The immunologic role of IL-23 in psoriatic arthritis: a potential therapeutic target.

INTRODUCTION: Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA. AREAS COVERED: This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: 'IL-23 and psoriatic arthritis,' 'Ustekinumab,' 'Guselkumab,' 'Risankizumab,' and 'Tildrakizumab.' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP. EXPERT OPINION: Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.

gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity.

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one ß-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 ß-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many ß-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

Therapeutic strategies and predictive models for Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma in adults based on data of two Chinese medical centers.

OBJECTIVE: This study aims to establish an effective predictive model for predicting Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma (TFE3-RCC) and develop optimal therapeutic strategies. METHODS: Data from 4961 patients diagnosed with renal cell carcinoma at two medical centers in China were retrospectively analyzed. A cohort of 1571 patients from Zhejiang Provincial People's Hospital (Ra cohort) was selected to construct the model. Another cohort of 1124 patients from the Second Affiliated Hospital of Zhejiang Chinese Medical University was used for external validation (the Ha cohort). All patients with TFE3-RCC in both cohorts were included in the Ta cohort for the prognostic analysis. Univariate and multivariate binary logistic regression analyses were performed to identify independent predictors of the predictive nomogram. The apparent performance of the model was validated. Decision curve analysis was also performed to assess the clinical utility of the developed model. Factors associated with progression and prognosis in the Ta cohort were analyzed using the log-rank method, and Cox regression analysis and Kaplan-Meier survival curves were used to describe the effects of factors on prognosis and progression. RESULTS: Univariate and multivariate logistic regression analyses demonstrated that age, sex, BMI, smoking, eosinophils, and LDL were independent predictors of TFE3-RCC. Therefore, a predictive nomogram for TFE3-RCC, which had good discriminatory power (AUC = 0.796), was constructed. External validation (AUC = 0.806) also revealed good predictive ability. The calibration curves displayed good consistency between the predicted and observed incidences of TFE3-RCC. Invasion of regional lymph nodes, tyrosine kinase inhibitors, and surgical methods were independent factors associated with progression. Tyrosine kinase inhibitors are independent prognostic factors. CONCLUSION: This study not only proposed a high-precision clinical prediction model composed of various variables for the early diagnosis of Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma but also optimized therapeutic strategies through prognostic analysis.

Clinical effect of micturition interruption exercise on urinary incontinence after radical prostatectomy.

PURPOSE: To explore the effectiveness of micturition interruption exercise in improving the incidence of urinary incontinence after radical prostatectomy. MATERIALS AND METHODS: With a retrospective case-control study, 96 patients admitted in the Second Affiliated Hospital of Zhejiang Chinese Medical University from August 2014 to August 2020 and underwent radical prostatectomy were collected as the subjects. Those patients who used micturition interruption exercise (n = 48) were set as the therapy group, and the control group was collected according to the ratio of 1:1; the patients used Kegel exercise (n = 48) to compare the rehabilitation of urinary incontinence in patients and the effect of training compliance on rehabilitation. RESULTS: The recovery time of urinary incontinence in the therapy group was significantly shorter than that of the control group. In the therapy group, 83.3% of patients with training compliance reached an average or above, while the control group only accounted for 58.3%. International Consultation on Incontinence Questionnaire Short-Form score of the therapy group was lower than that of the control group after surgery. Spearman analysis suggests that there is a negative correlation between the postoperative urinary incontinence recovery time and compliance with the micturition interruption exercise. CONCLUSIONS: Micturition interruption exercise could not only improve the compliance of patients with exercise, but also significantly shorten the recovery time of urinary incontinence after radical prostatectomy.

Nano-herb medicine and PDT induced synergistic immunotherapy for colon cancer treatment.

A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8+ T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.

Immune Modulator and Low-Temperature PTT-Induced Synergistic Immunotherapy for Cancer Treatment.

Immunotherapy has shown great potential in cancer therapeutics but has limitations of the insufficient activation of dendritic cells (DCs) and immune-suppressive microenvironment. To overcome these obstacles, a cascade synergistic immunotherapy nanosystem (denoted as CpG@PDA-FA) was designed to elevate anticancer immune response. The combination nanosystem including a photothermal agent polydopamine (PDA) and immunomodulator CpG oligodeoxynucleotides (CpG ODNs). On the one hand, polydopamine (PDA) acts as a photothermal agent to induce low-temperature PTT. It leads to immunogenic cell death (ICD), a programmed cell death pathway, which can activate DCs and enhance the antitumor immune response of T cells. On the other hand, CpG ODNs further promote maturation and migration of DCs as well as ameliorates the immunosuppression microenvironment of the tumor (TME). This paper focuses on a cancer synergistic treatment of ICD-induced immunotherapy by low-temperature PTT and ameliorates TME by immunomodulator CpG ODNs. We proved that CpG@PDA-FA NPs realized a remarkable synergistic treatment effect compared with respective single PTT or CpG therapy in the maturation of DCs and activation of T cells. In addition, CpG@PDA-FA NPs also reduced myeloid-derived suppressor cells and regulatory T cells to relieve immunosuppression. Hence, CpG@PDA-FA NPs provide a bidirectional immunotherapy strategy for tumor inhibition and highlight the cascade effects of low-temperature PTT and immunotherapy.

