Abstract A large body of clinical data and observational studies suggest that intestinal flora is associated with ulcerative colitis (UC). However, the causal relationship between gut flora and UC remains to be determined. To investigate the potential causal relationship between intestinal flora and UC, a two-sample Mendelian randomization (MR) analysis was performed in this study. We obtained genome-wide association data for gut flora and UC from published GWAS databases and performed dual sample MR analysis using inverse variance weighting (IVW) to identify potential UC beneficial or deleterious gut flora. Sensitivity analysis, including multi potency and heterogeneity assays, was performed to validate the stability of MR primary assays. In this study, we found a negative correlation between three genera of bacteria and the risk of UC developing into beneficial floras. They include Genus Butyrivibrio [OR = 0.908, 95%CI (0.835, 0.987), P = 0.0229]; Genus Clostridiuminnocuumgroup [OR = 0.847, 95%CI (0.752, 0.955), P = 0.00646]; and Genus Lactococcus [OR = 0.886, 95%CI (0.796, 0.986), P = 0.0263]. The analysis of pleiotropy showed that the MR-Egger regression intercept P > 0.05 for all three, and the Q-pval > 0.05 for the heterogeneity analysis, indicating that there was no pleiotropy or heterogeneity in the above-mentioned bacterial groups. This study expands the intestinal flora associated with UC risk and provides a theoretical basis for further relevant experiments and clinical studies.
Objective:To compare drug leakage treatment with ice conpress with lidocaine,Dexamethasone,VitB 12 injection and injection of Dexamethasone,VitB 12.Method:In experiment group,leakage had been treated with lidocaine,Dexametharovce,VitB 12 and ice compress;In control group,leakage had been treated with Dex and VitB 12.Result:In experiment group,there are no skin change,less vein occlusure,or local scar formation;In control skin recovery need 10 days or so.In experiment group,painess show moderate because of shorter duration of needle inplantation,removemnt and injection also because of ice compress.Conclusion:Ice compress,lidocaine,Dex,VitB 12 can treat chemotherapy drugs leakage,with less painess,shorter duration,shorter recovery time for skin.
In this dissertation, I focus on the development of novel MS-based strategies to identify and quantify DNA lesions formed in isolated DNA and in cells to monitor the progression of enzymatic reactions in vitro and glyoxal or methylglyoxal exposure in vivo . In addition, a combined SILAC, one-step affinity purification and LC-MS/MS approach was employed for identifying systematically cellular proteins capable of binding to 6-thioguanine-containing duplex DNA. In Chapter 2, a stable isotope dilution coupled with LC-MS/MS/MS method was developed to quantify accurately DNA advance glycation end products (AGEs) including N 2 -carboxymethyl-2l-deoxyguanosine ( N 2 -CMdG), and two diastereomers of N 2 -(1-carboxyethyl)-2l-deoxyguanosine ( N 2 -CEdG) induced by hyperglycemia in calf thymus DNA, cellular DNA, rat and mouse tissues and human blood samples. The results showed that N 2 -CMdG and N 2 -CEdG were stable and the level of N 2 -CMdG and two diastereomers of N 2 -CEdG were higher in the liver tissues of diabetic mice than those of the healthy control. This work shows that N 2 -CMdG and N 2 -CEdG might serve as molecular biomarkers for monitoring glyoxal and methylglyoxal exposure.In Chapter 3, I established a novel restriction enzyme digestion coupled with LC-MS/MS method to investigate the effect of 6-thioguanine on the Hpa II- and DNMT1-mediated methylation of cytosine in synthetic duplex DNA. Moreover, the level of global cytosine methylation in different leukemia cell lines upon 6-thioguanine treatment was evaluated by an offline HPLC method. These results provided important new knowledge about the antileukemic effects of 6-thioguanine. In Chapter 4, 6-thioguanine and its metabolite, S 6 -methylthio-2l-deoxyguanosine in genomic DNA of five different cancer cell lines were accurately quantified by using LC-MS/MS. The data support our hypothesis that, after being incorporated into DNA, 6-thioguanine instead of S 6 -methylthio-2l-deoxyguanosine plays the major role to exert the cytotoxic effects of thiopurines. In addition, another nucleotide metabolite, 6-thioguanosine triphosphate was extracted and quantified by LC-MS/MS. In Chapter 5, a strategy, including SILAC, affinity purification and LC-MS/MS, was employed to identify nuclear proteins that are capable of binding to 6-thioguanine-containing duplex DNA. The outcome of the study will facilitate the exploration of other mechanisms involved in the cytotoxicity of the thiopurine drugs.
