4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1ß. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

Palladium-Catalyzed Synthesis of Indanone via C-H Annulation Reaction of Aldehydes with Norbornenes.

A novel methodology for the synthesis of indanone derivates has been developed. The palladium-catalyzed annulation reaction of o-bromobenzaldehydes with norbornene derivatives is achieved through extremely concise reaction processes. The indanone skeleton was established directly via C-H activation of the aldehyde group under a mild reaction condition. This method is simple and practical, which simplified the traditional synthesis method for the rapid construction of indanone.

The compared study about femoral stem malalignment with or without the special curved rasp during DAA total hip arthroplasty.

OBJECTIVE: To investigate whether the application of a curved rasp on the femoral side is effective in reducing the incidence of stem malalignment in total hip replacement with direct anterior approach (DAA-THA), followed by the analysis of the independent risk factors affecting stem malalignment. METHODS: Retrospective analysis was carried out covering 160 patients undergoing DAA-THA from January 2019 to December 2021, with Tri-Lock (BPS, Depuy) stem applied in all 113 patients were screened according to inclusion and exclusion criteria. The data of gender, age, body mass index, preoperative diagnoses, Dorr classification, FAR ratio, pelvic morphology ratio, WOMAC scores, were analyzed to explore the independent factors influencing the malalignment of the femoral prosthesis implantation. Then data of patients were divided into group A and group B according to whether the curved rasp was taken during the operation. The chi-square test was performed to compare the incidence of femoral stem malalignment between the two groups. RESULTS: There revealed two independent risk factors: BMI and FAR ratio that affected femoral stem malalignment. The increased BMI was associated with a higher probability of femoral stem malalignment (P<0.05), the probability of malalignment of femoral stem in FAR ratio<1 was 1.15 times higher than that in FAR>1(OR = 1.15, 95% CI: 1.03-1.28, P<0.05). Further grouping analysis showed that the incidence of femoral stem malalignment in patients with intraoperative application of curved rasp was 27%, while in patients without curved rasp, the incidence of femoral stem malalignment increased significantly to 48.7%(P<0.05). The placement angle of prosthesis in group A was significantly better than that in group B, especially mild femoral stem malalignment (0%) and severe femoral stem malalignment (2.70%), and the difference was statistically significant (P < 0.05). There found no significant difference in age, gander, intraoperative complications and last follow-up assessment of WOMAC scores between the two groups of patients. CONCLUSIONS: In DAA-THA, BMI and FAR ratio act as the independent risk factors for femoral stem malalignment. Intraoperative use of a curved rasp significantly reduces the incidence of malalignment of the femoral stem.

MicroRNA-22-3p ameliorates Alzheimer's disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus.

BACKGROUND: Studies have suggested that many down-regulated miRNAs identified in the brain tissue or serum of Alzheimer's disease (AD) patients were involved in the formation of senile plaques and neurofibrillary tangles. Specifically, our previous study revealed that microRNA-22-3p (miR-22-3p) was significantly down-regulated in AD patients. However, the molecular mechanism underlying the down-regulation of miR-22-3p has not been comprehensively investigated. METHODS: The ameliorating effect of miR-22-3p on apoptosis of the Aß-treated HT22 cells was detected by TUNEL staining, flow cytometry, and western blotting. The cognition of mice with stereotaxic injection of agomir or antagomir of miR-22-3p was assessed by Morris water maze test. Pathological changes in the mouse hippocampus were analyzed using hematoxylin and eosin (HE) staining, Nissl staining, and immunohistochemistry. Proteomics analysis was performed to identify the targets of miR-22-3p, which were further validated using dual-luciferase reporter analysis and western blotting analysis. RESULTS: The miR-22-3p played an important role in ameliorating apoptosis in the Aß-treated HT22 cells. Increased levels of miR-22-3p in the mouse hippocampus improved the cognition in mice. Although the miR-22-3p did not cause the decrease of neuronal loss in the hippocampus, it reduced the Aß deposition. Proteomics analysis revealed Sox9 protein as the target of miR-22-3p, which was verified by the luciferase reporter experiments. CONCLUSION: Our study showed that miR-22-3p could improve apoptosis and reduce Aß deposition by acting on Sox9 through the NF-κB signaling pathway to improve the cognition in AD mice. We concluded that miR-22-3p ameliorated AD by targeting Sox9 through the NF-κB signaling pathway in the hippocampus.

