An innovative label-free electrochemical aptamer sensor: utilizing Ti3C2Tx/MoS2/Au NPs for accurate interleukin-6 detection.

In the medical field, changes in interleukin-6 (IL-6) concentration serve as essential biomarkers for monitoring and diagnosing various conditions, including acute inflammatory responses such as those seen in trauma and burns, and chronic illnesses like cancer. This paper detailed a label-free electrochemical aptamer sensor designed for IL-6 quantification. A composite material consisting of Ti3C2Tx and MoS2 was successfully synthesized to fabricate this sensor. The synergistic effect of MoS2's catalytic action on hydrogen peroxide (H2O2), used as a signalling marker, when combined with the exceptional conductivity and large specific surface area of Ti3C2Tx, not only enables an increased loading of MoS2 but also significantly boosts the electrochemical response. The in situ-reduced Au NPs provided stable immobilization sites for DNA aptamers (DNAapt) and facilitated electron transfer, ensuring accurate IL-6 recognition. Under optimal conditions, the aptamer sensor exhibited a wide linear range (5 pg/mL to 100 ng/mL) and a low limit of detection (LOD) of 2.9 pg/mL. Its sensing performance in human serum samples highlights its potential as a promising clinical analysis tool.

The prognostic impact of tumor location in non-muscle-invasive bladder cancer patients undergoing transurethral resection: insights from a cohort study utilizing chinese multicenter and SEER registries.

OBJECTIVE: Most bladder cancers are non-muscle invasive bladder cancer (NMIBC), and transurethral resection of bladder tumors (TURBT) is the standard treatment. However, postoperative recurrence remains a significant challenge, and the influence of bladder tumor location on prognosis is still unclear. This study aims to investigate how tumor location affects the prognosis of NMIBC patients undergoing TURBT and to identify the optimal surgical approach. METHODS: A multicenter study was conducted, which included Chinese NMIBC data from 15 hospitals (1996-2019) and data from 17 registries of the Surveillance, Epidemiology, and End Results database (SEER) (2000-2020). Patients initially diagnosed with NMIBC and undergoing TURBT or partial cystectomy were analyzed, with cases lost to follow-up or with missing data excluded. The study investigated the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) among patients with different tumor locations. Kaplan-Meier, Cox regression, and propensity score matching methods were employed to explore the association between tumor location and prognosis. Stratified populations were analyzed to minimize bias. RESULTS: This study included 118,477 NMIBC patients and highlighted tumor location as a crucial factor impacting post-TURBT prognosis. Both anterior wall and dome tumors independently predicted adverse outcomes in two cohorts. For anterior wall tumors, the Chinese cohort showed hazard ratios (HR) for OS of 4.35 (P < 0.0001); RFS of 2.21 (P < 0.0001); SEER cohort OS HR of 1.10 (P = 0.0001); DSS HR of 1.13 (P = 0.0183). Dome tumors displayed similar trends (Chinese NMIBC cohort OS HR of 7.91 (P < 0.0001); RFS HR of 2.12 (P < 0.0001); SEER OS HR of 1.05 (P = 0.0087); DSS HR of 1.14 (P = 0.0006)). Partial cystectomy significantly improved the survival of dome tumor patients compared to standard TURBT treatment (P < 0.01). CONCLUSION: This study reveals the significant impact of tumor location in NMIBC patients on the outcomes of TURBT treatment, with tumors in the anterior wall and bladder dome showing poor post-TURBT prognosis. Compared to TURBT treatment, partial cystectomy improves the prognosis for bladder dome tumors. This study provides guidance for personalized treatment and prognosis management for NMIBC patients.

Molecular engineering to elevate reactive oxygen species generation for synergetic damage on lipid droplets and mitochondria.

