Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Humans ; Perinatology ; Delivery of Health Care

Humans ; Transcranial Magnetic Stimulation ; Pain Management ; Psychotic Disorders/therapy* ; Depressive Disorder, Major ; Treatment Outcome ; Transcranial Direct Current Stimulation

Stem cell transplantation holds a promising future for central nervous system repair. Current challenges, however, include spatially and temporally defined cell differentiation and maturation, plus the integration of transplanted neural cells into host circuits. Here we discuss the potential advantages of neuromodulation-based stem cell therapy, which can improve the viability and proliferation of stem cells, guide migration to the repair site, orchestrate the differentiation process, and promote the integration of neural circuitry for functional rehabilitation. All these advantages of neuromodulation make it one potentially valuable tool for further improving the efficiency of stem cell transplantation.

Objective:To compare the results of high-resolution colonic manometry (HRCM) in patients with four subtypes of constipation: slow transit constipation(STC), outlet obstruction constipation (OOC), mixed STC and OOC, and normal transit constipation(NTC), and to explore the intestinal motility characteristics of patients with different subtypes of constipation.Methods:From 20th January 2017 to 20th September 2020, the HRCM results of 225 patients with functional constipation who visited the Department of Anorectal Surgery of Tianjin Union Medical Center were retrospectively analyzed. According to the results of colonic transit test, 225 patients were divided into STC group (108 cases), OOC group (36 cases), mixed group (28 cases) and NTC group (53 cases). General information such as Wexner constipation scores, clinical symptoms (decreased desire to defecate, sensation of anorectal blockage, hand-assisted defecation, spontaneous bowel movements frequency<3 times per week), the incidence, frequency within one day (hereinafter referred to as frequency), average velocity, average wave amplitude, average duration of contraction, average length of contraction, and the dynamic index (DI) of average pressure of high-amplitude propagating contraction (HAPC), as well as the frequency, average wave amplitude, average duration of contraction, and the DI of average pressure of low-amplitude propagating contraction (LAPC) were compared among the four groups. One-way ANOVA and multiple comparison, Kruskal-Wallis test and chi-square test were used for statistical analysis.Results:The Wexner constipation scores of the STC, OOC, mixed and NTC group were 13.17±4.04, 13.97±4.55, 11.36±4.03 and 11.58±4.06, respectively, and the difference was statistically significant ( F=3.879, P<0.05). The Wexner consipation scores of the STC and OOC group were both higher than the mixed and NTC group, and the difference were statistically significant (One-way ANOVA and multiple comparison, all P<0.05). The proportion of decreased desire to defecate, sensation of anorectal blockage, hand-assisted defecation, spontaneous bowel movements frequency<3 times per week of STC, OOC, mixed and NTC group were 47.2% (51/108), 36.1% (13/36), 14.3% (4/28), 20.8% (11/53); 42.6% (46/108), 75.0% (27/36), 46.4% (13/28), 64.2% (34/ 53); 31.5% (34/108), 38.9% (14/36), 3.6% (1/28), 18.9% (10/53); 90.7% (98/108), 77.8% (28/36), 82.1% (23/28) and 62.3% (33/53), and the differences were statistically significant ( χ2=17.093, 12.463, 13.437 and 18.927; all P<0.01). The proportion of decreased desire to defecate of STC group was higher than that of mixed and NTC group, and spontaneous bowel movements frequency<3 times per week was higher than that of OOC and NTC group, and the differences were statistically significant ( χ2=10.014, 10.518, 4.418 and 19.016; all P<0.05). The proportion of sensation of anorectal blockage of OOC group was higher than that of STC and mixed group, and the proportion of hand-assisted defecation was higher than that of the mixed and NTC group, and the differences were statistically significant ( χ2= 9.511, 5.486, 10.948 and 4.363, all P<0.05). The incidence of HAPC in STC, OOC, mixed and NTC groups was 39.8% (43/108), 36.1% (13/36), 57.1% (16/28), and 60.4% (32/53), respectively, and the difference was statistically significant ( χ2=8.880, P=0.031). The incidence of HAPC in STC group and OOC group were lower than that of NTC group, and the differences were statistically significant ( χ2=6.041 and 5.050, P=0.014 and 0.025). There were no statistically significant difference in the frequency, average velocity, average amplitude, average duration of contraction, average length of contraction and DI of pressure of HAPC in four groups, and there were no statistically significant difference in the frequency, average amplitude, average duration of contraction, and DI of pressure of LAPC in the four groups (all P>0.05). Conclusions:Doctors can more clearly and objectively observe the intestinal motility characteristics of patients with different subtypes of constipation through HRCM. HRCM provides a strong basis for the diagnosis and further treatment of functional constipation, and has a high clinical application value.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The metabolic changes of atrial myocytes, especially lipid metabolism, have a significant impact on the electrical signals and structural remodeling of atrial tissue, and play an important role in the occurrence and development of AF. The reduction of fatty acid oxidation ratio and increased aerobic glycolysis ratio are characteristic changes of tissue metabolic remodeling in AF. In this review, we will introduce the latest research status of lipid metabolism in AF from aspects of AF metabolism, clinical treatment and diagnosis and prognosis.

