Objective:To analyze the problems and risk factors of the investigator initiated out-of-range trial, propose countermeasures and suggestions, and provide reference for improving project standardization and quality, and preventing research risks.Methods:Through literature analysis and field research, combined with personal work experience, this study sorted and analyzed the problems in the regulation of out-of-range IIT conducted in hospital, and proposed countermeasures.Results:Through analysis, it was found that the current out-of-range IIT trial in China faces 5 problems: imperfect management regulations, incomplete IIT management organizational system in medical institutions, insufficient scientificity of research protocols, insufficient ethical review, and insufficient research funds.Conclusions:Out-of-range IIT is of great significance in promoting pharmaceutical innovation. Standardized management of such projects requires the efforts of regulatory authorities, medical institutions, and ethics committees, as well as the continuous improvement of researchers' awareness and research capabilities to promote the orderly, high-quality, and rapid development of IIT. Based on the above analysis, this article proposed countermeasures and suggestions: at the national level, summarize practical experience from various regions as soon as possible, improve IIT management regulations and technical guidelines; establishing clinical research and design guidance departments in medical institutions and strengthening scientific review; the ethics committee formulates ethical review standards and processes for out-of-range IIT projects to enhance review capabilities; establish a normalized clinical research training mechanism in hospitals; expand and standardize the channels for IIT funding.

Objective This objective of this study was to investigate the effects of long chain non-coding RNA GAS5(ln-cRNA GAS5)on the proliferation,invasion ability and PTEN/Akt/mTOR signaling pathway of cervical cancer cells,and to elucidate the possible mechanism of lncRNA GAS5 in cervical cancer.Methods Real-time quantitative reverse transcription polymerase chain reaction(qRT-PCR)was used to detect the levels of lncRNA GAS5 in human cervical cancer HeLa cells,C33A cells,Caski cells,Siha cells and normal cervical epithelial End1/E6E7 cells.HeLa cells were divided into the blank control group(BC group),negative con-trol group(NC group)and overexpressing lncRNA GAS5 group(GAS5 group);Siha cells were divided into the blank control group(BC group),negative control siRNA group(si-NC group)and siRNA-lncRNA GAS5 group(si-GAS5).The CCK8 assay was used to measure proliferation of cervical cancer cells.The Transwell was used to measure the invasion and migration capabilities of cervical cancer cells.Western blot was used to determine the expression of proliferating cell nuclear antigen(PCNA),matrix metalloproteinase(MMP)-2,MMP-9,PTEN,Akt,phosphorylated Akt(p-Akt),mTOR and p-mTOR proteins in cervical cancer cells.Results The results showed that the levels of lncRNA GAS5 in HeLa cells,C33A cells,Caski cells and Siha cells were lower than that in End1/E6E7 cells(P＜0.001).Compared with the NC group,overexpression of lncRNA GAS5 in HeLa cells resulted in a decrease in the cell proliferation,invasion,and migration abilities,as well as a decrease in the levels of PCNA,MMP-2,MMP-9,p-Akt,and p-mTOR proteins(P＜0.001),while an increase in the level of PTEN protein(P＜0.001).Compared with the si-NC group,inhibition of ln-cRNA GAS5 expression in Siha cells resulted in increased the cell proliferation,invasion,and migration abilities,as well as increased the levels of PCNA,MMP-2,MMP-9,p-Akt,and p-mTOR proteins(P＜0.001),while decreased the level of PTEN protein(P＜0.001).Conclusion The level of lncRNA GAS5 in cervical cancer cells is reduced,and lncRNA GAS5 can inhibit the proliferation,invasion and migration abilities of cervical cancer cells,as well as activate the PTEN/Akt/mTOR signaling pathway.

Oral squamous cell carcinoma(OSCC)is the predominant type of oral cancer,while some patients may develop oral multiple primary cancers(MPCs)with unclear etiology.This study aimed to investigate the clinicopathological characteristics and genomic alterations of oral MPCs.Clinicopathological data from patients with oral single primary carcinoma(SPC,n=202)and oral MPCs(n=34)were collected and compared.Copy number alteration(CNA)analysis was conducted to identify chromosomal-instability differences among oral MPCs,recurrent OSCC cases,and OSCC patients with lymph node metastasis.Whole-exome sequencing was employed to identify potential unique gene mutations in oral MPCs patients.Additionally,CNA and phylogenetic tree analyses were used to gain preliminary insights into the molecular characteristics of different primary tumors within individual patients.Our findings revealed that,in contrast to oral SPC,females predominated the oral MPCs(70.59%),while smoking and alcohol use were not frequent in MPCs.Moreover,long-term survival outcomes were poorer in oral MPCs.From a CNA perspective,no significant differences were observed between oral MPCs patients and those with recurrence and lymph node metastasis.In addition to commonly mutated genes such as CASP8,TP53 and MUC16,in oral MPCs we also detected relatively rare mutations,such as HS3ST6 and RFPL4A.Furthermore,this study also demonstrated that most MPCs patients exhibited similarities in certain genomic regions within individuals,and distinct differences of the similarity degree were observed between synchronous and metachronous oral MPCs.

