Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.

Efficacy and safety of dienogest in the treatment of deep infiltrating endometriosis: A meta-analysis.

OBJECTIVE: To systematically review and conduct a meta-analysis to assess the effectiveness of dienogest (DNG) in the prolonged conservative drug management of deep infiltrating endometriosis (DIE). The findings from this study are intended to serve as a valuable reference for clinical decision-making regarding medication in the context of DIE. METHODS: Following the PRISMA Statement, we searched EMBASE, PubMed, The Cochrane Library, Web of Science, and Medline databases for relevant literature published in the public domain from the date of establishment of the database until October 2023. Subsequently, all English publications on clinical studies using DNG for the treatment of DIE were included. Studies involving surgical intervention or drug therapy for postoperative recurrence were excluded. All literature included in the review underwent risk assessment of bias. Two evaluators independently screened the publications, conducted a quality assessment of each article and extracted data. We used Revman 5.4 for the meta-analysis of the included literature. RESULTS: Our final analysis consisted of five clinical studies, involving a total of 256 patients. We found that there were significant improvements in the following indicators post-medication as compared to levels before taking the medication: dysmenorrhea (MD = 4.24, 95 % CI: 2.92-5.56, P < 0.00001), non-menstrual pelvic pain (MD = 3.11, 95 % CI: 2.34-3.88, P < 0.00001), dyspareunia (MD = 1.93, 95 % CI: 1.50-2.37, P < 0.00001), dyschezia (MD = 2.48, 95 % CI: 1.83-3.12, P < 0.00001), and rectosigmoid nodule size (MD = 0.32, 95 % CI: 0.18-0.46, P < 0.00001). Compared with pre-medication levels, the following indicators were significantly worse: headache (RR = 0.03, 95 % CI: 0.00-0.23, P = 0.0006), decreased libido (RR = 0.08, 95 % CI: 0.01-0.62, P = 0.02); and there was no significant improvement in dysuria (P > 0.05). CONCLUSION: DNG showed efficacy in relieving pain-related symptoms and significantly reducing the size of the lesions when used in the drug conservative treatment of DIE.

Development of a prognostic model for long-term survival of young patients with bladder cancer: a retrospective analysis of the SEER Database.

OBJECTIVES: This study aims to present the clinical characteristics of young patients with bladder cancer (YBCa), evaluate related risk factors and construct a nomogram based on data acquired from the Surveillance, Epidemiology, and End Results (SEER) Database. DESIGN: Retrospective analysis of the SEER Database (2004-2015) for primary YBCa. SETTING AND PARTICIPANTS: Data for YBCa (defined as those aged 40 years or younger) were extracted from the SEER Database, which covers approximately 28% of the US population, using the SEER*Stat software (V.8.4.0.1). A total of 1233 YBCa were identified. Patients were randomly assigned to the training and validation sets. The database included clinicopathological features, demographic information and survival outcomes, such as age, gender, race, year of diagnosis, marital status at diagnosis, primary tumour site, histological type, tumour grade, tumour, node, metastases (TNM) staging, treatment regimen for the primary tumour, cause of death and survival time. A nomogram model was developed using univariate and multivariate analyses. The prediction model was validated using the consistency index (C-index), calibration curve and receiver operating characteristic curve. PRIMARY OUTCOME MEASURES: 3-year, 5-year and 10-year overall survival (OS). RESULTS: 1233 YBCa from 2004 to 2015 were randomly assigned to the training set (n=865) and validation set (n=368). Age, marital status, tumour grade, histological type and TNM staging were included in the nomogram. The C-index of the model was 0.876. The 3-year, 5-year and 10-year OS area under the curve values for the training and validation sets were 0.949, 0.923 and 0.856, and 0.919, 0.890 and 0.904, respectively. Calibration plots showed that the nomogram had a robust predictive accuracy. CONCLUSIONS: To our knowledge, this is the first study to establish a precise nomogram predicting the 3-year, 5-year and 10-year OS in YBCa based on multivariate analyses. Our nomogram may serve as a valuable reference for future diagnostics and individualised treatments for YBCa. However, external validation is warranted to assess the accuracy and generalisability of our prognostic model.

