUSIONS: Our MR study has uncovered genetic evidence linking smoking intensity and the occurrence of diaphragmatic hernia. The risk of developing diaphragmatic hernia rises in tandem with the intensity of smoking. This emphasizes the crucial role of regularly advising patients to cease smoking in clinical settings.

[Intervention effect of apocynin on silicosis induced by silica in rats].

Objective: To investigate the intervention effect and its mechanism of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) on silicosis induced by silica (SiO(2)) in rats. Methods: In October 2021, 24 SPF SD male rats were divided into control group, silicosis model group and apocynin intervention group according to random number table method, with 8 rats in each group. SiO(2) was exposed by one-time intratracheal instillation. The rats in the apocynin intervention group were intraperitoneally injected with apocynin 50 mg/kg, 3 times a week, on the second day after treatment. The rats were sacrificed 28 days later, and lung coefficients were calculated after lung tissues were weighed. Hematoxylin-eosin staining and Masson staining were used to observe the lung histopathological changes in each group, respectively. The levels of NOX, reactive oxygen species (ROS), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in lung tissue were detected. The expressions of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). The level of hydroxyproline (HYP) was detected by alkaline hydrolysate. The expressions of transforming growth factor beta 1 (TGF-ß1), E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) in lung tissue were detected by Western blotting. Results: Compared with the control group, the body weight of silicosis model group was decreased, the lung tissue showed obvious inflammatory infiltration and fibrosis, and the levels of lung coefficient, IL-1ß, IL-6, TNF-α and TGF-ß1 were significantly increased (P<0.05). Compared with the silicosis model group, the lung tissue injury in the apocynin intervention group was significantly improved, the lung coefficient, NOX, ROS, MDA, IL-1ß, IL-6, TNF-α and TGF-ß1 levels were decreased, and the activity of GSH-Px was increased (P<0.05). Compared with the silicosis model group, the expressions of HYP and α-SMA were decreased and the level of E-cad was increased in the apocynin intervention group (P<0.05) . Conclusion: Apocynin may alleviate SiO(2)-induced fibrosis in silicosis rats by reducing oxidative stress, the release of inflammatory factors and inhibiting the process of epithelial-mesenchymal transition.

[Role of blood markers in predicting the failure of prosthesis removal and antibiotic-loaded bone cement spacer implantation for treatment of periprosthetic joint infection].

Objective: To investigate the value of inflammation,coagulation and nutrition markers in predicting the failure of prosthesis removal and antibiotic-loaded bone cement spacer implantation for treatment of periprosthetic joint infection(PJI). Methods: A retrospective study was conducted on 70 patients who undertook prosthesis removal and antibiotic-loaded bone cement spacer implantation due to PJI from June 2016 to October 2020 in the Department of Orthopedics,Henan Provincial People's Hospital. There were 28 males and 42 females,aged (65.5±11.9) years (range: 37 to 88 years). Patients were divided into two groups as the successful group and the failed group depended on whether reinfection occurred after prosthesis removal and antibiotic-loaded bone cement spacer implantation at the last follow up. Patient demographics,laboratory values (C-reactive protein (CRP),erythrocyte sedimentation rate (ESR),ESR and CRP ratio (ESR/CRP),white blood cell count(WBC),platelet count(PLT),hemoglobin(HB),total lymphocyte count(TLC),albumin、fibrinogen(FIB),CRP and albumin ratio (CAR),prognostic nutritional index(PNI)),and reinfection rates were assessed. Comparison between groups was conducted by the independent sample t test or χ2test. Receiver operating characteristic (ROC) curve was plotted,and the area under the curve (AUC),optimal diagnostic threshold,sensitivity,and specificity were analyzed to predict the failure of prosthesis removal and antibiotic-loaded bone cement spacer implantation. Results: All patients were followed up for at least two years,and the follow-up time was (38.4±15.2) months (range: 24 to 66 months). Fifteen patients suffered failure after prosthesis removal and antibiotic-loaded bone cement spacer implantation,while the other 55 patients succeeded. The overall failure rate of prosthesis removal and antibiotic-loaded bone cement spacer implantation in PJI treatment was 21.4%. Level of preoperative CRP ((35.9±16.2)mg/L),PLT ((280.0±104.0)×109/L) and CAR (1.3±0.8) in successful group were lower than CRP ((71.7±47.3)mg/L),PLT ((364.7±119.3)×109/L) and CAR (2.5±2.0) in failed group (all P<0.05).Whereas,level of preoperative ESR/CRP (3.3±3.1), Albumin ((35.3±5.2)g/L) and PNI (43.6±6.2) in successful group were higher than ESR/CRP (1.6±1.4),Albumin ((31.3±4.8)g/L) and PNI (39.2±15.1) in failed group (all P<0.05). AUC of ROC curve,optimal threshold value,sensitivity and specificity of CRP,ESR/CRP, PLT, Albumin,CAR and PNI for the predicting failure of prosthesis removal and antibiotic-loaded bone cement spacer implantation were 0.776(95%CI:0.660 to 0.867),35.4 mg/L,86.7%,67.3%;0.725(95%CI:0.605 to 0.825),1.0,60.0%,78.2%;0.713(95%CI:0.593 to 0.815),253,93.3%,47.3%;0.721(95%CI:0.601 to 0.822),35.7,93.3%,49.1%;0.772(95%CI:0.656 to 0.863),1.1,86.7%,67.3%;0.706(95%CI:0.585 to 0.809),45.7,100%,41.8% respectively. Conclusion: In patients with PJI,CRP>35.4,ESR/CRP≤1.0 and CAR>1.1 could predict the failure of prosthesis removal and antibiotic-loaded bone cement spacer implantation.