Objective To compare the efficacy and safety of vedolizumab(VDZ)and infliximab(IFX)for moderate to severe ulcerative colitis(UC)patients through a multicenter retrospective cohort study.Methods All patients with moderate to severe UC who were naive to biologic agents and treated with IFX or VDZ for at least 14 weeks at 3 hospitals in Southwest China between January 2021 and January 2023 were retrospectively enrolled.The efficacy evaluation indicators,including steroid-free clinical remission rates,clinical remission rates and endoscopic remission rates at weeks 14 and 52 were compared between the 2 groups.The occurrence of adverse events during treatment were recorded.Taking whether mucosal healing could be achieved after 14 and 52 weeks of treatment as the dependent variable,firstly,univariate analysis was performed to analyze the risk factors affecting mucosal healing at weeks 14 and 52,and then multivariate logistic regression analysis was applied to identify the independent risk factors of mucosal healing at the 2 time points.Results A total of 151 patients with moderate to severe UC were included,after propensity score matching(PSM),each group included 57 patients.There were no significant differences in the steroid-free clinical remission rate and clinical remission rate between the 2 groups at weeks 14 and 52(P＞0.05).The endoscopic remission rate at week 14 was significantly higher in the VDZ group than the IFX group[40.4％(23/57)vs 22.8％(13/57),P=0.044],but no such difference was observed at week 52[64.5％(20/31)vs 59.5％(22/37),P=0.669].Multivariate logistic regression analysis showed that left-sided disease(E2)[vs pancolitis(E3)](OR=0.46,95％CI:0.21～0.98,P=0.045)was independent risk factor for mucosal healing at week 14 and a disease duration ≥36 months(OR=0.25,95％CI:0.09～0.66,P=0.005)was independent risk factor for mucosal healing at week 52.No statistical difference was observed in the incidence of adverse events between the 2 groups(1.8％vs 7.0％,P=0.360).Conclusion VDZ and IFX have similar efficacy and safety,and both can be used as first-line options for patients with moderate to severe UC.

OBJECTIVES: Ozone is widely applied to treat allergic skin diseases such as eczema, atopic dermatitis, and contact dermatitis. However, the specific mechanism remains unclear. This study aims to investigate the effects of ozonated oil on treating 2,4-dinitrochlorobenzene (DNCB)-induced allergic contact dermatitis (ACD) and the underling mechanisms. METHODS: Besides the blank control (Ctrl) group, all other mice were treated with DNCB to establish an ACD-like mouse model and were randomized into following groups: a model group, a basal oil group, an ozonated oil group, a FcεRI-overexpressed plasmid (FcεRI-OE) group, and a FcεRI empty plasmid (FcεRI-NC) group. The basal oil group and the ozonated oil group were treated with basal oil and ozonated oil, respectively. The FcεRI-OE group and the FcεRI-NC group were intradermally injected 25 µg FcεRI overexpression plasmid and 25 µg FcεRI empty plasmid when treating with ozonated oil, respectively. We recorded skin lesions daily and used reflectance confocal microscope (RCM) to evaluate thickness and inflammatory changes of skin lesions. Hematoxylin-eosin (HE) staining, real-time PCR, RNA-sequencing (RNA-seq), and immunohistochemistry were performed to detct and analyze the skin lesions. RESULTS: Ozonated oil significantly alleviated DNCB-induced ACD-like dermatitis and reduced the expressions of IFN-γ, IL-17A, IL-1β, TNF-α, and other related inflammatory factors (all P<0.05). RNA-seq analysis revealed that ozonated oil significantly inhibited the activation of the DNCB-induced FcεRI/Syk signaling pathway, confirmed by real-time PCR and immunohistochemistry (all P<0.05). Compared with the ozonated oil group and the FcεRI-NC group, the mRNA expression levels of IFN-γ, IL-17A, IL-1β, IL-6, TNF-α, and other inflammatory genes in the FcεRI-OE group were significantly increased (all P<0.05), and the mRNA and protein expression levels of FcεRI and Syk were significantly elevated in the FcεRI-OE group as well (all P<0.05). CONCLUSIONS Ozonated oil significantly improves ACD-like dermatitis and alleviated DNCB-induced ACD-like dermatitis via inhibiting the FcεRI/Syk signaling pathway.
Animals ; Mice ; Dinitrochlorobenzene/metabolism* ; Skin/metabolism* ; Cytokines/metabolism* ; Interleukin-17/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Dermatitis, Allergic Contact/pathology* ; Dermatitis, Atopic/chemically induced* ; Signal Transduction ; RNA, Messenger/metabolism* ; Mice, Inbred BALB C

