The prognostic significance and clinical relevance of stem cell characteristic in bladder cancer.

Background: Bladder cancer (BLCA) is a common malignant tumor of urinary system and prognostic biomarkers are needed for better clinical decision-making and patient management. Cancer stem cells (CSCs) are involved in carcinogenesis, development, metastasis and recurrence of BLCA. This study explored the prognostic and predictive value of CSCs-related genes and laid the groundwork for precision treatment development in BLCA. Methods: The mRNA data and corresponding clinical information obtained from TCGA-BLCA cohort was used to discover biomarkers and develop CSCs-related prognostic model, which was further validated in GSE32548 and GSE32894 datasets. In addition, the association between CSCs-related risk score and therapeutic efficacy was analyzed to explore the potential predictive value of the prognostic model. Results: We identified four CSCs-related subtypes and 900 differentially expressed genes (DEGs) among subtypes. Then the CSCs-related prognostic model was built based on 16 CSCs-related DEGs with the most significant prognostic value. Patients in the low-risk group had better overall survival than those in high-risk group (P < 0.001; HR, 0.42; 95 %CI, 0.31-0.57). Multivariable Cox analysis in training and test sets confirmed the independence of CSCs-related risk score as a prognostic factor (P < 0.05). The difference of survival between two risk groups were probably due to the significantly varied immune microenvironment based on the analysis of infiltrated immune cells. Additionally, the risk score was significantly associated with chemotherapy sensitivity and the response to anti-PD-L1 therapy (P < 0.05) which suggested a potential predictive value of CSCs-related risk model. Conclusion: We established a risk classifier based on 16 CSCs-related genes for predicting survival in patients with BLCA. The CSCs-related risk model has both prognostic value and potential predictive value for therapeutic efficacy, which brings us closer to understanding the important role of CSCs in BLCA and may provide guidance for clinical treatment decision-making and patient management. The clinical utility of the CSCs-related risk classifier warrants further studies.

Deciphering a cell death-associated signature for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell carcinoma, accounting for about 30% of all lung cancers. Yet, the evaluation of prognostic outcome and therapy response of patients with LUSC remains to be resolved. This study aimed to explore the prognostic value of cell death pathways and develop a cell death-associated signature for predicting prognosis and guiding treatment in LUSC. METHODS: Transcriptome profiles and corresponding clinical information of LUSC patients were gathered from The Cancer Genome Atlas (TCGA-LUSC, n = 493) and Gene Expression Omnibus database (GSE74777, n = 107). The cell death-related genes including autophagy (n = 348), apoptosis (n = 163), and necrosis (n = 166) were retrieved from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases. In the training cohort (TCGA-LUSC), LASSO Cox regression was used to construct four prognostic signatures of respective autophagy, apoptosis, and necrosis pathway and genes of three pathways. After comparing the four signatures, the cell death index (CDI), the signature of combined genes, was further validated in the GSE74777 dataset. We also investigated the clinical significance of the CDI signature in predicting the immunotherapeutic response of LUSC patients. RESULTS: The CDI signature was significantly associated with the overall survival of LUSC patients in the training cohort (HR, 2.13; 95% CI, 1.62‒2.82; P < 0.001) and in the validation cohort (HR, 1.94; 95% CI, 1.01‒3.72; P = 0.04). The differentially expressed genes between the high- and low-risk groups contained cell death-associated cytokines and were enriched in immune-associated pathways. We also found a higher infiltration of naive CD4+ T cells, monocytes, activated dendritic cells, neutrophils, and lower infiltration of plasma cells and resting memory CD4+ T cells in the high-risk group. Tumor stemness indices, mRNAsi and mDNAsi, were both negatively correlated with the risk score of the CDI. Moreover, LUSC patients in the low-risk group are more likely to respond to immunotherapy than those in the high-risk group (P = 0.002). CONCLUSIONS: This study revealed a reliable cell death-associated signature (CDI) that closely correlated with prognosis and the tumor microenvironment in LUSC, which may assist in predicting the prognosis and response to immunotherapy for patients with LUSC.

A prognostic 15-gene model based on differentially expressed genes among metabolic subtypes in diffuse large B-cell lymphoma.

