Background: Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma (ccRCC). This investigation aims to identify genes associated with sunitinib resistance and elucidate potential molecular pathways in ccRCC. Methods: To identify differentially expressed genes (DEGs) in sunitinib-resistant ccRCC cells and their parental cells, bioinformatic analysis was performed on the GSE216494 dataset. Protein-protein interaction (PPI) network and topological analyses pinpointed a hub gene. Sunitinib-resistant A498 and 786-O cell lines were employed for in vitro validation. Sunitinib sensitivity and cell proliferation were evaluated using functional assays, such as colony formation and Cell Counting Kit-8 (CCK-8). Protein interactions and signaling pathway activity are investigated using co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, and immunofluorescence. In resistant cells and patient-derived organoids (PDOs), the therapeutic potential of olaparib, either by itself or in conjunction with sunitinib, was assessed. Results: Sunitinib-resistant cells and patient tissues were shown to exhibit consistent upregulation of poly (ADP-ribose) polymerase 9 (PARP9). PARP9 knockdown sensitized resistant cells to sunitinib, suppressing proliferation. Conversely, its overexpression induced resistance in parental cells. Additionally, STAT1 and PARP9 interact to promote nuclear translocation and STAT1 phosphorylation. Activation of the STAT1/IRF1 axis further enhanced the expression of ISG15 and IFIT1. Olaparib treatment can increase sunitinib-resistant ccRCC cells. Olaparib can weaken the STAT1/IRF1 signaling pathway and prevent sunitinib-resistant ccRCC cells from proliferating. Importantly, combination treatment with olaparib and sunitinib showed superior antitumor efficacy in ccRCC PDOs. Conclusion: This study demonstrates that PARP9 promotes sunitinib resistance in ccRCC by activating the STAT1/IRF1 pathway and upregulating ISG15/IFIT1.

This review systematically analyzes the relationship between the immune microenvironment characteristics of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer (CRC) and the efficacy of immune checkpoint inhibitors (ICIs). The article emphasizes that this tumor subtype has a high mutation burden, abundant neoantigens, and significant immune cell infiltration, explaining its high sensitivity to immunotherapy, while also pointing out that some patients exhibit primary non-response or subsequent resistance. Based on single-cell and spatial omics, as well as multi-omics integration analyses, the authors reveal the complexity and heterogeneity of key immune cell subpopulations, spatial distribution, and resistance mechanisms (such as abnormal Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, human leukocyte antigen (HLA) loss, and metabolic reprogramming, and propose the necessity of multi-time-point dynamic monitoring and multimodal combination therapy. The study underscores that, in the future, standardized data integration and the establishment of artificial intelligence (AI) prediction models will be required to facilitate the implementation of precise, individualized immunotherapy strategies, thereby further improving clinical efficacy.

After 70% partial hepatectomy (PHx), the metabolic pathways leading to hepatocyte lipid droplet accumulation during liver regeneration remain unclear. Aquaporin 5 (Aqp5) is an aquaporin that facilitates the transport of both water and hydrogen peroxide (H2O2). In this study, we observed delayed liver regeneration following PHx in Aqp5 knockout (Aqp5-/-) mice. Considering the role of Aqp5 in H2O2 transport, we hypothesized that deficiency in Aqp5 may induce oxidative stress and hepatocyte injury. Through the measurement of reactive oxygen species (ROS) and redox-related indices, we observed significant alterations in ROS levels as well as malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in regenerating livers lacking Aqp5 compared to wild-type controls. Oil Red O and 4-hydroxynonenal (4-HNE) staining results indicated that Aqp5 deficiency caused lipid accumulation during liver regeneration. The transcriptome sequencing results showed that the PPAR pathway is inhibited during the liver regeneration process in Aqp5 gene-knockout mice. The administration of the WY-14643 agonist, which targets the PPAR pathway, significantly mitigated delayed liver regeneration by enhancing hepatocyte proliferation and reducing lipid accumulation caused by Aqp5 deficiency. Our findings highlight the crucial role of Aqp5 in regulating H2O2 levels and lipid metabolism through the PPAR pathway during liver regeneration.