Medical image segmentation and reconstruction of prostate tumor based on 3D AlexNet.

BACKGROUND: Prostate cancer is a disease with a high incidence of tumors in men. Due to the long incubation time and insidious condition, early diagnosis is difficult; especially imaging diagnosis is more difficult. In actual clinical practice, the method of manual segmentation by medical experts is mainly used, which is time-consuming and labor-intensive and relies heavily on the experience and ability of medical experts. The rapid, accurate and repeatable segmentation of the prostate area is still a challenging problem. It is important to explore the automated segmentation of prostate images based on the 3D AlexNet network. METHOD: Taking the medical image of prostate cancer as the entry point, the three-dimensional data is introduced into the deep learning convolutional neural network. This paper proposes a 3D AlexNet method for the automatic segmentation of prostate cancer magnetic resonance images, and the general network ResNet 50, Inception -V4 compares network performance. RESULTS: Based on the training samples of magnetic resonance images of 500 prostate cancer patients, a set of 3D AlexNet with simple structure and excellent performance was established through adaptive improvement on the basis of classic AlexNet. The accuracy rate was as high as 0.921, the specificity was 0.896, and the sensitivity It is 0.902 and the area under the receiver operating characteristic curve (AUC) is 0.964. The Mean Absolute Distance (MAD) between the segmentation result and the medical expert's gold standard is 0.356 mm, and the Hausdorff distance (HD) is 1.024 mm, the Dice similarity coefficient is 0.9768. CONCLUSION: The improved 3D AlexNet can automatically complete the structured segmentation of prostate magnetic resonance images. Compared with traditional segmentation methods and depth segmentation methods, the performance of the 3D AlexNet network is superior in terms of training time and parameter amount, or network performance evaluation. Compared with the algorithm, it proves the effectiveness of this method.

[Prostatic fibrosis: Progress in studies].

The prostate volume is not enlarged in some patients with lower urinary tract symptoms (LUTS). Evidence shows that prostate fibrosis, in addition to BPH and smooth muscle dysfunction, is one of the causes of LUTS, and that its occurrence is related to inflammation of various causes, ischemia, hypoxia and drugs, with the differentiation, aggregation and activation of myofibroblasts involved in its pathogenesis. Therefore, anti-inflammation and anti-fibrosis strategies may be considered as potential targets for the treatment of LUTS. This article presents an overview on the causes of prostatic fibrosis, its diagnosis, its association with LUTS, and the advances in its treatment.

Urothelial carcinoma of the bladder with abundant myxoid stroma: A case report and literature review.

INTRODUCTION: Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We summarized the clinicopathological features, immunophenotype, diagnosis, and differential diagnosis of this type of bladder cancer, in order to improve the understanding of surgeons and pathologists. PATIENT CONCERNS: An 83-year-old female presented with hematuria and frequent micturition, without odynuria, hypogastralgia, or fever. DIAGNOSIS: The computed tomography scan demonstrated extensive tumors in the anterior wall of the bladder and a soft tissue shadow anterior to the sacrum. Cystoscopy showed massive wide-based tumors located on the anterior and lateral walls of the bladder, with no tumor involving the bladder neck. Multiple punch biopsies were performed, the histologic evaluation of which revealed a poorly differentiated invasive UCs with myxoid stroma. INTERVENTIONS: The patient underwent a laparoscopic radical cystectomy and cutaneous ureterostomy. OUTCOMES: The patient discharged without any complications. Histologic evaluation revealed an invasive UC; the most prominent feature was an abundant myxoid stroma that covered approximately 80% of the lesion and the tumor cells were arranged in cords, small nests, or a sheet-like structure. Immunohistochemically, the tumor cells were positive for CK19, CK20, VEGF, EGFR, p63, 34ßE12, MUC1, GATA3, uroplakin3, and TopII (rate = 15%), while the Ki-67 proliferation index was 10%. The myxoid stroma in the mesenchyme stained positively with AB-PAS and colloidal iron, and some tumor cells stained positive for colloidal iron. Considering the histologic, histochemical, and immunohistochemical findings, a diagnosis of UC with abundant myxoid stroma was made. After surgery, the regular follow-up was continued in clinic, and there was no recurrence for 2 years. CONCLUSION: Morbidity associated with UC with abundant myxoid stroma is very low. The diagnosis mainly depends on histopathological and immunohistochemical findings.