The outcomes of patients with diffuse large B-cell lymphoma (DLBCL) vary widely, and about 40% of them could not be cured by the standard first-line treatment, R-CHOP, which could be due to the high heterogeneity of DLBCL. Here, we aim to construct a prognostic model based on the genetic signature of metabolic heterogeneity of DLBCL to explore therapeutic strategies for DLBCL patients. Clinical and transcriptomic data of one training and four validation cohorts of DLBCL were obtained from the GEO database. Metabolic subtypes were identified by PAM clustering of 1,916 metabolic genes in the 7 major metabolic pathways in the training cohort. DEGs among the metabolic clusters were then analyzed. In total, 108 prognosis-related DEGs were identified. Through univariable Cox and LASSO regression analyses, 15 DEGs were used to construct a risk score model. The overall survival (OS) and progression-free survival (PFS) of patients with high risk were significantly worse than those with low risk (OS: HR 2.86, 95%CI 2.04-4.01, p < 0.001; PFS: HR 2.42, 95% CI 1.77-3.31, p < 0.001). This model was also associated with OS in the four independent validation datasets (GSE10846: HR 1.65, p = 0.002; GSE53786: HR 2.05, p = 0.02; GSE87371: HR 1.85, p = 0.027; GSE23051: HR 6.16, p = 0.007) and PFS in the two validation datasets (GSE87371: HR 1.67, p = 0.033; GSE23051: HR 2.74, p = 0.049). Multivariable Cox analysis showed that in all datasets, the risk model could predict OS independent of clinical prognosis factors (p < 0.05). Compared with the high-risk group, patients in the low-risk group predictively respond to R-CHOP (p = 0.0042), PI3K inhibitor (p < 0.05), and proteasome inhibitor (p < 0.05). Therefore, in this study, we developed a signature model of 15 DEGs among 3 metabolic subtypes, which could predict survival and drug sensitivity in DLBCL patients.

A DNA Damage Response Related Signature to Predict Prognosis in Patients with Acute Myeloid Leukemia.

The prognosis of acute myeloid leukemia (AML) is disappointing in most subtypes and varies widely. DNA damage response (DDR) is associated with prognosis and immunotherapy in multiple cancers. Here, we identify a signature of eight DDR-related genes associated with overall survival, which stratifies AML patients into high- and low-risk groups. Patients in low-risk group were more likely to respond to sorafenib. The signature could be an independent prognostic predictor for patients treated with ADE and ADE plus gemtuzumab ozogamicin. Therefore, this DDR prognostic signature might be applied to prognostic stratification and treatment selection in AML patients, which warrants further studies.

Circulating cell-free DNA for cancer early detection.

Effective screening modalities are currently available for only a small subset of cancers, and they generally have suboptimal performance with complicated procedures. Therefore, there is an urgent need to develop simple, accurate, and non-invasive methods for early detection of cancers. Genetic and epigenetic alterations in plasma circulating cell-free DNA (cfDNA) have shown the potential to revolutionize methods of early detection of cancers and facilitate subsequent diagnosis to improve survival of patients. The medical interest in cfDNA assays has been inspired by emerging single- and multi-early detection of cancers studies. This review summarizes current technological and clinical advances, in the hopes of providing insights into the development and applications of cfDNA assays in various cancers and clinical scenarios. The key phases of clinical development of biomarkers are highlighted, and the future developments of cfDNA-based liquid biopsies in early detection of cancers are outlined. It is hoped that this study can boost the potential integration of cfDNA-based early detection of cancers into the current clinical workflow.

Zanubrutinib monotherapy in relapsed/refractory mantle cell lymphoma: a pooled analysis of two clinical trials.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P = 0.235) and OS (median: NE vs. 38.2 months, P = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile.

Neurotoxicity of HIV-1 Tat is attributed to its penetrating property.

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients. HIV-1 Tat protein can penetrate cell membrane freely and secrete into extracellular medium. Exo-Tat loses this penetrating property. HIV-1 Tat protein can damage the synaptic membranes contributing to the development of dementia in HIV-1 infected patients. To investigate whether the penetrating property attributes to synaptic damage in vivo, we have generated adeno-associated viruses AAV-Tat and AAV-Exo-Tat viruses. Vehicle control or AAV viruses (1 × 1012 GC/mouse in 200 µl PBS) were injected into Balb/cj mice via tail veins. The mRNA and protein expression levels in blood, brain, heart, intestine, kidney, liver, lung, muscle and spleen were determined on day 21. Intravenously injected AAV-Tat or AAV-Exo-Tat mainly infects liver and heart. Short-term expression of Tat or Exo-Tat doesn't change the expression levels of neuronal cytoskeletal marker ß3-tubulin and synaptic marker postsynaptic density 95 protein (PSD-95). Wild-type Tat, but not Exo-Tat, reduces the expression level of synaptic marker synaptophysin significantly in mice, indicating that penetrating property of HIV-1 Tat protein attributes to synaptic damage.