Key gene network related to primary ciliary dyskinesia in hippocampus of patients with Alzheimer's disease revealed by weighted gene co-expression network analysis.

BACKGROUND: Alzheimer's disease (AD) is closely related to aging, showing an increasing incidence rate for years. As one of the main brain regions involved in AD, hippocampus has been extensively studied due to its association with many human diseases. However, little is known about its association with primary ciliary dyskinesia (PCD). MATERIAL AND METHODS: The microarray data of hippocampus on AD were retrieved from the Gene Expression Omnibus (GEO) database to construct the co-expression network by weighted gene co-expression network analysis (WGCNA). The gene network modules associated with AD screened with the common genes were further annotated based on Gene Ontology (GO) database and enriched based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The protein-protein interaction (PPI) network was constructed based on STRING database to identify the hub genes in the network. RESULTS: Genes involved in PCD were identified in the hippocampus of AD patients. Functional analysis revealed that these genes were mainly enriched in ciliary tissue, ciliary assembly, axoneme assembly, ciliary movement, microtubule based process, microtubule based movement, organelle assembly, axoneme dynamin complex, cell projection tissue, and microtubule cytoskeleton tissue. A total of 20 central genes, e.g., DYNLRB2, ZMYND10, DRC1, DNAH5, WDR16, TTC25, and ARMC4 were identified as hub genes related to PCD in hippocampus of AD patients. CONCLUSION: Our study demonstrated that AD and PCD have common metabolic pathways. These common pathways provide novel evidence for further investigation of the pathophysiological mechanism and the hub genes suggest new therapeutic targets for the diagnosis and treatment of AD and PCD. SUBJECTS: Bioinformatics, Cell Biology, Molecular Biology, Neurology.

Knockdown of lncRNA IGF2BP2-AS1 inhibits proliferation and migration of oral squamous cell carcinoma cells via the Wnt/ß-catenin pathway.

BACKGROUND: Long non-coding RNA IGF2BP2 antisense RNA1 (lncRNA IGF2BP2-AS1) has been used to predict the overall survival rate of lung squamous cell carcinoma. This research aims to investigate the effect of IGF2BP2-AS1 in oral squamous cell carcinoma (OSCC). METHODS: The TCGA database was applied to evaluate the level of IGF2BP2-AS1 and its correlation with the clinicopathological characteristics of OSCC. The levels of IGF2BP2-AS1 in 30 OSCC and 20 normal tissue samples were detected by RT-qPCR. The distributions of IGF2BP2-AS1 in two OSCC cell lines (ie, Cal27 and SCC9) were detected by FISH. Colony formation, flow cytometry, wound-healing, transwell, and Western blotting analyses were used for evaluating the effect of IGF2BP2-AS1 on OSCC progression. RESULTS: In comparison with the normal tissue samples, OSCC showed higher expression of IGF2BP2-AS1. High expression of IGF2BP2-AS1 was associated with poor survival in OSCC patients. Results of FISH showed that IGF2BP2-AS1 was mainly present in the cytoplasm. Further in vitro functional tests demonstrated that downregulation of IGF2BP2-AS1 in Cal27 and SCC9 cells significantly inhibited cell proliferation and migration, leading to cell-cycle arrest and cell apoptosis. Western blotting showed that expressions of ß-catenin, Cyclin D1, Bcl-2, and MMP2 were downregulated, whereas Bax was upregulated following knockdown of IGF2BP2-AS1. The inhibitory effect of knockdown of IGF2BP2-AS1 on migration could be partially reversed by the Wnt/ß-catenin pathway stimulator LiCl. CONCLUSION: Our results suggest that knockdown of IGF2BP2-AS1 suppresses cell growth, migration and promotes apoptosis in OSCC cells, providing a new molecular target for OSCC.