With the global trend of aging, stress urinary incontinence is becoming more common in older adults, which may have some impact on patients' quality of life. Social alienation can generate negative emotions such as anxiety, depression, loneliness, and morbid stigma, and reduce patients' quality of life. However, the current status of social alienation is different among different older adult female patients with stress urinary incontinence. Therefore, this study categorizes older adult female stress urinary incontinence patients through potential analysis to understand the category characteristics of social alienation level of older adult female stress urinary incontinence patients, and explores the influencing factors of social alienation level of different categories of older adult female stress urinary incontinence patients, which can provide a reference to personalized intervention programs for the characteristics of social alienation of older adult female stress urinary incontinence in the future. A convenience sampling method was used to select 365 cases of older adult female stress urinary incontinence patients from March 2023 to April 2024 in three communities in Jinzhou City. The General Information Questionnaire, the Family Care Index Scale, the Toronto Alexithymia Scale, and the General Alienation Scale were used to conduct the survey. A total of 365 respondents were included, and three potential categories of social alienation were finally identified, namely, low social alienation (29.0%), medium social alienation-self alienation (49.4%), and high social alienation (21.6%). The results of multifactorial logistic regression analysis showed that occupational status, marital status, whether living alone, place of residence, BMI, whether other chronic diseases, level of narrative disorders, and level of family care were the influencing factors of social alienation in older adult female patients with stress urinary incontinence (P < 0.05). The social alienation of older adult female patients with stress urinary incontinence is characterized by a significant number of categories, and healthcare professionals can identify the characteristics and influencing factors of each category at an early stage, which can provide a basis for the development of targeted clinical interventions to help patients reduce the level of social alienation.
Inhibition of the PD-1/PD-L1 interaction through small-molecule inhibitors is a promising therapeutic approach in cancer immunotherapy. Herein, we utilized BMS-202 as the lead compound to develop a series of novel PD-1/PD-L1 small-molecule inhibitors with a naphthyridin scaffold. Among these compounds, X14 displayed the most potent inhibitory activity for the PD-1/PD-L1 interaction (IC50 = 15.73 nM). Furthermore, X14 exhibited good binding affinity to both human PD-L1 (KD = 14.62 nM) and mouse PD-L1 (KD = 392 nM). In particular, X14 showed favorable pharmacokinetic properties (oral bioavailability, F = 58.0%). In the 4T1 (mouse breast cancer cells) syngeneic mouse model, intragastric administration of X14 at 10 mg/kg displayed significant antitumor efficacy (TGI = 66%). Mechanistic investigations revealed that X14 effectively enhanced T-cell infiltration within the tumor microenvironment. Our study demonstrates that compound X14 exhibits potential as a candidate compound for the development of orally effective small-molecule inhibitors targeting PD-1/PD-L1.
Effective systemic therapy is often necessary to treat hepatocellular carcinoma (HCC). We synthesized a Gal-PPE nanogel consisting of a cross-linked polyphosphate core and galactosylated poly(ethylene glycol) arms for enhanced doxorubicin delivery to diethylnitrosamine-induced HCC in rats. The Gal-PPE nanogel exhibited high affinity to HepG2 cells in vitro, mediated by the asialoglycoprotein receptor. In vivo studies revealed that the Gal-PPE nanogel was taken up more efficiently by hepatocytes, in contrast to m-PPE nanogel. Consequently, doxorubicin delivery with Gal-PPE significantly inhibited the progress of HCC, reducing neoplastic liver nodules and prolonging the survival time of HCC rats more significantly. These results demonstrate the potential of Gal-PPE as a nanocarrier for improved HCC chemotherapy.
Objective To investigate the synergistic effects of rosiglitazone(ROZ)and cisplatin on the growth of the human endometrial cancer cell line KLE xenografted to nude mice.Methods KLE cells were transplanted into nude mice to form the study model.When the models were established,they were randomly divided into 6 groups:the control group(A),the cisplatin1 mg/kg group(B),the cisplatin 3 mg/kg group(C),the ROZ 50 mg/kg group(D),the cisplatin1 mg/kg+ROZ 50 mg/kg group(E),and cisplatin 3 mg/kg+ROZ 50 mg/kg group(F).Cisplatin was given by intraperitoneal injection every two days and ROZ was intragastrically administered every day.During the period of observation,the volumes of the transplanted tumors were measured every 4 days.The tumor growth inhibitory rates of each group were calculated.Also,the curves of BALB/c-nude mice growth were drawn.After 38 days,BALB/c-nude mice were euthanized and xenograft tumors were measured.Expression of NF-κB and PTEN protein in subcutaneous tumors were determined by immunohistochemical method with an image analysis system.Results Significant differences in tumor inhibitory rates were found between the treatment groups and the control group(P0.05).The tumor inhibitory rate of B,C,D,E,F 5 group was 24.41%,43.34%,49.67%,78.02%,84.78%,respectively,and the combination group showed synergistic effect on inhibiting the growth of the xenografts.Contrary to the control group,expression of subcutaneous tumor NF-κB was down-regulated and PTEN was obviously up-regulated by rosiglitazone and its combination with cisplatin.Conclusion Rosiglitazone could enhance inhibition of the growth of endometrial tumor in combination with cisplatin.
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