Bladder cancer kills nearly 170,000 people worldwide each year. Over the past 4 decades, the systematic treatment of metastatic and locally advanced bladder cancer has mainly consisted of platinum-based chemotherapy. In the last 10 years, the development of next-generation sequencing have led to rapid characterization of whole-genome sequencing of bladder cancer, which gives us a better understanding of the pathogenesis of bladder cancer. Based on indications of high mutation burden, and microsatellite instability-high/deficient mismatch repair, immune checkpoint inhibitors have been studied in metastatic and locally advanced bladder cancer as well as bladder-sparing, and shows a good response in these specific indications. Besides, clinically significant expressed molecular targets are used to develop cancer targeted drugs, such as fibroblast growth factor receptor inhibitors and antibody-drug coupling agents. The exploration of molecular characteristics and subtypes of bladder cancer and the development of new drugs and treatment strategy have also stimulated more clinical studies of bladder cancer. Here, we review advances in the treatment of bladder cancer and clinical practice of next-generation sequencing, highlight important advances in immunotherapy for bladder cancer, preliminarily summarize molecular features of bladder cancer for clinical practice, and came up with direction for future treatment development.

In order to prevent safety hazards and economic losses caused by sudden battery failures, accurately assessing the state of health (SOH) of lead-acid batteries is essential. Electrochemical impedance spectroscopy (EIS), a noninvasive and information-rich characterization technology, has proven effective for this purpose. This review focuses on the application of EIS in evaluating lead-acid battery SOH. We first provide a comprehensive overview of primary aging mechanisms and their corresponding impedance signatures. We then systematically analyze conventional methods for extracting SOH information from EIS data, including equivalent circuit models, characteristic frequency selection, distribution of relaxation times (DRT), and machine learning. A comparative approach is employed to evaluate the advantages, limitations, and applicable scenarios of each method. Finally, we discuss key challenges in the online application of EIS and offer perspectives on future development trends. This review synthesizes recent research findings and methodological advances to promote intelligent health management technologies for lead-acid batteries.

Cell-free total nucleic acid (cfTNA)-based liquid biopsy (LBx) offers a minimally invasive alternative to tissue-based next-generation sequencing (NGS). Most NGS-based LBx assays require several days for results. This study validated a rapid NGS-based LBx assay with a 2-day turnaround time (TAT). Patient plasma samples were used to validate the Oncomine Precision Assay for single-nucleotide variants (SNVs), insertion and deletions (indels), and fusions across 50 genes on the Genexus Sequencer. Manual extraction using the QIAamp cfTNA Kit was performed to optimize fusion detection. Analytical sensitivity in synthetic controls (N = 20) using the automated workflow was 99.2% for SNVs and 95% for indels, with 100% specificity (allele frequency ≥0.5%). In clinical samples (N = 107), sensitivity was 99.4% for SNVs and 100% for indels; specificity was 100% for both, compared with orthogonal assays. Manual extraction improved overall performance compared with the automated extraction and was used for the final clinical workflow. Analytical sensitivity of fusions in synthetic controls (N = 22) was 98.9%, with 100% specificity (≥7 copies). In clinical samples (N = 38), sensitivity and specificity for both SNVs and indels were 100% and 99.9%, respectively; sensitivity for fusions was 72.2%; and specificity was 100%. Overall precision was >99%, and average TAT was ≤2 days. This study reports the feasibility and validation of a 2-day TAT NGS-based cfTNA assay that can potentially reduce time to treatment.

The inadequate nerve networks in regenerated bladders remain a significant challenge in bladder tissue engineering. Our previous studies have demonstrated that incorporating basic fibroblast growth factor (bFGF) and urine-derived stem cells (USCs) into bladder acellular matrix (BAM) enhances bladder repair. While these approaches have shown promising results in regenerating bladder epithelium and smooth muscle, the outcomes of neural regeneration are still not satisfactory. Therefore, this study introduces the 1-14aa sequence from the NGF polypeptide (NMP), a small molecule NGF peptidomimetic, which could improve neural regeneration in the body. Utilizing the tissue inhibitors of metalloproteinases (TIMP) that is cleaved by MMP-2 to design an MMP-2 responsive NMP delivery system, which could control the release of NMP according to the amount of MMP-2 in the local microenvironment. By chemical cross-linking, NMP-TIMP and bFGF were conjugated with BAM seeded with USCs to compose BAM/USCs/bFGF/NMP-TIMP functional biomaterial. Using a rat bladder reconstruction model, the functional biomaterial significantly enhanced the regeneration of endothelial cells, capillaries, smooth muscle cells, nerve fibers, and the bladder functions. In summary, the BAM/USCs/bFGF/NMP-TIMP functional biomaterial may offer a promising strategy for tissue-engineered bladder by promoting bladder regeneration, especially the regeneration of bladder nerves.