During the proliferative phase of liver regeneration, insufficient regulation of hepatocyte hydrogen peroxide (H2O2) overproduction can result in oxidative stress and hepatocyte death. This study aims to investigate the influence of Aquaporin 5 (Aqp5) on liver regeneration by evaluating its role in reactive oxygen species (ROS) generation and NLRP3-GSDMD-mediated pyroptosis. A 70 % partial hepatectomy (PHx) model was established in Aqp5-/- mice to evaluate the pathological changes in the liver. Reactive oxygen species (ROS) production was assessed using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. Aqp5 deficiency significantly increased ROS production, the number of TUNEL-positive cells, and disrupted mitochondrial membrane potential in the liver of Aqp5-deficient mice. The impact of Aqp5 on ROS/NLRP3/Gasdermin-D (GSDMD)-mediated pyroptosis was examined through the administration of N-acetyl-L-cysteine (NAC, an ROS scavenger) or disulfiram (DSF, a GSDMD inhibitor). In Aqp5-deficient mice, the regenerative liver exhibited increased expression of NLRP3, enhanced activation of caspase-1 and GSDMD, as well as elevated secretion of IL-1β. Treatment with DSF significantly attenuated GSDMD-mediated pyroptosis triggered by Aqp5 deficiency in the regenerating liver. Furthermore, the administration of NAC to Aqp5-deficient mice resulted in a reduction in the expression levels of NLRP3, the activity levels of caspase-1 and GSDMD, as well as the release of IL-1β. Our findings indicate that the deficiency of Aqp5 facilitates GSDMD activation through the production of ROS. The suppression of ROS or inhibition of GSDMD significantly alleviates the damage and pyroptosis observed in Aqp5-deficient regenerative liver.

Mitochondria play a crucial role in energy production and are intimately associated with ocular function. Mitochondrial dysfunction can trigger oxidative stress and inflammation, adversely affecting key ocular structures such as the lacrimal gland, lens, retina, and trabecular meshwork. This dysfunction may compromise the barrier properties of the trabecular meshwork, impeding aqueous humour outflow, elevating intraocular pressure, and resulting in optic nerve damage and primary open-angle glaucoma. Additionally, impaired mitochondrial homeostasis can contribute to dry eye, cataracts, and age-related macular degeneration (AMD) by disrupting the function of the lacrimal gland, lens, and macula. Imbalanced mitochondrial homeostasis primarily involves four pathological features: disruption of mitochondrial quality control, mitochondrial damage (inducing inflammation), excessive production of mitochondrial reactive oxygen species (ROS) (initiating oxidative stress), and disturbances in mitochondrial calcium (Ca2+) homeostasis. Oxidative stress and inflammation are central mechanisms of cellular injury. Pharmacological strategies aimed at reducing excessive ROS, restoring redox balance, and mitigating oxidative and inflammatory damage show therapeutic promise. Moreover, enhancing mitochondrial function through pharmacological agents, replacing damaged mitochondria, and promoting mitochondrial rejuvenation represent emerging treatment avenues. This review explores the relationship between mitochondrial dysfunction and ocular diseases such as dry eye, glaucoma, cataracts, and AMD, with a focus on associated mechanisms and potential therapeutic interventions.

Triple-negative breast cancer (TNBC) poses a significant challenge owing to its complex pathological features and treatment resistance. In recent years, immune checkpoint blockade (ICB) therapy has shown satisfactory results in the treatment of TNBC. ICB therapy targeting T cells' inhibitory receptors and innate immune checkpoints has gradually become a research hotspot. However, a study has found that compared with single immune checkpoint inhibition, dual ICB has a more significant therapeutic effect. This study aimed to develop an engineered nanocarrier, aLS@VpNPs, loaded with the photosensitizer verteporfin and coated with TNBC cell membranes loaded with antilymphocyte activation gene-3 (anti-LAG3) and sialic acid binding immunoglobulin-like lectin 10 (Siglec10) proteins for delivering combination therapies. The biomimetic vector can mimic the surface characteristics of tumor cells, showing better biocompatibility and efficient tumor-targeting ability. Under photodynamic therapy (PDT), reactive oxygen species (ROS) are generated at the tumor site to directly kill cancer cells and induce immunogenic cell death, transforming "cold tumors" into "hot tumors" and further enhancing the efficacy of dual ICB targeting T cells and macrophages. In summary, this approach improves drug delivery efficiency and therapeutic precision and activates the host immune system through the synergistic mechanisms of PDT and ICB. In addition, the study reveals potential mechanisms for the combined therapy in modulating the tumor microenvironment, offering effective strategies and directions for TNBC treatment.