[Genomics of next generation sequencing in pediatric B-acute lymphoblastic leukemia and its impact on minimal residual disease].

Objective: To describe the gene mutation profile of newly diagnosed pediatric B-acute lymphoblastic leukemia (B-ALL) and analyze its effect on minimal residual disease (MRD). Methods: A total of 506 newly diagnosed B-ALL children treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from September 2018 to July 2021 were enrolled in this retrospective cohort study. The enrolled children were divided into MRD ≥1.00% group and <1.00% group according to MRD results on the 19th day since chemotherapy, and MRD ≥0.01% group and <0.01% group according to MRD results on the 46th day. Clinical characteristics and gene mutations of two groups were compared. Comparisons between groups were performed with chi-square test or Fisher's exact test. Independent risk factors of MRD results on the 19th day and the 46th day were analyzed by Logistic regression model. Results: Among all 506 patients, there were 318 males and 188 females. On the 19th day, there were 114 patients in the MRD ≥1.00% group and 392 patients in the MRD <1.00% group. On the 46th day, there were 76 patients in the MRD ≥0.01% group and 430 patients in the MRD <0.01% group. A total of 187 gene mutations were detected in 487 (96.2%) of 506 children. The most common gene mutations were signal transduction-related KRAS gene mutations in 111 cases (22.8%) and NRAS gene mutations in 99 cases (20.3%). Multivariate analysis showed that PTPN11 (OR=1.92, 95%CI 1.00-3.63), KMT2A (OR=3.51, 95%CI 1.07-11.50) gene mutations and TEL-AML1 (OR=0.48, 95%CI 0.27-0.87), BCR-ABL1 (OR=0.27, 95%CI 0.08-0.92) fusion genes and age >10 years (OR=1.91, 95%CI 1.12-3.24) were independent influencing factors for MRD ≥1.00% on the 19th day. BCORL1 (OR=2.96, 95%CI 1.18-7.44), JAK2 (OR=2.99, 95%CI 1.07-8.42) and JAK3 (OR=4.83, 95%CI 1.50-15.60) gene mutations and TEL-AML1 (OR=0.43, 95%CI 0.21-0.87) fusion gene were independent influencing factors for MRD ≥0.01% on the 46th day. Conclusions: Children with B-ALL are prone to genetic mutations, with abnormalities in the RAS signaling pathway being the most common. Signal transduction related PTPN11, JAK2 and JAK3 gene mutations, epigenetic related KMT2A gene mutation and transcription factor related BCORL1 gene mutation are independent risk factors for MRD.

