Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia.

DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear "blebs" that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulated in DYT1 cells and exhibits abnormal subcellular distribution in a cholinergic MNs-specific manner. Such dysregulation of LMNB1 can be recapitulated by either ectopic expression of the mutant TOR1A gene or shRNA-mediated downregulation of endogenous TOR1A in healthy control MNs. Interestingly, downregulation of LMNB1 can largely ameliorate all the cellular defects in DYT1 MNs. These results reveal the value of disease modeling with human patient-specific neurons and indicate that dysregulation of LMNB1, a crucial component of the nuclear lamina, may constitute a major molecular mechanism underlying DYT1 pathology.SIGNIFICANCE STATEMENT Inaccessibility to patient neurons greatly impedes our understanding of the pathologic mechanisms for dystonia. In this study, we employ reprogrammed human patient-specific motor neurons (MNs) to model DYT1, the most severe hereditary form of dystonia. Our results reveal disease-dependent deficits in nuclear morphology and nucleocytoplasmic transport (NCT). Most importantly, we further identify LMNB1 dysregulation as a major contributor to these deficits, uncovering a new pathologic mechanism for DYT1 dystonia.

Ultrasound elastography: a novel tool for the differential diagnosis of pleural effusion.

INTRODUCTION: Traditional thoracic ultrasound (TUS) is often the initial tool used to help diagnose malignant pleural effusion (MPE). Ultrasound elastography, a relatively new technique, has been used to differentiate malignant disease from benign disease by evaluating tissue "stiffness". However, no studies evaluating the efficacy of ultrasound elastography for diagnosing MPE are available. We assessed the value of ultrasound elsatography for diagnosing MPE prospectively. METHODS: All 244 enrolled patients were divided into a development set and a validation set in chronological order. The cut-off elasticity index was established using a receiver operating characteristic curve constructed from the continuous data of the patients in the development set. The diagnostic performance of ultrasound elastography was compared with that of TUS in the validation set. RESULTS: In the development set, the mean elasticity index (47.25 kPa) was the optimal cut-off. In the validation set, pleural ultrasound elastography had a sensitivity of 83.64%, a specificity of 90.67%, a positive predictive value of 86.79%, a negative predictive value of 88.31%, a positive likelihood ratio of 8.96 and a negative likelihood ratio of 0.18 for diagnosing MPE. The sensitivity of ultrasound elastography was significantly higher (p=0.006) than that of TUS (60%). CONCLUSION: Pleural ultrasound elastography is a better technique than TUS for differentiating MPE from benign pleural disease.

Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors.

Various combinations of cardiogenic transcription factors, including Gata4 (G), Hand2 (H), Mef2c (M) and Tbx5 (T), can reprogram fibroblasts into induced cardiac-like myocytes (iCLMs) in vitro and in vivo. Given that optimal cardiac function relies on distinct yet functionally interconnected atrial, ventricular and pacemaker (PM) cardiomyocytes (CMs), it remains to be seen which subtypes are generated by direct reprogramming and whether this process can be harnessed to produce a specific CM of interest. Here, we employ a PM-specific Hcn4-GFP reporter mouse and a spectrum of CM subtype-specific markers to investigate the range of cellular phenotypes generated by reprogramming of primary fibroblasts. Unexpectedly, we find that a combination of four transcription factors (4F) optimized for Hcn4-GFP expression does not generate beating PM cells due to inadequate sarcomeric protein expression and organization. However, applying strict single-cell criteria to GHMT-reprogrammed cells, we observe induction of diverse cellular phenotypes, including those resembling immature forms of all three major cardiac subtypes (i.e. atrial, ventricular and pacemaker). In addition, we demonstrate that cells induced by GHMT are directly reprogrammed and do not arise from an Nxk2.5(+) progenitor cell intermediate. Taken together, our results suggest a remarkable degree of plasticity inherent to GHMT reprogramming and provide a starting point for optimization of CM subtype-specific reprogramming protocols.

Postsynaptic FMRP bidirectionally regulates excitatory synapses as a function of developmental age and MEF2 activity.