This retrospective aims to develop a comprehensive predictive model based on CT radiomic features and clinical parameters, facilitating early preoperative diagnosis of pyonephrosis. Clinical and radiological data from 311 patients treated for upper urinary tract stones with obstructive pyelohydronephrosis, between January 2018 and May 2023, were retrospectively collected. Univariate and multivariate logistic regression analyses were conducted on clinical data to identify independent risk factors for pyonephrosis. A clinical model was developed using logistic regression. The 3D Slicer software was employed to manually delineate the region of interest (ROI) in the preoperative CT images, corresponding to the area of pyelohydronephrosis, for feature extraction. The optimal radiomic features were selected to construct radiomic models and calculate the radiomic score (Radscore). Subsequently, a combined clinical–radiomic model—the nomogram—was established by integrating the Radscore with independent risk factors. Univariate and multivariate logistic regression analyses identified cystatin C, Hounsfield Unit (HU) of pyonephrosis, history of ipsilateral urological surgery, and positive urine culture as independent risk factors for pyonephrosis (P < 0.05). Fourteen optimal radiomic features were selected from CT images to construct four radiomic models, with the Naive Bayes model demonstrating the best predictive performance in both training and validation sets. In the training set, the AUCs for the clinical model, radiomic model, and nomogram were 0.902, 0.939, and 0.991, respectively; in the validation set, they were 0.843, 0.874, and 0.959. Both calibration and decision curves showed good agreement between the predicted probabilities of the nomogram and the actual occurrences. The nomogram, constructed from CT radiomic features and clinical variables, provides an effective non-invasive predictive tool for pyonephrosis, surpassing both clinical and radiomic models.

Background The study aimed to evaluate the differences in prostate cancer (PCa) detection rates between novice and experienced resident physicians using free-hand cognitive fusion transperineal prostate biopsy (fTP-Bx) through propensity score matching (PSM). Methods A retrospective analysis was conducted on a cohort of patients who underwent fTP-Bx procedures. The needle biopsies were performed by two groups of surgical doctors with varying levels of prostate biopsy experience (Novice Group and Experienced Group) between March 1, 2023, and March 1, 2024. The PSM method was employed to compare the differences in cancer detection-related parameters between various groups of differing prostate biopsy experience levels. Results In total, 398 patients were included in the study, with 196 in the Experienced Group and 202 in the Novice Group. Prior to PSM, significant differences were observed between the groups in terms of operation duration (p = 0.014) and multiparametric MRI results (mpMRI, p = 0.009). However, after adjusting for confounding factors through PSM, there were no differences in the absolute number of cores involved, percentage of cores involved, clinically significant prostate cancer (csPCa) detection rates, and overall PCa detection rates between the different prostate biopsy experience groups. Despite potential variations in operation duration related to different levels of needle biopsy experience, there were no distinctions observed between novice and experienced doctors in terms of prostate cancer detection, particularly concerning csPCa. Conclusions Novice resident physicians have the ability to complete qualified fTP-Bx.

PurposeTo develop and validate a nomogram for preoperative prediction of lymph node metastasis in patients with progressive muscle-invasive bladder cancer.Materials and methodsWe retrospectively recruited patients, divided them into training and validation cohorts, and gathered patient demographics, pathology data of transurethral bladder tumor resection specimens, imaging findings, and laboratory information. We performed logistic regression analyses, both single-variable and multi-variable, to investigate independent preoperative risk variables and develop a nomogram. Both internal and external validations were conducted to evaluate the predictive performance of this nomogram.ResultsThe training cohort consisted of 144 patients with advanced muscle-invasive bladder cancer, while the validation cohort included 62 individuals. The independent preoperative risk factors identified were tumor pathology grade, platelet count, tumor size on imaging, and lymph node size, which were utilized to develop the nomogram. The model demonstrated high predictive accuracy, as evidenced by the area under the receiver operating characteristic curve values of 0.898 and 0.843 for the primary and external validation cohorts, respectively. Calibration curves and decision curve analysis showed a good performance of the nomogram in both cohorts, indicating its high clinical applicability.ConclusionA nomogram for preoperative prediction of lymph node metastasis in patients with advanced muscle-invasive bladder cancer was successfully developed; its accuracy, reliability, and clinical value were demonstrated. This new tool would facilitate better clinical decisions regarding whether to perform complete lymph node dissection in cases of radical cystectomy.