Impact of exosomal HIV-1 Tat expression on the human cellular proteome.

HIV-1 exists in a latent form in all infected patients. When antiretroviral therapy is stopped, viral replication resumes. The HIV-1 Tat protein is a potent activator of viral transcription. Our previous work has demonstrated that exosomal formulations of Tat can reverse HIV-1 latency in primary CD4+ T lymphocytes isolated from long term antiretroviral treated individuals suggesting a potential role for Tat as a therapeutic HIV-1 Latency Reversal Agent (LRA). Here, we employed the label-free proteomic approach for profiling the proteomic changes associated with exosomal Tat production in human cell lines. Comparative proteomic analysis revealed that >30% peptides were differentially expressed in abundance in the Tat-expressing cell line compared with relevant controls. As expected, many of the known Tat-interactor proteins were upregulated. Tat expression also led to the upregulation of antioxidant proteins suggesting Tat-mediates an oxidative burst. Gene ontology and pathway analyses of these differentially expressed proteins showed enrichment of extracellular vesicular exosome and spliceosome localized proteins and proteins involved with transcriptional and translational mechanisms. Our work suggests that HIV-1 Tat expression leads to perturbations in cellular protein expression. In vivo administration of Tat using HIV/SIV animal models needs to be performed to assess the physiologic significance of Tat-induced proteomic changes prior to developing HIV-1 Tat as an LRA.

Long-term efficacy and safety of paliperidone palmitate once-monthly in Chinese patients with recent-onset schizophrenia.

Background: The subgroup analysis of a primary study (NCT01051531) evaluated the effect of long-term paliperidone palmitate once-monthly (PP1M) therapy in Chinese patients with recent-onset schizophrenia responding unsatisfactorily to previous oral antipsychotics. Patients and methods: This 18-month, open-label study consisted of 3 phases - screening (7 days), treatment (18 months) and end-of-study/withdrawal visit. All enrolled patients (18-50 years) received PP1M: 150 mg eq. (day 1), 100 mg eq. (day 8) followed by a once-monthly flexible dose (50, 75, 100 or 150 mg eq.). Efficacy and safety were assessed. Results: Among the 118 enrolled Chinese patients, 68 completed the treatment (mean age: 25.6 years; male: 54.7%). A clinically meaningful change from baseline to day 548 was observed in Positive and Negative Syndrome scale (primary endpoint, mean [SD]: -15.3 [20.76]), Personal and Social Performance scale (15.9 [19.65]), Clinician Global Impression-schizophrenia score (-1.2 [1.54]) and Medication Satisfaction Questionnaire score (0.9 [1.73]). Commonly reported treatment-emergent adverse events (TEAEs) included insomnia (13.9%), injection-site pain (13.9%), upper respiratory tract infection (13.0%), restlessness (13.0%) and akathisia (13.0%). Serious TEAEs were reported in 9.3% patients with schizophrenia being most common (6.5%) and one death (suicide) was observed. Conclusion: Efficacy of PP1M corroborate findings from earlier studies and no new safety concerns emerged in this Chinese subgroup of patients with schizophrenia.

Impact of paliperidone palmitate one-month formulation on relapse prevention in patients with schizophrenia: A post-hoc analysis of a one-year, open-label study stratified by medication adherence.