Association between C-reactive protein and all-cause mortality among critically ill patients with acute kidney injury.

AIM: To explore the relationship between C-reactive protein (CRP) and mortality in critically ill patients with acute kidney injury (AKI). MATERIALS AND METHODS: A total of 580 patients diagnosed with AKI within 48 hours of ICU admission between September 2017 and August 2019 were enrolled. Patients were followed for all-cause mortality in-hospital and then up to 2 years after discharge. We performed two multivariate regression analysis to assess the association between CRP and mortality, and conducted stratified analysis to assess whether the effect of the CRP differed across subgroups. RESULTS: According to initial CRP quartiles, patients were divided into 4 groups (quartile 1, CRP ≤ 2.87 mg/L; quartile 2, CRP: 2.87 - 25.95 mg/L; quartile 3, CRP: 25.95 - 111.51 mg/L; quartile 4, CRP > 111.51 mg/L). Patients with high CRP levels have higher APACHE-II score, longer length of stay in the ICU, and higher mortality. In multivariate regression analysis, high CRP was associated with the increased risk of in-hospital mortality after adjusting for age, gender, surgical grade, heart rate, serum potassium, serum chloride, coronary heart disease, and atherosclerotic cerebral infarction (quartile 4 vs. quartile 1, OR: 3.810, 95% CI: 2.081 - 6.973). For 2-year mortality, the increased trend was still significant with the OR (95% CI) of the quartile 4 group of 5.117 (2.678 - 9.780) after adjusting for confounders. Subgroup analyses detected in each group showed that the in-hospital and 2-year risk of mortality increased with higher CRP levels. CONCLUSION: Higher CRP level was associated with the increased risk of mortality in critically ill patients with AKI.

Body pain and functional disability predict falls in Chinese older adults: a population-based cohort study.

BACKGROUND: Falls are major health care concerns for older adults. Pain is associated with increased falls in older adults. However, the impact of pain on functional disability and how this might predispose Chinese older adults to fall is unclear. AIM: The aim of the current study was to examine whether functional disability mediates the association of any pain, back and/or shoulder pain (B-S pain) and leg and/or knees pain (L-K pain) with falls and serious falls. METHODS: The study included 7619 community-dwelling older adults aged 60 years and above from the China Health and Retirement Longitudinal Study. Baseline data were from Wave 3 and fall outcomes were from Wave 4. Functional disability was measured by the ADLs and IADLs scales. We used a logistic regression model to investigate associations between pain and fall outcomes and KHB method to estimate the mediating effects of ADL/IADL disability on pain-fall relationship. RESULTS: After fully adjusting for covariates, the three pain measures (any pain, back and/or shoulder pain, leg and/or knees pain) were significantly associated with fall outcomes. When body pain was compared with no body pain, the proportion mediated by the ADL disability was 28.43% for falls, while the proportion mediated by IADL disability was 17.96% for falls. For associations between specific parts of body pain and falls, the proportions mediated by the ADL disability were 34.18% and 35.89% in back and/or shoulder pain and leg and/or knees pain, respectively, but the proportions reduced to 21.98% and 20.82% when mediated by the IADL disability. However, there were no significant contributions of ADL/IADL disability for the association between specific part of body pain and serious falls. CONCLUSIONS: Pain in general and pain in specific body sites were significantly associated with an increased risk of fall among older adults living in community in China. Functional disability partially mediated the relationship of pain with falls.

Direct anterior versus posteriorlateral approachs for clinical outcomes after total hip arthroplasty in the treatment of severe DDH.

