Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination.

Tumor in situ vaccination (ISV) strategies have emerged in clinical trials as promising approaches, involving the release of tumor antigens through local radiotherapy and intratumorally adjuvant injections. However, the current fabrication strategy for achieving a sustainable immune response to ISV remains a pressing challenge. In this study, we present an empowered sustainable ISV method for antitumor therapy using 177Lu-labeled manganese-doped mesoporous hydroxyapatite (177Lu/Mn-HAP) microspheres. The ISV enables the sustained utilization of tumor antigens, leading to the activation of dendritic cells and polarization of macrophages toward the M1 subtype. Consequently, it facilitates the generation of potent CD8+ T-cell responses, enhancing the antitumor effects of internal radiation in both primary and distant tumors. Importantly, this approach achieves complete remission in all tumor-bearing mice and stimulates immune memory to prevent tumor recurrence. Our study highlights a universal and safe ISV strategy capable of inducing potent tumor-specific and sustainable immune response.

Neutrophils-mediated bioinspired nanoagents for noninvasive monitoring of inflammatory recruitment dynamics and navigating phototherapy in rheumatoid arthritis.

Neutrophils play a crucial role in inflammatory immune responses, but their in vivo homing to inflammatory lesions remains unclear, hampering precise treatment options. In this study, we employed a biomineralization-inspired multimodal nanoagent to label neutrophils, enabling noninvasive monitoring of the dynamic process of inflammatory recruitment and guiding photothermal therapy in rheumatoid arthritis. Our nanoagents allowed visualization of neutrophil fate through magnetic resonance imaging, photoacoustic imaging, and fluorescence imaging in the first and second near-infrared windows. Histopathology and immunofluorescence analysis revealed pronounced inflammatory cell infiltration in rheumatoid arthritis compared to the normal limb. Furthermore, the recruitment quantity of neutrophils positively correlated with the inflammatory stage. Additionally, the inherent photothermal effect of the nanoagents efficiently ablated inflammatory cells during the optimal homing time and inflammatory phase. This neutrophil imaging-guided photothermal therapy precisely targeted inflammatory nuclei in rheumatoid arthritis and downregulated pro-inflammatory cytokines in serum. These results demonstrate that in vivo tracking of inflammatory immune response cells can significantly optimize the treatment of inflammatory diseases, including rheumatoid arthritis.

Radioresponsive Delivery of Toll-like Receptor 7/8 Agonist for Tumor Radioimmunotherapy Enabled by Core-Cross-Linked Diselenide Nanoparticles.

The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local radiotherapy in vivo remains a significant challenge in order to minimize off-target toxicity, reduce radiation-induced immunosuppression, and maximize synergistic radioimmunotherapy efficacy. In this study, we report the development of core-cross-linked diselenide nanoparticles (dSeNPs) as carriers for radioresponsive delivery of the toll-like receptors 7/8 agonist through systemic administration to achieve combined radioimmunotherapy of tumors. The dSeNPs were fabricated from a ring-opening reaction between 2,2'-diselenidebis(ethylamine) and the ethylene oxide group of an amphiphilic block copolymer. The diselenide bonds were naturally protected in the core of the self-assembled nanostructure, making the dSeNPs extremely stable in the physiological environment. However, they exhibited dose- and time-dependent radiosensitivity, meaning that X-ray irradiation could spatiotemporally control the release of R848 from the dSeNPs. In vivo results showed that local radioresponsive R848 release from dSeNPs greatly improved the synergistic efficacy of combined radioimmunotherapy via the programmed cooperative immune system activation process. This process included macrophage polarization, dendritic cell maturation, and cytotoxic T cell activation. Our findings suggest that core-cross-linked dSeNPs are a promising platform for combined radiotherapy due to their spatiotemporal controllability of radioresponsive drug release.

Harnessing astaxanthin-loaded diselenium cross-linked apotransferrin nanoparticles for the treatment of secretory otitis media.