Rates of synapse formation and elimination change over the course of postnatal development, but little is known of molecular mechanisms that mediate this developmental switch. Here, we report that the dendritic RNA-binding protein fragile X mental retardation protein (FMRP) bidirectionally and cell autonomously regulates excitatory synaptic function, which depends on developmental age as well as function of the activity-dependent transcription factor myocyte enhancer factor 2 (MEF2). The acute postsynaptic expression of FMRP in CA1 neurons of hippocampal slice cultures (during the first postnatal week, P6-P7) promotes synapse function and maturation. In contrast, the acute expression of FMRP or endogenous FMRP in more mature neurons (during the second postnatal week; P13-P16) suppresses synapse number. The ability of neuronal depolarization to stimulate MEF2 transcriptional activity increases over this same developmental period. Knockout of endogenous MEF2 isoforms causes acute postsynaptic FMRP expression to promote, instead of eliminate, synapses onto 2-week-old neurons. Conversely, the expression of active MEF2 in neonatal neurons results in a precocious FMRP-dependent synapse elimination. Our findings suggest that FMRP and MEF2 function together to fine tune synapse formation and elimination rates in response to neuronal activity levels over the course of postnatal development.

Association between statin usage and prostate cancer prevention: a refined meta-analysis based on literature from the years 2005-2010.

INTRODUCTION: Statins are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. It was found that statins can be associated with the occurrence of prostate cancer. However, no consensus has been concluded. MATERIALS AND METHODS: In the present study, we provide a refined meta-analysis on the association between statins and prostate cancers. Our objective is to offer a congruent recognition of the impact of statins on prostate cancer. RESULTS: Our refined analysis has included seven previous publications from the years 2005 to 2010. CONCLUSIONS: Based on the results, we concluded that there were associations for statin usage in preventing prostate cancer (OR 1.195, 95% CI 1.018-1.403, p = 0.029). Different from previous meta-analyses, our positive conclusion is primarily based on the recent new published literature, which supported the efficiency of statin use to control prostate cancer. More specific efforts for excluding the influence of other factors are crucial in further assessment of the efficiency of statin use.

Research on Intelligent Sports Training System for Golf Based on Body Sense Recognition.

In recent years, significant advances in the development of computer vision technology have produced many platforms and systems that combine computer technology and sports-assisted training, including intelligent systems that are integrated with golf training and instruction. However, the existing intelligent systems for golf-assisted teaching usually use three-dimensional depth information, which will significantly increase the cost of intelligent systems. In this paper, the extraction of golf club slope is carried out on the basis of golf sport video capture using a common monocular camera in order to match the club slope information with the professional coach swing video information. At the same time, in order to facilitate the interframe matching, the joint point information is complemented using the projection approximation point algorithm, and the segmentation of the swing video is performed using the complemented human hand joints and the fixed characteristics of the golf swing. Then, in order to solve the problem that human joints will have the same joint angle under different movements, the human limb joint angles are defined and then the swing movements in the user video frames are evaluated.

In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury.

Adult neurogenesis plays critical roles in maintaining brain homeostasis and responding to neurogenic insults. However, the adult mammalian spinal cord lacks an intrinsic capacity for neurogenesis. Here we show that spinal cord injury (SCI) unveils a latent neurogenic potential of NG2+ glial cells, which can be exploited to produce new neurons and promote functional recovery after SCI. Although endogenous SOX2 is required for SCI-induced transient reprogramming, ectopic SOX2 expression is necessary and sufficient to unleash the full neurogenic potential of NG2 glia. Ectopic SOX2-induced neurogenesis proceeds through an expandable ASCL1+ progenitor stage and generates excitatory and inhibitory propriospinal neurons, which make synaptic connections with ascending and descending spinal pathways. Importantly, SOX2-mediated reprogramming of NG2 glia reduces glial scarring and promotes functional recovery after SCI. These results reveal a latent neurogenic potential of somatic glial cells, which can be leveraged for regenerative medicine.

Association of brain-derived neurotrophic factor genetic Val66Met polymorphism with severity of depression, efficacy of fluoxetine and its side effects in Chinese major depressive patients.

BACKGROUND: Preclinical studies have shown that brain-derived neurotrophic factor (BDNF) may be involved in antidepressant action, and the BDNF gene has been suggested to be involved in the pharmacological treatment of major depressive disorder (MDD). In this study, the relationship between BDNF Val66Met polymorphism (Single Nucleotide Polymorphism Database ID: rs6265) and severity of depression, efficacy of fluoxetine and its side effects was tested in Chinese patients with MDD. METHODS: Patients with MDD took the oral selective serotonin reuptake inhibitor (SSRI) fluoxetine (20 mg/day) for 6 weeks. Its clinical efficacy and side effects were measured by the 17-item Hamilton Rating Scale for Depression and the Treatment-Emergent Symptoms Scale (TESS), respectively. The patients were genotyped for Val66Met polymorphism of the BDNF gene. RESULTS: In the multivariate regression analysis, there was no significant association between severity of depression and BDNF Val66Met polymorphism. There was no association between efficacy of fluoxetine and BDNF Val66Met polymorphism, but there was a marginal positive suggestion that heterozygous patients tended to have a better remission with fluoxetine in comparison with homozygous analogs. Insomnia and decreased sexual desire, side effects of fluoxetine, may have an association with the BDNF Val66Met polymorphism, and Met allele carriers showed a lower incidence of these side effects. CONCLUSIONS: These results indicate that there was a lack of association between severity of depression and BDNF Val66Met polymorphism in Chinese patients with MDD. The BDNF Val66Met polymorphism may play a major role in the efficacy and side effects of SSRI (fluoxetine) in Chinese patients with MDD.