BackgroundChronic Kidney Disease (CKD) is a common severe complication after radical nephrectomy in patients with renal cancer. The timely and accurate prediction of the long-term progression of renal function post-surgery is crucial for early intervention and ultimately improving patient survival rates.ObjectiveThis study aimed to establish a machine learning model to predict the likelihood of long-term renal dysfunction progression after surgery by analyzing patients' general information in depth.MethodsWe retrospectively collected data of eligible patients from the Affiliated Hospital of Qingdao University. The primary outcome was upgrading of the Chronic Kidney Disease stage between pre- and 3-year post-surgery. We constructed seven different machine-learning models based on Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), Extreme Gradient Boosting (XGBoost), Light Gradient Boosting Machine (Lightgbm), Gaussian Naive Bayes (GaussianNB), and K-Nearest Neighbors (KNN). The performance of all predictive models was evaluated using the area under the receiver operating characteristic curve (AUC), precision-recall curves, confusion matrices, and calibration curves.ResultsAmong 360 patients with renal cancer who underwent radical nephrectomy included in this study, 185 (51.3%) experienced an upgrade in Chronic Kidney Disease stage 3-year post-surgery. Eleven predictive variables were selected for further construction of the machine learning models. The logistic regression model provided the most accurate prediction, with the highest AUC (0.8154) and an accuracy of 0.787.

Background: Hemorrhage is the most common and dangerous complication after percutaneous nephrolithotripsy (PCNL). Therefore, this study introduces the management experience of bleeding complications in our center. Methods: This retrospective study included 77 patients with severe bleeding after PCNL. Forty patients were included in the conservative group, 13 in the transfusion group, and 24 in the embolization group. The characteristics of postoperative bleeding were analyzed, including changes in hemoglobin and hematocrit, bleeding inducement, bleeding management, and clinical Results: Forty patients received conservative treatment. Their mean hemorrhage time was 6.5 days (range, 3-14 days), and their mean decreased hemoglobin was 33.8 g/L (range, 13-61 g/L). Thirteen patients received only conservative treatment and blood transfusions. Their mean hemorrhage time was 11 days (range, 2-17 days), and their mean decreased hemoglobin was 49 g/L (range, 25-85 g/L). Twenty-four patients required renal angiography and renal artery embolization (RAE). Their average time from PCNL to RAE was 11 days (range, 3-25 days). Hemoglobin levels decreased by an average of 52.8 g/L (range, 19-89 g/L). A decrease in hematocrit >= 14.65% was a significant indicator for post-PCNL RAE. Conclusions: A decreased hemoglobin level can be used as a reference for decisions regarding embolization; However, it should not be used as an absolute criterion. Conservative treatment and embolization are effective for achieving hemostasis. Appropriate treatment methods should be comprehensively determined based on clinical manifestations, bleeding inducement, and blood index changes.