BACKGROUND: The total hip arthroplasty (THA) has gained popularity in in the treatment of severe developmental dysplasia of the hip (DDH). the posterior lateral approach (PLA) has good clinical efficacy and has been confirmed by the majority clinicians. Nevertheless, controversy exists regarding longer-term benefits of the direct anterior approach (DAA). The objective of this study was to investigate the clinical efficacy and placement of S-ROM prosthesis in the treatment of severe DDH by The total hip arthroplasty (THA) with different surgical approaches. METHODS: A retrospective analysis was performed on 42 patients with severe DDH admitted to our hospital from August 2015 to February 2022, who were treated with S-ROM prosthesis for total hip arthroplasty and subtrochanteric osteotomy of the femur. They were divided into DAA group and PLA group according to different surgical approaches. Perioperative indicators and imaging data were collected. RESULTS: The surgery time, intraoperative blood loss, and creatine kinase difference in DAA group and PLA group was without a statistically significant difference (P > 0.05). The postoperative length of hospitalization was shorter in the DAA group than in the PLA group (6.50 ± 3.15 vs 9.18 ± 4.93, P = 0.045). The acetabular abduction angles、the acetabular anteversion angles, the safe area ratio, The difference of femoral eccentricity, and the vertical difference of rotation center in DAA group and PLA group, there was no statistical significance (P > 0.05). Statistically significant differences were detected the horizontal difference of rotation center (P = 0.044). CONCLUSIONS: Total hip arthroplasty with S-ROM prosthesis is a feasible procedure for severe dysplastic DDH. The clinical efficacy and prosthesis placement parameters of DAA approach are advantage to those of PLA approach.

Naringin attenuates cisplatin- and aminoglycoside-induced hair cell injury in the zebrafish lateral line via multiple pathways.

Exposure to ototoxic drugs is a significant cause of hearing loss that affects about 30 thousand children with potentially serious physical, social and psychological dysfunctions every year. Cisplatin (CP) and aminoglycosides are effective antineoplastic or bactericidal drugs, and their application has a high probability of ototoxicity which results from the death of hair cells (HCs). Here, we describe the therapeutic effect of the flavonoid compound naringin (Nar) against ototoxic effects of cisplatin and aminoglycosides include gentamicin (GM) and neomycin (Neo) in zebrafish HCs. Animals incubated with Nar (100-400 µmol/L) were protected against the pernicious effects of CP (150-250 µmol/L), GM (50-150 µmol/L) and Neo (50-150 µmol/L). We also provide evidence for the potential mechanism of Nar against ototoxicity, including antioxidation, anti-apoptosis, promoting proliferation and hair cell regeneration. We found that mRNA levels of the apoptotic- and pyroptosis-related genes are regulated by Nar both in vivo and in vitro. Finally, by proving that Nar does not affect the anti-tumour efficacy of CP and antibacterial activity of aminoglycosides in vitro, we highlight its value in clinical application. In conclusion, these results unravel a novel therapeutic role for Nar as an otoprotective drug against the adverse effects of CP and aminoglycosides.

Lamivudine improves cognitive decline in SAMP8 mice: Integrating in vivo pharmacological evaluation and network pharmacology.

The reverse transcriptase inhibitors such as lamivudine (3TC) play important roles in anti-ageing, but their effects on neurodegenerative diseases caused by ageing are not clear, especially on the functions of the nervous system such as cognition. In this study, we administered 3TC to senescence-accelerated mouse prone 8 (SAMP8) mice by gastric perfusion (100 mg/kg) for 4 weeks. Our results showed that 3TC significantly improved the ageing status of SAMP8 mice, especially the decline of cognitive ability evaluated by the Morris water maze test. To further investigate the molecular mechanisms of improving the ageing status of SAMP8 mice by 3TC, the qPCR and tissue staining methods were used to study the brain tissues (i.e., hippocampus and cortex) of mice, while the network pharmacology analysis was applied to investigate the potential targets of 3TC. The results showed that the mRNA levels of genes related to long interspersed element-1, type 1 interferon response, the senescence-associated secretion phenotype and the Alzheimer's disease in the hippocampus and cortex of SAMP8 mice were increased due to senescence, but this trend was reversed partially by 3TC. Results of histological studies showed that 3TC reduced the death of hippocampal neurons, while the results of network pharmacology analysis indicated that 3TC may exert its influence through multiple pathways, including the oestrogen signalling and the PI3K/Akt and neuroactive ligand-receptor interaction signalling pathways, which we have verified through in vitro experiments. These findings provide evidence for the therapeutic potential of 3TC in the treatment of neurodegenerative diseases.