Wide surgical margins improve prognosis for HCC with microvascular invasion.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the sixth leading cause of malignant tumors worldwide. Liver resection is a pivotal treatment modality for HCC. Surgical margin plays an important role in decreasing recurrence and improving prognosis for HCC patients. MATERIALS AND METHODS: This paper aimed to perform a systematic review of the literature in regard to surgical margin in HCC patients with microvascular invasion (MVI). RESULTS: Residual MVI due to insufficient surgical margins is the main origin of postoperative recurrence and metastasis in HCC patients. A wide surgical margin (WSM) significantly improves oncological outcomes and long-term survival in HCC patients with MVI. Progress in the preoperative prediction of MVI may contribute to precise surgical decision-making in the future. CONCLUSIONS: WSM was associated with better outcomes in HCC patients with MVI. WSM is recommended for well-preserved liver function HCC patients who are predicted to have a high risk of MVI preoperatively.

[Genetic characteristics and survival analysis of 27 cases of juvenile myelomonocytic leukemia].

Objective: To investigate the genetic and genomic profiling of juvenile myelomonocytic leukemia (JMML) and factors affecting its survival rate. Methods: Clinical characteristics, cytogenetics, molecular biology results and survival status of children with 27 JMML cases admitted to the Hematology Department of Children's Hospital, Capital Institute of Pediatrics from December 2012 to December 2021 were analyzed retrospectively, and the outcomes of the children were followed up. Kaplan-Meier method was used for survival analysis. Univariate analysis was used for analyzing factors affecting the overall survival (OS) rates of patients who received hematopoietic stem cell transplantation (HSCT). Log-Rank test was used for comparison of survival curves. Results: Among 27 JMML cases, there were 11 males and 16 females. The age of disease onset was 28 (11,52) months. There are 20 cases of normal karyotype, 4 cases of monosomy 7, 1 case of trisomy 8,1 case of 11q23 rearrangement and 1 case of complex karyotype. A total of 39 somatic mutations were detected.Those involved in RAS signal pathway were the highest (64%(25/39)), among which PTPN11 mutation was the most frequent (44% (11/25)). A total of 17 cases (63%) received HSCT, 8 cases (30%) did not receive HSCT, and 2 cases (7%) lost follow-up. For children receiving transplantation, the follow-up time after transplantation was 47 (11,57) months. The 1-year OS rate of high-risk transplantation group (17 cases) and high-risk non transplantation group (6 cases) was (88±8)% and (50±20)% respectively, with a statistically significant difference (χ2=5.01, P=0.025). The 5-year OS rate of the high-risk transplantation group was (75±11)%. The survival time of those who relapsed or progressed to acute myeloid leukemia after transplantation was significantly shorter than that of those who did not relapse (χ2=6.80, P=0.009). The OS rate of patients with or without PTPN11 mutation was (81±12) % and (67±19)% respectively (χ2=0.85, P=0.356). Conclusions: The main pathogenesis involved in JMML is gene mutation related to RAS signaling pathway, and the most common driver gene of mutation is PTPN11. Allogeneic HSCT can significantly improve the survival rate of high-risk JMML patients. The recurrence or progression after transplantation was related to poor prognosis.

[Study on reproductive toxicity of nano-cadmium sulfide with different particle sizes on male mice].