Secretory otitis media (SOM) is a clinical condition characterized by the accumulation of fluids and oxidative stress in the middle ear, leading to hearing impairment and infection complications. One potential solution for mitigating oxidative stress associated with SOM is the use of antioxidants such as astaxanthin. However, its effectiveness is limited due to its poor bioavailability and rapid oxidation. Herein, we developed a novel diselenium-crosslinked apotransferrin enriched with astaxanthin (AST@dSe-AFT) nanoparticles to augment the transport of astaxanthin across biological membranes, resulting in increased bioavailability and reduced oxidative stress in SOM. Our research demonstrated that AST@dSe-AFT efficiently accumulated in the middle ear, allowing for controlled delivery of astaxanthin in response to reactive oxygen species and reducing oxidative stress. Additionally, AST@dSe-AFT stimulated macrophages to polarize towards M2 phenotype and neutrophils to polarize towards N2 phenotype, thereby facilitating an anti-inflammatory response and tissue restoration. Importantly, AST@dSe-AFT exhibited no toxicity or adverse effects, suggesting its potential for safety and future clinical translation. Our findings suggested that AST@dSe-AFT represents a promising approach for the treatment of secretory otitis media and other oxidative stress-related disorders.

Radiotherapy-Triggered In Situ Tumor Vaccination Boosts Checkpoint Blockaded Immune Response via Antigen-Capturing Nanoadjuvants.

In situ vaccination (ISV) formed with the aid of intratumorally injected adjuvants has shed bright light on enhancing the abscopal therapeutic effects of radiotherapy. However, the limited availability of antigens resulting from the radiotherapy-induced immunogenic cell death largely hampers the clinical outcome of ISV. To maximally utilize the radiotherapy-induced antigen, we herein developed a strategy by capturing the radiotherapy-induced antigen in situ with a nanoadjuvant comprised of CpG-loaded Fe3O4 nanoparticles. The highly efficient click reaction between the maleimide residue on the nanoadjuvant and sulfhydryl group on the antigen maximized the bioavailability of autoantigens and CpG adjuvant in vivo. Importantly, combined immune checkpoint blockade can reverse T cell exhaustion after treatment with radiotherapy-induced ISV, thereby largely suppressing the treated and distant tumor. Mechanistically, metabolomics reveals the intratumorally injected nanoadjuvants disrupt redox homeostasis in the tumor microenvironment, further inducing tumor ferroptosis after radiotherapy. Overall, the current study highlights the immense potential of the innovative antigen-capturing nanoadjuvants for synergistically enhancing the antitumor effect.

Comparative study of female pelvic floor among undeformed high-resolution thin-sectional anatomical (visible human) images and MRI and ultrasound images.

PURPOSE: Using visible human, MRI and ultrasound images, we aim to provide an anatomical basis for the identification and diagnosis of pelvic floor structure and disease by ultrasound imaging. METHODS: One Chinese visible human (CVH) image, one American visible human image, 9 MRI images of normal volunteers, and 40 ultrasound images of normal volunteers or pelvic organ prolapse patients were used. Pelvic organs, pelvic floor muscles, and the connective tissue in CVH, VHP, MRI, and ultrasound images were selected for comparative study. RESULTS: We successfully identified the boundary of the anal sphincter complex, including the subcutaneous, superficial, and deep parts of the external anal sphincter, conjoined longitudinal muscles and internal anal sphincter; the levator ani muscle (LAM), including the internal and external parts of the pubovisceral muscle and the superficial and deep parts of the puborectal muscle; the urethral sphincter complex, including the urethral sphincter proper and the urethral compressor; and the perineal body, the rectoperineal muscle and superficial transverse perineal muscle. CONCLUSIONS: We successfully recognized and studied the location, subdivisions, 2D morphology and spatial relationships of the LAM, anal sphincter complex, urethral sphincter complex and perineal body in ultrasound images, thereby helping sonologists or clinicians accurately identify pelvic floor muscles and supporting structures in ultrasound images.

[Multiple precision behavioral therapy for mild to moderate stress urinary incontinence with sexual dysfunction in women].