BackgroundSerpinB2 is expressed in airway epithelial cells in nasal polyps and asthma in association with Type-2 inflammation. Allergic rhinitis (AR) is similarly associated with Type-2 inflammation and mucus hypersecretion. MUC5AC has been reported to be regulated by IL-13 in nasal epithelial cells (NECs). This study aimed to evaluate SerpinB2 expression in AR and determine whether SerpinB2 regulates MUC5AC via STAT6 signaling.MethodsSerpinB2 gene expression in single-cell RNA sequencing databases was analyzed through bioinformatics approaches. SerpinB2 and MUC5AC expression levels were evaluated in intermittent or persistent AR patients and healthy controls (HC). Colocalization of SerpinB2 and MUC5AC was assessed by immunofluorescence. Fresh NECs were cultured at air-liquid interface with or without IL-13, SerpinB2 Dicer-substrate short interfering RNAs (DsiRNAs) transfection, exogenous SerpinB2, and pSTAT6 inhibitors. SerpinB2, MUC5AC, and STAT6 were analyzed using qRT-PCR, Western blot, immunofluorescence, and ELISA.ResultsSerpinB2 expression was significantly increased in both intermittent and persistent AR compared to normal mucosa from HC. SerpinB2 correlated with MUC5AC expression and colocalized with MUC5AC in NECs from AR patients. In primary NECs in vitro, IL-13 induced both SerpinB2 and MUC5AC expression. Knockdown or overexpression of SerpinB2 correspondingly decreased or increased MUC5AC expression in NECs. STAT6 inhibition similarly reduced SerpinB2-induced MUC5AC expression.ConclusionsSerpinB2 is upregulated in AR NECs and contributes to MUC5AC expression through STAT6 signaling pathway activation. Therefore, targeting SerpinB2 may have therapeutic value in treating AR patients.

Aims/Background Type 2 diabetes mellitus (T2DM) has been reported as a critical contributor to peri-implantitis. Hyperglycemia and associated metabolic changes in diabetes promote cellular senescence. This study aims to investigate the significance of aging-related secretory factors, known as senescence-associated secretory phenotypes (SASPs), in peri-implant crevicular fluid (PICF) in diagnosing type 2 diabetes mellitus-associated peri-implantitis (T2DM-PI). Methods This study included 72 patients with T2DM-PI (designated as a T2DM-PI group) and 45 patients with peri-implantitis (as a control group). The patients were selected at the Linping Campus of the Second Affiliated Hospital of Zhejiang University School of Medicine between December 2021 and December 2023. Patients in both groups were further divided into the middle-aged group and the elderly group. Furthermore, patients were stratified as the middle-aged peri-implantitis (M-PI) group, the middle-aged type 2 diabetes mellitus-associated peri-implantitis (M-DPI) group, the elderly peri-implantitis (E-PI) group, and the elderly type 2 diabetes mellitus-associated peri-implantitis (E-DPI) group. Baseline characteristics and the level of SASPs in PICF were compared between the two groups. We analyzed the factors influencing the occurrence of peri-implantitis in type 2 diabetes, conducted multiple collinearity testing on the selected variables, and incorporated variables with a variance inflation factor (VIF) <5 into a multi-factor binary logistic regression analysis to identify independent risk factors for type 2 diabetes mellitus-associated peri-implantitis. Furthermore, a receiver operating characteristic (ROC) curve was constructed to assess the diagnostic value of SASP levels in patients with T2DM-PI. Results Compared to the control group, the level of SASPs was significantly higher in the T2DM-PI group, with elevated SASP levels positively correlated with the severity of periodontal indicators. Binary logistic regression analysis identified body mass index (BMI), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and matrix metalloproteinase 8 (MMP8) as independent risk factors for the occurrence of T2DM-PI in the middle-aged group (p < 0.05). BMI was found to be an independent risk factor for T2DM-PI in the elderly group (p < 0.05). The ROC curve analysis revealed that IL-1β had the highest diagnostic accuracy among the middle-aged T2DM-PI, with an area under the curve (AUC) of 0.861, a sensitivity of 85.40%, and a specificity of 82.10%. BMI demonstrated the highest diagnostic accuracy in elderly T2DM-PI, with an AUC of 0.904, a sensitivity of 100%, and a specificity of 70.60%. Conclusion Elevated SASP levels in PICF are associated with the severity of periodontal index outcomes in patients with T2DM-PI. Furthermore, SASP levels hold significant diagnostic performance for T2DM-PI.

