Objective:To study the correlation between deposition of C4d along peritubular capillaries (PTC) and interstitial eosinophilic infiltration in renal allografts.Methods:Deposition of C4d in kidneys was assayed by indirect immunoflourescence of the renal allograft biopsies.Twenty-six patients were demonstrated strongly diffuse staining of PTC,who were defined as C4d+ group,while the biopsies of thirty patients with acute rejection exhibited negative for PTC C4d staining served as the controls,who were defined as C4d-group.Eosinophils were counted under microscope.Results:The C4d+group was demonstrated significantly greater interstitial eosinophilic infiltration than did the C4d-group(P

Objective To investigate the inhibition effects of an hTERT-promoter-dependent oncolytic adenovirus Ad-VT that expresses apoptin on human prostatic carcinoma cell PC-3. Methods MTT assay was used to measure viability of PC-3 cell which was infected by recombinant adenovirus.The viability was measured at time points of 12,24,36,48,60,72,84 and 96 h after infection.AO/EB staining,DAPI staining,Annexin V assay were used to investigate the lethal effect and style of Ad-VT on PC-3 cell in vitro.The Caspases were measured by whole cell extraction of PC-3 cells 48hrs after infection. Results Ad-VT,Ad-VP3 and Ad-GT inhibited the proliferation of PC-3 cell in vitro.Ad-VT and Ad-GT were more effective than Ad-VP3 on cell growth,P ＜ 0.05.At 48,72,96 h time points,the inhibition effect of Ad-VT on PC-3 cell exhibited a dose related manner.When infection at MOI 100,the inhibition effect of Ad-VT on PC-3 cells exhibited time related manner.The AO/EB staining,DAPI staining,Annexin V assay,Annexin V assays and Caspase assays showed that Ad-VT inhibited the proliferation of PC-3 cells by inducing apoptosis of prostate cancer cells,Loss of cytoplasmic membrane integrity. Conclusions The hTERT-promoterdependent oncolytic adenovirus Ad-VT could effectively suppress prostate cancer cells PC-3 growth.

Imaging is an essential tool in the management of spinal disorders. Most spine surgeons focus on bony structures and the spinal cord when reading imaging examinations, while the interpretation of the morphology and characteristics of soft tissues such as paraspinal muscles and fat has been a "relative blind spot". As the imaging features of the non-bony structures of the spine have been studied and reinterpreted, it has become clear that these non-bony structural changes are also associated with spinal diseases. Soft tissue parameters such as "paraspinal muscle cross-sectional area," "subcutaneous fat thickness," and "paraspinal muscle fat infiltration rate" on CT, MRI, and other imaging studies have been shown to play a role in spine diseases, and have been shown to be reproducible in the diagnosis, treatment and prognosis of spinal disorders and have potential for clinical application. In addition, the association of sarcopenia and spinal epidural lipomatosis with spinal disorders is gaining attention. In recent years, with a better understanding of the pathogenesis of spinal disorders, techniques such as 3D gait analysis and photographic postural measurement have also shown promise in the diagnosis and assessment of the outcome of degenerative spinal disorders and adolescent idiopathic scoliosis. In view of this, this article summarizes the latest research progress in the basic and clinical aspects of non-bony structures of the spine and analyzes the significance of the imaging features of these non-bony structures in the basic research and diagnosis of spinal diseases.

The changes in intestinal flora are usually associated with different gastrointestinal diseases, and intestinal flora homeostasis can enhance immune tolerance and regulate intestinal immune balance.Previous studies have found that the increase of the relative abundance of Bacteroides fragilis (B.fragilis) in Bacteroides intestinalis can significantly enhance the expression of intestinal regulatory T cells (Treg) and anti-inflammatory cytokines, thus alleviating intestinal inflammation.However, the mechanism of B.fragilis regulating intestinal immunity is still unclear.In this study, an acute colitis model was constructed by giving 3% DSS in drinking water solution to SPF-grade C57BL/6 mice for 7 days, and exogenous supplementation B.fragilis was given to mice by gastric gavage to study its regulatory effect on intestinal immunity and its mechanism of action.The results showed that B.fragilis could improve the intestinal flora disorder in mice with colitis and increase the content of short-chain fatty acids (SCFAs), the main metabolite of the intestinal flora.By extracting mouse tissue lymphocytes, naive CD4+ T cells, and liposome-modified siRNA knockdown mouse Smad3, it was further discovered by flow cytometry that B.fragilis induced the expression of intestinal Treg cells and related cytokines through the TGF-β/Smad3 signaling pathway, which enhanced intestinal regulatory immunity and alleviated colitis.It was also found that B.fragilis activated TGF-β by increasing the expression of reactive oxygen species (ROS), thus inducing Treg cell differentiation and playing an immunomodulatory role.

