Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.
Animals ; Humans ; Mice ; Lymphatic Metastasis/pathology* ; Disease Models, Animal ; Cell Line, Tumor

Objective:To evaluate the effectiveness and safety of treatment with Burosumab in pediatric X-linked hypophosphatemia (XLH) patients.Methods:In this retrospective case study, 4 children with pediatric XLH, who were treated with Burosumab in Beijing Children′s Hospital, Capital Medical University and Shandong Provincial Hospital affiliated to Shandong First Medical University from July 2022 to December 2023, were selected as the study objects. We collected and analyzed their clinical characteristics, biochemical indicators, imaging results, and treatment. The children were followed up every 3 months until December 2023, and the clinical outcomes and adverse drug reactions after treatment were evaluated.Results:Of the 4 patients, 3 were males and 1 was female; they were aged 6.7, 2.9, 2.1, and 2.3 years, respectively. Three patients had previously received treatment with phosphate supplements and active vitamins, but their wadding gait and lower limb deformities did not improve significantly, neither did their imaging changes of active richets. The initial dose of Burosumab in the 4 patients was 0.8 mg/kg, administered subcutaneously every 2 weeks, with a treatment course of 0.8-1.3 years. The fasting serum phosphorus and tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) of the 4 patients before treatment were 0.72, 0.95, 0.81, 0.66 mmol/L and 0.67, 0.85, 0.87, 0.61 mmol/L, respectively. At the last follow-up, the fasting serum phosphorus and TmP/GFR levels were significantly increased (0.96, 1.09, 1.09, 0.90 mmol/L, and 0.85, 0.79, 1.03, 0.98 mmol/L, respectively). Among them, only the TmP/GFR level (1.17 mmol/L) in case 2 achieved normal values at 3 months post-therapy, while the rest did not reach the normal range for children of the same age. After treatment, the alkaline phosphatase levels of all patients gradually decreased (the values were 461, 240, 423, and 237 U/L, respectively), and the ALP levels in cases 2 and 4 returned to normal at the last visit. Case 4 showed a slight increase in parathyroid hormone (PTH) levels after 9 months of treatment, while the PTH levels in the rest 3 cases remained normal. Case 1 underwent a 6-minute walking test, and the walking distance increased from 245 m to 570 m. Abnormal gait, lower limb deformity, and the severity of rickets in the 4 patients had all improved. No adverse drug reactions such as nephrocalcinosis, local skin injection reaction, hyperphosphatemia, or vitamin D deficiency were observed.Conclusion:Burosumab can improve clinical symptoms in children with XLH with a good safety profile.

Objective To prepare T cell immunoglobulin domain and mucin domain 1 protein-1(TIM-1)-Fc fusion protein,and to investigate the intervention effect of TIM-1-FC fusion protein on ovabumin(OVA)-induced asthma mice as well as its po-tential mechanism.Methods Through genetic engineering,pcDNA3.1(+)-TIM-1-Fc plasmid was constructed and stably transfected into CHO cells.Cell culture supernatant was collected and purified,and TIM-1-Fc fusion protein was ob-tained.Mouse model of allergic asthma was established by intraperitoneal injection of OVA aluminum hydroxide solution.The mice were randomly divided into control group,asthma group and TIM-1-Fc intervention group.The TIM-1-Fc intervention group included TIM-1-Fc nasal drop group and TIM-1-Fc injection group.20 min before each intervention,40 μL ovalbumin sa-line solution(OVA-NS)was used for nasal drops.Protein TIM-1-Fc nasal drops group(1 μg/40 μL TIM-1-Fc nasal drops was administrated in each mouse)and TIM-1-Fc injection group(6 μg/200 μL TIM-1-Fc was injected intraperitoneally in each mouse)were interfered with TIM-1-Fc fusion,once a day for 7 days.Normal saline was used as replacement in the control group.Hematoxylin-eosin staining(HE)was used to observe the pathological changes of lung tissue.Flow cytometry was used to detect the proportion of type 2 helper T cells(Th2),type 17 helper T cells(Th17),regulatory T cells(Treg)and the levels of related cytokines in peripheral blood of mice.Results TIM-1-Fc fusion protein and OVA-induced allergic asthma mouse model was successfully constructed.Compared with asthma group,TIM-1-Fc fusion protein could significantly reduce airway inflam-matory injury and lung tissue injury in asthmatic mice.TIM-1-Fc fusion protein intervention could significantly reduce the pro-portion of TIM-1 CD4+T cells and TIM-1+Th17 cells in peripheral blood,increase the number of TIM-1+Treg cells,signifi-cantly reduce the proportion of Th2 and Th17 cells,and increase the proportion of Treg cells.It could modulate Th1/Th2 and Th17/Treg immune imbalances in asthma.Conclusion TIM-1-Fc fusion protein improves airway inflammation and lung tissue injury in OVA-induced allergic asthma mice,and its mechanism may be related to the immune regulation of Th1/Th2 and Th17/Treg by TIM-1-Fc fusion protein.