OBJECTIVE: To explore the clinical effect of multiple precision behavioral therapy (MPBT) on mild to moderate stress urinary incontinence (SUI) with female sexual dysfunction (FSD) in women. METHODS: We randomly divided 90 female patients with mild to moderate SUI with FSD into three groups of an equal number: control group A, control group B and an MPBT group, treated by electrical stimulation, Kegel training and MPBT, respectively, all for 8 weeks. Using International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), Incontinence Impact Questionnaire (IIQ-7), Female Sexual Function Indexes (FSFI) and Glazer protocol, we evaluated the clinical effects, recorded the cost of treatment, and compared them among the three groups of patients. RESULTS: Totally, 87 of the patients completed the treatment, 27 in control group A, 30 in control group B and 30 in the MPBT group. There was no significant difference in the baseline data among the three groups (P > 0.05). ICIQ-SF and IIQ-7 scores, FSFI and Glazer values were remarkably improved in the MPBT group after treatment (P < 0.05). The therapeutic effect was significantly better and the treatment cost markedly lower in the MPBT than in the control groups (P < 0.05). CONCLUSION: Multiple precision behavioral therapy can effectively improve the clinical symptoms of mild to moderate stress urinary incontinence and sexual dysfunction in women, with low cost and high safety.

Automatic segmentation of the female pelvic floor muscles on MRI for pelvic floor function assessment.

Background: Pelvic organ prolapse (POP) is a pelvic floor dysfunction disease which affects females. The volume of pelvic floor muscle, especially the levator ani muscle (LAM), is an important indicator of pelvic floor function. However, muscle volume measurements depend on manual segmentation, which is clinically time-consuming. In this work, we present an efficient automatic segmentation model of pelvic floor muscles with magnetic resonance imaging (MRI) based on DenseUnet, to achieve muscle volume calculation and provide a reference for the assessment of pelvic floor function. Methods: A total of 49 female pelvic floor magnetic resonance (MR) series were retrospectively enrolled from the First Affiliated Hospital of Army Military Medical University between 2013 and 2021, including 21 normal participants and 28 patients with stage 1-4 POP. The LAM, internal obturator muscle (IOM), and external anal sphincter (EAS) were manually segmented. An improved DenseUnet was proposed for automatic segmentation of these 3 muscles. The Dice similarity coefficient (DSC), Hausdorff distance (HD), and average symmetrical surface distance (ASSD) were used to evaluate segmentation results. The segmentation performance of the improved DenseUnet was compared with those of standard DenseUnet, ResUnet, Unet++, and Unet. Results: The improved DenseUnet showed a good performance. The average DSC and standard deviation of the LAM, IOM, and EAS was 0.758±0.151, 0.716±0.173, and 0.810±0.147, respectively. The average HD was 22.41, 19.00, and 36.01 mm, respectively; and the average ASSD was 3.66, 3.80, and 5.23 mm, respectively. The average DSC and standard deviation of the normal group and POP group was 0.779±0.166 and 0.757±0.154, respectively. There was no significant difference between the muscle volume of the improved DenseUnet and manual segmentation (all P values >0.05). The average total segmentation time for 1 case was 10.18 s on our setup, which is much lower than the manual segmentation time of 45 minutes. Conclusions: The improved DenseUnet segments the pelvic floor muscles in MRI quickly and efficiently, with good precision and faster speed than those of manual segmentation. This can assist doctors in quickly segmenting pelvic floor muscles, calculating muscle volume, and further evaluating pelvic floor function.

Mechanistic study for drug induced cholestasis using batch-fabricated 3D spheroids developed by agarose-stamping method.

Cell spheroid culture can recapitulate the tissue microstructure and cellular responses in vivo. While there is a strong need to understand the modes of toxic action using the spheroid culture method, existing preparation techniques suffer from low efficiency and high cost. Herein, we developed a metal stamp containing hundreds of protrusions for batch bulk preparation of cell spheroids in each well of the culture plates. The agarose matrix imprinted by the stamp can form an array of hemispherical pits, which facilitated the fabrication of hundreds of uniformly sized rat hepatocyte spheroids in each well. Chlorpromazine (CPZ) was used as a model drug to investigate the mechanism for drug induced cholestasis (DIC) by agarose-stamping method. Hepatocyte spheroids showed a more sensitive detection of hepatotoxicity compared to 2D and Matrigel-based culture systems. Cell spheroids were also collected for staining of cholestatic protein and showed a CPZ-concentration-dependent decrease of bile acid efflux related proteins (BSEP and MRP2) and tight junction (ZO-1). In addition, the stamping system successfully delineated the DIC mechanism by CPZ that may be associated with the phosphorylation of MYPT1 and MLC2, two central proteins in the Rho-associated protein kinase pathway (ROCK), which were significantly attenuated by ROCK inhibitors. Our results demonstrated a large-scale fabrication of cell spheroids by the agarose-stamping method, with promising benefits for exploring the mechanisms for drug hepatotoxic responses.