Objective:In order to strictly prevent academic misconduct, effectively improve the understanding and judgment ability of researchers on medical ethics issues involved in papers, and ensure scientific and standardized research results, strict ethical review is crucial.Methods:It mainly reviews whether the clinical research paper to be submitted has obtained an ethical approval certificate, whether the content of the paper exceeds the scope of ethical approval permission or violates research ethical standards, etc., and establishing a sound paper ethics review mechanism.Results:This paper summarizes the issues, points and considerations of ethical review before submission of clinical research papers, hoping to provide some practical methods and references for the ethical review of clinical research papers in China.Conclusions:Medical and health institutions mostly carry out biomedical research involving humans, and should pay more attention to ethical norms and requirements, educate and guide researchers to strengthen ethical awareness, and improve their attention and judgment ability to medical ethical issues in papers.

Objective:To analyze the epidemic situation of plague among animals in the foci of Meriones unguiculatus in Inner Mongolia Plateau, and to find out key influencing factors affecting the epidemic of the plague, and to provide theoretical basis for the prediction, early warning and risk assessment of the plague. Methods:The monitoring data including gerbils density, gerbils body flea index, plague epidemic intensity, etc., as well as environmental data including temperature, precipitation and El Ni?o activity (Southern Oscillation Index, SOI) from 19 banners (counties, cities and districts) in Ulanqab Plateau area, the foci of Meriones unguiculatus in Inner Mongolia Plateau were selected. The methods of correlation analysis, structural equation model and rank correlation were used to analyze the epidemic and key influencing factors of plague among animals in the foci. Results:The plague epidemic cycle in the foci of Meriones unguiculatus in Inner Mongolia Plateau was 5 to 10 years. The correlation analysis results showed that all the factors had influence on each other. Structural equation model screened out that the main influencing factors of plague epidemic were SOI, gerbils density and temperature. SOI had a negative effect on plague epidemic intensity (-0.022) and temperature (-0.029), while gerbils density had a positive effect on plague epidemic intensity (0.014), and temperature had a negative effect on plague epidemic intensity (-0.065). In rank correlation, when the gerbils density was at a high value, the probability of high plague epidemic intensity in that year was 4/9; when SOI was at a low value, the probability was 5/9; when the temperature was at a low value, the probability was 5/9. When the plague epidemic intensity was at a high value in that year, the probability of the plague epidemic intensity being high in the following year was 5/8; when the gerbils density was at a high value in that year, the probability was 4/9; when SOI was at a low value in that year, the probability was 4/9. Conclusion:Climate and biological factors can affect prevalence of plague, and countermeasures should be taken in advance to prevent plague outbreaks when El Ni?o phenomenon, low temperature, high density of gerbils, and high previous-year prevalence of plague appear.

Objective:To study the different region (DFR) genotyping of 15 strains of Yersinia pestis from Inner Mongolia. Methods:Fifteen strains of Yersinia pestis isolated from Otog Banner and Darhan Muminggan Joint Banner in Meriones unguiculatus plague foci in Inner Mongolia Plateau, Zhengxiangbai Banner in Spermophilus dauricus plague foci in the Songliao Plain in 2019 were amplified by PCR, and identified DFR genotyping. Results:Two strains of Yersinia pestis in Otog Banner jointly deleted DFR loci 1, 6, 7, 13, 15, 16, 17, 18, 23, and 13 strains of Yersinia pestis in Darhan Muminggan Joint Banner and Zhengxiangbai Banner jointly deleted DFR loci 1, 6, 7, 12, 13, 15, 16, 17, 18 and 23. G17 and G20 were classified as genotyping by comparison with DFR locus distribution and genotyping results. Conclusion:The genotyping of Yersinia pestis in the natural foci of Meriones unguiculatus plague foci in Inner Mongolia Plateau and Spermophilus dauricus plague foci in the Songliao Plain is the same as that of the historical strain.