BACKGROUND: Limited data are available to help identify patients with schizophrenia who are most likely to benefit from long-acting injectable antipsychotics. AIM: To investigate the efficacy of long-acting injectable antipsychotic paliperidone palmitate one-month formulation for preventing relapses, factors influencing time to first relapse, and the effect of different antipsychotic adherence levels on time to first relapse in Chinese patients with schizophrenia. METHODS: This was a post-hoc analysis from an open-label, single-arm study of stable patients (Positive and Negative Syndrome Scale total score <70; n=367) receiving paliperidone palmitate one-month formulation at the end of an acute 13-week treatment phase, who entered a naturalistic one-year follow-up period, either continuing with flexibly dosed paliperidone palmitate one-month formulation (75-150 mg eq.) or switching to another antipsychotic(s). RESULTS: There were 362/367 patients (age=31.4±10.75 years) included in the analysis of time to first relapse (primary outcome) and 327/362 patients (39/327, poor antipsychotic adherence (<80%)) willing to receive antipsychotics were included in the exposure/adherence analysis. Overall, 84.6% (95% confidence interval=79.2-88.7) patients remained relapse-free. Poor adherence during follow-up (hazard ratio=2.97, 95% confidence interval=1.48-5.98, p=0.002) and frequent hospitalizations in the previous year (hazard ratio=1.29, 95% confidence interval=1.02-1.62, p=0.03) were associated with a significant risk of shorter time to first relapse in the univariate analysis. In patients with poor adherence, 'no use' (hazard ratio=13.13, 95% confidence interval=1.33-129.96, p=0.03) and 'interrupted use' (hazard ratio=11.04, 95% confidence interval=1.03-118.60, p=0.047) of paliperidone palmitate one-month formulation (vs continued use) showed a significantly higher risk of relapse; this was not observed in patients with good (≥80%) antipsychotic adherence. No new safety concerns were identified. CONCLUSION: Continued use of paliperidone palmitate one-month formulation/long-acting injectable antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence.

Factors related to improvement of symptoms, function, and caregiver burden in Chinese patients with schizophrenia after switching to paliperidone palmitate once-monthly from oral antipsychotics.

BACKGROUND: Paliperidone palmitate once-monthly (PP1M) demonstrated symptomatic and functional remission in patients with schizophrenia. This post hoc analysis aimed to identify factors associated with improved clinical outcomes in patients switching to PP1M (75-150 mg eq.). METHODS: The improved patient outcomes were observed as Positive and Negative Symptom Scale (PANSS, symptoms) score <70:66.7% (407/610), Personal and Social Performance (PSP, function) score >70:34.3% (199/581), and Involvement Evaluation Questionnaire (IEQ, caregiver burden) reduction ≥6:50.2% (270/538). Independent variables including demographics, disease duration, employment status, and clinical scores were screened individually using a univariate analysis and subsequently, variables (cutoff p<0.15) were analyzed using a multivariate regression analysis for association with better clinical outcomes at week 13. RESULTS: The factors significantly associated with favorable clinical outcomes were reduction in PANSS at week 5 (odds ratio [OR]=1.14, 95% CI=1.11-1.17) with symptom reduction; baseline PSP total score (OR=1.07, 95% CI=1.05-1.10), PSP change at week 5 (OR=1.07, 95% CI=1.05-1.10), PANSS reduction at week 5 (OR=1.06, 95% CI=1.03-1.08) with functional improvement, reduction in PANSS at week 5 (OR=1.02, 95% CI=1.01-1.03), and total IEQ score at baseline (OR=1.09, 95% CI=1.07-1.11) with caregiver burden reduction. CONCLUSION: Thus, symptom and functional improvements with caregiver burden reduction were observed in patients, and PANSS reduction at week 5 was commonly associated with favorable outcomes.

Exosomal Tat protein activates latent HIV-1 in primary, resting CD4+ T lymphocytes.

Replication competent HIV-1 persists in a subpopulation of CD4+ T lymphocytes despite prolonged antiretroviral treatment. This residual reservoir of infected cells harbors transcriptionally silent provirus capable of reigniting productive infection upon discontinuation of antiretroviral therapy. Certain classes of drugs can activate latent virus but not at levels that lead to reductions in HIV-1 reservoir size in vivo. Here, we show the utility of CD4+ receptor targeting exosomes as an HIV-1 latency reversal agent (LRA). We engineered human cellular exosomes to express HIV-1 Tat, a protein that is a potent transactivator of viral transcription. Preparations of exosomal Tat-activated HIV-1 in primary, resting CD4+ T lymphocytes isolated from antiretroviral-treated individuals with prolonged periods of viral suppression and led to the production of replication competent HIV-1. Furthermore, exosomal Tat increased the potency of selected LRA by over 30-fold in terms of HIV-1 mRNA expression, thereby establishing it as a potentially new class of biologic product with possible combinatorial utility in targeting latent HIV-1.

