Objective To construct a nonparametric proportional hazards (PH) model for mixed informative interval-censored failure time data for predicting the risks in heart transplantation surgeries. Methods Based on the complexity of mixed informative interval-censored failure time data, we considered the interdependent relationship between failure time process and observation time process, constructed a nonparametric proportional hazards (PH) model to describe the nonlinear relationship between the risk factors and heart transplant surgery risks and proposed a two-step sieve estimation maximum likelihood algorithm. An estimation equation was established to estimate frailty variables using the observation process model. I-spline and B-spline were used to approximate the unknown baseline hazard function and nonparametric function, respectively, to obtain the working likelihood function in the sieve space. The partial derivative of the model parameters was used to obtain the scoring equation. The maximum likelihood estimation of the parameters was obtained by solving the scoring equation, and a function curve of the impact of risk factors on the risk of heart transplantation surgery was drawn. Results Simulation experiment suggested that the estimated values obtained by the proposed method were consistent and asymptotically effective under various settings with good fitting effects. Analysis of heart transplant surgery data showed that the donor's age had a positive linear relationship with the surgical risk. The impact of the recipient's age at disease onset increased at first and then stabilized, but increased against at an older age. The donor-recipient age difference had a positive linear relationship with the surgical risk of heart transplantation. Conclusion The nonparametric PH model established in this study can be used for predicting the risks in heart transplantation surgery and exploring the functional relationship between the surgery risks and the risk factors.

Objective To construct a nonparametric proportional hazards (PH) model for mixed informative interval-censored failure time data for predicting the risks in heart transplantation surgeries. Methods Based on the complexity of mixed informative interval-censored failure time data, we considered the interdependent relationship between failure time process and observation time process, constructed a nonparametric proportional hazards (PH) model to describe the nonlinear relationship between the risk factors and heart transplant surgery risks and proposed a two-step sieve estimation maximum likelihood algorithm. An estimation equation was established to estimate frailty variables using the observation process model. I-spline and B-spline were used to approximate the unknown baseline hazard function and nonparametric function, respectively, to obtain the working likelihood function in the sieve space. The partial derivative of the model parameters was used to obtain the scoring equation. The maximum likelihood estimation of the parameters was obtained by solving the scoring equation, and a function curve of the impact of risk factors on the risk of heart transplantation surgery was drawn. Results Simulation experiment suggested that the estimated values obtained by the proposed method were consistent and asymptotically effective under various settings with good fitting effects. Analysis of heart transplant surgery data showed that the donor's age had a positive linear relationship with the surgical risk. The impact of the recipient's age at disease onset increased at first and then stabilized, but increased against at an older age. The donor-recipient age difference had a positive linear relationship with the surgical risk of heart transplantation. Conclusion The nonparametric PH model established in this study can be used for predicting the risks in heart transplantation surgery and exploring the functional relationship between the surgery risks and the risk factors.

Objective To compare and analyze the differences between customized models and commercial universal models in the segmentation of organs-at-risk in cervical cancer,and to investigate the feasibility of customized models.Methods A retrospective analysis was conducted on 270 cervical cancer patients.Senior clinicians manually delineated organs-at-risk,including the bladder,rectum,small intestine,pelvic bone marrow,femoral heads,and kidneys.The cases were randomly selected to develop customized models,with 202 cases allocated to the training set,38 cases to the test set,and 30 cases to the validation set.The universal and customized models were used for segmentation on the test set,and the automatic segmentation results obtained by the two models were compared with manual segmentation results to assess the performance of the customized model.Results Both customized model and universal model had comparable DSC values to manual segmentation,demonstrating satisfactory delineation outcomes(DSC values ranging from 0.7 to 0.9).However,in terms of deviation of centroid and 95％Hausdorff distance,the customized model surpassed the universal model.Conclusion Compared with the universal model,the customized model offers superior accuracy in delineating the structures of organs-at-risk in cervical cancer.As the customized model is optimized based on specific datasets,it provides precise support for clinical decision-making and holds promising applications in the treatment of cervical cancer.

METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on stemness maintenance of mouse embryonic stem cell (mESC). While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-independent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification. Mechanistically, METTL14, but not METTL3, binds H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression. The effects of METTL14 on regulation of H3K27me3 is essential for the transition from self-renewal to differentiation of mESCs. This work reveals a regulatory mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance, and differentiation of mESCs.
Animals ; Mice ; Methylation ; Chromatin ; Histones/metabolism* ; RNA, Messenger/genetics* ; Methyltransferases/metabolism* ; RNA/metabolism*

Objective:To evaluate the clinical efficacy of C-type endoscopic submucosal dissection (C-ESD) for rectal neuroendocrine tumors (NEN).Methods:The retrospective analysis was performed on data of 55 patients who underwent ESD for rectal NEN at the Department of Endoscopy in Quanzhou First Hospital from January 2018 to July 2021. Patients were divided into the C-ESD group ( n=28) and the conventional ESD group ( n=27). The dissection time, the dissection speed, the number of submucosal injections, the enbloc resection rate, the curative resection rate and the rate of postoperative complications of the two groups were compared. Results:There were no statistically significant differences in basic information between the two groups ( P>0.05). The dissection time was 13.8±4.2 min in the C-ESD group and 19.9±3.9 min in the conventional ESD group with statistically significant difference ( t=5.649, P<0.001). The dissection speed in the C-ESD group was 0.08±0.04 cm 2/min, which was faster than 0.06±0.04 cm 2/min in the conventional ESD group ( t=2.218, P=0.031). The number of submucosal injections in the C-ESD group was less than that in the conventional ESD group [2 (1, 2) VS 3 (2, 3), Z=-8.701, P<0.001]. The lesions were enbloc resected in both groups. The curative resection rate in the C-ESD group was 100.0% (28/28) and 88.9% (24/27) in the conventional ESD group with statistically significant difference ( P=0.011). There were 7 cases of postoperative complications in the conventional ESD group, including 1 delayed bleeding, 5 delayed perforation and 1 muscularis propria injury, while no postoperative complications occurred in the C-ESD group ( P=0.004). Conclusion:C-ESD is a safe and effective treatment strategy for colorectal NEN, which can shorten the dissection time, improve the dissection speed, reduce the number of submucosal injections, improve the curative resection rate, and reduce complications.

The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.

ObjectiveTo investigate the status of self-management in patients with spinal cord injury and the related factors. MethodsFrom May, 2020 to February, 2021, 255 patients from a spinal cord injury club were enrolled, and investigated with the general information questionnaire, self-management ability scale, Chronic Disease Self-efficacy Scale through internet. Multiple linear stepwise regression was used to explore the related factors. ResultsThe scores of disease symptom management, daily life management, intermittent catheterization behavior management, emotional management and social return were (40.458±9.122), (33.945±6.800), (36.709±8.736) and (25.011±4.932), respectively. The average score for the single question of daily life management was the highest (3.772±0.755), while emotional management and social return was the lowest (3.573±0.705). Duration of intermittent catheterization, family members' attitude, self-efficacy and occupation were the related factors of symptom management (R² = 0.135, F = 7.744, P < 0.001). Self-efficacy, duration of intermittent catheterization, use of hydrophilic coated catheters and complications were the related factors of daily life management (R² = 0.173, F = 13.042, P < 0.001). Self-efficacy, duration of intermittent catheterization, use of hydrophilic coated catheters and medical insurance were the related factors of intermittent catheterization behavior management (R² = 0.141, F = 10.259, P < 0.001). Self-efficacy, duration of intermittent catheterization, complications and frequency of intermittent catheter in the last week were the related factors of emotional management and social regression dimensions (R² = 0.282, F = 19.590, P < 0.001). ConclusionThe self-management of patients with spinal cord injury by clean intermittent catheterization is at medium level. Moreover, it may be affected by many factors. Some of them can be targets of intervention.