Smoothened loss is a characteristic of neuroendocrine prostate cancer.

PURPOSE: Hedgehog (Hh) signaling promotes castration-resistant prostate cancer by supporting androgen-independent prostate cancer cell development and growth; however, its role in neuroendocrine prostate cancer (NEPC) has not yet been explored. In this study, we assessed the expression of key genes involved in Hh signaling in prostate cancer and investigated the potential role of smoothened (SMO) in the pathogenesis of NEPC. METHODS: Six public datasets, each containing cases of prostate adenocarcinoma (AdPC) and NEPC, were analyzed to compare the differential messenger RNA (mRNA) expression of six classic Hh signaling genes. The SMO, synaptophysin, chromogranin A (CHGA) and androgen receptor (AR) proteins were evaluated in human tissues from 5 cases of NEPC, 2 cases of AdPC mixed with NEPC, 2 cases of AdPC with neuroendocrine differentiation and 22 cases of high-grade AdPC as determined by an immunohistochemistry assay. Gene set enrichment analysis (GSEA) was performed to identify relevant genetic signatures associated with SMO expression based on the public datasets. Stable SMO-knockdown LNCaP and C4-2B cells were established with a lentiviral system, and the expression of SMO, Gli1, AR, prostate-specific antigen (PSA), and REST was assessed by real-time polymerase chain reaction and western blot. Secreted PSA in the conditioned medium was assessed by ELISA. Gli1 was ectopically expressed performed by the transfection of Gli1 complementary DNA into SMO-knockdown LNCaP cells, and western blot was used to assess of AR and PSA expression. RESULTS: The mRNA level of SMO was dramatically downregulated in NEPC samples compared with AdPC samples in all 6 public datasets. SMO protein loss was observed in 100% of NEPC samples but in only 9% (2 of 22) of high-grade AdPC samples. GSEA results showed that SMO loss was closely correlated with AR signaling activity. Stable SMO knockdown significantly attenuated AR signaling activity and suppressed AR expression, while Gli1 overexpression partially reversed the inhibitory effects of SMO knockdown on AR signaling activity and AR expression in LNCaP and C4-2B cells. CONCLUSION: These results demonstrate that SMO loss is a characteristic of NEPC and that detecting SMO by IHC could aid pathologists in NEPC diagnosis. SMO loss may promote NEPC pathogenesis by modulating AR signaling.

Characterization of a bacterial strain Lactobacillus paracasei LP10266 recovered from an endocarditis patient in Shandong, China.

BACKGROUND: Lactobacilli are often recognized as beneficial partners in human microbial environments. However, lactobacilli also cause diseases in human, e.g. infective endocarditis (IE), septicaemia, rheumatic vascular disease, and dental caries. Therefore, the identification of potential pathogenic traits associated with lactobacilli will facilitate the prevention and treatment of the diseases caused by lactobacilli. Herein, we investigated the genomic traits and pathogenic potential of a novel bacterial strain Lactobacillus paracasei LP10266 which has caused a case of IE. We isolated L. paracasei LP10266 from an IE patient's blood to perform high-throughput sequencing and compared the genome of strain LP10266 with those of closely related lactobacilli to determine genes associated with its infectivity. We performed the antimicrobial susceptibility testing on strain LP10266. We assessed its virulence by mouse lethality and serum bactericidal assays as well as its serum complement- and platelet-activating ability. The biofilm formation and adherence of strain LP10266 were also studied. RESULTS: Phylogenetic analysis revealed that strain LP10266 was allied with L. casei and L. paracasei. Genomic studies revealed two spaCBA pilus clusters and one novel exopolysaccharides (EPS) cluster in strain LP10266, which was sensitive to ampicillin, penicillin, levofloxacin, and imipenem, but resistant to cefuroxime, cefazolin, cefotaxime, meropenem, and vancomycin. Strain LP10266 was nonfatal and sensitive to serum, capable of activating complement 3a and terminal complement complex C5b-9 (TCC). Strain LP10266 could not induce platelet aggregation but displayed a stronger biofilm formation ability and adherence to human vascular endothelial cells (HUVECs) compared to the standard control strain L. paracasei ATCC25302. CONCLUSION: The genome of a novel bacterial strain L. paracasei LP10266 was sequenced. Our results based on various types of assays consistently revealed that L. paracasei LP10266 was a potential pathogen to patients with a history of cardiac disease and inguinal hernia repair. Strain LP10266 showed strong biofilm formation ability and adherence, enhancing the awareness of L. paracasei infections.