Safety and efficacy of paliperidone palmitate 1-month formulation in Chinese patients with schizophrenia: a 25-week, open-label, multicenter, Phase IV study.

RATIONALE: Long-acting injectable (LAI) paliperidone palmitate 1-month formulation (PP1M) has demonstrated acceptable tolerability and favorable clinical outcomes in Western and Asian patients with schizophrenia. Hence, analysis of the outcomes of long-term PP1M treatment specifically in Chinese patients is of interest. OBJECTIVE: The aim of this study is to evaluate the long-term safety and efficacy of PP1M treatment in Chinese patients with schizophrenia. METHODS: In this 25-week, open-label, Phase IV study, patients (18-65 years) diagnosed with schizophrenia and having a baseline Positive and Negative Syndrome Scale (PANSS) total score of 60-120 (inclusive) were enrolled. All patients received injections of PP1M 150 mg eq. (day 1) and 100 mg eq. (day 8), followed by a flexible once-monthly maintenance dosing (75, 100, or 150 mg eq.). RESULTS: Of the 353 patients, 234 (66.3%) completed the study treatment (mean age, 31.1 years; 52.7% men). The PANSS total score (primary end point) improved significantly over the 6-month treatment period (mean [standard deviation] change from baseline to end of treatment, -27.2 [18.30]; P<0.0001). The Clinical Global Impressions-Severity and Personal and Social Performance scores (secondary end points) also improved significantly (P<0.0001). At 6 months, PP1M had a positive impact on medication satisfaction, adherence, and increased preference for LAIs. Treatment-emergent adverse events (TEAEs) were reported by 181 (51.3%) patients (TEAEs ≥5%: extrapyramidal disorder [15.3%], akathisia [10.5%], blood prolactin increase [8.8%], insomnia [5.4%]). A total of 8 deaths were reported, including 4 completed suicides. CONCLUSION: Long-term treatment with PP1M was efficacious, and no new safety concerns were identified in Chinese patients with schizophrenia. Overall, the results were comparable with observations from previous studies.

Efficacy, acceptability and tolerability of 8 atypical antipsychotics in Chinese patients with acute schizophrenia: A network meta-analysis.

OBJECTIVE: We aimed to create hierarchies of the efficacy, acceptability and tolerability of eight atypical antipsychotics in the treatment of Chinese patients with acute schizophrenia. METHOD: We systematically searched for RCT articles published between January 1st 2005 and December 31st 2014 in electronic databases (Medline, Pubmed, Embase, the Cochrane Library and ClinicalTrial.gov for studies in English and the China National Knowledge Infrastructure, Wan Fang, and VIP Information/Chinese Scientific Journals Database for studies in Chinese). The primary outcome was efficacy, as measured by the change of PANSS total score. Pairwise comparisons were performed using random-effects model by the Dersimonian-Laird method and network meta-analyses were performed in a Bayesian set. RESULTS: Sixty high-quality RCTs with 6418 participants were included. A pattern of superiority from olanzapine, paliperidone and amisulpride was seen in the primary outcome. Only paliperidone was found better than aripiprazole (odds ratio, 0.49 [95% credible intervals, 0.25 to 0.99]), ziprasidone (0.42 [0.21 to 0.85]) and quetiapine (0.36 [0.13 to 0.93]) in terms of all-cause discontinuation. The best and worst drugs in terms of weight gain, EPS and somnolence were aripiprazole and olanzapine, clozapine and amisulpride, aripiprazole and clozapine, respectively. The rank of efficacy did not change substantially in sensitivity analyses or in meta-regressions. CONCLUSION: Our findings provided the hierarchies of eight antipsychotics in efficacy, acceptability and tolerability. These findings are expected to help Chinese clinicians to select the appropriate antipsychotic drug for their patients.

Stem-loop binding protein is a multifaceted cellular regulator of HIV-1 replication.