Objective: To investigate the reproductive toxicity of cadmium sulfide nanoparticles (Nano-CdS) with different particle sizes on male mice. Methods: In January 2019, 30 SPF grade male mice were randomly divided into a control group, an experimental group[CdS Ⅰ group (particle size approximately 5 nm), and a CdS Ⅱ group (particle size approximately 50 nm) ], with 10 mice in each group. The experimental group was orally gavaged with 100 mg/kg, once a day, while the control group was gavaged with an equal volume of physiological saline for 45 consecutive days. After 45 days, levels of cadmium accumulation in testis were determined directly by AAS, deformity and testicular histopathological changes were also observed. Serum testosterone levels were measured by enzyme-linked immunosorbentassay (ELISA), expression levels of P450scc, 17ß-HSD and P450c17 mRNA were determined by real-time PCR. P450c17 protein was determinated by Western Blot. Results: The histopathological results showed that the testes of the experimental group mice showed varying degrees of damage; Ultrastructural observation showed that the ultrastructure of mouse testicular cells in each experimental group showed varying degrees of mitochondrial expansion and disappearance of cristae, as well as irregular nuclear membranes. The degree of damage in CdS Ⅰ group was milder than that in CdS Ⅱ group. Compared with the control group, the cadmium content in the testes of the CdS Ⅰ and CdS Ⅱ groups significantly increased (P=0.001, 0.001), and the CdS Ⅱ group was higher than the CdS Ⅰ group (P=0.001). Compared with the control group, the levels of testosterone in the CdS Ⅰ and CdS Ⅱ groups decreased with statistical significance (P=0.001, 0.001). Real time fluorescence quantitative PCR results showed that compared with the control group, the experimental group's P450scc, 17ß-HSD. The expression levels of 17ß-HSD and P450c17 mRNA were significantly reduced, with statistically significant differences (P=0.001, 0.001, 0.001), and CdS Ⅱ group 17ß-HSD. The expression levels of 17ß-HSD and P450c17 mRNA were significantly lower than those of CdS Ⅰ group (P=0.001, 0.036). The Western Blot assay results showed that the expression levels of P450c17 protein in the testes of CdS Ⅰ and CdS Ⅱ groups of mice were significantly reduced, with statistical significance (P=0.001, 0.001) ; And the CdS Ⅱ group was significantly lower than the CdS Ⅰ group (P=0.001). According to Spearman correlation analysis, testosterone levels are correlated with P450scc, P450c17, 17ß-HSD mRNA. There is a highly positive correlation between 17ß-HSD mRNA levels, with statistically significant differences (r(s)=0.88, 0.80, 0.70, P=0.001, 0.001, 0.004) . Conclusion: Nano cadmium sulfide may induce reproductive toxicity by reducing the expression levels of key enzyme genes and enzyme protein activity in testosterone and its synthesis in mice, and the CdS Ⅱ group has a stronger toxic effect.

The Burden of Colorectal Cancer Attributable to Diet Low in Fiber from 1990 to 2019: A Global, Regional and National Analysis.

OBJECTIVES: The colorectal cancer (CRC) burden is increasingly high. The aim of this study was to investigate temporal and geographical trends in CRC deaths and disability-adjusted life-years (DALYs) attributable to diet low in fiber globally from 1990 to 2019. DESIGN: Cross-sectional study. SETTING: The study based on the Global Burden of Disease Study (GBD) 2019. PARTICIPANTS: The population comprised individuals from 204 countries and territories who were diagnosed with CRC attributable to diet low in fiber from 1990 to 2019. MEASUREMENTS: Deaths, DALYs, age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR) for CRC attributable to diet low in fiber were described, and estimated annual percentage change (EAPC) was further calculated to assess the burden in different regions, countries, sexes, and age groups. Additionally, we explored the association between EAPC and ASMR/ASDR (in 1990) and Human Development Index (HDI, in 2019). RESULTS: From 1990 to 2019, global ASMR and ASDR for CRC attributable to diet low in fiber decreased slightly, but the corresponding deaths and DALYs increased by 63.37% and 51.36%, respectively. Those burden varied considerably between regions and countries. The burden was higher in high, high-middle and middle SDI regions, especially in Asia and Western Europe, but when HDI > 0.7, an increasingly rapid decline in ASMR and ASDR was revealed. Unexpectedly, many less well-developed countries within the traditionally low deaths and DALYs regions of Africa, Central Latin America, and Middle East showed gradual increases in ASMR and ASDR. CONCLUSION: The global burden of CRC attributable to diet low in fiber has decreased over the last 30 years, but remains at a high level. It is essential for decision-makers to take targeted measures for improving population awareness and intake of dietary fiber.

PRC1 plays an important role in lung adenocarcinoma and is potentially targeted by fostamatinib.

OBJECTIVE: Lung adenocarcinoma (LUAD) is one of the most common cancers in the world. Protein regulator of cytokinesis 1 (PRC1) plays a role in the tumorigenesis and development of several cancers, including LUAD. The aim of the present study is to assess the characteristics of PRC1 in LUAD in order to find a potential drug that targets PRC1. MATERIALS AND METHODS: We investigated the prognostic value of PRC1 in patients with LUAD using Cox analysis of the RNA sequencing data from The Cancer Genome Atlas (TCGA) portal. A link between PRC1 and LUAD progression, cigarette smoking mutation count, aneuploidy, and hypoxia scores was assessed. The relationship between PRC1 and tumor-infiltrating immune cells in LUAD was analyzed and Gene Set Enrichment Analysis (GSEA) was used to study the PRC1-related biological process and signal pathways. Potential drugs targeting PRC1 were identified using DrugBank database and molecular docking. RESULTS: PRC1 expression was significantly increased in LUAD. PRC1 could be, therefore, a prognostic biomarker for predicting overall survival in LUAD. PRC1 expression was also related to cancer stage and patient's smoking history. PRC1 positively correlated with mutation count, aneuploidy and hypoxia scores. It was also significantly related to tumor-infiltrating immune cells, especially the activated mast cells. GSEA revealed that PRC1 might be correlated with cell cycle, cytokinesis and p53 signaling pathway. Additionally, fostamatinib was found to be a potential drug targeting PRC1. CONCLUSIONS: PRC1 may have a prognostic value for patients with LUAD, and be correlated with the mutation count, aneuploidy, hypoxia and tumor-infiltrating immune cells. Fostamatinib was found to be a potential drug targeting PRC1 in LUAD.