Unilateral Nephrectomy is one of the most common treatments for surgical diseases of the kidney but often results in postsurgical acute kidney injury (AKI). In the current study, we aimed to investigate the risk factors for AKI in patients who have received Unilateral Nephrectomy. We retrospectively analysed 528 patients who underwent Unilateral Nephrectomy for different etiologies between January 2013 and December 2018 at the Affiliated Hospital of Qingdao University. We recorded the prevalence and severity of AKI, age, gender, diabetes, body mass index (BMI), hypertension, preoperative renal function, etiology, performed surgically, anaemia, albumin, coagulation, lactate dehydrogenase, nitrogen (BUN), and uric acid. Univariate and multivariate logistic regression analyses were used to investigate the predictors of AKI in patients with Unilateral Nephrectomy. Overall, 218 of the 528 patients (41.2%) developed AKI during their hospitalisation. Univariate analysis showed that AKI was significantly associated with gender (male, OR = 1.866, P = 0.001), overweight (OR = 2.19, P = 0.0002), and surgical approach (OR = 1.7, P = 0.018), while multivariate logistic regression analysis showed that male gender (OR = 1.953, P = 0.001), overweight (OR = 2.176, P = 0.001), and preoperative renal function (OR = 0.507, P = 0.001) were independent factors for AKI. Regression analysis among different etiologies showed significant differences in postoperative AKI. After Unilateral nephrectomy, AKI is more likely to occur in overweight male patients with normal kidney function. AKI occurred more frequently in patients who are kidney donors, but rarely in those with non-function kidneys.

Purpose:Abnormalities in aquaporins are implicated in the pathological progression of dry eye syndrome. Retinoic acid (RA) regulates cellular proliferation, differentiation, and apoptosis in the cornea, thereby being associated with dry eye disease (DED). The objective of this study is to explore the underlying mechanisms responsible for RA metabolic abnormalities in corneas lacking aquaporin 5 (AQP5). Methods:Dry eye (DE) models were induced via subcutaneous scopolamine hydrobromide. Aqp5 knockout (Aqp5-/-) mice and DE mice were utilized to assess corneal epithelial alterations. Tear secretion, goblet cell counts, and corneal punctate defects were evaluated. The impact of Aqp5 on RA-related enzymes and receptors was investigated using pharmacological RA or SR (A JunB inhibitor), a transcription factor JunB inhibitor, treatment in mouse corneal epithelial cells (CECs), or human corneal epithelial cells (HCECs). The HCECs and NaCl-treated HCECs underwent quantitative real-time PCR (qRT-PCR), immunofluorescent, Western blot, and TUNEL assays. The regulation of transcription factor JunB on Aldh1a1 was explored via ChIP-PCR. Results:Aqp5 and Aldh1a1 were reduced in both CECs of DE mice and NaCl-induced HCECs. Aqp5-/- mice exhibited DE phenotype and reduced Aldh1a1. RA treatment reduced apoptosis, promoted proliferation, and improved the DE phenotype in Aqp5-/- mice. JunB enrichment in the Aldh1a1 promoter was identified by ChIP-PCR. SR significantly increased Aldh1a1 expression, Ki67, and ΔNp63-positive cells, and decreased TUNEL-positive cells in CECs and HCECs. Conclusions:Our findings demonstrated the downregulation of Aqp5 expression and aberrant RA metabolism in DE conditions. Knockout of Aqp5 resulted in reduced production of RA through activation of JunB, subsequently leading to the manifestation of DE symptoms.

BACKGROUND:Prior research has demonstrated that people with cataracts are more likely to experience anxiety and depression co-occurring when the condition advances to a degree that impairs vision beyond its physiological effects. According to network theory, there is a connection between the interplay of anxiety and depression and the genesis of comorbidity. Using a network viewpoint, our study examined the network properties of anxiety-depression in cataract patients to pinpoint central and bridge symptoms as well as possible intervention targets for more focused and successful therapies. METHOD:A total of 1,254 cataract patients were enrolled in our study. The Nine-item Patient Health Questionnaire (PHQ-9) and the Seven-item Generalized Anxiety Disorder scale (GAD-7) were used to measure depression and anxiety symptoms, respectively. The R 4.3.3 software was utilized for network model building and descriptive statistics. Furthermore, we displayed a "Thoughts of death" flow network. RESULT:In the network, A5 "Restlessness"- D7 "Concentration difficulties" showed the strongest edge. A2 "Uncontrollable worry" and D2 "Depressed or sad mood" could be identified as the central symptoms. A7 "Afraid something will happen" and D7 "Concentration difficulties" could be identified as bridge symptoms. The strongest edge in the flow network was D9 "Thoughts of death"-D6 "Feeling of worthlessness". CONCLUSION:"Uncontrollable worry", "Depressed or sad mood", "Afraid something will happen" and "Concentration difficulties" could be potential targets for the prevention of anxiety and depression in cataract patients. Furthermore, this study emphasizes how important it is to prevent suicide in cataract patients, and the symptom "Feeling of worthlessness" can be used as an effective target.