A rare subset of HIV-1-infected individuals is able to maintain plasma viral load (VL) at low levels without antiretroviral treatment. Identifying the mechanisms underlying this atypical response to infection may lead to therapeutic advances for treating HIV-1. Here, we developed a proteomic analysis to compare peripheral blood cell proteomes in 20 HIV-1-infected individuals who maintained either high or low VL with the aim of identifying host factors that impact HIV-1 replication. We determined that the levels of multiple histone proteins were markedly decreased in cohorts of individuals with high VL. This reduction was correlated with lower levels of stem-loop binding protein (SLBP), which is known to control histone metabolism. Depletion of cellular SLBP increased promoter engagement with the chromatin structures of the host gene high mobility group protein A1 (HMGA1) and viral long terminal repeat (LTR), which led to higher levels of HIV-1 genomic integration and proviral transcription. Further, we determined that TNF-α regulates expression of SLBP and observed that plasma TNF-α levels in HIV-1-infected individuals correlated directly with VL levels and inversely with cellular SLBP levels. Our findings identify SLBP as a potentially important cellular regulator of HIV-1, thereby establishing a link between histone metabolism, inflammation, and HIV-1 infection.

Paliperidone extended-release tablets in Chinese patients with schizophrenia: meta-analysis of randomized controlled trials.

BACKGROUND: Previous meta-analyses have compared paliperidone extended-release (ER) tablets with other antipsychotics, but none have involved Chinese patients or studies from People's Republic of China. Further, the results of these meta-analyses may not be applicable to Chinese patients. In the present study, we evaluated the efficacy, safety, and acceptability of paliperidone ER compared with other second-generation antipsychotics (SGAs) for Chinese patients with schizophrenia. METHODS: Randomized controlled studies of paliperidone ER and other SGAs as oral monotherapy in the acute phase treatment of schizophrenia were retrieved from Medline, Embase, and the Cochrane Library (CENTRAL), as well as from Chinese databases including the China National Knowledge Infrastructure, Wanfang, and VIP Information/Chinese Scientific Journals Database. We pooled data on response rates, chance of withdrawal due to adverse events, probability of adverse events, and odds of withdrawal for any reason. RESULTS: Fifty randomized controlled trials were identified. The response rate for paliperidone ER was significantly higher than that of other pooled SGAs (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.72-0.96) and ziprasidone (RR 0.57, 95% CI 0.39-0.82). Paliperidone ER significantly reduced the chance of withdrawal due to adverse events and the chance of any adverse events compared with other pooled SGAs (RR 0.32, 95% CI 0.17-0.58 and RR 0.88, 95% CI 0.79-0.97) and risperidone (RR 0.31, 95% CI 0.14-0.67 and RR 0.70, 95% CI 0.57-0.86). The incidence of extrapyramidal symptoms on paliperidone ER was comparable with other pooled SGAs (RR 0.94, 95% CI 0.66-1.35) and significantly lower than that of risperidone (RR 0.56, 0.41-0.77) but higher than that of olanzapine (RR 1.88, 95% CI 1.05-3.36). Paliperidone ER was superior to other pooled SGAs (RR 0.32, 95% CI 0.21-0.49 and RR 0.50, 95% CI 0.35-0.72) and olanzapine (RR 0.23, 95% CI 0.15-0.33 and RR 0.33, 95% CI 0.23-0.47) as far as weight gain and somnolence were concerned. Further, prolactin-related adverse events caused by paliperidone ER were comparable with other pooled SGAs (RR 1.30, 95% CI 0.73-2.33), but outnumbered those caused by olanzapine (RR 7.53, 95% CI 2.05-27.71). CONCLUSION: Paliperidone ER is efficacious, safe, and well accepted when compared with other pooled SGAs for the treatment of Chinese patients with schizophrenia.

ISL-1 is overexpressed in non-Hodgkin lymphoma and promotes lymphoma cell proliferation by forming a p-STAT3/p-c-Jun/ISL-1 complex.