Primary Bladder Non-Hodgkin Lymphoma: A Case Report.

Primary bladder lymphoma, a rare form of non-Hodgkin's lymphoma, is diagnosed through histopathology and immunostaining. Most bladder lymphomas are of the B-cell type, with a higher incidence in women and often presenting with hematuria. This report details an exceptionally rare case of primary bladder T-cell lymphoma. A 50-year-old male, without hematuria or other symptoms, was diagnosed during a routine ultrasound. A computed tomography scan showed a tumor located in the anterior, right, and posterior walls. The patient underwent transurethral resection of the bladder lesion. Pathological examination of the tumor showed that it was composed of lymphoid tissue, in accordance with peripheral T-cell lymphoma of non-Hodgkin subtype.

The effects of a galectin-3 inhibitor on bladder pain syndrome in mice with cyclophosphamide-induced cystitis.

AIMS: To explore the effect of blocking galectin-3 in the bladder pain syndrome associated with interstitial cystitis. METHODS: A galectin-3 inhibitor was used to treat mice with cyclophosphamide-induced cystitis. The expression of galectin-3 in bladder tissues and urine was examined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. Suprapubic-pelvic pain, bladder voiding, bladder pain-like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1ß (IL-1ß), nerve growth factor (NGF), IL-6, and tumor necrosis factor α (TNF-α) were measured by ELISA. RESULTS: Increases in galectin-3 levels, inflammation, bladder weight, and bladder pain-related symptoms were observed in bladders with cyclophosphamide-induced cystitis. Administration of the galectin-3 inhibitor significantly mitigated bladder pain-related symptoms and inflammatory response. In response to the 500 µM dose of the galectin-3 inhibitor, nociceptive behaviors, nociceptive score, and bladder-to-body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 µM Gal-3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin-3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP-induced mice, there were significant changes in the levels of IL-1ß (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL-6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF-α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal-3 inhibitor subgroup (500 µM), and 500 µM Gal-3 inhibitor reduced mast cell infiltration ratios by 71.8%. CONCLUSIONS: The galectin-3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide-induced cystitis. Thus, galectin-3 inhibitors may be novel agents in interstitial cystitis treatment.

Ultrasensitive Biochemical Sensing Platform Enabled by Directly Grown Graphene on Insulator.

To fabricate label-free and rapid-resulting semiconducting biosensor devices incorporating graphene, it is pertinent to directly grow uniform graphene films on technologically important dielectric and semiconducting substrates. However, it has long been intuitively believed that the nonideal disordered structures formed during direct growth, and the resulted inferior electrical properties will inevitably lead to deteriorated sensing performance. Here, graphene biosensor chips are constructed based on direct plasma-enhanced chemical vapor deposition (PECVD) grown graphene on a 4-inch silicon wafer with excellent film uniformity and high yield. To surprise, optimal operations of graphene biosensors permit ultrasensitive detection of SARS-CoV-2 virus nucleocapsid protein with dilutions down to sub-femtomolar concentrations. Such impressive limit of detection (LOD) is comparable to or even outperforms that of the state-of-the-art biosensor devices based on high-quality graphene. Further noise spectral characterizations and analysis confirms that the LOD is limited by molecular diffusion and/or known interference signals such as drift and instability of the sensors, rather than the electrical merits of the graphene devices along. Hence, result sheds light on processing directly grown PECVD graphene into high-performance sensor devices with important economic benefits and social significance.

CAV1 and KRT5 are potential targets for prostate cancer.

Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis.

Malignant glomus tumor of prostate: A case report.