OBJECTIVE To provide a reference for improving the relevant standard operating procedures （SOP） and biological sample management in drug clinical trials. METHODS According to Good Clinical Practice， Data On-site Verification Points of Drugs Clinical Trials， Human Genetic Resources Management Regulations Implementation Rules， Qualification Examination Rules of Drug Clinical Trials Institution， based on the experience of managing clinical trials programs， the irregularities in biological samples management were analyzed by using statistical quality control tables and protocol deviation （PD） reported by sponsors， in the context of the quality control of drug clinical trials projects managed by the author from July 2016 to May 2023. The precautions in various aspects of sample management were put forward. RESULTS & CONCLUSIONS A total of 101 biospecimen- related irregularities were found in the 60 drug clinical trials projects. Biological sample collection， preservation， and handling were the aspects with the highest incidence of irregular operations in biological sample management， accounting for 37.62%， 25.74%， and 21.78%， respectively. Regulating the management of biospecimens requires multiple efforts. The institutional office and the ethics committee carefully reviewed the consistency of the protocols， informed consent， and genetic office application involving biospecimen collection and handling when the project was initiated. Institutional office quality controllers should pay attention to the attendance and training of authorized personnel at project initiation. The principal investigator， research nurse， collector， handler， transporter， relevant personnel of the central laboratory， and institutional office quality controller have their roles during the project implementation phase. On this basis， all parties involved in the management of biological samples should do a good job of effective communication， find problems and report them in time， and conduct special studies on key aspects.

OBJECTIVE To investigate the current situation of clinical trial institutions in Chongqing after the recording system of clinical trial institutions, and to put forward suggestions. METHODS A total of 34 clinical trial institutions in Chongqing were selected as the research objects. The research contents mainly included the basic situation of the institutions, staffing, hardware and software construction, project operation and work difficulties, etc. Combined with the research results, suggestions were put forward for the difficulties of the new and old institutions in the operation of clinical trial institutions. RESULTS A total of 29 questionnaires were collected and 29 were valid. The release of clinical trial resources in Chongqing were not sufficient and uniform, there were problems such as insufficient incentive policies, lack of information platform construction, and the number and professional degrees of practitioners need to be improved. The new institutions had certain advantages in project load, office space and willingness to undertake, but it was restricted by principle investigator qualification, project experience and institutional reputation. CONCLUSION It is suggested to clarify the incentive mechanism, enhance the enthusiasm of clinical trials and establish a standardized training mechanism for clinical trial professionals. Make full use of the information platform to improve the efficiency of clinical trials, build a regional information platform to share information and resources, and accelerate the development of regional clinical trials.

OBJECTIVE To investigate the job mo bility of cl inical research coordinators （CRCs） and clinical research associates（CRAs）in Chongqing ，and to explore the feasible methods to improve the job stability of CRCs and CRAs. METHODS Questionnaire survey was conducted to investigate the job mobility of 200 CRCs and CRAs working in 22 drug clinical trial institutions of Chongqing. The contents included basic information ，job mobility ，and reasons for mobility. RESULTS & CONCLUSIONS Totally 178 valid questionnaires were recovered ，with an efficient recovery rate of 89.00％，of which 110 were recovered from CRCs and 68 were recovered from CRAs. Among the surveyed CRCs and CRAs ，the age distribution was mainly 20-30 years old ，accounting for 87.27％ and 82.35％ of the respective population respectively. The overall educational degree of CRAs were slightly higher than those of CRCs. The majors and previous work experience were mainly related to medicine ；the proportion of other non-medicine-related professions who switched to CRCs was higher than that of CRAs. Totally 88.18％ had CRC working experience within 3 years；after having 1-＜3 years of work experience ，50.00％ had worked in 2 or more work units. Totally 64.70％ had CRA working experience within 3 years；after having 1-＜3 years of work experience ，70.37％ had worked in 2 or more work units. CRCs handled 5.38 items of clinical trials and completed 1.22 items on average ；CRAs handled 7.47 items and completes 2.04 items on average. Main reasons of CRCs and CRAs for job-hopping included low salary below expectations，few promotion opportunities ，and too much workload ，accounting for 83.64％/80.88％，45.45％/39.71％，31.82％/ 26.47％，respectively. As an important part of clinical trials ，CRCs and CRAs had high job mobility. It is suggested to establish a unified industry standard ，standardize the management rights and responsibilities of CRCs and CRAs ，optimize the working mode of CRCs and CRAs ，and improve professional identity and sense of belonging ，so as to improve the job stability of relevant