Purpose:Due to the lack of clear screening guidelines for different populations, identify strategies for obstructive sleep apnea (OSA) in the outpatient population are unclear, a large number of potential OSA outpatients have not been identified in time. The purpose of our study was to evaluate the applicability and accuracy of artificial intelligence sleep screening in outpatients and to provide a reference for OSA screening in different populations. Methods:A type IV wearable artificial intelligence sleep monitoring (AISM) device was used to screen adults in the sleep clinic of the Sleep Medical Center for OSA screening, and the general demographic data of the patients were collected. The epidemiological characteristics obtained by AISM screening were analysed. The accuracy of the AISM for the diagnosis of OSA was evaluated and compared with that of polysomnography (PSG). Results:A total of 1492 participants completed all the studies. The data included 1448 cases total, including 1096 male patients and 352 female patients, with 620 of the total patients being overweight (42.82%) and 429 being obese patients (29.63%). The prevalence of males was 78.19%, and that of females was 55.97% (χ2 = 95.72, P < 0.001). In males, the risk of moderate to severe OSA was 74.21% in obese people, while in females, the risk was 50%. Age, body mass index (BMI) and the oxygen desaturation index (ODI) were positively correlated and negatively correlated with the lowest and mean oxygen saturation. A total of 100 participants completed both PSG and AISM monitoring, and the accuracies of the AISM in diagnosing mild and moderate-to-severe OSA were 94% and 98%, respectively. Conclusion:The AISM exhibits good accuracy, and the use of an objective and convenient sleep detection device to screen a large sample population of outpatients is feasible. The prevalence of OSA in adults in sleep clinics is high, and age, sex, and BMI are risk factors for OSA.

BackgroundPatients with haematological malignancies are immunocompromised and prone to respiratory infections, but identification of causative pathogens is challenging. The aim of this study was to analyse the ability of targeted next-generation sequencing (tNGS) to detect pathogens in immunocompromised patients.MethodstNGS and conventional microbiological tests (CMT) were performed on samples from the respiratory tract of 99 patients with suspected respiratory infections. Metagenomic next-generation sequencing (mNGS) was conducted in parallel in 43 patients. Comparative analysis was conducted using the Pearson χ2 test and Fisher’s exact test, as appropriate.ResultsThe overall microbial detection rates for tNGS were 100% (23/23) in the upper respiratory tract and 96.1% (99/103) in the lower respiratory tract. Microorganism colonization was detected by tNGS in 80.8% (97/120) of cases. The sensitivity of tNGS was approximately 30% higher than that of CMT (87.7% vs. 52.5%; P < 0.001), but tNGS had a lower specificity (33.3% vs. 83.3%; P = 0.242). tNGS improved the overall treatment success rate by 69.7% (69/99 cases) in CMT true-negative or CMT-partially matched cases. In the paired respiratory tNGS and mNGS cases, tNGS verified 73.3% (11/15) cases of infection, while mNGS only verified 40% (P = 0.139).ConclusionsMost immunosuppressed patients are colonized by microorganisms, and require prompt identification of the cause of any infections. tNGS has promising diagnostic potential and offers valuable information for optimizing antibiotic therapy, especially when compared to CMT.

Significance:Optical coherence tomography angiography (OCTA) is a noninvasive technique dedicated to high-resolution microvasculature imaging. However, the projection artifacts of large pial vessels make it difficult to visualize the underlying microvessels, challenging its 3D vascular imaging ability. Aim:We propose a dual acquisition scheme-based 3D OCTA method aimed at simultaneously mitigating projection artifacts and enhancing the detection of capillary networks. Approach:In this study, we introduce an approach incorporating a dual data acquisition scheme with optimally oriented flux (OOF) filtering to address this problem. The repeated A-scan acquisition scheme and corresponding data processing algorithm were used to address the projection artifact issue underneath large pial vessels, whereas repeated B-scan acquisition-based data processing was used to image the capillary network. Results:With such a processing scheme, the projection artifacts can be effectively suppressed, whereas the high detection sensitivity to small vessels of repeat B-scan OCTA can be preserved, thus enabling high-sensitivity 3D imaging of the cerebral vasculature after OOF filtering. Conclusions:The results demonstrate the capability of the proposed method for 3D OCTA imaging, which may play an important role in cerebral microvascular dysfunction-related disease studies.

PURPOSE. Glaucoma is the leading cause of irreversible blindness worldwide and encompasses a group of diseases characterized by optic nerve atrophy and visual field defects. Acute intraocular pressure (IOP) elevation is a key driver of retinal inflammation and optic nerve damage, often accompanied by microglial activation and dysregulated ferroptosis pathways. Vitamin K1, a fat-soluble vitamin, possesses anti-inflammatory and antioxidant properties, and has the potential to regulate ferroptosis. However, its mechanisms in alleviating retinal inflammation following acute IOP elevation remain unclear. METHODS. In vivo, we established a mouse model of acute ocular hypertension to evaluate the protective effects of vitamin K1 on the retina and visual function. Transcriptome sequencing was used to explore the underlying mechanisms by which vitamin K1 exerts its effects. Immunofluorescence and Western blot were used to assess retinal inflammation and observe ferroptosis in microglia. In vitro, we developed a BV2 cell OGDR model to investigate the regulatory effects of vitamin K1 on iron metabolism and inflammation in microglia. RESULTS. Our findings demonstrated that acute IOP elevation led to microglial activation, along with iron overload and ferroptosis in microglia. Further analyses revealed that microglial ferroptosis was accompanied by an upregulation of inflammatory cytokine gene expression and protein levels. Vitamin K1 intervention, however, inhibited microglial ferroptosis, alleviated retinal inflammation, minimized retinal ganglion cell (RGC) loss, and protected visual function. CONCLUSIONS. In conclusion, this study demonstrates that vitamin K1 exerts a protective effect by modulating microglial ferroptosis, thereby alleviating acute ocular hypertension-induced retinal inflammation.

Enhancing neurological recovery and improving the prognosis of spinal cord injury have gained research attention recently. Spinal cord injury is associated with a complex molecular and cellular microenvironment. This complexity has prompted researchers to elucidate the underlying pathophysiological mechanisms and changes and to identify effective treatment strategies. Traditional approaches for spinal cord injury repair include surgery, oral or intravenous medications, and administration of neurotrophic factors; however, the efficacy of these approaches remains inconclusive, and serious adverse reactions continue to be a concern. With advancements in tissue engineering and regenerative medicine, emerging strategies for spinal cord injury repair now involve nanoparticle-based nanodelivery systems, scaffolds, and functional recovery techniques that incorporate biomaterials, bioengineering, stem cell, and growth factors as well as three-dimensional bioprinting. Ideal biomaterial scaffolds should not only provide structural support for neuron migration, adhesion, proliferation, and differentiation but also mimic the mechanical properties of natural spinal cord tissue. Additionally, these scaffolds should facilitate axon growth and neurogenesis by offering adjustable topography and a range of physical and biochemical cues. The three-dimensionally interconnected porous structure and appropriate physicochemical properties enabled by three-dimensional biomimetic printing technology can maximize the potential of biomaterials used for treating spinal cord injury. Therefore, correct selection and application of scaffolds, coupled with successful clinical translation, represent promising clinical objectives to enhance the treatment efficacy for and prognosis of spinal cord injury. This review elucidates the key mechanisms underlying the occurrence of spinal cord injury and regeneration post-injury, including neuroinflammation, oxidative stress, axon regeneration, and angiogenesis. This review also briefly discusses the critical role of nanodelivery systems used for repair and regeneration of injured spinal cord, highlighting the influence of nanoparticles and the factors that affect delivery efficiency. Finally, this review highlights tissue engineering strategies and the application of biomaterial scaffolds for the treatment of spinal cord injury. It discusses various types of scaffolds, their integrations with stem cells or growth factors, and approaches for optimization of scaffold design.

Background: Urine-derived stem cells (USCs) were considered to be an ideal source of stem cells for repairing urological diseases. However, the proliferative ability of USCs significantly decreased when cultured on plastic dishes, which limited their clinical application. It was found that collagen gels could promote the proliferation of USCs, but the underlying molecular mechanisms were unclear. Objective: The study aims to investigate the role of the mechanically activated cation channel Piezo1 and the transcriptional coactivator YAP in the regulation of proliferation of USCs on collagen gels. Methods: USCs were cultured on collagen gels (group COL), or plastic dishes (group NON). MTT assay, Scratch assay, EDU staining, and immunofluorescence (IF) of Ki67 were performed to evaluate the proliferation of USCs; IF of YAP was conducted to observe its nuclear localization; calcium imaging experiment was executed to evaluate the function of Piezo1; western blot was used to compare changes in protein expression of YAP, LATS1, ERK1/2, and p-ERK1/2. In addition, the regulatory effect of YAP on the proliferative capacity of USCs was confirmed by intervening YAP with its inhibitor verteporfin (VP); and the inhibitor or activator of Piezo1, GsMTx4 or Yoda1 was used to explore the effect of Piezo1 on the nuclear localization of YAP, the proliferation of USCs and the regeneration of injured bladder. Results: The results showed that cell proliferation was significantly enhanced in USCs in the COL group with the nuclear accumulation of YAP compared with the NON group and VP attenuated these effects. The expression and function of Piezo1 were higher in the COL group compared with the NON group. Blockage of Piezo1 by GsMTx4 decreased nuclear localization of YAP, the proliferation of USCs, and caused the failure of bladder reconstruction. Activation of Piezo1 by Yoda1 increased the nuclear expression of YAP, and the proliferation of USCs, which further improved the regeneration of the injured bladder. Finally, the ERK1/2 rather than LATS1 was revealed to participate in the Piezo1/YAP signal cascades of USCs proliferation. Conclusion: Taken together, Piezo1-ERK1/2-YAP signal cascades were involved in regulating the proliferation ability of USCs in collagen gels which would be beneficial for the regeneration of the bladder.

Neuroinflammation, characterized by microglial activation and the release of multiple inflammatory mediators, is a key factor in acute glaucomatous injury leading to retinal ganglion cell (RGC) death and ultimately irreversible vision loss. Irisin, a novel exercise-induced myokine, has demonstrated anti-inflammatory activity in ischemia/reperfusion injuries across multiple organs and has displayed a significant neuroprotective role in experimental stroke disease models. This study examined the protective impact of irisin and investigated its potential mechanism involved in this process utilizing an acute ocular hypertension (AOH)-induced retinal injury model in mice and a microglia inflammation model induced by lipopolysaccharide (LPS). There was a transient downregulation of irisin in the retina after AOH injury, with parallel emergence of retinal neuroinflammation and RGC death. Irisin attenuated retinal and optic nerve damage and promotes the phenotypic conversion of microglia from M1 to M2. Mechanistically, irisin significantly upregulated the expression of integrin alpha VI35, pAMPK, and autophagy-related markers. Integrin alpha VI35 was highly expressed on microglia but hardly expressed on RGC. The integrin alpha VI35 inhibitor cilengitide, the AMPK inhibitor dorsomorphin, and the autophagy inhibitor 3Methyladenine (3 -MA) blocked the neuroprotective effects of irisin. Our results suggest irisin attenuates acute glaucoma-induced neuroinflammation and RGC death by activating integrin alpha VI35/AMPK in microglia and promoting autophagy. It should be considered a potential neuroprotective therapy for acute glaucoma.

IntroductionAngle-closure glaucoma is a common type of glaucoma in Asian populations. However, the role of inflammatory cytokines in angle-closure glaucoma is yet to be elucidated. Therefore, this study aimed to examine the expression of interleukin-4 (IL-4) and IL-12 in the aqueous humor of patients with chronic primary angle-closure glaucoma (CPACG) and elucidate the correlations between IL-4 and IL-12 concentrations in the aqueous humor, the degree of visual field defects, and retinal nerve fiber layer (RNFL) thickness in patients with CPACG.MethodsAqueous humor samples were obtained from 31 patients diagnosed with CPACG at the Shaoxing People’s Hospital between April 2022 and March 2023 and from 30 individuals with cataract (control). Based on the degree of the mean defect (MD), patients were divided into three groups: group A (MD ≤ −6dB, n= 10), group B (−6dB< MD< −12dB, n= 9), and group C (MD ≥ − 12dB, n= 12). RNFL thickness was measured using an optical coherence tomograph, and the concentrations of IL-4 and IL-12 in the aqueous humor were measured using Luminex technology.ResultsAqueous humor concentration of IL-4 was significantly higher (p = 0.036) in the CPACG group than in the cataract group. However, there was no significant difference (p > 0.05) in IL- 12 concentration between the two groups. Additionally, there were no significant differences (p > 0.05) in IL-4 and IL-12 levels among patients with varying degrees of visual field defects (groups A, B, and C). Spearman’s correlation analysis showed that IL-4 and IL-12 concentrations were not correlated (p > 0.05) with RNFL thickness around the optic disc and the degree of visual field defects.DiscussionConclusively, IL-4 may play an important role in the pathogenesis of CPACG. Given that IL-4 and IL-12 concentrations in the aqueous humor were not significantly correlated with RNFL thickness and the degree of visual field defects, the increase in IL-4 and IL-12 expression may not induce apoptosis and loss of retinal ganglion cells or affect RNFL thickness as well as the degree of visual field defects.

[This retracts the article DOI: 10.3892/etm.2020.8996.].

ObjectiveNasopharyngeal carcinoma (NPC) patients frequently present with distant metastasis (DM), which is typically associated with poor prognosis. This study aims to develop and apply machine learning models to predict DM, overall survival (OS), and cancer-specific survival (CSS) in NPC patients to provide optimal tools for improved predictive accuracy and performance.MethodsWe retrieved over 8,000 NPC patient samples with associated clinical information from the Surveillance, Epidemiology, and End Results (SEER) database. Utilizing two methods for handling missing values—imputation or deletion—we created various cohorts: DM-all, DM-slim, OS-all, OS-slim, CSS-all, and CSS-slim. Five machine learning models were deployed for the binary classification task of DM, and their performance was evaluated using the area under the curve (AUC). For the survival prediction tasks of OS and CSS, we constructed 45 combinations using nine survival machine learning algorithms. The Concordance Index (C-index), 5-year AUC, and Brier score assessed model accuracy. Patients were stratified into two risk groups for survival analysis, and the survival curves were presented.ResultsThis study examines the relationships between clinical factors and survival in NPC patients. The analysis, visualized through forest plots, indicates that demographic and clinical variables like gender, marital status, tumor grade, and stage significantly affect metastatic risks and survival. Specifically, factors such as advanced stages increase metastasis and survival risks, while enhanced treatments improve survival rates. In the cohort for DM prediction, results revealed that the random forest model was the most effective, with an AUC of 0.687. In contrast, when predicting overall survival (OS), the random survival forest (RSF) model consistently showed superior performance with the highest mean C-index of 0.802, a 5-year AUC of 0.857, and a Brier score of 0.167. Similarly, for cancer-specific survival (CSS) prediction, the RSF model demonstrated a mean C-index of 0.822, a 5-year AUC of 0.884, and a Brier score of 0.165. An online Shiny server was developed to allow the models to be used freely and efficiently via http://npcml.shinyapps.io/NPCpre.ConclusionThis study successfully established an online tool by machine learning models for NPC metastasis and survival prediction, providing valuable references for clinicians.

Introduction: Acute kidney injury (AKI) was a disease with a high mortality mainly caused by renal ischemia/reperfusion injury (I/R). Although the current non-targeted administration of vascular endothelial growth factor (VEGF) for AKI had been revealed to facilitate the recovery of renal I/R, how to targeted deliver VEGF and to retain it efficiently in the ischemic kidney was critical for its clinical application. Methods: In present study, bi-functional KIT-PR1P peptides were constructed which bond VEGF through PR1P domain, and targeted ischemic kidney through KIT domain to interact with biomarker of AKIkidney injury molecule-1 (Kim-1). Then the targeted and therapeutic effects of KIT-PR1P/VEGF in AKI was explored in vitro and in vivo. Results: The results showed KIT-PR1P exhibited better angiogenic capacity and targeting ability to hypoxia HK-2 cells with up-regulated Kim-1 in vitro. When KIT-PR1P/VEGF was used for the treatment of renal I/R through intravenous administration in vivo, KIT-PR1P could guide VEGF and retain its effective concentration in ischemic kidney. In addition, KIT-PR1P/VEGF promoted angiogenesis, alleviated renal tubular injury and fibrosis, and finally promoted functional recovery of renal I/R. Conclusion: These results indicated that the bi-functional KIT-PR1P peptides combined with VEGF would be a promising strategy for the treatment of AKI by targeting to Kim-1. (c) 2023, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.