Targeting STING Activation by Antigen-Inspired MnO2 Nanovaccines Optimizes Tumor Radiotherapy.

Immune checkpoint blockers therapy can improve the radiotherapy-induced immunosuppression by enhancing interferon secretion, but still suffer from low clinical response rate and potential adverse effects. Mn2+ -mediated activation of interferon gene stimulator (STING) pathway provides an alternative for combination radioimmunotherapy of tumor. However, it is still a challenge for specific delivery of Mn2+ to innate immune cells and targeting activation of STING pathway. Herein, a novel antigen-inspired MnO2 nanovaccine is fabricated as Mn2+ source and functionalized with mannose, enabling it to target innate immune cells to activate the STING pathway. Meanwhile, the release of Mn2+ in the intracellular lysosomes can also be for magnetic resonance imaging to monitor the dynamic distribution of nanovaccines in vivo. The targeting activation of STING pathway can enhance radiotherapy-induced immune responses for inhibiting local and distant tumors, and resisting tumor metastasis. The study proposes an optimized radiotherapy strategy through targeting STING activation of antigen-inspired nanovaccines.

Chemotherapy-Sensitized In Situ Vaccination for Malignant Osteosarcoma Enabled by Bioinspired Calcium Phosphonate Nanoagents.

How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously eliciting in situ antitumor immunity. However, targeted chemoimmunotherapy lacks a reliable delivery system. To address this issue, we herein developed a bioinspired calcium phosphonate nanoagent that was synthesized by chemical reactions between Ca2+ and phosphonate residue from zoledronic acid using bovine serum albumin as a scaffold. In addition, methotrexate combination with a phosphorothioate CpG immunomodulator was also loaded for pH-responsive delivery to enable synergistic chemoimmunotherapy of osteosarcoma. The calcium phosphonate nanoagents were found to effectively accumulate in osteosarcoma for nearly 1 week, which is favorable for exerting the vaccination effects in situ by maturing dendritic cells and priming CD8+ T cells to suppress the osteosarcoma progression and pulmonary metastasis through controlled release of the three loaded agents in the acidic tumor microenvironment. The current study may thus offer a reliable delivery platform for achieving targeted chemotherapy-induced in situ antitumor immunity.

Fibrinogen/poly(l-lactide-co-caprolactone) copolymer scaffold: A potent adhesive material for urethral tissue regeneration in urethral injury treatment.

Since a scarcity of sufficient grafting materials, several complications can arise after urothelial defect reconstruction surgery, including severe hypospadias. Accordingly, developing alternative therapies, such as urethral restoration via tissue engineering are needed. In the present study, we developed a potent adhesive and repairing material using fibrinogen-poly(l-lactide-co-caprolactone) copolymer (Fib-PLCL) nanofiber scaffold to achieve effective urethral tissue regeneration after seeding with epithelial cells on the surface. The in vitro result found the Fib-PLCL scaffold promoted the attachment and viability of epithelial cells on their surface. The increased expression levels of cytokeratin and actin filaments were observed in Fib-PLCL scaffold than PLCL scaffold. The in vivo urethral injury repairing potential of Fib-PLCL scaffold was evaluated using a rabbit urethral replacement model. In this study, a urethral defect was surgically excised and replaced with the Fib-PLCL and PLCL scaffolds or autograft. As expected, the animals healed well after surgery in the Fib-PLCL scaffold group, and no significant strictures were identified. As expected, the cellularized Fib/PLCL grafts have induced the luminal epithelialization, urethral smooth muscle cell remodelling, and capillary development all at the same time. Histological analysis revealed that the urothelial integrity in the Fib-PLCL group had progressed to that of a normal urothelium, with enhanced urethral tissue development. Based on the results, the present study suggests that the prepared fibrinogen-PLCL scaffold is more appropriate for urethral defect reconstruction.

A critical assessment of clustering algorithms to improve cell clustering and identification in single-cell transcriptome study.

Cell clustering is typically the initial step in single-cell RNA sequencing (scRNA-seq) analyses. The performance of clustering considerably impacts the validity and reproducibility of cell identification. A variety of clustering algorithms have been developed for scRNA-seq data. These algorithms generate cell label sets that assign each cell to a cluster. However, different algorithms usually yield different label sets, which can introduce variations in cell-type identification based on the generated label sets. Currently, the performance of these algorithms has not been systematically evaluated in single-cell transcriptome studies. Herein, we performed a critical assessment of seven state-of-the-art clustering algorithms including four deep learning-based clustering algorithms and commonly used methods Seurat, Cosine-based Tanimoto similarity-refined graph for community detection using Leiden's algorithm (CosTaL) and Single-cell consensus clustering (SC3). We used diverse evaluation indices based on 10 different scRNA-seq benchmarks to systematically evaluate their clustering performance. Our results show that CosTaL, Seurat, Deep Embedding for Single-cell Clustering (DESC) and SC3 consistently outperformed Single-Cell Clustering Assessment Framework and scDeepCluster based on nine effectiveness scores. Notably, CosTaL and DESC demonstrated superior performance in clustering specific cell types. The performance of the single-cell Variational Inference tools varied across different datasets, suggesting its sensitivity to certain dataset characteristics. Notably, DESC exhibited promising results for cell subtype identification and capturing cellular heterogeneity. In addition, SC3 requires more memory and exhibits slower computation speed compared to other algorithms for the same dataset. In sum, this study provides useful guidance for selecting appropriate clustering methods in scRNA-seq data analysis.

[Effect of functional acupoint electrical stimulation combined with tadalafil on erectile dysfunction in middle-aged and elderly patients].

OBJECTIVE: To investigate the application effect of functional acupoint electrical stimulation combined with tadara irregular administration in middle-aged and elderly patients with erectile dysfunction (ED), and to provide reference for clinical treatment. METHODS: A total of 40 middle-aged and elderly patients with ED admitted to the pelvic floor Center of our hospital from March 2021 to March 2023 were randomly divided into two groups with 20 cases in each group.The control group was treated with tadalafil regularly, and the observation group was treated with functional acupoint electrical stimulation on the basis of this treatment. The total course of treatment was 6 weeks.The clinical efficacy of the two groups was compared. The therapeutic efficacy was evaluated by the International Erectile Function Index (IIEF-5), penile hardness score (EHS), serum total testosterone (TT) level, sexual satisfaction scale (SS) and pelvic floor electromyography, and the occurrence of adverse events was recorded. RESULTS: The total effective rate of the observation group was significantly higher than that of the control group (90% vs 70%, P < 0.05). After 6 weeks of treatment, both groups showed improvements in IIEF-5, EHS, SS, and TT compared to before treatment (P < 0.01). However, the improvement in the observation group was significantly better than that in the control groupï¼»IIEF-5: (22.13±2.11) vs (19.69±2.04), EHS: (3.68±0.47) vs (2.89±0.60), SS: (77.41±7.59) vs (70.32±7.28), TT: (13.43±3.89) nmol/L vs (8.85±3.02) nmol/L, all P < 0.01ï¼½; There were no significant changes in pelvic floor muscle electromyography values in the control group before and after treatment (P > 0.05), while in the observation group, pelvic floor muscle electromyography values (PFMV) in the pre-resting phase, fast muscle (Type II muscle) phase, slow muscle (Type I muscle) phase, endurance testing phase, and post-resting phase all improved compared to before treatment and were superior to the control group (P < 0.05). CONCLUSION: Functional acupoint electrical stimulation combined with tadara irregular administration can improve the therapeutic effect of middle-aged and elderly patients with ED, improve pelvic floor function, safe and reliable.

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

Bismuth nanomaterials as contrast agents for radiography and computed tomography imaging and their quality/safety considerations.

Contrast agents for radiography and computed tomography (CT) scans are substances that can enhance the contrast of blood vessels and soft tissue with detailed imaging information of the diseased sites. However, the large doses, short circulation time and adverse effects are the intrinsic limitations of CT contrast agents, preventing their extended and safe use in the clinical setting. Bismuth nanoparticles (NPs) have gained attention for the high X-ray absorption of bismuth elements with acceptable biocompatibility, showing their potential to be translated into commercialized CT contrast agents. Compared with traditional iodine contrast agents, bismuth NPs are characterized by prolonged circulation time and enhanced contrast, largely due to the surface modification and enhanced permeability and retention effect of NPs. Bismuth NPs can also be flexibly upgraded into sophisticated nanoagents for multimodal imaging and therapeutic purposes by complexation with supporting chemicals, small molecule drugs, fluorescence labels, and other functional agents. Additionally, the affinity and retention of the bismuth NPs in the diseased sites can be further improved by modification of the targeting moiety on the NPs surface. However, a simple synthetic process and low complexity of bismuth NPs are highly recommended for scaling out and quality control of nanoagents with commercialization potential. Since product safety is a prerequisite for the translation of bismuth NPs from bench to the clinic, we focus on recent advances in the distribution, elimination, and toxicity of bismuth NPs previously reported. Finally, we delineate the associated mechanisms for nephrotoxicity and the strategy to reduce the toxicity of bismuth NPs. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Efficacy of Yun-type pelvic floor optimal training therapy and PFMT on middle aged women with mild to moderate overactive bladder: a randomized controlled trial.

Background: The symptoms of overactive bladder (OAB) are highly bothersome to patients. In behavioral therapy, traditional pelvic floor muscle training (PFMT) can be boring and monotonous, which can cause poor compliance. It's important to establish a new safe and effective crotch-pelvic floor functional reconstruction training method [Yun-type pelvic floor optimal training (Yun-type training)] for OAB patients. Methods: This randomized, double-blind, crossover trial recruited a total of 150 women with mild to moderate OAB. Patients were randomly assigned to receive Yun-type training (n=83) or PFMT (n=67). The intervention group was first given Yun-type training for 6 weeks, then switched to PFMT for 6 weeks after 2 weeks of elution. Patients in the control group were first treated with PFMT for 6 weeks, and changed to the use of Yun-type training for 6 weeks after 2 weeks of elution. The primary endpoint was overactive bladder symptom scores (OABSS) after 6 and 14 weeks of Yun-type training and PFMT. Results: Yun-type training could significantly improve OABSS compared with PFMT after 6 and 14 weeks (P<0.001). Yun-type training was associated with an improvement in urine, urgency, urge urinary incontinence (UUI), urogenital distress inventory-6 (UDI-6), patient's perception of bladder condition (PPBC), voiding volume (VV), incontinence impact questionnaire-7 (IIQ-7), female sexual function index (FSFI), sexual desire, arousal, pain, satisfaction, pelvic floor muscle tone, type I muscle strength, type II muscle strength, and sex partner satisfaction as compared with PFMT after 6 and 14 weeks. Moreover, nocturia, maximum flow rate (Qmax), and climax in the Yun-type training group were significantly improved after 6 weeks, and the average flow rate (Qave) was improved after 14 weeks in the Yun-type training group. Conclusions: Yun-type training could yield additional benefits on OAB symptoms, sexual function, and sex partner satisfaction as compared with PFMT. The superior sexual function resulting from Yun-type training can be explained by the fact that it can contract deep and superficial muscle layers, resulting in increased vaginal wall pressure and blood flow, which further improves FSFI and sex partner satisfaction. It could lead to a new non-invasive treatment for OAB patients. Trial Registration: Chinese Clinical Trial Registry ChiCTR-INR-17012192.

Study of female pelvic floor muscle in overactive bladder based on MRI 3D reconstruction.