Abstract Background: Chronic kidney disease (CKD) is a common postoperative complication in patients who undergo radical nephrectomy for renal tumours. However, the factors influencing long-term renal function require further investigation. Objective: This study aimed to investigate the trends in renal function changes and risk factors for renal function deterioration in patients with renal tumours after radical nephrectomy. Results: We analysed the data from 329 patients with renal tumours undergoing radical nephrectomies between January 2013 and December 2018. We monitored the changes in the patient’s renal function before and after surgery for 3 years. The progression of renal function was determined by the progression and degradation of CKD stages. Univariate and multivariate logistic regression analyses were used to analyse the causes of renal function progression. In this study, 43.7% of patients had postoperative acute kidney injury (AKI) and 48.3% had upgraded CKD stages. Further research revealed that the patient’s renal function levelled off 3 months following surgery. Additionally, renal function changes during these 3 months have a substantial impact on the progression of long-term renal function in patients. Conclusion: AKI may be an indicator of short-term postoperative changes in renal function. Renal function tests should be performed in patients with AKI after radical nephrectomy to monitor the progression of functional impairment, particularly within the first 3 months after radical nephrectomy.

Objective: This retrospective aims to develop a comprehensive predictive model based on CT radiomic features and clinical parameters, facilitating early preoperative diagnosis of pyonephrosis. Methods: Clinical and radiological data from 311 patients treated for upper urinary tract stones with obstructive pyelohydronephrosis, between January 2018 and May 2023, were retrospectively collected. Univariate and multivariate logistic regression analyses were conducted on clinical data to identify independent risk factors for pyonephrosis. A clinical model was developed using logistic regression. The 3D Slicer software was employed to manually delineate the region of interest (ROI) in the preoperative CT images, corresponding to the area of pyelohydronephrosis, for feature extraction. The optimal radiomic features were selected to construct radiomic models and calculate the radiomic score (Radscore). Subsequently, a combined clinical-radiomic model—the nomogram—was established by integrating the Radscore with independent risk factors. Results: Univariate and multivariate logistic regression analyses identified cystatin C, Hounsfield Unit (HU) of Pyonephrosis, history of ipsilateral urological surgery, and positive urine culture as independent risk factors for pyonephrosis (P<0.05). Fourteen optimal radiomic features were selected from CT images to construct four radiomic models, with the Naive Bayes model demonstrating the best predictive performance in both training and validation sets. In the training set, the AUCs for the clinical model, radiomic model, and nomogram were 0.902, 0.939, and 0.991, respectively; in the validation set, they were 0.843, 0.874, and 0.959. Both calibration and decision curves showed good agreement between the predicted probabilities of the nomogram and the actual occurrences. Conclusion: The nomogram, constructed from CT radiomic features and clinical variables, provides an effective non-invasive predictive tool for pyonephrosis, surpassing both clinical and radiomic models.

Abstract Background Chronic kidney disease (CKD) is a common postoperative complication in patients who undergo radical nephrectomy for renal tumours. However, the factors influencing long-term renal function require further investigation. Objective This study was designed to investigate the trends in renal function changes and risk factors for renal function deterioration in renal tumour patients after radical nephrectomy. Methods We monitored changes in renal function before and after surgery for 3 years. The progression of renal function was determined by the progression and degradation of CKD stages. Univariate and multivariate logistic regression analyses were used to analyse the causes of renal function progression. Results We analysed the data of 329 patients with renal tumours who underwent radical nephrectomies between January 2013 and December 2018. In this study, 43.7% of patients had postoperative acute kidney injury (AKI), and 48.3% had CKD at advanced stages. Further research revealed that patients’ renal function stabilized 3 months after surgery. Additionally, renal function changes during these 3 months have a substantial impact on the progression of long-term renal function changes in patients. Conclusion AKI may be an indicator of short-term postoperative changes in renal function. Renal function tests should be performed in patients with AKI after radical nephrectomy to monitor the progression of functional impairment, particularly within the first 3 months after radical nephrectomy.