Objective:To assess the value of cerebral small vessel disease (CSVD) burden in predicting prognosis in acute ischemic stroke (AIS) patients with anterior circulation large vessel occlusion (LVO) after endovascular therapy (EVT).Methods:The study was a cross-sectional study. A total of 242 patients with AIS due to anterior circulation LVO received EVT in the First Affiliated Hospital of Nanjing Medical University from February 2018 to September 2022. The clinical and imaging data of all patients were analyzed retrospectively. On follow-up MRI within 7 days after EVT, CSVD features [white matter hyperintensity (WMH), lacune, perivascular space, cerebral microbleed, cerebral atrophy] and CSVD burden score (0-5) was evaluated. Modified Rankin scale (mRS) score at 90 days after EVT was assessed. Patients were categorized into a mild burden group (0-1 points) and a moderate-severe burden group (2-5 points) based on CSVD burden score. Meanwhile, patients were categorized into a good prognosis group (0-2 points) and a bad prognosis group (3-6 points) based on mRS score at 90 days after EVT. Mann-Whitney U test and χ2 test were used to compare the difference of clinical and imaging indexes between the 2 groups, and variables with P<0.1 in the univariate analysis were included in the multifactorial logistic regression to screen for independent factors to predict the prognosis. Results:There were 169 patients in the good prognosis group and 73 patients in the bad prognosis group out of 242 patients. Compared with the good prognosis group, age, incidence of hyperlipidemia, baseline National Institutes of Health Stroke Scale (NIHSS) scores, incidence of hemorrhagic conversion, CSVD burden scores, incidence of periventricular WMH scores of 3 and/or deep WMH scores≥2, and incidence of moderate-severe cerebral atrophy of patients in the bad prognosis group were higher, and the incidence of complete recanalization was lower (all P<0.05). Multivariate analysis showed hyperlipemia ( OR=8.438, 95% CI 1.691-42.119, P=0.009), baseline NIHSS score ( OR=1.103, 95% CI 1.047-1.162, P<0.001), complete recanalization ( OR=0.131, 95% CI 0.038-0.454, P=0.001) and hemorrhage transformation ( OR=1.952, 95% CI 1.031-3.697, P=0.040) were independent factors for the prognosis of EVT in patients with LVO AIS. There were 157 cases in the mild burden group and 85 cases in the moderate-severe burden group. The 90-day mRS score was higher in the moderate-severe burden group compared with the mild burden group ( Z=-2.24, P=0.025). Conclusion:CSVD burden has some clinical implications in predicting the prognosis of EVT in patients with anterior circulation LVO AIS.

Colorectal cancer (CRC) has a high incidence and mortality rate worldwide. Its lesions are associated to gene mutation, epigenetic changes and activation of related signaling pathways. microRNAs (miRNAs) are a class of non-coding RNAs of 20-24 nt in length that can regulate the expression of target mRNAs and control various cellular mechanisms. As a novel marker for the treatment and prognosis of colorectal cancer, miRNAs are closely related to the occurrence and progression of colorectal cancer. In this review, we summarize the miRNAs dysregulated in CRC tissues, analyze the relationship between specific miRNAs and CRC proliferation, metastasis, apoptosis, and chemotherapy, and present the clinical applications of miRNAs in CRC treatment and prognosis.

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
Humans ; Cell Cycle/physiology* ; Cell Division ; Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism*

Objective To explore the effect and mechanism of penehyclidine hydrochloride (PHCD) on vascular endothelial injury in septic rats. Methods Fifty male SD rats were randomly divided into control group, lipopolysaccharide (LPS) induced sepsis group (model group), low dose PHCD (0.3 mg/kg) group, medium dose PHCD (1.0 mg/kg) group and high dose PHCD (3.0 mg/kg) groups, ten mice for each group. Normal saline was injected into the tail vein of the control group, and 10 mg/kg lipopolysaccharide (LPS) was injected into the tail vein of the rats in other groups to prepare the sepsis rat models. After the models were successfully established, low, medium and high doses (0.3, 1.0, 3.0 mg/kg) of PHCD solution were injected into the tail vein of the rats of corresponding groups. Wet/dry mass ratio (W/D) of lung tissue of rats in each group was measured, and ELISA was used to assay interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 content and rat plasma angiopoietin 2 (Ang2) content in bronchoalveolar lavage fluid (BALF). HE staining was used to observe the pathological changes of lung tissues. Immunohistochemical staining was used to observe the expression of Ang2 in the right lung tissues. Western blot analysis was performed to detect Ang2 and vascular endothelial cadherin (VE-cadherin) protein in lung tissues. Results Compared with the control group, the W/D ratio of the lung tissues of rats in the model group and the contents of IL-1β, IL-6 and TNF-α in BALF were significantly increased; the lung tissues showed obvious pathological damage, with up-regulation of Ang2 expression and down-regulation of VE-Cadherin expression. Compared with the model group, the W/D ratio of the lung tissues of rats in three PHCD treatment groups and the contents of IL-1β, IL-6 and TNF-α in BALF were significantly reduced; the pathological damage of lung tissue was significantly reduced, with down-regulation of Ang2 expression and up-regulation of VE-cadherin expression. Conclusion PHCD can reduce LPS-induced lung inflammation in rats with sepsis by regulating the Ang2/VE-Cadherin pathway, thereby improving vascular endothelial injury.
Rats ; Mice ; Animals ; Male ; Lipopolysaccharides/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Angiopoietin-2/pharmacology* ; Interleukin-6/metabolism* ; Rats, Sprague-Dawley ; Lung ; Acute Lung Injury/metabolism* ; Sepsis/metabolism*

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone