Objective To analyze the types and distribution of microbiome in intestinal and lung tissues of children with asthma, and to explore the correlation between microbiota changes and asthma. Methods From 2021 to 2023, a total of 28,939 children with asthma who visited Ezhou Central Hospital, Maternal and Child Health Hospital or Ezhou Egang Hospital were selected as the study subjects, and 2,000 healthy children who underwent outpatient physical examinations at these three hospitals during the same period were selected as the control group. The distribution and characteristics of intestinal and pulmonary microbiome in the two groups were analyzed by 16SrDNA sequencing. Logistic regression analysis model was used to analyze the correlation between microbiota distribution and asthma occurrence. Results In the intestinal tissues of children with asthma compared to healthy children, the abundance of Bacteroidetes at the phylum level decreased, while the abundance of Firmicutes and Proteobacteria increased significantly (P<0.05), and the abundance of Prevotalle and Clostridium at the genus level increased significantly. In lung tissues of asthmatic children compared to health children, the abundance of Firmicutes at the phylum level decreased while the abundance of Proteobacteria increased significantly (P<0.05), and the abundance of Neisseria, Prevotella and Actinomyces at the genus level increased significantly. Binary logistic regression results showed that the abundances of Lactobacillus (OR=0.842, 95% CI: 0.533-0.947), Bacteroides fragilis (OR=0.649, 95%CI: 0.377-0.890), Bifidobacterium (OR=0.901, 95% CI: 0.633-0.994), and Parabacteroides distasonis (OR=0.547, 95% CI: 0.192-0.708) in the intestinal tissues were all protective factors for the asthma in children. In the lung tissue, the abundance of Neisseria (OR=2.140, 95% CI: 1.749-3.305) was a risk factor for the asthma in children, and Prevotella (OR=0.691, 95% CI: 0.491-0.926) was a protective factor for the asthma in children (P<0.05). Conclusion The dysbiosis of intestinal and pulmonary microbiome is closely related to the occurrence of asthma in children, and the detection of microbiota is of great significance for the diagnosis of childhood asthma.

Neuroendocrine carcinoma (NEC) represents a category of malignant tumors originating from neuroendocrine cells. Given that NEC cells exhibit characteristics of both neural and endocrine cells, they can hijack neuronal signaling pathways and dynamically regulate the expression of neuronal lineage markers during tumor metastasis, thereby constructing a microenvironment conducive to tumor growth and metastasis. Conversely, alterations in the tumor microenvironment can enhance the interactions between neurons and tumor cells, ultimately synergistically promoting the metastasis of NEC. This review highlights recent advancements in the field of cancer neuroscience, uncovering neuronal lineage markers in NEC that facilitate tumor dissemination through mediating crosstalk, bidirectional communication, and synergistic interactions between tumor cells and the nervous system. Consequently, the latest findings in tumor neuroscience have enriched our understanding of the biological mechanisms underlying tumor metastasis, opening new research avenues for a deeper comprehension of the complex biological processes involved in tumor metastasis, particularly brain metastasis. This review provides a comprehensive review of the crosstalk between tumor cells and neural signaling in the metastasis of NEC.
.
Humans ; Carcinoma, Neuroendocrine/metabolism* ; Signal Transduction ; Animals ; Neoplasm Metastasis ; Neurons/pathology* ; Tumor Microenvironment ; Cell Communication

Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.

Objective:To investigate the clinical features, molecular etiology, and treatment of a family with Treacher Collins Syndrome 2 (TCS2).Methods:Information of the proband (female, 8 years old) including medical history and family history was collected. Physical examination and examinations concerning laboratory, audiology, and radiology were performed on the proband. Physical examination was also performed on the family members. Genomic DNA of proband was extracted for whole exome sequencing, and then the genomic DNA of family members was extracted for Sanger sequencing. POLR1D and TCS2 related literatures published before August 31,2023 were searched and sifted in PubMed and CKNI databases. The clinical characteristics of TCS2 were summarized. Results:The proband had poor hearing since childhood, with pure tone audiometry indicating conductive hearing loss. She had a smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities. Temporal bone CT scan revealed deformities in the left external ear canal, bilateral middle ear and inner ear. A bone-conduction hearing aid device was surgically implanted, resulting in restoration of almost normal hearing levels. The proband′s mother also had a slightly smaller jaw. Genetic analysis revealed a novel heterozygous variant NM_015972.4:c.38_47del in the POLR1D gene in the proband, which was inherited from her mother. A review of the literature revealed no clear evidence of genotype-phenotype correlation in TCS2. Conclusions:Molecular diagnosis plays a vital role in the diagnosis of TCS2. Patients with normal facial phenotype may be carriers of pathogenic variants in the POLR1D gene and have the risk of passing it to the offsprings with complete penetrance. Proper bone conductive hearing devices can improve the quality of life of TCS2 patients.

Objective To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism.Methods Sixteen pregnant Kunming mice were randomly assigned into two groups(n=8)for intratracheal instillation of PBS or PM2.5 suspension at 1.5,7.5,and 12.5 days of gestation.The pregnancy outcome of the mice was observed,and placental zonal structure and vascular density of the labyrinth area were examined with HE staining,followed by detection of ferroptosis-related indexes in the placenta.In cultured human trophoblasts(HTR8/SVneo cells),the effects of PM2.5 exposure and treatment with metformin on cell viability,proliferation,migration,invasion,and tube formation ability were evaluated using CCK8 assay,EDU staining,wound healing assay,Transwell experiment,and tube formation experiment;the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting.Results M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight(all P<0.001).PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis.In cultured HTR8/SVneo cells,PM2.5 significantly inhibited proliferation,migration,invasion,and angiogenesis of the cells by causing ferroptosis.Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation,migration,invasion,and angiogenesis of the cells,and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity,reduced MDA and Fe2+ levels,and upregulated GPX4 and SLC7A11 protein expression(P<0.05 or 0.01).Conclusion PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice,and metformin can effectively alleviate PM2.5-induced trophoblast impairment.

Objective To evaluate the efficacy of medroxyprogesterone acetate(MA)plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia(AEH)and early-stage grade 1 endometrial adenocarcinoma(G1 EAC)and the recurrence rate after treatment.Methods Sixty patients(aged 20-42 years)with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups(n=30)to receive oral MA treatment at the daily dose of 160 mg(control)or MA plus oral metformin(850 mg,twice a day)for at least 6 months.The treatment could extend to 12 months until a complete response(CR)was achieved,and follow-up hysteroscopy and curettage were performed every 3 months.For all the patients who achieved CR,endometrial expressions of IGFBP-rP1,p-Akt and p-AMPK were detected immunohistochemically.Results A total of 58 patients completed the treatment.After 9 months of treatment,23(76.7%)patients in the combined treatment group and 20(71.4%)in the control group achieved CR;two patients in the control group achieved CR after converting to the combined treatment.The recurrence rate did not differ significantly between the control group and combined treatment group(30.0%vs 22.7%,P>0.05).Ten(35.7%)patients in the control group experienced significant weight gain of 5.7±6.1 kg,while none of the patients receiving the combined treatment exhibited significant body weight changes.Compared with the control group,the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression.Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC,and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

Objective To investigate the protective effect of metformin against PM2.5-induced functional impairment of placental trophoblasts and explore the underlying mechanism.Methods Sixteen pregnant Kunming mice were randomly assigned into two groups(n=8)for intratracheal instillation of PBS or PM2.5 suspension at 1.5,7.5,and 12.5 days of gestation.The pregnancy outcome of the mice was observed,and placental zonal structure and vascular density of the labyrinth area were examined with HE staining,followed by detection of ferroptosis-related indexes in the placenta.In cultured human trophoblasts(HTR8/SVneo cells),the effects of PM2.5 exposure and treatment with metformin on cell viability,proliferation,migration,invasion,and tube formation ability were evaluated using CCK8 assay,EDU staining,wound healing assay,Transwell experiment,and tube formation experiment;the cellular expressions of ferroptosis-related proteins were analyzed using ELISA and Western blotting.Results M2.5 exposure of the mice during pregnancy resulted in significantly decreased weight and number of the fetuses and increased fetal mortality with a reduced placental weight(all P<0.001).PM2.5 exposure also caused obvious impairment of the placental structure and trophoblast ferroptosis.In cultured HTR8/SVneo cells,PM2.5 significantly inhibited proliferation,migration,invasion,and angiogenesis of the cells by causing ferroptosis.Metformin treatment obviously attenuated PM2.5-induced inhibition of proliferation,migration,invasion,and angiogenesis of the cells,and effectively reversed PM2.5-induced ferroptosis in the trophoblasts as shown by significantly increased intracellular GSH level and SOD activity,reduced MDA and Fe2+ levels,and upregulated GPX4 and SLC7A11 protein expression(P<0.05 or 0.01).Conclusion PM2.5 exposure during pregnancy causes adverse pregnancy outcomes and ferroptosis and functional impairment of placental trophoblasts in mice,and metformin can effectively alleviate PM2.5-induced trophoblast impairment.

Objective To evaluate the efficacy of medroxyprogesterone acetate(MA)plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia(AEH)and early-stage grade 1 endometrial adenocarcinoma(G1 EAC)and the recurrence rate after treatment.Methods Sixty patients(aged 20-42 years)with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups(n=30)to receive oral MA treatment at the daily dose of 160 mg(control)or MA plus oral metformin(850 mg,twice a day)for at least 6 months.The treatment could extend to 12 months until a complete response(CR)was achieved,and follow-up hysteroscopy and curettage were performed every 3 months.For all the patients who achieved CR,endometrial expressions of IGFBP-rP1,p-Akt and p-AMPK were detected immunohistochemically.Results A total of 58 patients completed the treatment.After 9 months of treatment,23(76.7%)patients in the combined treatment group and 20(71.4%)in the control group achieved CR;two patients in the control group achieved CR after converting to the combined treatment.The recurrence rate did not differ significantly between the control group and combined treatment group(30.0%vs 22.7%,P>0.05).Ten(35.7%)patients in the control group experienced significant weight gain of 5.7±6.1 kg,while none of the patients receiving the combined treatment exhibited significant body weight changes.Compared with the control group,the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression.Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC,and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

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.