Correction: An NIR-responsive mesoporous silica nanosystem for synergetic photothermal-immunoenhancement therapy of hepatocellular carcinoma.

Correction for 'An NIR-responsive mesoporous silica nanosystem for synergetic photothermal-immunoenhancement therapy of hepatocellular carcinoma' by Han Yang et al., J. Mater. Chem. B, 2020, 8, 251-259.

An NIR-responsive mesoporous silica nanosystem for synergetic photothermal-immunoenhancement therapy of hepatocellular carcinoma.

To create a more precise, efficient imaging and therapeutic strategy is a big challenge for the current treatment of hepatocellular carcinoma (HCC). Photothermal therapy (PTT) has attracted enormous attention due to its non-invasive property and precise spatial and temporal control. Here, we developed a strategy to realize superior imaging performance and treatment, utilizing an indocyanine green (ICG) and sorafenib (S) co-loaded mesoporous silica nanosystem for synergetic PTT/immuno-enhanced therapy. We proved that (ICG+S)@mSiO2 could be easily endocytosed by H22 cells, carried out outstanding real-time fluorescence imaging, and enhanced cytotoxicity abilities by near-infrared radiation (NIR) in vitro. Moreover, (ICG+S)@mSiO2 also had excellent fluorescence imaging ability, displayed a remarkable photothermal tumor killing effect and immune enhancement capability under 808 nm irradiation in an H22 tumor-bearing mice model, without apparent adverse effects in other organs. This study provides a new strategy for the development of a PTT/immuno-enhanced synergistic theranostic nanosystem of HCC.

Nanoparticle-based diagnostic and therapeutic systems for brain tumors.

Brain tumors, especially the most prevalent and aggressive glioblastoma, remain among the deadliest of all types of cancer due to inefficient theranostic options. They have a limited therapeutic window because of physiological barriers such as the blood-brain barrier (BBB), blood cerebrospinal fluid (CSF) barrier and interstitial fluid (ISF) that restrict the penetration of imaging probes and therapeutic drugs. In order to achieve more accurate brain tumor diagnosis and better therapeutic effects, many strategies have been explored; among them multifunctional nanoparticles offer a novel and potential opportunity depending on their size effects, and their optical, magnetic, photodynamic and other properties. After modification, nanoparticles can cross the BBB and specifically accumulate in the tumor site, thereby achieving accurate tumor imaging and drug release. This review is focused on various types of nanoparticles that are being used for improving nano-carriers of diagnostic and therapeutic agents into brain tumors and also provides a concise summary of various multifunctional theranostic strategies, particularly in clinical applications. In this manner, we provide evidence for the key role of nanoparticle based diagnosis and therapy systems in brain tumors.

Astragaloside III Enhances Anti-Tumor Response of NK Cells by Elevating NKG2D and IFN-γ.

Natural killer (NK) cells play an irreplaceable role in the development of colon cancer, in which antitumor function of NK cells was impaired. Astragaloside III is a natural compound from Astragalus that has been shown to have immunomodulatory effects in various systems. However, few studies have evaluated the antitumor effects of Astragaloside III through stimulating systemic immunity and regulating NK cells. In this study, flow cytometry, immunohistochemical analysis, and immunofunctional assays were performed to elucidate the functions of Astragaloside III in restoring antitumor function of NK cells. We demonstrated that Astragaloside III significantly elevated the expression of natural killer group 2D (NKG2D), Fas, and interferon-γ (IFN-γ) production in NK cells, leading to increased tumor-killing ability. Experiments in cell co-culture assays and CT26-bearing mice model further confirmed that Astragaloside III could effectively impede tumor growth by increasing infiltration of NK cells into tumor and upregulating the antitumor response of NK cells. We further revealed that Astragaloside III increased IFN-γ secretion of NK cells by enhancing the expression of transcription factor T-bet. In conclusion, the effective anti-tumor function of Astragaloside III was achieved through up-regulation of the immune response of NK cells and elevation of NKG2D, Fas, and IFN-γ production.

Fibroblast growth factor 16 stimulates proliferation but blocks differentiation of rat stem Leydig cells during regeneration.

