To analyze potential adverse drug events(ADEs) associated with ustekinumab and upadacitinib in the treatment of inflammatory bowel disease(IBD) based on an international authoritative database, thereby providing evidence for clinical medication safety.

OBJECTIVE To investigate the effects of formononetin （FMN） on the apoptosis of intestinal epithelial cells in inflammatory bowel disease （IBD） rats and its possible mechanism. METHODS IBD rat model was constructed by using trinitrobenzene sulfonic acid （TNBS） induction. Forty-eight rats with successful modeling were divided into model group （normal saline）， low-dose and high-dose FMN groups （20 and 40 mg/kg FMN）， and high-dose FMN+YAP inhibitor Verteporfin （VTPF） group （40 mg/kg FMN+10 mg/kg VTPF）， with 12 rats in each group. Another 12 rats were set as the normal group （normal saline）. They were given drug/normal saline， once a day， for 7 consecutive days. After the last administration， the disease activity index （DAI） of rats was calculated， and the colon length of rats in each group was measured. The pathological changes in the colon tissue of rats were observed. The levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6） and IL-10 in serum were detected， and the apoptosis of intestinal epithelial cells was detected. The expressions of Yes associated protein （YAP）， cleaved cysteine-containing aspartate proteolytic enzyme 3 （cleaved-caspase-3）， B-cell lymphoma-2 （Bcl-2） and Bcl-2 associated X protein （Bax） were detected in colon tissue of rats. RESULTS Compared with the normal group， DAI score， the levels of TNF-α and IL- 6， the apoptotic rate of intestinal epithelial cells， and the expressions of cleaved-caspase-3 and Bax protein in the model group were increased greatly （P＜0.05）； the length of the colon was greatly decreased （P＜0.05）， and the serum level of IL-10 and the protein expressions of YAP and Bcl-2 were greatly reduced （P＜0.05）. The cell morphology of colon tissue was abnormal， with disordered arrangement and inflammatory cell infiltration. Compared with IBD group， the above indexes of rats were improved significantly in low-dose and high-dose FMN groups （P＜0.05）， in dose-dependent manner （P＜0.05）. VTPF significantly alleviated the effects of FMN on the above indexes of IBD rats （P＜0.05）. CONCLUSIONS FMN may promote the expression of YAP by inhibiting the Hippo/YAP signaling pathway， thereby inhibiting apoptosis of intestinal epithelial cells in IBD rats.

Objective:To determine the value of colonoscopy in the diagnosis and treatment of patients with immune checkpoint inhibitor-induced colitis.Methods:Patients who developed colitis and underwent colonoscopy after receiving immune checkpoint inhibitors(ICIs)therapy at Tianjin Medical University General Hospital between December 2020 and December 2023 were reviewed,according to the guidelines of the Chinese Society of Clinical Oncology for the management of ICI-related toxicity.The effect of the treatment and the rela-tionship between prognosis and the pathological features of colonoscopy were analyzed.Results:Patients with ICI-associated colitis who un-derwent colonoscopy had a more than 3 degrees diarrhea,and diffused inflammatory features such as mucosal erythema,exudate,erosion,loss of vascular markings,and edema were observed under the microscope,and the presence of ulcers greater than 1 cm in diameter and/or more than 2 mm deep indicate a poor prognosis for enteritis.Histopathological studies showed changes in glandular structures,such as cryptitis and crypt abscess.The pathological colonoscopic manifestations of patients with microscopic enteritis were inconsistent,and more deep samples should have been taken.Conclusions:The toxicity grading of ICI-associated colitis is not limited to clinical manifestations,but refers to the multi-dimensional analysis of colonoscopic features and histopathological characteristics.Soft colonoscopy can be used as an important follow-up method for patients with colitis,owing to its ease of operation and good tolerance.