Comparison of Different Methods for the Diagnosis of Mycobacterium Tuberculosis and Rifampin-Resistance.

BACKGROUND: Xpert MTB/RIF is recommended by the World Health Organization (WHO) for a rapid and simultaneous detection of Mycobacterium tuberculosis (Mtb) and rifampicin resistance specific to patients who have symptoms and signs. METHODS: The aim of this study was to evaluate the diagnostic significance possessed by various assays specific to the detection of Mtb. This study included 345 suspected TB patients who received treatment at the Shandong Public Health Clinical Center during May 2019 and August 2019. Related data included demographics, gender, age, past medical history (PMH), country of birth, country of residence, clinical information and laboratory test outcomes. The smear method was performed three times, the BD960 method was conducted two times and the MTB/ RIF and Xpert Ultra (phlegm precipitation) assays were performed once. All methods were completed simultaneously. RESULTS: The Xpert Ultra MTB (phlegm precipitation) method exhibited the highest consistency and sensitivity, followed by the Xpert MTB, Mtb culture, and smear methods, respectively. The Xpert Ultra MTB method also exhibited a significantly higher detection rate relative to the smear method (X2 = 13.411, p < 0.001). CONCLUSIONS: Xpert MTB/RIF along with Xpert Ultra (phlegm precipitation) exhibited higher sensitivity specific for the diagnosis of TB and rifampicin-resistance. The combined effects of these four methods showed outstanding sensitivity compared with single methods alone.

Effect of baffle structure on flow field characteristics of orbitally shaken bioreactor.

Disposable orbitally shaken bioreactors have been widely used for mammalian cell culture in suspension. Three kinds of baffle structures: vertical baffle, inclined baffle and horizontal baffle were designed in this work. The flow fields of the shaking bioreactor with different baffle structures were simulated, and the turbulence, dissolved oxygen and shear strain rate of the bioreactor were analyzed. The results showed that the quasi-steady-state flow patterns of the unbaffled shaking bioreactors were broken for the bioreactors with the strengthening effects of baffles. The mixing and the oxygen volumetric mass transfer coefficient (kLa) (simulated results) were improved significantly, and the shear strain rates were also increased greatly for the baffle bioreactors. The shear strain rates of the baffle bioreactors were mainly in the range of 0-20 s-1, and they were still low enough for CHO cell cultures.

SOX2 has dual functions as a regulator in the progression of neuroendocrine prostate cancer.

The mechanisms underlying the lineage switching from prostate adenocarcinoma (AdPC) to lethal neuroendocrine prostate cancer (NEPC) have yet to be completely elucidated. In this study, RNA sequencing data from a unique patient-derived xenograft NEPC model and a clinical NEPC cohort were used to identify the potential genes driving NEPC progression. Enrichr analysis resulted in the identification of SRY-related HMG-box gene 2 (SOX2) as a potential repressor that causes decrease in the expression of AdPC specific genes in NEPC. Assays involving the stable overexpression of SOX2 in LNCaP and CWR22RV1 cells validated this role of SOX2 in vitro. Mechanistic studies showed that the repressor role of SOX2 was attributed to the marked global hypomethylation of histone H3, which was driven by the activation of lysine-specific demethylase 1 (LSD1). Furthermore, Enrichr also predicted SOX2 as a driver gene involved in the upregulation of NEPC specific genes. However, SOX2 alone could only marginally induce the expression of some neuroendocrine markers in vitro, which was consistent with previous reports. Moreover, we also elucidated the molecular features of LNCaP-SOX2 cells that may confer resistance to androgen-deprivation therapy (ADT) and the inclination toward neuroendocrine transdifferentiation. The results of this study reveal a novel mechanism for SOX2 in the progression of NEPC via LSD1-mediated global epigenetic modulation. This discovery suggests that LSD1 may be a selective target for the prevention of NEPC progression.

The red distribution width and the platelet distribution width as prognostic predictors in gastric cancer.

BACKGROUND: Increasing attention is focused on the relationship of inflammation biomarkers with malignant tumors. The purpose of the present study was to detect whether the preoperative the red distribution width (RDW) and the platelet distribution width (PDW) can be used to distinguish patients with gastric cancer (GC) or early stage GC from the healthy controls and predict the progression and prognosis of the GC. METHODS: The RDW and PDW values of 227 patients with GC and 164 patients with early GC were retrospectively analyzed comparing with 101 healthy controls. In addition, the clinicopathological features, survival curves and prognosis of the patients with GC were compared between the high and low groups according to the RDW and PDW values. RESULTS: Significant higher RDW and lower PDW were detected in patients with GC and early GC compared to the healthy controls. A higher RDW was significantly associated with older age, a larger tumor diameter, deeper tumor infiltration, and lymph node metastasis while a lower PDW was significantly associated with male, older age, a larger tumor diameter, deeper tumor infiltration, elevated CEA and CA125. Increased RDW was significantly associated with worse overall survival (OS) and disease-free survival (DFS) for GC (P = 0.042 and P = 0.033, respectively) and early GC (P = 0.037 and P = 0.009, respectively) while decreased PDW indicated a significantly association with poor DFS for early GC (P = 0.006). Univariate and multivariate survival analysis showed that RDW and PDW can act as independent prognostic factors for DFS (P = 0.028 and P = 0.020) in patients with early GC. CONCLUSION: The preoperative RDW and PDW were simple and convenient predictive factors for the progression and prognosis of patients with GC.

The Podocyte Count Detected by an Improved Immunocytochemical Method has Higher Diagnostic Efficiency than Enzyme-Linked Immunosorbent Assay and Serum Cystatin C to Evaluate the Early Stage Damage of Glomerular.

BACKGROUND: In renal diseases, earlier injury to glomerular may lead to the abscission of podocyte. The number of podocyte in urine may reflect the severity of glomerular damage. Podocalyxin (PCX) was considered as a podocyte marker. Many methods were used to detect podocyte. Applications of these methods were limited by tricky, expensive, and low accuracy. Here, we improved an immunocytochemical method to count the number of podocyte in urine. METHODS: In this study, we counted the numbers of podocyte in urine by our improved method and detected the PCX levels in urine by enzyme-linked immunosorbent assay (ELISA) in glomerulopathy patients and healthy controls. The serum levels of cystatin C (CysC), blood urea nitrogen (BUN), creatinine (CR), uric acid (URIC), and ß2-Microglobulin (ß2-MG) in all subjects were detected. Correlation analysis and diagnostic efficiencies comparisons among immuocytochemical method, ELISA, and the biochemistry index were also performed. RESULTS: The podocyte counts in patients were significantly higher than controls. Podocytes counts positively correlated with PCX concentrations and the serum CysC. The podocyte count had higher diagnostic efficiency than PCX concentrations detected by ELISA and serum CysC. CONCLUSIONS: The podocyte count detected by our improved method had higher diagnostic efficiency than ELISA and serum CysC.