BACKGROUND: This study examined the three-dimensional (3D) morphological changes of the urination and urinary continence anatomical structures in overactive bladder (OAB) patients, to offer a morphological data for OAB diagnosis and treatment. METHODS: Eleven OAB patients, 9 healthy females and 22 pelvic organ prolapse (POP) patients were enrolled and underwent MRI scans. The anatomical components of urination (bladder detrusor) and the urinary continence (main part of the urethral sphincter, compressor urethrae, and levator ani muscle (LAM) were 3D reconstructed and measured with Amira software. We also analyze the relativity between pelvic floor muscle's morphological parameters among the volunteers, OAB and POP group. RESULTS: Through 3D reconstruction, increased thickness and volume of the bladder detrusor were found in the OAB patients compared with volunteers (3.1 ± 0.7 mm vs. 1.9 ± 0.3 mm; P = 0.000 and 50,632.0 ± 19,724.7 mm3 vs. 23,386.6 ± 7826.3 mm3; P = 0.001). The volume of LAM showed no significant difference between the OAB patients and volunteers (27,089.4 ± 5015.0 mm3 vs. 27,294.4 ± 4461.4 mm3; P = 0.924); whereas, LAM's volume of the POP patients was significantly larger than that of the volunteers (34,130.6 ± 7968.3 mm3 vs. 27,294.4 ± 4461.4 mm3; P = 0.023). The thickness and volume of the main part of urethral sphincter were significantly lower in the OAB patients compared with volunteers (2.2 ± 0.5 mm vs. 2.7 ± 0.3 mm; P = 0.018 and 2558.6 ± 703.2 mm3 vs. 23,267.3 ± 681.9 mm3; P = 0.035). The volume of the compressor urethrae was significantly lower in the OAB patients than that in the volunteers (630.3 ± 301.2 mm3 vs. 866.1 ± 514.2 mm3; P = 0.247). CONCLUSIONS: In OAB patients, the bladder detrusor has long-term tension and contraction, which thickened muscle and increased volume, and aggravate urination. The compressor urethral and main part of urethral sphincter are weaker and the anterior part of LAM hiatus is relaxed, easily resulting in leakage of urine and ultimately incontinence. The MRI 3D reconstruction and measurement can help to evaluate pelvic floor urination and continence function, and accurately diagnose.

Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment.

Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.

Efficacy of optimized pelvic floor training of YUN combined with pelvic floor magnetic stimulation on female moderate stress urinary incontinence and sexual function: a retrospective cohort study.

Background: Owing to its tediousness and monotony, traditional pelvic floor muscle training (PFMT) is difficult to ensure the correctness of exercise, and it is difficult for patients to adhere to treatment. We designed this study to evaluate and analyze the efficacy of optimized pelvic floor training of YUN combined with pelvic floor magnetic stimulation on female moderate stress urinary incontinence (SUI) and sexual function. Methods: This is a retrospective cohort study. This study was carried out in 95 female patients with moderate SUI. The inclusion criteria were as follows: premenopausal women aged 25-45; moderate SUI; over 3 months of disease duration; informed consent and cooperation with treatment and follow-up. The participants in group 1 (control group, n=46) were treated with pelvic floor magnetic stimulation, while those in group 2 (trial group, n=49) were treated with pelvic floor magnetic stimulation combined with optimized pelvic floor training of YUN. Evaluations were scheduled before the treatment (0 week), after 6 weeks of treatment (6 weeks), and after 12 weeks of treatment (12 weeks). And compare the differences between the two groups. Results: There was no significant difference in age, body mass index (BMI), duration of disease, and abdominal leak point pressure (ALPP) between the two groups (P>0.05). The total effective rate of the trial group was higher than that of the control group (89.80%, 44/49 vs. 78.26%, 36/46) (P<0.05). The electromyographic values, the International Consultation on Incontinence Questionnaire Short Form (ICI-Q-SF) score, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (PISQ-12) score, physiological factors, and emotional factors were all improved significantly in both groups after active treatment, and the improvement of the trial group was more obvious (P<0.05). Conclusions: Optimized pelvic floor training of YUN combined with pelvic floor magnetic are more effective for the treatment of female moderate SUI and sexual function. It has become a safe, effective, and well tolerated new type of pelvic floor functional reconstruction training method with good patient compliance.