Objective:To explore the predictive value of early serum tumor markers (STM) , neutrophil to lymphocyte ratio (NLR) , platelet to lymphocyte ratio (PLR) combination score on the efficacy of gastric cancer immunotherapy.Methods:A total of 76 patients with gastric cancer who received immunotherapy at Second Affiliated Hospital of Shandong First Medical University from January 1, 2020 to June 30, 2022 were selected. Patients' leading STM, NLR, PLR were collected. Optimal cut-off value of NLR and PLR were determined by the receiver operating characteristic (ROC) curve. The clinical efficacy and prognosis of different leading STM, NLR, PLR and combined scores in gastric cancer patients received immunotherapy were analyzed. ROC curve was used to evaluate the predictive efficiency of each index and the combined score. Cox regression model was used to analyze the factors affecting patients' survival.Results:The best truncation value for NLR was 2.75, and the best truncation value for PLR was 175.9. All patients completed at least 2 cycles of immunotherapy, the objective response rate (ORR) was 23.7% (18/76) , and the disease control rate (DCR) was 88.2% (67/76) . There were no significant differences in ORR [ (20.9% (9/43) vs. 27.3% (9/33) ], DCR [83.7% (36/43) vs. 93.9% (31/33) ] between the high NLR group ( n=43) and low NLR group ( n=33) ( χ2=0.42, P=0.519; χ2=1.02, P=0.313) . There were no significant differences in ORR [27.3% (12/44) vs. 18.8% (6/32) ], DCR [81.8% (36/44) vs. 96.9% (31/32) ] between the high PLR group ( n=44) and low PLR group ( n=32) ( χ2=0.75, P=0.388; χ2=2.71, P=0.555) . The ORR for the high combined score group ( n=39) and low combined score group ( n=37) was 17.9% (7/39) and 29.7% (11/37) , respectively, with no statistically significant difference ( χ2=1.46, P=0.230) ; the DCR was 79.5% (31/39) and 97.3% (36/37) , respectively, with a statistically significant difference ( χ2=4.19, P=0.041) . The median progression free survival (PFS) and overall survival (OS) of 76 patients were 8.0 and 12.0 months. The median PFS in the high NLR group and low NLR group was 7.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=7.95, P=0.005) ; the median OS was 12.0 and 14.0 months, respectively, with no statistically significant difference ( χ2=1.04, P=0.307) . The median PFS in the high PLR group and low PLR group was 8.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=3.90, P=0.048) ; the median OS was 13.0 and 13.0 months, respectively, with no significant difference ( χ2=0.02, P=0.896) . The median PFS in the high combined score group and low combined score group was 7.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=13.52, P<0.001) ; the median OS was 12.0 and 14.0 months, respectively, with a statistically significant difference ( χ2=5.02, P=0.025) . ROC curve analysis showed that the area under curve (AUC) of leading STM, NLR, PLR and combined score to predict the efficacy of gastric cancer immunotherapy was 0.662, 0.697, 0.601 and 0.773. Univariate analysis showed that, surgery ( HR=0.59, 95% CI: 0.36-0.95, P=0.031) , leading STM ( HR=0.57, 95% CI: 0.34-0.93, P=0.026) , NLR ( HR=0.54, 95% CI: 0.34-0.87, P=0.011) , combined score ( HR=0.42, 95% CI: 0.26-0.68, P<0.001) were all influencing factors for PFS in gastric cancer patients received immunotherapy; tumor stage ( HR=0.30, 95% CI: 0.12-0.75, P=0.011) , leading STM ( HR=0.28, 95% CI: 0.15-0.50, P<0.001) , combined score ( HR=0.55, 95% CI: 0.31-0.96, P=0.036) were all influencing factors for OS in gastric cancer patients received immunotherapy. Multivariate analysis showed that, leading STM ( HR=0.56, 95% CI: 0.33-0.98, P=0.041) was an independent influencing factor for PFS in gastric cancer patients received immunotherapy; tumor stage ( HR=0.29, 95% CI: 0.11-0.76, P=0.012) , leading STM ( HR=0.32, 95% CI: 0.17-0.58, P<0.001) , combined score ( HR=0.46, 95% CI: 0.25-0.82, P=0.009) were all independent influencing factors for OS in gastric cancer patients received immunotherapy. Conclusion:The combined score of leading STM, NLR and PLR is an independent factor influencing OS in patients receiving immunotherapy for gastric cancer, and can predict the efficacy of immunotherapy for gastric cancer.