Objective To investigate the effects of intestinal microbiota of patients with chronic constipation on the expression of serotonin transporter (SERT) and the bowel movement in mice.Methods Fecal samples of patients with slow transit constipation met Rome Ⅲ criteria and healthy normal controls were collected and made into fecal microbiota solution.Twenty specfic pathogen free (SPF) mice were divided into experiment group and control group.The mice of two groups were both pre-treated with streptomycin to establish the germ-free mice model.The mice of control group were gavaged with mixed fecal microbiota solution of healthy normal controls and the mice of experiment group were gavaged with mixed fecal microbiota solution of patients with chronic constipation.Mice were sacrificed after fed for 15 days.Defecation parameters and ink discharge time of mice were detected.The expressions of SERT mRNA and SERT protein in mice intestinal tissues were detected with real time-polymerase chain reaction and Western blotting.The 5-hydroxytryptamine (5-HT) levels of mice intestinal tissues were evaluated by enzyme-linked immunosorbent assay (ELISA) and double immunofluorescent staining.The methods of t test and Chi-square test were performed for statistical analysis.Results On the 15th day,the total number of the feces within 2 h of the experiment group and control group was 8.55±1.83 and 12.14±2.90,respectively,and the difference was statistically significant (t=3.33,P＜0.05).The weight of feces were (151.90 ± 32.42) mg and (246.72 ± 64.01) mg,respectively,and the difference was statistically significant (t=4.18,P＜0.01).The dry weight of feces were (65.52±11.76) mg and (92.93±23.07) mg,respectively,and the difference was statistically significant (t=3.37,P＜0.05).The water content of feces were (56.63 ± 3.01) ％ and (61.95 ± 3.70) ％,respectively,and the difference was statistically significant (t=3.57,P＜0.05).The defecating time of first black feces of the experiment group and control group were (83.24±11.31) min and (69.06±2.72) min,respectively,and the difference was statistically significant (t=-2.74,P＜0.05).The expressions of SERT mRNA and SERT protein levels in mice intestine tissues of the experiment group were significantly higher than those of the control group (t =2.61,-6.89;both P＜0.05).5-HT level of mice intestinal tissues of the experimental group and control group were (151.69± 10.18) ng/mL and (198.77 ± 25.99) ng/mL,respectively,and the difference was statistically significant (t=-4.13,P＜0.01).Conclusion Intestinal microbiota of patients with chronic constipation may influence the expression of SERT in the mice intestinal tissues,and then decrease the level of 5-HT,slowing the bowel movement in mice.

Ulcerative colitis is an inflammatory disease of colon and rectum whose etiology is still unclear.Infliximab is an anti-tumor necrosis factor antibody,which has been approved recently by the United States FDA for the treatment of ulcerative colitis to reduce signs and symptoms,to induce clinical remission and healing of the intestinal mucosa.Total proctocolectomy with pouch-anal anastomosis are the standard operation for ulcerative colitis now.The perioperative infliximab use,operation timing and procedures are the important factors affecting prognosis of patients in the era of infliximab therapy.

Objective To initially explore the feasibility and quality control of producing fecal-derived microbiota enteric capsules.Methods Fecal-derived microbiota was put into double layered enteric capsules.The bacteria colony numbers of fresh prepared glycerol containing fecal-derived microbiota liquid,glycerol containing and glycerol free fecal-derived microbiota after stored at -80 ℃ for 72 h were counted with standard plate count methods in order to investigate the stability after frozen.Methylene blue was taken as the standard,resistance to acid and release rate of capsules was evaluated.The t test was performed for statistical analysis.Results The preparation process of double layered microbiota capsules was simple and practicable.The data of 12 plates of each microbiota were acquired.The number of bacteria colony of fresh prepared glycerol containing fecal-derived microbiota ((5.08 ±1.37)×107 colony-forming units (cfu)/mL)was significantly more than that of the group without glycerin ((1.73±0.64)×107 cfu/mL)at -80 ℃for 72 h (t = 7.621 ,P <0.01).There was no significant difference in the number of bacteria colony between glycerin containing frozen fecal-derived microbiota ((4.67±1 .56)×10 7 cfu/mL)and fresh fecal-derived microbiota (t = 0.694,P = 0.495).Regression equations were achieved with fecal-derived microbiota containing methylene blue,and there was a good linear relation between 0.5 μg/mL and 8.0 μg/mL.Three fecal-derived microbiota enteric capsules containing methylene blue were prepared.Their resistance to acid was 96.0%,99.1 %,and 95 .5 %,while the release rate was 88.6%,95 .1 % and 86.5 %, respectively.All met the requirement of Chinese Pharmacopoeia to enteric capsules.Conclusion The preparation of double layered fecal-derived microbiota enteric capsules had feasible technology and stable quality,which could provide reference in prevention and treatment of diseases related with colonic microbiota imbalance.

Background and purpose: Malignant tumors often relapsed or metastasized after first-line chemotherapy and needed second-line or above treatment. We conducted this study to deifne the maximum-tolerated dose (MTD) of lobaplatin with ifxed docetaxel for Chinese patients in previously treated solid tumors. Methods:Escalating doses of lobaplatin with fixed docetaxel were administered in a modified Fibonacci sequence. The initial doses were lobapla-tin 30 mg/m2 and docetaxel 60 mg/m2, respectively. Escalating doses was 5 mg/m2. The regimen was repeated every 21 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be one dose level below the level at which DLT appeared. Results:Seventeen patients received fifty-eight cycles chemotherapy at lobaplatin of levelⅠ(30mg/m2), levelⅡ(35 mg/m2)and levelⅢ(40 mg/m2). Cases of complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD) for the whole group were 0, 1, 10 and 3, respectively. Response rate (RR, CR+PR) and disease control rate (DCR, CR+PR+SD) were 7.1%(1/14) and 78.6%(11/14), respectively. The most common toxicity was leukopenia. Three DLTs occurred in 3 patients in the whole group, including 2 DLTs in dose levelⅢ. We declared thus levelⅡwas MTD. Conclusion:MTD of lobaplatin in our re-search was 35 mg/m2 combined with fixed dose of docetaxel. This combination regimen was well tolerated.