Objective:To verify the efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis.Methods:In this randomized, double-blinded, placebo-controlled trial, 262 postmenopausal women were enrolled. Patients were randomized to receive daily oral minodronate 1 mg with supplements of 500 mg calcium and 200 U vitamin D 3 ( n=130) or placebo ( n=132) with daily supplements of 500 mg calcium and 200 U vitamin D 3, for 48 weeks. The primary endpoint was the average bone mineral density (BMD) change in the lumbar vertebrae 48 weeks post-treatment. Secondary outcome measures was the incidence of vertebral fractures. Safety assessments included the rate of adverse events. Results:At the end of 48 weeks treatment, the average BMD change rate from baseline were: full analysis set results: (3.52±4.82)% in the minodronate group and (2.00±5.74)% in the placebo group; per-protocol set results: (3.99±5.05)% in the minodronate group and (2.07±6.20)% in the placebo group; the differences were all significant (all P<0.05). Vertebral fracture occured in 3 patients (2.3%, 3/132) in the placebo group, and 1 case (0.8%, 1/130) in the minodronate group ( P>0.05). The incidence of adverse events was 71.5% (93/130) in the minodronate group and 78.0% (103/132) in the placebo group ( P>0.05). Conclusion:Minodronate is effective and safe in the treatment of postmenopausal osteoporosis without severe side effects.

Objective:To study the predictive value of superb microvascular imaging(SMI) in evaluating therapeutic efficacy of hepatic cancer treated by percutaneous radiofrequency ablation(PRFA).Methods:From Feb 2017 to Feb 2018, 55 patients (male: 31, female: 24, age range: 37-68 years, mean age: 56years) with 72 hepatic carcinoma lesions (length: 21.3-45.6 mm, average: 31.2 mm) were detected by SMI and contrast-enhanced CT(CECT)before PRFA. One month after treatment, more than two imaging examinations (CECT, CEMR, ultrasonic imaging) were used as the "gold standard" to evaluate the complete ablation rates. Consistency between the SMI grading and the arterial phase enhancement of CECT was analyzed by the Kappa-test.Results:Before PRFA, SMI showed 12 lesions (16.7%) to be in grade Ⅰ, 28 lesions (38.9%) in grade Ⅱ and 32 lesions (44.4%) in grade Ⅲ. The arterial phase of CECT showed 37 lesions (51.4%) to have no obvious enhancement and 35 lesions (48.6%) to have obvious enhancement. Consistency analysis showed that there was a high consistency between SMI and CECT(Kappa=0.861, P<0.001). The higher the SMI grading, the more obvious the enhancement on CECT. The complete ablation rates of the grade Ⅰ, grade Ⅱ and grade Ⅲ lesions were 100%(12/12), 92.9%(26/28) and 71.9%(23/32), respectively. The complete ablation rate of the lesions in grade Ⅲ was significantly lower than that in grade Ⅰ and grade Ⅱ (both P<0.05). Conclusion:SMI showed a good consistency with CECT in evaluating the blood flow signals of hepatic cancer, SMI grading could be used in predicting the therapeutic efficacy of hepatic cancer treated by PRFA.

【Objective】 To explore the application value of preoperative gastroscopic carbon nanoparticles labeling in patients undergoing laparoscopic radical gastric cancer surgery. 【Methods】 We included cases of laparoscopic radical gastric cancer surgery at The First Affiliated Hospital of Xi’an Jiaotong University from January 2017 to December 2019. Some cases received submucosal injection of carbon nanoparticles under the gastroscope before surgery. The effects of carbon nanoparticles labeling on the number of lymph nodes detected， operation duration and surgical complications were compared and analyzed. 【Results】 A total of 397 patients undergoing laparoscopic radical gastric cancer surgery were enrolled. Among them， 78 cases underwent gastroscopic carbon nanoparticles tracer labeling before operation. No complications were observed. The total number of lymph nodes detected by pathology after surgery in the carbon nanoparticles group significantly increased ［（22.0（4.0） vs. 22.0（3.0）， P=0.033）］ while the operation time significantly reduced ［（185.0±37.48）min vs. （213.4±23.66）min， P<0.001］ compared with those in the control group. New gastric cancer lesions were revealed by gastroscopy in three cases （3.8%） of carbon nanoparticles labeling， and the original planned operation method was changed in two cases （2.6%）. 【Conclusion】 Preoperative endoscopic carbon nanoparticles tracer labeling can not only help shorten the time of laparoscopic radical surgery for gastric cancer and increase the number of total lymph nodes detected for more accurate TNM staging， but also provide an opportunity for the discovery of synchronous multiple gastric cancer.