Association of BDNF Val66Met polymorphism with both baseline HRQOL scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine.

OBJECTIVE: To explore the association of brain-derived neurotrophic-factor (BDNF) Val66Met polymorphism with both baseline health related quality of life (HRQOL) scores and improvement in HRQOL scores in Chinese major depressive patients treated with fluoxetine. METHODS: Patients with major depressive disorder (MDD) took fluoxetine (20 mg/day) for 6 weeks. The HRQOL was measured with the Medical Outcomes Study Short Form-36 (SF-36) at baseline and at 6th week. Patients were genotyped for Val66Met polymorphism of BDNF gene. RESULTS: There was a significant association between social function (SF) and BDNF Val66Met polymorphism, and patients with Met/Met genotype had better SF (compared with Val/Val P = 0.004; compared with Val/Met P = 0.005). A significant association was found between improvement in SF and BDNF Val66Met polymorphism, and patients with Met/Met genotype had poorer improvement in SF (compared with Val/Val P = 0.010; compared with Val/Met P = 0.001). Similar association was found between improvement in mental component summary (MCS) and BDNF Val66Met polymorphism, and patients with Met/Met genotype had poorer improvement in MCS (compared with Val/Val P = 0.066; compared with Val/Met P = 0.006). CONCLUSIONS: These results indicate that there may be association between BDNF Val66Met polymorphism and both baseline HRQOL (SF) scores and improvement in HRQOL (SF, MCS) scores in Chinese major depressive patients treated with fluoxetine.

[Orthotopic T pouch ileal neobladder: evaluations of urodynamics and upper urinary tract functions].

OBJECTIVE: To evaluate the urodynamics and functions of upper urinary tract in a substitute of orthotopic T pouch ileal bladder. METHODS: From June 2004 through September 2009, 90 patients underwent the construction of an orthotopic T pouch ileal neobladder after radical cystectomy for muscle-invasive bladder cancer. The radiographic or ultrasound evaluation of upper urinary tract, determination of renal functions and urodynamic evaluation of T pouch ileal neobladder were performed by data analysis. RESULTS: Renal function as determined by serum creatinine remained in a normal range in all patients. Temporary dilation of renal pelvic and ureter was observed in 18 patients (20.0%) at Day 45 post-operation and then disappeared spontaneously in the late follow-up. A slight dilation of collecting system was found in other 4 patients (4.4%), but there was no negative impact on renal function. Reflux into afferent limb of neobladder was observed in 4 patients (4.4%) by cystography. Excellent daytime and nighttime continence was reported in 100% and 82.2% of evaluated patients respectively. The urodynamic assessment showed a mean capacity of (316 ± 96) ml with a mean intra-bladder pressure of (16 ± 10) cm H2O. These evaluated patients voided with a mean maximum intra-bladder pressure of (87 ± 25) cm H2O, a mean maximum flow rate of (17 ± 10) ml/s and a mean residual urine of (33 ± 29) ml. CONCLUSION: With an intermediate follow-up, the functional results of T pouch ileal neobladder are encouraging with an excellent capacity and compliance, successful daytime and nighttime continence and anti-reflux mechanism.