Objective To investigate secondary bile acid induced canceration process of intestinal adenoma and effects on intestinal microflora in Apcmin/+ mice.Methods Forty four-week-old mice (20 Apcmin/+mice and 20 wild-type C57BL/6J mice) were divided into four groups:wild-type control group (regular drinking water),wild-type deoxycholic acid (DOC) group (with 0.2 ％ DOC in drinking water),Apcmin/+ control group and Apcmin/+ DOC group.Fecal pellets of Apcmin/+ mice were collected at 0 week and 12 week after administration.The changes of intestinal microflora were analyzed by pyrosequencing.All mice were sacrificed after 12 weeks.The number,size and location of intestinal adenoma were observed.The pathological type of adenoma was evaluated after hematcxylin-eosin (HE) staining.Proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry.Cell apoptosis was determined by in situ terminal deoxynucleotidyl transferase mediated dUTP nick end labeling technique (TUNEL).Independent t test was used for the quantitative data comparison between two groups.Results No intestinal tumors were found in the wild-type mice.The total number of intestinal adenoma of Apcmin/+ DOC group significantly increased,compared with that of Apcmin/+ control group (57.00 ± 3.07 vs 21.50± 4.69,t=20.03,P＜0.01),the increase of the adenoma with maximum diameter between 1 to 2 mm was most significant (30.62± 7.73 vs 7.75 ± 4.59,t =8.04,P＜ 0.05),the rate of adenoma canceration also significantly increased compared with that of Apcmin/+ control group.The percentage of PCNA positive cells significantly increased compared with that of Apcmin/+ control group ((90.17 ± 2.14) ％ vs (41.97 ± 4.26) ％,t=31.97,P＜0.01).The percentage of cell apoptosis significantly declined ((1.40± 1.12) ％ vs (7.50 ± 0.65)％,t =14.90,P＜ 0.01).The diversity of intestinal flora of Apcmin/+ DOC group significantly decreased.The ratio of Firmicutes and Bacteroidetes significantly increased compared with control group (0.586 7±0.148 4 vs 0.387 3±0.013 6,t=2.36,P＜0.05).The number of pathogenic bacteria increased in Apcmin/+ DOC group and probiotics significantly decreased.Conclusion DOC can induce intestinal flora imbalance in Apcmin/+ mice and promote intestinal adenoma into adenocarcinoma through increasing tumor cell proliferation and inhibiting cell apoptosis.

Objective: To detect the expression of CDX2, COX-2, and NF-κB in the tissues of gastric carcinoma (GC), precancerous lesions, and normal gastric mucosa and to in vestigate the correlation among CDX2, COX-2, and NF-κB. Methods:Data on the expression of CDX2, COX-2, and NF-κB were evaluated using immunohistochemistry in 60 cases with GC, 45 cases with precancerous lesions, and 20 cases with normal tissues. The protein levels in different pathological tissues, as well as their correlation with GC, were analyzed. Results:The positive rates of NF-κB and COX-2 proteins were significantly higher in GC group than those in precancerous lesion and normal tissue groups (P<0.05). CDX2 was expressed in GC and precancerous lesion groups but poorly expressed in the normal mucosa. The positive rate of CDX2 expression was significantly higher in precancerous lesion group than that in GC group (P<0.01). NF-κB expression was positively correlated with COX-2 in GC (P<0.01), whereas CDX2 expression was negatively correlated with COX-2 and NF-κB in GC (P<0.01). Conclusion:CDX2, COX-2, and NF-κB are possibly correlated with one another, and they cooperate during the onset, progression, and metastasis of GC.

Sixty patients with ulcerative colitis (UC),including 28 males and 32 females were enrolled in the study.Color Doppler ultrasonographic scans were performed and the disease activity was estimated base on the Sourtherland score index (DAI).On the sonography the colon with active inflammatory disease showed bowel wall thickening,alteration of layers structure or even discrimination and increased vascular signals.Using DAI as the gold standard,the sensitivity,specificity,positive predictive value,negative predictive value and accurate rate for ultrasonography in assessment of UC activity were 90.0％ (36/40),75.0％ ( 15/20),87.8％ (36/41),78.9％ (15/19),85.0％ (51/60),respectively.In conclusion,Color Doppler ultrasonography provides a convenient technique for assessment of bowel involvement and inflammatory activity in ulcerative colitis with high sensitivity and accuracy.