We reported an 85-year-old patient with malignant glomus tumor (GT) of the prostate. He presented with urinary frequency for more than 2 years and gross hematuria for 7 days. Computed tomography scan showed that the prostate was markedly irregularly enlarged, and the boundary between the prostate and the posterior wall of the bladder was unclear. Bilateral kidneys and ureters were dilated. Biochemical examinations showed that the serum potassium was 7.24 mmol/L and the serum creatinine was 974.6 µmol/L. Transurethral diagnostic resection was performed after restoring homeostasis through several times of bedside blood filtration. The pathological diagnosis was malignant GT. The patient's renal function recovered after bilateral nephrostomy, and he refused further treatment and was out of contact after 9 months. We summarize the clinical and histopathological features of malignant GT of the prostate in order to improve the early recognition of the disease by clinicians.

Disorder-tuned conductivity in amorphous monolayer carbon.

Correlating atomic configurations-specifically, degree of disorder (DOD)-of an amorphous solid with properties is a long-standing riddle in materials science and condensed matter physics, owing to difficulties in determining precise atomic positions in 3D structures1-5. To this end, 2D systems provide insight to the puzzle by allowing straightforward imaging of all atoms6,7. Direct imaging of amorphous monolayer carbon (AMC) grown by laser-assisted depositions has resolved atomic configurations, supporting the modern crystallite view of vitreous solids over random network theory8. Nevertheless, a causal link between atomic-scale structures and macroscopic properties remains elusive. Here we report facile tuning of DOD and electrical conductivity in AMC films by varying growth temperatures. Specifically, the pyrolysis threshold temperature is the key to growing variable-range-hopping conductive AMC with medium-range order (MRO), whereas increasing the temperature by 25 °C results in AMC losing MRO and becoming electrically insulating, with an increase in sheet resistance of 109 times. Beyond visualizing highly distorted nanocrystallites embedded in a continuous random network, atomic-resolution electron microscopy shows the absence/presence of MRO and temperature-dependent densities of nanocrystallites, two order parameters proposed to fully describe DOD. Numerical calculations establish the conductivity diagram as a function of these two parameters, directly linking microstructures to electrical properties. Our work represents an important step towards understanding the structure-property relationship of amorphous materials at the fundamental level and paves the way to electronic devices using 2D amorphous materials.

Study on the protective effect of OM-MSCs on Golgi apparatus after intracerebral hemorrhage in Sprague-Dawley rats.

INTRODUCTION: The present study aimed to assess alterations in apoptosis rate, Golgi morphology and GOLPH3 expression following intracerebral hemorrhage (ICH) both before and after intervention with OM-MSCs. The objective was to investigate the impact of ICH on Golgi apparatus (GA) stress and to explore the potential protective effects of OM-MSCs on GA following ICH. MATERIAL AND METHODS: A total of 54 Sprague-Dawley rats were allocated into three experimental groups: sham operation group, ICH group and OM-MSCs group. ICH models were established by collagenase method while OM-MSCs were cultured in vitro. In OM-MSCs intervention group, one million OM-MSCs were stereotactically injected into unilateral striatum of rats 48 hours after ICH modeling while other two groups received an equivalent volume of PBS. Brain tissues were collected at 1 day, 3 day and 7 day post intervention and subsequently assessed for cellular apoptosis, morphological change of GA and expression of GOLPH3. The obtained data were subjected to statistical analysis by SPSS 21.0. RESULTS: 1. Apoptosis rate in the 1 d and 3 d ICH groups was significantly higher compared to sham operation group (P < 0.05), but significantly lower compared to OM-MSCs intervention group (P < 0.05). 2. While no noticeable morphological changes were observed in sham operation group, GA in ICH group exhibited a significant increase fragmentation. After OM-MSCs intervention, the fragmentation of GA decreased significantly. 3. On 3 d, expression of GOLPH3 in ICH group was significantly higher than that in sham operation group (P < 0.05) but significantly lower than that of OM-MSCs intervention group (P < 0.05). CONCLUSIONS: The rate of apoptosis, fragmentation of GA, and expression of GOLPH3 exhibited significant increases following ICH in SD rats. Conversely, all of these factors demonstrated significant decreases subsequent to early intervention with OM-MSCs, thereby exerting neuroprotective effects.

lncRNA MIR4435-2HG Accelerates the Development of Bladder Cancer through Enhancing IQGAP3 and CDCA5 Expression.