OBJECTIVE To learn the common proto col deviation （PD）in the process of drug clinical trials and discuss the methods and precautions for preventing and reducing PD so as to provide reference for the standardization of drug clinical trials. METHODS According to Good Clinical Practice ，Notice on Issuing Guidelines for Planning and Reporting of Data Management and Statistical Analysis of Drug Clinical Trials ，Guidelines for Ethical Review of Drug Clinical Trials ，ICH E 3，ICH E 6（R2）and other regulations ，the PD reported in the relevant projects managed by the author from March 2017 to February 2022，as well as the PD found in the submission materials and project quality control ，were sorted out and statistically analyzed. RESULTS & CONCLUSIONS A total of 39 drug clinical trials were included ，and 212 subjects were selected. In all projects ，258 PDs were reported，including 28 major PD （accounting for 10.85％）and 230 ordinary PD （accounting for 89.15％）. The report of PD mainly included missed inspections/tests （93 reports，accounting for 36.05％），lack of visits （36 reports，accounting for 13.95％）， inspection/testing out-of-window （29 reports，accounting for 11.24％），dosage and usage of test drugs （28 reports，accounting for 10.85％），drug over-temperature/missing temperature （21 reports，accounting for 8.14％），etc. Avoiding and reducing the occurrence of PD requires the efforts of multiple parties ：the sponsor designs a reasonable protocol with appropriate interview rate and window period after listening to the opinions of multiple parties ；the investigators and clinical research coordinator should strengthen their own learning and training ，and be familiar with the protocol ，Good Clinical Practice and corresponding regulations；the compliance education of the subjects should be strengthened ；the institutional offices and ethics committees should conduct multi-angle and whole-process supervision and management when a drug clinical trial is approved ，in progress ，and jsyj- concluded，to ensure the safety rights and interests of the zdcxX0079） subjects and the quality of clinical trials. On this basis ，all parties should communicate effectively and timely ，report PD in time ，and conduct special studies on major PD that have com occurred and key links that are prone to PD.

BACKGROUND: Previous studies have suggested that screen time (ST) has a negative effect on children's emotional and behavioral health, but there are few longitudinal studies that have been conducted with infants and toddlers. This study sought to examine the effect of ST in early childhood on emotional and behavioral problems in children aged 4 years, based on a birth cohort study in China. METHODS: A total of 2492 children aged 4 years were enrolled in this study. The parents and guardians of each child completed a questionnaire that included items eliciting information on children's birth information, socio-demographic information at baseline, and ST at each follow-up. Emotional and behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) at 4 years of age. Multivariate logistic analysis was used to explore the effects of ST on emotional and behavioral problems. RESULTS: The percentages of children with ST > 0 h/day at age 0.5 years, ST > 2 h/day at age 2.5 years, and ST > 2 h/day at age 4 years were 45.7, 55.5, and 34.5% respectively. The prevalence of emotional and behavioral problems was 10.8%. ST at 6 months was a risk factor for emotional symptoms and hyperactivity at the age of 4 years. ST at age 2.5 years was a risk factor for hyperactivity at the age of 4 years. However, ST at age 4 years was a risk factor for total difficulties, conduct problems, peer problems, hyperactivity, and prosocial behavior. CONCLUSIONS Higher ST exposure at early childhood is associated with later emotional and behavioral problems. In particular, sustained high ST exposure is a risk factor for behavioral problems. These findings suggested the importance of controlling ST to prevent the occurrence of emotional and behavioral problems in the early years.
Altruism ; Child, Preschool ; China/epidemiology* ; Cohort Studies ; Emotions ; Female ; Humans ; Male ; Prevalence ; Problem Behavior/psychology* ; Psychomotor Agitation/psychology* ; Screen Time