Précis: Lower response of aqueous outflow pathway structures after pilocarpine could be observed in primary open angle glaucoma (POAG) patients, which is likely to be helpful for understanding intraocular pressure (IOP) evaluation in glaucoma. Purpose: To evaluate the morphologic changes in the trabecular meshwork (TM), Schlemm canal (SC), scleral spur (SS), and ciliary muscle after miosis in patients with POAG and healthy individuals. Methods: A total of 30 patients with POAG and 26 healthy controls were recruited. All participants underwent complete ophthalmologic examinations, including IOP and swept-source optical coherence tomography (OCT), before and 1 hour after the local administration of pilocarpine (2%). OCT measurements included TM thickness and width, SC diameter and area, SS length, ciliary muscle thickness, and ciliary muscle angle (CMA). Results: Pilocarpine administration induced a decline in IOP (15.6±2.3–14.6±2.2 mm Hg), decrease in nasal SS length (196.31±47.75–171.52±33.93 μm), decrease in TM thickness (90.18±16.43–83.02±13.74 μm), and increase in SC diameter (134.84±32.28–162.08±48.67 μm) and SC area (3851.37±1455.07–4801.39±1762.37 μm 2 ) among healthy controls. In contrast, no significant changes in IOP and OCT measurements were found in patients with POAG. At baseline, CMA was independently correlated with IOP in normal eyes. After miosis, the change in TM thickness was independently correlated with changes in IOP in normal eyes; in eyes with POAG, changes in SS length and CMA were independently associated with changes in IOP. Conclusions: Topical pilocarpine-induced morphologic changes to outflow pathway structures in healthy individuals without significant changes in POAG. The lower response observed in patients with glaucoma may be relevant to understanding IOP changes.

This paper is concerned with the non-periodic superlinear Schrodi-nger equation -?u + V(x)u = f (x, u), u ? H-1(R-N). Here, the Shrodinger operator -?+V is strongly indefinite, that is, possesses a infinite dimensional negative space, which leads to more difficulty in verifying the compactness conditions. We prove the existence, as well as multiplicity provided f (x, t) is odd in t, of solutions via variational methods.

Purpose To investigate the effect of endothelin-1 (ET-1) in excessive accumulation of extracellular matrix (ECM) of the trabecular meshwork (TM) and its role in intraocular pressure (IOP) regulation. Methods Cultured human TM cells (HTMCs) were treated with ET-1, ET-1 + ETA receptor (ETAR) antagonist BQ123, ET-1 + ETB receptor (ETBR) antagonist BQ788. The expressions of fibronectin (FN) and collagen type IV (Col IV) were evaluated by western blotting and immunofluorescence. A time course effect of ET-1 on the transcription level of connective tissue growth factor (CTGF) was investigated by qRT-PCR. Next, the transcription level of CTGF was downregulated by using antisense oligodeoxynucleotide sequence. Then HTMCs were treated with ET-1, and the expression levels of FN and Col IV were evaluated by western blotting. In addition, by using an ex-vivo model of cultured anterior eye segment, we explored the effect of ET-1 on IOP changes and the expressions of FN and Col IV. Results In cultured HTMCs, the expressions of FN and Col IV were significantly increased after ET-1 treatment, which were blocked by the pretreatment of ETAR antagonist BQ123, rather than ETBR antagonist BQ788. Besides, the CTGF mRNA level increased significantly and reached a peak after 48 h of ET-1 treatment. However, the effect of ET-1 on increasing the expressions of FN and Col IV in HTMCs could be inhibited by the downregulation of CTGF. In an ex-vivo model, IOP increased significantly after ET-1 administration, which could be blocked by BQ123 but not by BQ788. Furthermore, elevated expressions of FN and Col IV in TM were observed after ET-1 perfusion, and could be inhibited by BQ123 pretreatment. Conclusion Excessive ET-1 in aqueous humor could lead to the abnormal accumulation of FN and Col IV in TM via the ETA-CTGF pathway, thereby increasing IOP.