BACKGROUND: Insulin enhancer binding protein-1 (ISL-1), a LIM-homeodomain transcription factor, is essential for the heart, motor neuron and pancreas development. Recently, ISL-1 has been found in some types of human cancers. However, how ISL-1 exerts the role in tumor development is not clear. METHODS AND RESULTS: The expression of ISL-1 was assessed in 211 human lymphoma samples and 23 normal lymph node samples. Immunohistochemistry results demonstrated a markedly higher expression of ISL-1 in 75% of non-Hodgkin lymphoma (NHL) samples compared with that in normal lymph nodes or Hodgkin lymphoma (HL) samples. CCK-8 analysis, cell cycle assay and xenograft model were performed to characterize the association between ISL-1 expression level and biological functions in NHL. The results showed that ISL-1 overexpression obviously promoted NHL cells proliferation, changed the cell cycle distribution in vitro and significantly enhanced xenografted lymphoma development in vivo. Real-time PCR, Western blot, luciferase assay and ChIP assay were used to explore the potential regulatory targets of ISL-1 and the results demonstrated that ISL-1 activated the c-Myc expression in NHL by direct binding to a conserved binding site on the c-Myc enhancer. Further results revealed that ISL-1 could be positively regulated by the c-Jun N-terminal kinase (JNK) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Both the JNK and JAK/STAT signaling inhibitors could significantly suppressed the growth of NHL cells through the down-regulation of ISL-1 as demonstrated by CCK-8 and Western blot assays. Bioinformatic analysis and luciferase assay exhibited that ISL-1 was a novel target of p-STAT3 and p-c-jun. ChIP, Co-IP and ChIP-re-IP analysis revealed that ISL-1 could participate with p-STAT3 and p-c-Jun to form a p-STAT3/p-c-Jun/ISL-1 transcriptional complex that binds directly on the ISL-1 promoter, demonstrating a positive feedback regulatory mechanism for ISL-1 expression in NHL. CONCLUSIONS: Our results provide the first evidence that ISL-1 is tightly linked to NHL proliferation and development by promoting c-Myc transcription, and its aberrant expression was regulated by p-STAT3/p-c-Jun/ISL-1 complex activation.

Wnt-promoted Isl1 expression through a novel TCF/LEF1 binding site and H3K9 acetylation in early stages of cardiomyocyte differentiation of P19CL6 cells.

Islet 1 (ISL1), a marker of second heart field progenitors, plays a crucial role in cardiomyocyte differentiation and proliferation. However, little is known about transcriptional regulating mechanisms on Isl1 gene expression. Recent studies have demonstrated that Wnt/ß-catenin signaling regulates Isl1 expression during heart development. However, the detailed mechanisms still remain unclear. In the present study performed during differentiation of P19CL6 into cardiomyocytes, we explored the underlying regulating mechanisms on Wnt/ß-catenin-mediated Isl1 expression after we first confirmed that Wnt/ß-catenin signaling promoted cardiomyocyte differentiation partly through Isl1 activation. We found a novel TCF/LEF1 binding site that was located 2300 bp upstream of the Isl1 ATG. Furthermore, Wnt/ß-catenin signaling upregulated histone H3K9 acetylation on TCF/LEF1 binding sites on the Isl1 promoter, resulting in upregulation of Isl1 expression. This Wnt-mediated H3K9 acetylation on the Isl1 promoter was modulated by the acetyltransferase CREB-binding protein (CBP), instead of p300, through interaction with ß-catenin. Collectively, these results suggest that in early stages of cardiomyocyte differentiation Wnt/ß-catenin signaling promotes Isl1 expression via two ways: a novel TCF/LEF1 binding site and H3K9 acetylation conducted by CBP on the Isl1 promoter. To our knowledge, this is the first study reporting Wnt/ß-catenin-regulated H3K9 acetylation on promoters of its target genes. And this study gives new insights into transcriptional regulating mechanisms of Wnt-mediated Isl1 expression during cardiomyocyte differentiation.

POU homeodomain protein OCT1 modulates islet 1 expression during cardiac differentiation of P19CL6 cells.

Islet 1 (ISL1), a marker of cardiac progenitors, plays a crucial role in cardiogenesis. However, the precise mechanism underlying the activation of its expression is not fully understood. Using the cardiac differentiation model of P19CL6 cells, we show that POU homeodomain protein, OCT1, modulates Isl1 expression in the process of cardiac differentiation. Oct1 knock-down resulted in reduction of Isl1 expression and downregulated mesodermal, cardiac-specific, and signal pathway gene expression. Additionally, the octamer motif located in the proximal region of Isl1 promoter is essential to Isl1 transcriptional activation. Mutation of this motif remarkably decreased Isl1 transcription. Although both OCT1 and OCT4 bound to this motif, it was OCT1 rather than OCT4 that modulated Isl1 expression. Furthermore, the correlation of OCT1 in regulation of Isl1 was revealed by in situ hybridization in early embryos. Collectively, our data highlight a novel role of OCT1 in the regulation of Isl1 expression.