Aging-relevant human basal forebrain cholinergic neurons as a cell model for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is an adult-onset mental disorder with aging as a major risk factor. Early and progressive degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive impairments of AD. An aging-relevant cell model of BFCNs will critically help understand AD and identify potential therapeutics. Recent studies demonstrate that induced neurons directly reprogrammed from adult human skin fibroblasts retain aging-associated features. However, human induced BFCNs (hiBFCNs) have yet to be achieved. METHODS: We examined a reprogramming procedure for the generation of aging-relevant hiBFCNs through virus-mediated expression of fate-determining transcription factors. Skin fibroblasts were obtained from healthy young persons, healthy adults and sporadic AD patients. Properties of the induced neurons were examined by immunocytochemistry, qRT-PCR, western blotting, and electrophysiology. RESULTS: We established a protocol for efficient generation of hiBFCNs from adult human skin fibroblasts. They show electrophysiological properties of mature neurons and express BFCN-specific markers, such as CHAT, p75NTR, ISL1, and VACHT. As a proof-of-concept, our preliminary results further reveal that hiBFCNs from sporadic AD patients exhibit time-dependent TAU hyperphosphorylation in the soma and dysfunctional nucleocytoplasmic transport activities. CONCLUSIONS: Aging-relevant BFCNs can be directly reprogrammed from human skin fibroblasts of healthy adults and sporadic AD patients. They show promises as an aging-relevant cell model for understanding AD pathology and may be employed for therapeutics identification for AD.

[Medication combined with local hyperthermia: a desirable therapy for chronic prostatitis pain symptoms].

OBJECTIVE: To compare the effect of the combined therapy of medication with local hyperthermia with that of the simple local hyperthermia therapy in the treatment of pain symptoms of chronic prostatitis (CP). METHODS: Seventy-six CP patients aged 18-48 (mean 29.2 +/- 3.8) years, with the disease course of 3.5-180 (mean 8.0 +/- 1.2) months and NIH-CPSI pain score > or = 14, were equally randomized into a treatment group and a control. The former was treated by applying the CRS-2280E extraorgan short-wave capacitance field hyperthermia system to the prostate once an hour every other day for 7 times, combined with anal administration of 1 Qianliean suppository and oral doxazosin 4 mg before bedtime every night for 2 weeks, while the latter underwent simple local hyperthermia. All the patients were scored on NIH-CPSI and the therapeutic results were compared between the two groups. RESULTS: The pre- and post-treatment NIH-CPSI scores were (23.9 +/- 3.8) and (5.2 +/- 3.1) (P < 0.01) in the treatment goup and (24.5 +/- 4.3) and (11.6 +/- 3.4) (P < 0.01) in the control; the pre- and post-treatment scores on NIH-CPSI pain symptoms were (16.5 +/- 1.9) and (3.1 +/- 2.2) (P < 0.01) in the former and (15.9 +/- 1.7) and (8.2 +/- 2.0) (P < 0.01) in the latter. The total score on NIH-CPSI and that on NIH-CPSI pain symptoms were both significantly higher in the treatment group than in the control (P < 0.01). Within the treatment group, the score on NIH-CPSI pain symptoms was even more significantly improved in patients with the first attacks than in those already treated by other means (P < 0.01). No adverse effects were observed in either of the groups. CONCLUSION: Both the combined therapy of medication with local hyperthermia and simple local hyperthermia are effective, safe and tolerable in the treatment of CP pain symptoms, and the former is even more desirable, particularly for those with the first attacks of the symptoms.

Phenotypic Reprogramming of Striatal Neurons into Dopaminergic Neuron-like Cells in the Adult Mouse Brain.

Neuronal subtype is largely fixed in the adult mammalian brain. Here, however, we unexpectedly reveal that adult mouse striatal neurons can be reprogrammed into dopaminergic neuron-like cells (iDALs). This in vivo phenotypic reprogramming can be promoted by a stem cell factor (SOX2), three dopaminergic neuron-enriched transcription regulators (NURR1, LMX1A, and FOXA2), and a chemical compound (valproic acid). Although the site of action of the reprogramming factors remains to be determined, immunohistochemistry and genetic lineage mappings confirm striatal neurons as the cell origin for iDALs. iDALs exhibit electrophysiological properties stereotypical to endogenous dopaminergic rather than striatal neurons. Together, these results indicate that neuronal phenotype can be reengineered even in the adult brain, implicating a therapeutic strategy for neurological diseases.

Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons.

In vitro generation of motor neurons (MNs) is a promising approach for modeling motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS). As aging is a leading risk factor for the development of neurodegeneration, it is important to recapitulate age-related characteristics by using MNs at pathogenic ages. So far, cell reprogramming through induced pluripotent stem cells (iPSCs) and direct reprogramming from primary fibroblasts are two major strategies to obtain populations of MNs. While iPSC generation must go across the epigenetic landscape toward the pluripotent state, directly converted MNs might have the advantage of preserving aging-associated features from fibroblast donors. In this study, we confirmed that human iPSCs reset the aging status derived from their old donors, such as telomere attrition and cellular senescence. We then applied a set of transcription factors to induce MNs from either primary fibroblasts or iPSC-derived neural progenitor cells. The results revealed that directly reprogrammed MNs, rather than iPSC-derived MNs, maintained the aging hallmarks of old donors, including extensive DNA damage, loss of heterochromatin and nuclear organization, and increased SA-ß-Gal activity. iPSC-derived MNs did not regain those aging memories from old donors. Collectively, our study indicates rejuvenation in the iPSC-based model, as well as aging maintenance in direct reprogramming of MNs. As such, the directly reprogrammed MNs may be more suitable for modeling the late-onset pathogenesis of MNDs.

TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response.

Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.

Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients.

Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

Identification of new hub genes associated with bladder carcinoma via bioinformatics analysis.

AIMS AND BACKGROUND: Bladder carcinoma (BC) is one of the most common malignant cancers worldwide. Several genes related to the mechanism of BC have been studied in recent years, but the current understanding of BC is still rather limited. This study aimed to find new differentially expressed genes (DEGs) associated with the occurrence and development of BC. METHODS: In this work, we downloaded gene expression data from Gene Expression Omnibus under accession number GSE27448, which included 10 GeneChips from urinary BC tissues and 5 from normal tissues. DEGs were identified by the LIMMA package in R. Then the protein-protein interactions (PPIs) networks were analyzed with the database of Search Tool for the Retrieval of Interacting Genes, and gene ontology (GO) was applied to explore the underlying function of the DEGs using the Database for Annotation, Visualization and Integrated Discovery. RESULTS: A total of 2,068 DEGs were found between BC and normal tissues. These genes were involved in 49 functional clusters. The top 10 highest degree nodes, such as POLR2F/2H (DNA directed RNA polymerase II polypeptide F/polypeptide H) and RPS14/15 (ribosomal protein S14/S15), were proven to be hub nodes in the PPIs network. ITGA7 (integrin, alpha 7), GRB14 (growth factor receptor-bound protein 14), CDC20 (cell division cycle 20) and PSMB1 (proteasome subunit, beta type, 1) were significant DEGs identified in the functional clusters. CONCLUSIONS: Genes such as POLR2F/2H, RPS14/15, ITGA7, GRB14, CDC20 and PSMB1 were forecast to play important roles in the occurrence and progression of BC.

SOX2 reprograms resident astrocytes into neural progenitors in the adult brain.

Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1(+) neural progenitors and DCX(+) adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin(+) interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine.

Bioinformatics analysis of the target gene of fibroblast growth factor receptor 3 in bladder cancer and associated molecular mechanisms.

The aim of the present study was to elucidate the molecular mechanisms of fibroblast growth factor receptor 3 (FGFR3) activation via overexpression or mutation of the FGFR3 target gene in bladder cancer (BC). The transcription profile data GSE41035, which included 18 BC samples, containing 3 independent FGFR3 short hairpin (sh)RNA, and 6 control samples, containing enhanced green fluorescent protein (EGFP) shRNA, were obtained from the National Center of Biotechnology Information Gene Expression Omnibus database. The Limma package with multiple testing correction was used to identify differentially expressed genes (DEGs) between FGFR3 knockdown and control samples. Gene ontology (GO) and pathway enrichment analysis were conducted in order to investigate the DEGs at the functional level. In addition, differential co-expression analysis was employed to construct a gene co-expression network. A total of 196 DEGs were acquired, of which 101 were downregulated and 95 were upregulated. In addition, a gene signature was identified linking FGFR3 signaling with de novo sterol biosynthesis and metabolism using GO and pathway enrichment analysis. Furthermore, the present study demonstrated that the genes NME2, CCNB1 and H2AFZ were significantly associated with BC, as determined by the protein-protein interaction network of DEGs and co-expressed genes. In conclusion, the present study revealed the involvement of FGFR3 in the regulation of sterol biosynthesis and metabolism in the maintenance of BC; in addition, the present study provided a novel insight into the molecular mechanisms of FGFR3 in BC. These results may therefore contribute to the theoretical guidance into the detection and therapy of BC.

Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells.

Here we studied the cellular mechanisms of ursolic acid's anti-bladder cancer ability by focusing on endoplasmic reticulum stress (ER stress) signaling. We show that ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells. ER stress inhibitor salubrinal, or PERK silencing, diminishes ursolic acid-induced anti-T24 cell effects. Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and caspase-3 activation in T24 cells. Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. We suggest that ER stress contributes to ursolic acid's effects against bladder cancer cells.