Photodynamic therapy (PDT), characterized by high treatment efficiency, absence of drug resistance, minimal trauma, and few side effects, has gradually emerged as a novel and alternative clinical approach compared to traditional surgical resection, chemotherapy and radiation. Whereas, considering the limited diffusion distance and short lifespan of reactive oxygen species (ROS), as well as the hypoxic tumor microenvironment, it is crucial to design photosensitizers (PSs) with suborganelle specific targeting ability and low-oxygen dependence for accurate and highly efficient photodynamic therapy. In this study, we have meticulously designed three PSs, namely CIH, CIBr, and CIPh, based on molecular engineering. Theoretical calculation demonstrate that the three compounds possess good molecular planarity with calculated S1-T1 energy gaps (ΔES1-T1) of 1.04 eV for CIH, 0.92 eV for CIBr, and 0.84 eV for CIPh respectively. Notably, CIPh showcases remarkable dual subcellular targeting capability towards lipid droplets (LDs) and mitochondria owing to the synergistic effect of lipophilicity derived from coumarin's inherent properties combined with electropositivity conferred by indole salt cations. Furthermore, CIPh demonstrates exclusive release of singlet oxygen (1O2)and highly efficient superoxide anion free radicals(O2⦁-) upon light irradiation supported by its smallest S1-T1 energy gap (ΔES1-T1 = 0.84 eV). This leads to compromised integrity of LDs along with mitochondrial membrane potential, resulting in profound apoptosis induction in HepG2 cells. This successful example of molecular engineering guided by density functional theory (DFT) provides valuable experience for the development of more effective PSs with superior dual targeting specificity. It also provides a new idea for the development of advanced PSs with efficient and accurate ROS generation ability towards fluorescence imaging-guided hypoxic tumor therapy.

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis.

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

Assessment of treatment outcomes: cytoreductive surgery compared to radiotherapy in oligometastatic prostate cancer - an in-depth quantitative evaluation and retrospective cohort analysis.

BACKGROUND: The management of oligometastatic prostate cancer, defined by its few metastatic sites, poses distinct clinical dilemmas. Debates persist regarding the most effective treatment approach, with both cytoreductive surgery and radiotherapy being key contenders. The purpose of this research is to thoroughly evaluate and compare the effectiveness of these two treatments in managing patients with oligometastatic prostate cancer. METHODS: A comprehensive search of the literature was carried out to find pertinent publications that compared the results of radiation and cytoreductive surgery for oligometastatic prostate cancer. A meta-analysis was conducted in order to evaluate both short-term and long-term survival. Furthermore, utilizing institutional patient data, a retrospective cohort research was conducted to offer practical insights into the relative performances of the two treatment regimens. RESULTS: Five relevant studies' worth of data were included for this meta-analysis, which included 1425 patients with oligometastatic prostate cancer. The outcomes showed that, in comparison to radiation, cytoreductive surgery was linked to a substantially better cancer-specific survival (CSS) [hazard ratio (HR): 0.70, 95% (CI): 0.59-0.81, P <0.001] and overall survival (OS) [HR, 0.80; 95% (CI), 0.77-0.82; P <0.01]. The two therapy groups' Progression-Free Survival (PFS) and Castration-Resistant Prostate Cancer-Free Survival (CRPCFS), however, did not differ significantly (HR: 0.56, 95% CI: 0.17-1.06; HR: 0.67, 95% CI: 0.26-1.02, respectively). Out of the 102 patients who were recruited in the retrospective cohort research, 36 had cytoreductive surgery (CRP), 36 had radiation therapy (primary lesion), and 30 had radiation therapy (metastatic lesion). The follow-up time was 46.3 months (18.6-60.0) on average. The enhanced OS in the CRP group [OS interquartile range (IQR): 45-60 months] in comparison to the radiation group (OS IQR: 39.0-59.0 months and 25.8-55.0 months, respectively) was further supported by the cohort research. Furthermore, CRP had a better OS than both radiation (primary region) and radiotherapy (metastatic region), with the latter two therapeutic methods having similar OS. CONCLUSION: This meta-analysis and retrospective research provide valuable insights into the comparative efficacy of cytoreductive surgery and radiotherapy for oligometastatic prostate cancer. While short-term survival (PFS, CRPCFS) was similar between the two groups, cytoreductive surgery exhibited superior CSS and OS. Adverse event rates were manageable in both modalities. These findings contribute to informed treatment decision-making for clinicians managing oligometastatic prostate cancer patients. Further prospective studies and randomized controlled trials are essential to corroborate these results and guide personalized therapeutic approaches for this distinct subset of patients.

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway.

BACKGROUND: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.

Nickel(II)/Lewis acid catalysed olefin hydroamination and hydroarylation under mild conditions.

Aniline derivatives are important nitrogen-containing compounds with wide applications in chemicals, pharmaceuticals and agrochemicals. In the work described herein, nickel(II)/Lewis acid (LA) catalysed olefin hydroamination with anilines was explored for use in aniline derivative syntheses. The Ni(II)/LA catalysis proceeded smoothly under mild conditions, whereas using Ni(OAc)2 alone, the catalyst was inactive. Remarkably, the Markovnikov addition type products were obtained when substituted styrenes were used as the olefin source, while the anti-Markovnikov addition type products were obtained when the electron-deficient olefins such as acrylonitrile and acrylates were used. The mechanistic studies revealed that hydroamination of the styrene derivates proceeded via the amino-Ni(II)/LA attacking the carbocation intermediate which was generated by the protonation of the olefin, whereas for acrylonitrile and acrylates, it proceeded by a direct amino-Ni(II)/LA attack on the olefin by nucleophilic addition. In addition, the hydroarylation product was generated by the Hofmann-Martius rearrangement of the hydroamination product.

Delivery of gefitinib loaded nanoparticles for effectively inhibiting prostate cancer progression.

Androgen deprivation therapy is administered to suppress the growth of prostate cancer (PCa). However, some cells continue to proliferate independent of hormones, leading to the development of castration-resistant prostate cancer (CRPC). Overexpression of the epidermal growth factor receptor (EGFR) has been observed in CRPC and is associated with an unfavorable prognosis. Gefitinib (GEF) is an EGFR inhibitor used to treat patients with CRPC. Nevertheless, some clinical studies have reported that gefitinib does not result in prostate-specific antigen (PSA) or objectively measurable CRPC reactions. This lack of response may be attributed to the limited solubility in water, high side effects, low tumor aggregation, and insufficient tumor-specific reactions of GEF. In order to tackle these obstacles, we present a practical and efficient approach to administer GEF, encompassing the utilization of biocompatible nanostructures as a vehicle for drug delivery to augment its bioaccessibility and curative potency. Despite their small particle size, poly(D,L-lactide-co-glycolide) acid nanoparticles (PLGA NPs) exhibit a high drug-loading capacity, low toxicity, biocompatibility, biodegradability, and minimal immunogenicity. The drug delivery efficiency can be improved by employing GEF@PLGA NPs, which could also enhance drug cytotoxicity and impede the advancement of prostate cancer. Moreover, through experiments in vivo, it has been verified that GEF@PLGA NPs exhibit selective accumulation in the tumor and effectively restrain tumor growth. Therefore, the GEF@PLGA NPs hold great promise for the treatment of PCa.

Comprehensive assessment of the anterior segment in refraction corrected OCT based on multitask learning.

Anterior segment diseases are among the leading causes of irreversible blindness. However, a method capable of recognizing all important anterior segment structures for clinical diagnosis is lacking. By sharing the knowledge learned from each task, we proposed a fully automated multitask deep learning method that allows for simultaneous segmentation and quantification of all major anterior segment structures, including the iris, lens, cornea, as well as implantable collamer lens (ICL) and intraocular lens (IOL), and meanwhile for landmark detection of scleral spur and iris root in anterior segment OCT (AS-OCT) images. In addition, we proposed a refraction correction method to correct for the true geometry of the anterior segment distorted by light refraction during OCT imaging. 1251 AS-OCT images from 180 patients were collected and were used to train and test the model. Experiments demonstrated that our proposed network was superior to state-of-the-art segmentation and landmark detection methods, and close agreement was achieved between manually and automatically computed clinical parameters associated with anterior chamber, pupil, iris, ICL, and IOL. Finally, as an example, we demonstrated how our proposed method can be applied to facilitate the clinical evaluation of cataract surgery.

The Experiences of Female Partners of Patients With Erectile Dysfunction Due to Prostate Cancer Treatment in China: A Qualitative Exploration.

BACKGROUND: Because of sociocultural factors, Chinese female partners of patients with prostate cancer (PC) may have perspectives and needs that differ from the more published reports of female partners living in Western cultures. OBJECTIVES: The aim of this study was to explore the experiences of female partners of patients with PC experiencing erectile dysfunction in China. INTERVENTIONS/METHODS: In this interpretive descriptive design, qualitative data were collected from semistructured telephone interviews with purposively sampled participants from the urology outpatient unit in a hospital in South China. The interviews were audiotaped, transcribed, and analyzed using a constant comparison approach. RESULTS: Three themes emerged from the analysis of the participants' narratives: (a) acceptance of ceasing sex; (b) preserving intimacy through caregiving; and (c) the need for sexual health-related information. CONCLUSION: Participants in this study reported that their own sexuality and intimacy were affected by their partner's erectile dysfunction, but they adjusted to sexuality and intimacy changes through their caregiving of their husbands owing to Chinese traditional perspectives on women's obligations. They also reported having unmet informational needs in improving sexual well-being for the sake of their partners, lending further support to the likely benefit of couple-based educational interventions addressing sexual wellness in dyads affected by PC and erectile dysfunction. IMPLICATIONS FOR PRACTICE: The present study findings highlighted the need for more research attention to the support of Chinese female partners of patients with PC regarding sexual and intimate topics.

Preferences for potential benefits and risks for gene therapy in the treatment of sickle cell disease.

Objective of this study is to quantify benefit-risk tradeoffs pertaining to potential gene therapies among adults and parents/caregivers of children with sickle cell disease (SCD). A discrete-choice experiment survey was developed in which respondents selected their preferred treatment alternatives in a series of experimentally controlled pairs of hypothetical gene therapies and a "no gene therapy" option. Gene therapy alternatives were defined based on the chance of eliminating SCD symptoms, expected increases in life expectancy they could offer, treatment-related risk of death, and potential increases in lifetime cancer risk. Respondents made selections based on their current disease severity and in the context of expectations of worsened disease. Three clinical sites and 1 patient organization recruited 174 adult patients and 109 parents of children with SCD to complete the survey. Adult and parent respondents were generally willing to choose gene therapies, but the adults required higher expected levels of efficacy (ie, higher chance of eliminating symptoms) than parents to choose gene therapies that conferred mortality risks of ≥10%. When adults and parents of children with less severe symptoms were asked to consider scenarios of higher levels of disease severity, the increased risk tolerance, and the lowest acceptable level of efficacy for gene therapies with mortality risks dropped by >50%. Baseline SCD symptoms are a major driver of gene therapy acceptability. Adults and parents of patients with milder symptoms may prefer other treatment options; however, an expectation of symptoms deterioration triggers strong reassessment of the acceptable benefit-risk balance of this novel technology.

Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment.

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.

TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination.

BACKGROUND: Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE) significantly activates the calcium (Ca2+) signaling pathway and is involved in multiple steps of bone metastasis in PCa. However, the regulatory mechanism and target therapy of STIM1 is poorly defined. METHODS: Liquid chromatography-mass spectrometry analysis was performed to identify tetraspanin 18 (TSPAN18) as a binding protein of STIM1. Co-IP assay was carried out to explore the mechanism by which TSPAN18 inhibits STIM1 degradation. The biological function of TSPAN18 in bone metastasis of PCa was further investigated in vitro and in vivo models. RESULT: We identified that STIM1 directly interacted with TSPAN18, and TSPAN18 competitively inhibited E3 ligase tripartite motif containing 32 (TRIM32)-mediated STIM1 ubiquitination and degradation, leading to increasing STIM1 protein stability. Furthermore, TSPAN18 significantly stimulated Ca2+ influx in an STIM1-dependent manner, and then markedly accelerated PCa cells migration and invasion in vitro and bone metastasis in vivo. Clinically, overexpression of TSPAN18 was positively associated with STIM1 protein expression, bone metastasis and poor prognosis in PCa. CONCLUSION: Taken together, this work discovers a novel STIM1 regulative mechanism that TSPAN18 protects STIM1 from TRIM32-mediated ubiquitination, and enhances bone metastasis of PCa by activating the STIM1-Ca2+ signaling axis, suggesting that TSPAN18 may be an attractive therapeutic target for blocking bone metastasis in PCa.

Kv1.3 mediates ox-LDL-induced vascular smooth muscle cell proliferation through JAK2/STAT3 signaling pathway.

Kv1.3 channel has been shown to participate in regulating inflammatory activation, proliferation and apoptosis in several cell types. However, most of those existing studies focused on the ion-conducting properties of Kv1.3 in maintaining the resting potential and regulating Ca2+ influx. The aim of our study was to explore whether the Kv1.3-JAK2/STAT3 signaling pathway was involved in oxidized low density lipoprotein (ox-LDL) induced vascular smooth muscle cell (VSMC) proliferation. VSMCs from mouse aorta were cultured and treated with ox-LDL (25 µg/mL). The cell counting kit-8 was used to assess cell proliferation, and western blotting was performed to detect expression levels of Kv1.3, JAK2/STAT3, phosphorylated JAK2/STAT3, cyclin B1 and cyclin D1 in treated VSMCs. VSMCs were transfected with Kv1.3 small interfering RNA (Kv1.3-siRNA) or infected with a Kv1.3 lentiviral expression vector (Lv-Kv1.3) and treated with a JAK2 inhibitor LY2784544 to assess the role of Kv1.3 and JAK2/STAT3 signaling in mediating VSMC proliferation induced by ox-LDL. Ox-LDL induced cell proliferation and upregulated the expression of Kv1.3 in mouse VSMCs. In VSMCs transfected with Kv1.3-siRNA, ox-LDL was not efficient in inducing cell proliferation or the levels of proliferation associated proteins, cyclin B1 and cyclin D1. However, cell proliferation, cyclin B1 and cyclin D1 levels increased in VSMCs infected with Lv-Kv1.3. Levels of phosphorylated JAK2 and STAT3 were increased in ox-LDL-treated VSMCs, and this increase was prevented in VSMCs transfected with Kv1.3-siRNA. Treatment with the JAK2 inhibitor LY2784544 also prevented the increase in VSMCs proliferation treated with ox-LDL. Our findings demonstrated that Kv1.3 promoted proliferation of VSMCs treated with ox-LDL, and that this effect might be mediated through activation of the JAK2/STAT3 signaling pathway.

Eurycoma longifolia alkaloid components ameliorate hyperuricemic nephropathy via regulating serum uric acid level and relieving inflammatory reaction.

Hyperuricemia is an independent risk factor for chronic kidney disease. We have previously showed the uric-acid-lowering effect of Eurycoma longifolia Jack, yet the renal protective effect and mechanism of E. longifolia remain obscure. The mouse model of hyperuricemic nephropathy was induced by adenine combined with potassium oxonate in male C57BL/6 J mice. E. Longifolia alkaloid components could reduce the level of serum uric acid by regulating the expression of hepatic phosphoribosyl pyrophosphate synthase (PRPS), hypoxanthine-guanine phosphoribosyl transferase (HPRT), and renal urate transporter organic anion transporter 1 (OAT1) and ATP-binding box subfamily G member 2 (ABCG2) in HN mice. Additionally, E. Longifolia alkaloid components alleviated renal injury and function caused by hyperuricemia, which was characterized by improving renal histopathology, reducing urea nitrogen and creatinine levels. E. Longifolia alkaloid components treatment could reduce the secretion of pro-inflammatory factors by inhibiting the activation of NF-κB and NLRP3 inflammatory signaling pathways, including tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1 ß (IL-1ß), and regulated activated normal T cell expression and secretion proteins (RANTES). Meanwhile, E. longifolia alkaloid components improved renal fibrosis, inhibited the transformation of calcium-dependent cell adhesion molecule E (E-cadherin) to α-smooth muscle actin (α-SMA) transformation, and decreased collagen 1 expression in HN mice.

SYTL2 promotes metastasis of prostate cancer cells by enhancing FSCN1-mediated pseudopodia formation and invasion.

BACKGROUND: Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa. METHODS: Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2. RESULTS: We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2. CONCLUSIONS: Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

CD44 and HAP-Conjugated hADSCs as Living Materials for Targeted Tumor Therapy and Bone Regeneration.

Combining targeted tumor therapy with tissue regeneration represents a promising strategy for synergistic tumor therapy. In this study, a multifunctional living material is constructed with human-derived adipose stem cells (hADSCs) and antibody-modified hydroxyapatite nanorods (nHAP) for targeted drug delivery and bone regeneration following surgery. The living material delivers the therapeutics to the tumor site efficiently based on the strength of the inherent tumor tropism of hADSCs. The bioconjugation of nHAP with hADSCs via specific antibody modification is found to be biocompatible, even when loaded with the chemotherapeutic drug doxorubicin (Dox). The endocytosis of nHAP stimulates the osteogenic differentiation of hADSCs, promoting bone tissue regeneration. Moreover, the antibody-modified nHAP-hADSC conjugate exhibits targeted tumor delivery, which is further facilitated by pH-triggered release of Dox, inducing apoptosis of tumor cells with low toxicity to healthy tissues. Therefore, the present study provides a general strategy for engineering living materials to achieve targeted tumor therapy and bone tissue regeneration after surgery, which can be extended to other disease types.

Automatic measurement of anterior chamber angle parameters in AS-OCT images using deep learning.

The early assessment of angle closure is of great significance for the timely diagnosis and treatment of primary angle-closure glaucoma (PACG). Anterior segment optical coherence tomography (AS-OCT) provides a fast and non-contact way to evaluate the angle close using the iris root (IR) and scleral spur (SS) information. The objective of this study was to develop a deep learning method to automatically detect IR and SS in AS-OCT for measuring anterior chamber (AC) angle parameters including angle opening distance (AOD), trabecular iris space area (TISA), trabecular iris angle (TIA), and anterior chamber angle (ACA). 3305 AS-OCT images from 362 eyes and 203 patients were collected and analyzed. Based on the recently proposed transformer-based architecture that learns to capture long-range dependencies by leveraging the self-attention mechanism, a hybrid convolutional neural network (CNN) and transformer model to encode both local and global features was developed to automatically detect IR and SS in AS-OCT images. Experiments demonstrated that our algorithm achieved a significantly better performance than state-of-the-art methods for AS-OCT and medical image analysis with a precision of 0.941, a sensitivity of 0.914, an F1 score of 0.927, and a mean absolute error (MAE) of 37.1±25.3 µm for IR, and a precision of 0.805, a sensitivity of 0.847, an F1 score of 0.826, and an MAE of 41.4±29.4 µm for SS, and a high agreement with expert human analysts for AC angle parameter measurement. We further demonstrated the application of the proposed method to evaluate the effect of cataract surgery with IOL implantation in a PACG patient and to assess the outcome of ICL implantation in a patient with high myopia with a potential risk of developing PACG. The proposed method can accurately detect IR and SS in AS-OCT images and effectively facilitate the AC angle parameter measurement for pre- and post-operative management of PACG.

Singe intraoperative instillation of chemotherapy during radical cystectomy for bladder cancer: Oncological outcome and survival predictors.

PURPOSE: To clarify the necessity and effect of a single intraoperative instillation of chemotherapy during radical cystectomy. METHODS: Patients who underwent radical cystectomy for bladder cancer between January 2013 and April 2019 were retrospectively evaluated and divided into a non-instillation group and an instillation group according to the intraoperative instillation of chemotherapy. Univariate and multivariate Cox regression was used to determine the clinical predictors of overall survival and disease-free survival. Kaplan-Meier analysis and log-rank tests were performed to analyze overall survival and disease-free survival. RESULTS: Of the 320 patients who were enrolled in the study, 113 underwent radical cystectomy with intraoperative instillation of chemotherapy. Univariate Cox analysis showed that intraoperative instillation was not a risk factor for overall survival or disease-free survival (HR: 1.04, 95% CI: 0.66-1.63, p = 0.864; HR: 1.11, 95% CI: 0.76-1.62, p = 0.602, respectively). As shown in the Kaplan-Meier analysis, no significant differences were noted in overall survival (p = 0.857) and disease-free survival (p = 0.600) between the two groups. A subgroup analysis demonstrated that intraoperative instillation was not associated with a statistically better overall survival and disease-free survival in the nonmuscle invasive (p = 0.852 and 0.836) and muscle-invasive (p = 0.929 and 0.805) patients. CONCLUSION: A single intraoperative instillation of chemotherapy during radical cystectomy was not related to better disease-free survival or overall survival. It is unnecessary to consider single instillation of chemotherapy as a regular procedure during radical cystectomy.