Purpose:Dry eye disease (DED) is multifactorial and associated with nerve abnormalities. We explored an Aquaporin 5 (AQP5)-deficiency-induced JunB activation mechanism, which causes abnormal lacrimal gland (LG) nerve distribution through Slit2 upregulation and Netrin-1 repression. Methods:Aqp5 knockout (Aqp5-/-) and wild-type (Aqp5+/+) mice were studied. LGs were permeabilized and stained with neuronal class III β-tubulin, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP). Whole-mount images were acquired through tissue clearing and 3D fluorescence imaging. Mouse primary trigeminal ganglion (TG) neurons were treated with LG extracts and Netrin-1/Slit2 neutralizing antibody. Transcription factor (TF) prediction and chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR) experiments verified the JunB binding and regulatory effect on Netrin-1 and Slit2. Results:Three-dimensional tissue and section immunofluorescence showed reduced LG nerves in Aqp5-/- mice, with sympathetic and sensory nerves significantly decreased. Netrin-1 was reduced and Slit2 increased in Aqp5-/- mice LGs. Aqp5+/+ mice LG tissue extracts (TEs) promoted Aqp5-/- TG neurons axon growth, but Netrin-1 neutralizing antibody (NAb) could inhibit that promotion. Aqp5-/- mice LG TEs inhibited Aqp5+/+ TG axon growth, but Slit2 NAb alleviated that inhibition. Furthermore, JunB, a Netrin-1 and Slit2 TF, could bind them and regulate their expression. SR11302, meanwhile, reversed the Netrin-1 and Slit2 shifts caused by AQP5 deficiency. Conclusions:AQP5 deficiency causes LG nerve abnormalities. Persistent JunB activation, the common denominator for Netrin-1 suppression and Slit2 induction, was found in Aqp5-/- mice LG epithelial cells. This affected sensory and sympathetic nerve fibers' distribution in LGs. Our findings provide insights into preventing, reversing, and treating DED.

Abstract Introduction To evaluate efciency and safety of adjunct doxazosin therapy before semi-rigid ureteroscopy and RIRS for urinary stones. Method We respectively analysis the data of patients who underwent semi-rigid ureterosocpy and RIRS. The patients were divided into four group: patient underwent semi-rigid ureterosocpy with or without doxazosin per-surgery; patients underwent RIRS with or without doxazosin per-surgery. The following information was analysis for each patient: age; gender; stone’s laterality, location, and maximal diameter; successful access rate; and surgery complications. Result Total of 246 patients were concluded in the fnal analysis. Mean age, gender, laterality, stone’s laterality, location and maximal diameter were similar among each groups. The successful rate of patients underwent semi-rigid ureterosocpy with doxazosin 5 days per-surgery was 95% when was 79.69% of pateints without doxazosin. And the successful rate of patients underwent RIRS with doxazosin 5 days per-surgery was 84.09% and when was 57.41% of pateints without doxazosin. Duration of double-J stent post-surgery and complication rates were similar among groups. Conclusion Doxazosin could be used safely and effectively before both semi-rigid and flexible ureteroscopy.

Cataract is lens opacity, which is a common blinding eye disease worldwide. Aquaporin 5 (AQP5) is expressed in the human and mouse lenses. This study aimed to investigate the underlying mechanisms of AQP5 in the senescence of lens epithelial cells (LECs). Primary LECs were isolated and cultured from Aqp5+/+ and Aqp5-/- mice. Western blot or immunofluorescence staining of p16, Ki67, MitoSOX, JC-1 and phalloidin was used in the experiments to evaluate the changes in the primary LECs. The primary Aqp5-/- LECs showed increased p16 expression and mitochondrial reactive oxygen species, decreased mitochondrial membrane potential and activity, and cytoskeletal disorders. When the cells were pretreated with Mito-TEMPO, the Aqp5-/- mice showed decreased p16 expression, reduced mitochondrial dysfunction and cytoskeletal disorders. Our results revealed that AQP5 deficiency promotes the senescence of primary LECs through mitochondrial dysfunction. This provides a new perspective for the treatment of cataracts by regulating AQP5 expression.