Objective:To compare the short-term clinical efficacy, adverse reactions and pharmacoeconomics of advanced mutation negative lung adenocarcinoma treated by albumin-bound paclitaxel or pemetrexed combined with cisplatin.Methods:From September 2019 to October 2020, 80 patients with advanced lung adenocarcinoma diagnosed in the First Affiliated Hospital of Bengbu Medical College were divided into observation group and the control group according to the randomized digital table, with 40 cases in each group. The observation group received albumin-bound paclitaxel combined with cisplatin, and the control group received pemetrexed combined with cisplatin. After 2 cycles of treatment, the short-term efficacy and the adverse reactions of the two groups were evaluated. The cost of chemotherapy drugs and the average length of hospital stay were compared between the two groups.Results:The objective response rates of the observation group and the control group were 30.0% (12/40) and 32.5% (13/40), the disease control rates were 77.5% (31/40) and 82.5% (33/40) respectively, and there were no significant differences ( χ2=0.058, P=0.809; χ2=0.313, P=0.576). The adverse reactions of the two groups were mainly grade Ⅰ-Ⅱ. The incidences of leucopenia, neutropenia, thrombocytopenia, hemoglobin decreased, gastrointestinal reaction, liver function damage and renal function damage in the observation group were 20.0% (8/40), 20.0% (8/40), 20.0% (8/40), 17.5% (7/40), 37.5% (15/40), 12.5% (5/40) and 7.5% (3/40) respectively, those in the control group were 25.0% (10/40), 20.0% (8/40), 17.5% (7/40), 15.0% (6/40), 32.5% (13/40), 17.5% (7/40) and 5.0% (2/40) respectively, and there were no statistically significant differences between the two groups ( χ2=0.287, P=0.592; χ2<0.001, P>0.999; χ2=0.082, P=0.775; χ2=0.092, P=0.762; χ2=0.220, P=0.639; χ2=0.392, P=0.531; χ2<0.001, P>0.999). The median cost of chemotherapy drugs and the median length of hospital stay in the observation group were 7 453 yuan and 6 days respectively, which were less than 8 956 yuan and 7 days in the control group, with statistically significant differences ( Z=-3.057, P=0.002; Z=-2.733, P=0.006). Conclusion:The short-term efficacy of albumin-bound paclitaxel combined with cisplatin is equal to pemetrexed combined with cisplatin in treatment of advanced mutation negative lung adenocarcinoma, and the adverse reactions are similar. However, the average cost of chemotherapy drugs of albumin-bound paclitaxel combined with cisplatin is less than pemetrexed combined with cisplatin, and the average length of hospital stay is shorter.

Objective:To investigate the clinical and genetic features, and treatment of X-linked hypophosphatemic rickets (XLH).Methods:In this retrospective study, we reviewed the medical records of 25 pediatric patients with XLH who were admitted to Department of Endocrinology Genetics and Metabolism,Beijing Children′s Hospital from January 2010 to January 2020. The clinical characteristics, PHEX gene variants, as well as clinical outcome of the patients were summarized. To analyze the correlation between genotype and phenotype, the patients were divided into different subgroups according to the location of the variants, including N-terminal-located vs. C-terminal-located variant, and Zn-binding domain exon 17 or 19 variant vs. non-exon 17 or 19 variant. The age at onset, height standard deviation score (HtSDS), intercondylar or intermalleolar distance, fasting serum phosphorus, and HtSDS and intercondylar or intermalleolar distance at the final follow-up were compared by rank sum test or t text. Results:Among the 25 children with XLH, 8 were boys and 17 were girls. The median age of onset was 1.2 (1.0, 1.8) years, and the median age of diagnosis was 2.5 (1.5, 4.3) years. The main clinical manifestations were abnormal gait and lower limb deformity. The HtSDS was -2.0(-3.2, -0.8), and the intercondylar or intermalleolar distance was 4.5 (3.0, 6.0) cm. The fasting serum phosphorus level was 0.8 (0.7, 0.9) mmol/L, while the serum alkaline phosphatase level was (721±41) U/L and the serum calcium level was (2.5±0.1) mmol/L. Three patients (12%) had parathyroid hormone levels above the upper limit of the normal range. Twenty-five patients (100%) showed radiographic changes of active rickets. Nephrocalcinosis was found in 2 cases (9%). Twenty-four different PHEX variations were detected in 25 patients, among whom 11 (44%) had not been reported previously. No hot spot variation was found. No statistical differences (all P>0.05) were identified in clinical features and outcomes either in comparing patients with N-terminal (21 cases) and C-terminal (4 cases) variants, or in comparing patients with variant located in exon 17 or 19 (4 cases) or not (21 cases). Twenty-four cases (96%) were treated regularly with phosphate supplements and active vitamin D. After 2.7 (1.6, 5.0) years of follow-up, clinical symptoms were relieved in 96% (24/25) of the patients. The HtSDS after treatment had no significant difference compared to that before treatment (-2.0(-3.2, -0.8) vs.-2.0(-2.8, -1.1), Z =-0.156, P>0.05), while the intercondylar or intermalleolar distance after treatment was significantly reduced compared to that before treatment (4.5(3.0, 6.0) vs. 1.5(0, 3.3) cm, Z =-3.043, P<0.05). Bone X-rays were reexamined in 17 cases after treatment, and radiographic signs of rickets were improved. Eighteen cases had secondary hyperparathyroidism and 7 cases had nephrocalcinosis. Conclusions:The main clinical manifestations of XLH are abnormal gait, lower limb deformity and short stature. A high proportion of novel variations of PHEX gene but no hot spot variation neither genotype-phenotype correlation are found. Regular treatment with phosphate supplements and active vitamin D can significantly improve the symptoms except for the height. However, the rate of adverse events including secondary hyperparathyroidism and nephrocalcinosis seems to be high.