OBJECTIVES: We aim to investigate the effects of fibroblast growth factor 16 (FGF16) on Leydig cell regeneration in ethane dimethane sulphonate (EDS)-treated rat testis. METHODS: We intraperitoneally inject 75 mg/kg EDS to adult male Sprague Dawley rats and then intratesticularly inject FGF16 (0, 10 and 100 ng/testis/day) from post-EDS day 14 for 14 days. We investigate serum hormone levels, Leydig cell number, gene and protein expression in vivo. We also explore the effects of FGF16 treatment on stem Leydig cell proliferation in vitro. RESULTS: FGF16 lowers serum testosterone levels (21.6% of the control at a dose of 100 ng/testis) without affecting the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on post-EDS day 28 in vivo. FGF16 increases Leydig cell number at doses of 10 and 100 ng/mg without affecting Sertoli cell number, increases the percentage of PCNA-positive Leydig cells, and down-regulates the expression of Leydig cell genes (Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1 and Hsd17b3) and Sertoli cell genes (Fshr, Dhh and Sox9) and their proteins in vivo. FGF16 increases phosphorylation of AKT1 and AKT2 as well as EKR1/2 in vivo, indicating that it possibly acts via AKT1/ATK2 and ERK1/2 pathways. FGF16 also lowers medium testosterone levels and down-regulates the expression of Leydig cell genes (Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1 and Hsd17b3) but increases EdU incorporation into stem Leydig cells in vitro. CONCLUSIONS: These data suggest that FGF16 stimulates stem and progenitor Leydig cell proliferation but blocks their differentiation, thus lowering testosterone biosynthesis.

Induced pluripotent stem cell-derived conditional medium promotes Leydig cell anti-apoptosis and proliferation via autophagy and Wnt/ß-catenin pathway.

Leydig cell transplantation is a better alternative in the treatment of androgen-deficient males. The main purpose of this study was to investigate the effects of induced pluripotent stem cell-derived conditioned medium (iPS-CM) on the anti-apoptosis, proliferation and function of immature Leydig cells (ILCs), and illuminate the underlying mechanisms. ILCs were exposed to 200 µmol/L hydrogen peroxide (H2 O2 ) for 24 hours with or without iPS-CM treatments. Cell apoptosis was detected by flow cytometric analysis. Cell proliferation was assessed using cell cycle assays and EdU staining. The steroidogenic enzyme expressions were quantified with Western blotting. The results showed that iPS-CM significantly reduced H2 O2 -induced ILC apoptosis through down-regulation of autophagic and apoptotic proteins LC3-I/II, Beclin-1, P62, P53 and BAX as well as up-regulation of BCL-2, which could be inhibited by LY294002 (25 µmol/L). iPS-CM could also promote ILC proliferation through up-regulation of ß-catenin and its target proteins cyclin D1, c-Myc and survivin, but was inhibited by XAV939 (10 µmol/L). The level of bFGF in iPS-CM was higher than that of DMEM-LG. Exogenous bFGF (20 ng/mL) or Wnt signalling agonist lithium chloride (LiCl) (20 mmol/L) added into DMEM-LG could achieve the similar effects of iPS-CM. Meanwhile, iPS-CM could improve the medium testosterone levels and up-regulation of LHCGR, SCARB1, STAR, CYP11A1, HSD3B1, CYP17A1, HSD17B3 and SF-1 in H2 O2 -induced ILCs. In conclusion, iPS-CM could reduce H2 O2 -induced ILC apoptosis through the activation of autophagy, promote proliferation through up-regulation of Wnt/ß-catenin pathway and enhance testosterone production through increasing steroidogenic enzyme expressions, which might be used in regenerative medicine for future.

[Treatment of child extensive anxiety disorder with catgut implantation of point plus western medicine].

OBJECTIVE: To compare therapeutic effects and adverse effects between catgut implantation of point plus Wenlafaxin and simple Wenlafaxin on child extensive anxiety disorder. METHODS: Seventy cases were randomly divided into a treatment group and a control group, 35 cases in each group. The treatment group were treated with catgut implantation of points, once 2 weeks, 3 sessions constituting one course, with the 3 groups of points, (1) Ganshu (BL 18) and Danzhong (CV 17), (2) Dazhui (CV 14) and Zhongwan (CV 12), (3) Shenshu (BL 23) and Zhangmen (LR 13) alternated, in combination with oral administration of Wenlafaxin. The control group were treated with simple oral administration of Wenlafax-cin. All of them were treated for 6 weeks. RESULTS: The cured and markedly effective rate was 74.3% in the treatment group and 60.0% in the control group, with a significant difference between the two groups (P < 0.05). After treatment for 6 weeks, the HAMD score was significantly lower than that before treatment in the two groups. The following survey showed that the long-term therapeutic effect in the treatment group was better, with smaller dose and less adverse effects. CONCLUSION: Catgut implantation of point plus small dose of Wenlafaxin is a more ideal therapy for child extensive anxiety disorder.