Background: Bladder cancer (BCa) is one of the most prevalent cancers occurring in the urinary system. Long noncoding RNAs (lncRNAs), in recent years, have emerged as crucial regulators in various biological processes of tumors. Aim: To identify the role of MIR4435-2 host gene (MIR4435-2HG) and uncover its molecular mechanism in BCa. Methods: Firstly, quantitative real-time PCR (RT-qPCR) analysis was used to examine MIR4435-2HG expression in BCa cells. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and transwell assays were implemented to identify the role of MIR4435-2HG in BCa. RNA-binding protein immunoprecipitation (RIP), RNA pull down, and luciferase reporter assays were applied to explore the potential mechanism of MIR4435-2HG in BCa. Results: MIR4435-2HG was highly expressed in BCa. Moreover, MIR4435-2HG silencing abrogated BCa cell proliferation, migration, and invasion. In terms of underlying mechanism, MIR44352HG acted as a microRNA-2467-3p (miR-2467-3p) sponge to control the expression of IQ motif containing GTPase activating protein 3 (IQGAP3) and cell division cycle associated 5 (CDCA5), resulting in activation of the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and PI3K/AKT/mTOR signaling pathways. Conclusion: MIR4435-2HG involves in the progression of BCa, which might provide novel insights for BCa treatment.

Can preoperative ureteral stents reduce the incidence of ureteral stricture after radiotherapy in patients with cervical cancer?

OBJECTIVE: To determine the impact of preoperative stent placement on postradiotherapy stricture rate in patients with cervical cancer after radical resection. METHODS: This study was a retrospective analysis of data collected from 55 cervical cancer patients treated with radiotherapy between June 2016 and June 2020. Patients were divided into the stent and control groups. After 3 months, the stricture rate and the complications related to stent placement between the two groups were compared. RESULTS: There were 12 (46.2%) and 10 (34.5%) cases of ureteral stricture in the stent (n = 26) and control (n = 29) groups, respectively, three months after the end of radiotherapy. The incidence rates of ureter stricture in the two groups were not significantly different (P = 0.378). Moreover, there were 20 units (38.5%) and 15 units (25.9%) ureteral strictures in the stent and control groups, respectively. No significant difference in the incidence rates of ureteral strictures was found between the two groups (P = 0.157). There were 13 (50.0%) and 10 (34.5%) cases of ureteral stricture in the stent (n = 26) and control (n = 29) groups, respectively, six months after the end of the radiotherapy. The incidence rates of ureter stricture in the two groups were not significantly different (P = 0.244). Moreover, there were 21 units (40.4%) and 15 units (25.9%) ureteral strictures in the stent and control groups, respectively. No significant difference in the incidence rates of ureteral strictures was found between the two groups (P = 0.105). Complications related to stent placement such as urinary tract infections and bladder irritation were statistically significant (P = 0.006 and P = 0.036) between the two groups; while the other complications were not significantly different (P = 0.070, P = 0.092 and P = 0.586). CONCLUSIONS: Ureteral stents may not reduce the incidence of ureteral stricture after radiotherapy in patients with cervical cancer. The stent needs to be replaced regularly, and the complications related to stent placement may occur at any time. Thus, preoperative stent placement should be cautious for the clinical management of cervical cancer patients treated with postoperative radiotherapy.

Differential OAT methylation correlates with cell infiltration in tumor microenvironment and overall survival postradiotherapy in oral squamous cell carcinoma patient.

BACKGROUND: Given that DNA methylation and tumor microenvironment (TME) are susceptible to radiotherapy, we aimed to figure out specific differential DNA methylation to reflect oral squamous cell carcinoma (OSCC) prognosis and associated effect on TME changes postradiotherapy, performing as an efficient biomarker. MATERIALS AND METHODS: Differentially methylation analysis was performed using data from The Cancer Genome Atlas. Curves of Kaplan-Meier (K-M) survival, cumulative hazard and events, Cox proportional hazards, and linear regression model were conducted to screen and validate differential methylation genes, while multiple regression equation to analyze if ornithine aminotransferase (OAT) methylation correlates with radiotherapy. For correlation between OAT methylation and immune infiltrates, CIBERSORT and ESTIMATE algorithms were performed, following gene set enrichment analysis (GSEA) and ssGSEA analysis to evaluate biological process. RESULTS: Compared to normal tissues, only OAT in OSCC was differential significantly by K-M analysis (p = 0.0364). OAT hypermethylation was associated with increased overall survival (hazard ratio: 0.65, p = 0.0358). Radiotherapy correlated with OAT methylation (ß = -0.01, p = 0.0061); most patients with OAT hypermethylation were radiation-sensitive. Hypomethylated OAT correlated with higher cell infiltrations in TME. Neuroactive ligand-receptor interaction was most significantly related to OAT methylation (p = 9.2e-10). Sulfur metabolism was the most significantly in OAT hypermethylation group (p = 0.0041) and RIG-I-like receptor in OAT hypomethylation group (p = 0.0094). CONCLUSION: OAT methylation can serve as a predictor of OSCC prognosis postradiotherapy with potential mechanism by changing cell infiltrations in TME, but further experimental study deserves to carry out confirming the role and mechanism of OAT methylation in OSCC.

TGF-ßRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-ß signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-ßRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-ßRII in CAFs glucose metabolism and suggests that targeting TGF-ßRII in CAFs might represent a therapeutic approach for oral cancer.

Androgen deprivation­induced OPHN1 amplification promotes castration­resistant prostate cancer.

Androgen deprivation therapy (ADT) is used to treat prostate cancer (PCa). However, ADT may increase the expression of androgen receptor (AR) through the amplification of chromosome X. The gene oligophrenin 1 (OPHN1) is located in the same region as the AR gene, which could be amplified by ADT. Thus, the role of OPHN1 in PCa pathology was investigated. The expression status of OPHN1 in PCa was searched in The Cancer Genome Atlas (TCGA) database. Androgen­sensitive cells LNCaP and 22RV1 were cultured under ADT conditions, and then the expression of OPHN1 was evaluated by northern blotting. The expression of OPHN1 was enhanced or knocked down in LNCaP and 22RV1 cells by transfection. Subsequently, the LNCaP and 22RV1 cells were cultured under ADT, and the viability rate, apoptosis, and migration of cells were assessed by MTT, flow cytometry, and Transwell assay respectively. The expression of OPHN1 was also enhanced or knocked down in androgen­insensitive PC3 cells, and then the effects of OPHN1 on the viability, apoptosis, and migration of PC3 cells were assessed. A mouse xenograft model was created by injecting LNCaP cells with OPHN1 overexpression subcutaneously, and the tumor growth rates were monitored. In TCGA database, amplification of the OPHN1 gene was observed in the PCa tumors. ADT increased the expression of OPHN1 in LNCaP and 22RV1 cells (P<0.05). OPHN1 could promote resistance of LNCaP and 22RV1 cells to ADT by promoting cell survival and preventing their apoptosis (P<0.05). In addition, OPHN1 contributed to cell viability (P<0.05) and enhanced the migration ability in LNCaP, 22RV1 and PC3 cells (P<0.05). In the mouse model, the PCa xenograft with OPHN1 overexpression had a higher growth rate and was more resistant to the ADT condition (P<0.05). In summary, ADT induced the overexpression of OPHN1 in PCa, which facilitated PCa cell survival and promoted PCa progression.

The surgical outcomes of aortic valve replacement in patients with aortic valve lesions caused by Behcet's disease: lessons we learned.

BACKGROUND: For Behcet's disease patients with aortic root lesions, the disease often manifests as aortic valve regurgitation (AR). Following aortic valve replacement (AVR), many of these patients often suffer perivalvular leakage and valve dehiscence, requiring a second or third operation. In this study, we report the outcomes of 20 patients who underwent AVR to manage aortic root lesions caused by Behcet's disease, and the lessons we learned. METHODS: From October 2013 to September 2019, a total of 50 patients with Behcet's disease underwent AVR at our institution. Among them, isolated AVR was performed in 15 preoperatively undiagnosed cases. The other 5 patients were preoperatively diagnosed and underwent modified AVR. All patients were contacted for a follow-up. Valve function was evaluated using echocardiography. RESULTS: The 15 preoperatively undiagnosed patients [age: 38.4±12.6 years (range, 24-63 years); 9 males, 6 females] underwent isolated AVR as their primary procedure. Echocardiography revealed that valve dehiscence occurred in 13 (86.7%) patients postoperatively after a mean interval of 10.8±8.4 months. These patients accepted a second operation, and 1 of them accepted a third operation because of a pseudoaneurysm of the distal anastomosis site. For the other 5 patients [age: 38.8±9.5 years (range, 27-55 years); 4 males, 1 female] who underwent modified AVR, neither AR nor prosthetic valve detachment were observed during the echocardiography follow-up, and none required a secondary operation. CONCLUSIONS: For behcet's disease patients with AR, there was a high rate of valve dehiscence after isolated AVR. When compared with traditional AVR, we found that modified AVR was the optimal choice for patients who received standardized preoperative treatment.

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer.

To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

The hypothesis of tumor-associated macrophages mediating semi-phagocytosis of cancer cells in distant metastasis.

Tweetable abstract Tumor-associated macrophages might promote the distant metastasis of tumor cells by semi-phagocytosis. The authors propose that this newly discovered process occurs in tumor-associated macrophages and may lead to a novel approach for blocking cancer metastasis.

Bergenin inhibits bladder cancer progression via activating the PPARγ/PTEN/Akt signal pathway.

Bladder cancer is one of the most common malignant tumors in the urinary system with high mortality and morbidity. Evidence revealed that bergenin could affect the development of cancer. Here, we aimed to investigate the effect of bergenin on bladder cancer progression and its mechanism. The effect of bergenin on cell function was first detected, followed by assessing the changes of the epithelial-mesenchymal transition (EMT) in bergenin-treated cells. The effect of bergenin on peroxisome proliferator-activated receptor γ (PPARγ)/phosphatase and tensin homolog (PTEN)/Akt signal pathway was measured by Western blotting, followed by the rescue experiments. The results showed that bergenin treatment significantly decreased cell viability and increased G1 phase arrest, accompanied by reduced expression of Ki67, cycling D1, and cycling B1 in bladder cancer cells. Apoptosis was induced by bergenin in bladder cancer cells, as evidenced by increased Bax and cleaved caspase 3 protein levels and decreased Bcl-2 level in bergenin-treated cells. Meanwhile, the inhibition of the invasion, migration, and EMT was also observed in bergenin-treated cells. Mechanism studies showed that bergenin treatment could activate PPARγ/PTEN/Akt signal pathway, as evidence by the increased nucleus PPARγ and phosphatase and tensin homolog (PTEN) expression and decreased Akt expression. Moreover, PPARγ inhibitor administration inverted the effects of bergenin on bladder cancer cell function, including the proliferation, apoptosis, invasion, and migration in bladder cancer cells. Our findings revealed that bergenin could inhibit bladder cancer progression via activating the PPARγ/PTEN/Akt signal pathway, indicating that bergenin may be a potential therapeutic medicine for bladder cancer treatment.