Objective: To investigate the preparation of bioactive denatured acellular dermal matrix (DADM) from burn mice riched in mice bone marrow mesenchymal stem cells. Methods: Twelve BALB/c mice were collected and 20% total body surface area scalds (hereinafter referred to as burns) with deep partial thickness were inflicted on the back skin of each mouse. After removing epidermis, the burned skin were collected and divided into Triton X-100 group and elhylene diamine tetraacetic acid (EDTA) group according to the random number table, with 15 samples in each group. Samples in Triton X-100 group and EDTA group were respectively placed in mixture of 2.5 g/L Triton X-100 and 2.5 g/L trypsin solution and mixture of 0.2 g/L EDTA and 2.5 g/L trypsin solution for sustained vibration and elution for 24 hours to make mice DADM. The general appearance of DADM was observed. The structure and arrangement of collagen fibers of DADM were observed by scanning electron microscope and tissue structure of DADM were observed by fluorescence microscope. Bone marrow mesenchymal stem cells (BMSCs) from mice were transplanted in mice DADM in the two groups with concentration of 2×105 cells per well to prepare bioactive mice DADM. After cultured for 3 days, tissue structure of bioactive mice DADM was observed by hematoxylin and eosin staining, distribution and number of BMSCs of bioactive mice DADM were observed by immunofluorescence staining. Proliferation of BMSCs of bioactive mice DADM after cultured for 2 h, 1 d, 3 d, and 5 d was detected by cell count kit-8. Data were processed with analysis of variance for repeated measurement and t test. Results: (1) Mice DADM in the two groups were white in appearance with certain tenacity and elasticity. Mice DADM in the two groups maintained good three-dimensional porous network structure. Collagen fibers of mice DADM in EDTA group were with good continuity, and collagen fibers of mice DADM in Triton X-100 group were fractured in varying degrees. Mice DADM in the two groups were decellularized completely, and the collagen fibers were loose and arranged disorderly. The continuity of tissue structure of mice DADM in EDTA group was better than that of mice DADM in Triton X-100 group. (2) After cultured for 3 days, the BMSCs in bioactive mice DADM in the two groups were evenly distributed. The number of bioactive BMSCs in mice DADM in EDTA group was 37±7, which was significantly more than that of mice DADM in Triton X-100 group (25±8, t=0.128, P<0.05). The proliferation of bioactive BMSCs in mice DADM in Triton X-100 group and EDTA group was similar at 2 hours and on day 1 after cultured (t=1.292, 0.656, P>0.05). On 3, 5 days after cultured, the proliferation of bioactive BMSCs in mice DADM in EDTA group was significantly higher than that of mice DADM in Triton X-100 group (t=2.309, 14.128, P<0.05 or P<0.01). Conclusions Mice DADM prepared by decellularization of EDTA has better three-dimensional porous network structure and good continuity of collagen fiber. The BMSCs in bioactive DADM from burn mice prepared by transplanting BMSCs are evenly distributed with large quantity and strong proliferative capacity, which has the potential to be good autologous dermal substitute.

Objective To develop a PCR-ELISA assay for the rapid, specific and sensitive detec-tion of human seasonal influenza virus ( H1, H3 and B) by using molecular biological and immunological methods in combination.Methods The primers were designed according to the genes encoding the matrix protein ( M) , the H1 and H3 hemagglutinin ( HA) of influenza A virus and the nonstructural proteins ( B-NS) of influenza B virus and then were labeled with biotin.The PCR products were detected by ELISA by use of an internal catching probe labeled with DIG.Results The minimum copy numbers of genes encoding the M, H1, H3 and B-NS proteins detected by the established assay were 1.43?103 , 8.67?102 , 3.86?103 and 5.45?103 copies/μl, respectively, which indicated that the PCR-ELISA assay was about 10 times more sensitive than agarose gel electrophoresis in the detection of PCR products.No cross-reactions between the different subtypes of influenza virus or different species of virus were observed.Moreover, a total of 104 clin-ical specimens of influenza virus were examined by the PCR-ELISA assay, the results of which were consist-ent with those of the virus isolation method.Conclusion The newly developed PCR-ELISA assay was a highly sensitive and specific method for the rapid detection and subtyping of influenza virus, suggesting the possibility of using it in laboratory for the surveillance and detection of influenza virus.

Objective To establish a double-antibody sandwich ELISA for the rapid detection of shiga toxin typeⅡ ( StxⅡ) in shiga toxin-producing Escherichia coli ( STEC) infection. Methods A pool of murine hybridomas was used to screen out the optimal antibody pair for the establishment of double-anti-body sandwich ELISA. The established ELISA system was used to detect StxⅡin the culture supernatants of 16 clinical strains of STEC. Specificity and sensitivity of the established ELISA system were also evaluated. Results Two antibodies, S2D8 and S2C6, were successfully screened out, based on which the double-anti-body sandwich ELISA was set up. StxⅡand its variants rather than StxⅠwas detected in the culture super-natants of STEC with a lowest detection limit of 4 ng/ml. Its performance was consistent with that of commer-cial colloidal gold test kit, indicating the characteristics of good specificity and sensitivity. Conclusion The S2D8/S2C6-based ELISA laid a foundation for researches which designates the shiga toxin as a potential can-didate on the diagnosis and therapy of STEC infection.

Phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is involved in many important biological processes such as cell metabolism, growth, proliferation, and angiogenesis. And its high-level activation is closely related to the development and progression of many malignant tumors. In this paper, mTOR and PI3K/Akt/mTOR signaling pathway are introduced, and their action mechanisms in the development and progression of hepatocellular carcinoma, cholangiocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma are expounded, and then the role of mTOR inhibitors in the treatment of malignant hepatobiliary tumors is briefly described. It is thought that the PI3K/Akt/mTOR signaling pathway provides new therapeutic targets for malignant hepatobiliary tumors in advanced stage and the constant development of new mTOR inhibitors provides some new hope for the patients with malignant hepatobiliary tumors in advanced stage.