[Improved Mayo Endoscopic Score has a higher value for evaluating clinical severity of ulcerative colitis].

OBJECTIVE: To assess the value of Improved Mayo Endoscopic Score (IMES) for evaluation of the clinical severity of ulcerative colitis (UC). METHODS: We retrospectively analyzed the clinical and endoscopic data of 167 patients diagnosed with UC in Beijing Tsinghua Changgung Hospital from January, 2015 to November, 2021. The severity of endoscopic lesions was determined by Mayo Endoscopic Score (MES, 0-3 points) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score (0-8 points), and the scope of endoscopic lesions was evaluated based on the Montreal classification system. The IMES was established by combining the MES with the Montreal classification. RESULTS: The IMSE showed stronger correlations with modified Truelove and Witts Disease Severity, Mayo score and partial Mayo score (r=0.712, 0.784, and 0.703, respectively) than MES (r=0.642, 0.754, and 0.604, respectively), Montreal classification (r=0.598, 0.628, and 0.603, respectively) and UCEIS (r= 0.670, 0.767, and 0.677, respectively). ROC curve analysis showed that IMES was superior to MES, Montreal and UCEIS in diagnosis of severe and moderate- to-severe UC. IMES also showed stronger correlations with the laboratory indicators including CRP (r=0.583), WBC (r=0.235), HB (r=-0.280), PLT (r=0.352), ALB (r=-0.396) and ESR (r=0.471) than MES and Montreal classification. An IMES score of 5 was of greater value than a MES score of 3, E3, and UCEIS≥6 for predicting the administration of systemic hormones, immunosuppressants, or surgery in the near future. CONCLUSION: IMES can better reflect the clinical severity of UC and has good correlations with the laboratory indicators of the patients.

[Juglone induces proliferation inhibition and apoptosis of cervical cancer cells via promoting c-Myc ubiquitination].

OBJECTIVE: To observe the expression of c-Myc protein in cervical cancer HeLa cells and explore the effect of juglone on the proliferation and apoptosis of HeLa cells by affecting c-Myc ubiquitination. METHODS: HeLa cells treated with different concentrations (0, 10, 20, or 50 µmol/L) of juglone or with 20 µmol/L juglone for different time lengths were examined for expression of c-Myc protein with Western blotting. The half-life of c-Myc protein was determined using cycloheximide (CHX) and c-Myc protein degradation was detected using coimmunoprecipitation. We also assessed the effects of 20 µmol/L juglone combined with 0, 1.0 or 2.0 µmol/L MG132 (a proteasome inhibitor) on c-Myc expression. The effects of 20 µmol/L juglone on the proliferation and apoptosis of HeLa cells with RNA interference-mediated knockdown of c-Myc were evaluated with MTT assay and flow cytometry. RESULTS: Treatment with juglone significantly lowered c-Myc protein expression in HeLa cells in a concentration-and time-dependent manner (P < 0.05). Juglone obviously shortened the half-life of c-Myc protein, and the addition of MG132 significantly up-regulated the expression level of c-Myc protein (P < 0.05). Juglone treatment also promoted ubiquitination of c-Myc protein in HeLa cells. Compared with the cells transfected with a negative control construct, the cells transfected with si-c-Myc showed significantly decreased proliferation inhibition and a lowered cell rate with early apoptosis after juglone treatment (P < 0.05). CONCLUSION: Juglone inhibits proliferation and promotes apoptosis of HeLa cells by affecting the ubiquitination of c-Myc protein.