Objective To investigate the clinical and epidemiological characteristics of 135 confirmed cases of COVID-19 in Tianjin. Methods The clinical and epidemiological data of 135 cases of COVID-19 in Tianjin were collected, and the data were analyzed with descriptive method. The factors influencing the severity of the illness were analyzed. Results Among the 135 COVID-19 cases, 72 were males and 63 were females, the age of the cases was (48.62±16.83) years, and the case fatality rate was 2.22%. Local transmission caused 74.81% of the cases. A total of 33 clusters occurred, involving 85.92% of all COVID-19 cases. The median of the incubation period of COVID-19 was 6.50 days, the average generation interval was 5 days, and the household secondary transmission rate was 20.46%. Fever was the main symptom (78.63%), followed by cough (56.48%). Multivariate regression analysis indicated that age ( OR =1.038, 95% CI : 1.010-1.167) and the number of chronic underlying diseases ( OR =1.709, 95% CI : 1.052-2.777) were the risk factors of severe illness. Conclusions Fever was the main symptom at the early phase of COVID-19 in Tianjin, and the local cluster cases accounted for high proportion in confirmed COVID-19 cases reported in Tianjin. Severe illness was prone to occur in people with old age and multi underlying diseases. Strict isolation of close contacts and intensive care of high-risk groups are the main measures to reduce the morbidity and case fatality of COVID-19.

Objective: To analyze the epidemiological history, clinical manifestations, treatment and the short-term prognosis of 31 cases of 2019 novel coronavirus(2019-nCoV) infection in children from six provinces (autonomous region) in northern China. Methods: A retrospective analysis of the epidemiological history, clinical symptoms, signs, laboratory examinations, chest imaging, treatment and the short-term prognosis of 31 cases of 2019-nCoV was conducted. The patients were diagnosed between January 25th, 2020 and February 21st, 2020 in 21 hospitals in 17 cities of six provinces(autonomous region) of Shaanxi, Gansu, Ningxia, Hebei, Henan and Shandong. Results: The age of the 31 children with 2019-nCoV infection was 7 years and 1 month (6 months -17 years). Nine cases (29%) were imported cases. Other 21 cases (68%) had contact with confirmed infected adults. One case (3%) had contact with asymptomatic returnees from Wuhan. Among the 31 children, 28 patients (90%) were family cluster cases. The clinical types were asymptomatic type in 4 cases (13%), mild type in 13 cases (42%), and common type in 14 cases (45%). No severe or critical type existed. The most common symptom was fever (n=20, 65%), including 1 case of high fever, 9 cases of moderate fever, 10 cases of low fever. Fever lasted from 1 day to 9 days. The fever of fifteen cases lasted for ≤3 d, while in other 5 cases lasted > 3 d. Other symptoms included cough (n=14, 45%), fatigue (n=3, 10%) and diarrhea (n=3, 9%). Pharyngalgia, runny nose, dizziness, headache and vomiting were rare. In the early stage, the total leukocytes count in peripheral blood decreased in 2 cases (6%), the lymphocytes count decreased in 2 cases (6%), and the platelet count increased in 2 cases (6%).Elevation of C-reactive protein (10%, 3/30), erythrocyte sedimentation rate(19%,4/21), procalcitonin(4%,1/28), liver enzyme(22%, 6/27) and muscle enzyme (15%, 4/27) occurred in different proportions. Renal function and blood glucose were normal. There were abnormal chest CT changes in 14 cases, including 9 cases with patchy ground glass opacities and nodules, mostly located in the lower lobe of both lungs near the pleural area. After receiving supportive treatment, the viral nucleic acid turned negative in 25 cases within 7-23 days. Among them, 24 children (77%) recovered and were discharged from hospital. No death occurred. Conclusions In this case series, 2019-nCoV infections in children from six provinces (autonomous region) in northern China are mainly caused by close family contact. Clinical types are asymptomatic, mild and common types. Clinical manifestations and laboratory examination results are nonspecific. Close contact history of epidemiology, nucleic acid detection and chest imaging are important bases for diagnosis. After general treatment, the short-term prognosis is good.