Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells

Undifferentiated nasopharyngeal carcinomas (NPCs) are commonly present with latent EBV infection. However, events regulating EBV infection at early stages of the disease and the role of EBV in disease pathogenesis are largely undefined. Genetic alterations leading to activation of cyclin D1 signaling in premalignant nasopharyngeal epithelial (NPE) cells have been postulated to predispose cells to EBV infection. We previously reported that loss of p16, a negative regulator of cyclin D1 signaling, is a frequent feature of NPC tumors. Here, we report that early premalignant lesions of nasopharyngeal epithelium overexpress cyclin D1. Furthermore, overexpression of cyclin D1 is closely associated with EBV infection. Therefore we investigated the potential role of cyclin D1 overexpression in dysplastic NPE cells in vitro. In human telomerase reverse transcriptase-immortalized NPE cells, overexpression of cyclin D1 or a p16-resistant form of CDK4 (CDK4(R24C)) suppressed differentiation. This suppression may have implications for the close association of EBV infection with undifferentiated NPC. In these in vitro models, we found that cellular growth arrest and senescence occurred in EBV-infected cell populations immediately after infection. Nevertheless, overexpression of cyclin D1 or a p16-resistant form of CDK4 or knockdown of p16 in the human telomerase reverse transcriptase-immortalized NPE cell lines could counteract the EBV-induced growth arrest and senescence. We conclude that dysregulated expression of cyclin D1 in NPE cells may contribute to NPC pathogenesis by enabling persistent infection of EBV.published_or_final_versio

Enhanced IL-6/IL-6R Signaling Promotes Growth and Malignant Properties in EBV-Infected Premalignant and Cancerous Nasopharyngeal Epithelial Cells

Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells. © 2013 Zhang et al.published_or_final_versio

Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

Background: Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented.Methods: In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models.Results: Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R.Conclusions: Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC. © 2013 Tsang et al.; licensee BioMed Central Ltd

Coherent THz imaging using the self-mixing effect in quantum cascade lasers

We demonstrate that the self-mixing effect in THz QCLs can be used for three-dimensional coherent imaging; swept-frequency interferometry for imaging and materials analysis; and high-resolution inverse synthetic aperture radar imaging

A randomized, controlled clinical trial: the effect of mindfulness-based cognitive therapy on generalized anxiety disorder among Chinese community patients: protocol for a randomized trial

<b>Background</b> Research suggests that an eight-week Mindfulness-Based Cognitive Therapy (MBCT) program may be effective in the treatment of generalized anxiety disorders. Our objective is to compare the clinical effectiveness of the MBCT program with a psycho-education programme and usual care in reducing anxiety symptoms in people suffering from generalized anxiety disorder.<p></p> <b>Methods and Design</b> A three armed randomized, controlled clinical trial including 9-month post-treatment follow-up is proposed. Participants screened positive using the Structure Clinical Interview for DSM-IV (SCID) for general anxiety disorder will be recruited from community-based clinics. 228 participants will be randomly allocated to the MBCT program plus usual care, psycho-education program plus usual care or the usual care group. Validated Chinese version of instruments measuring anxiety and worry symptoms, depression, quality of life and health service utilization will be used. Our primary end point is the change of anxiety and worry score (Beck Anxiety Inventory and Penn State Worry Scale) from baseline to the end of intervention. For primary analyses, treatment outcomes will be assessed by ANCOVA, with change in anxiety score as the baseline variable, while the baseline anxiety score and other baseline characteristics that significantly differ between groups will serve as covariates.<p></p> <b>Discussion</b> This is a first randomized controlled trial that compare the effectiveness of MBCT with an active control, findings will advance current knowledge in the management of GAD and the way that group intervention can be delivered and inform future research

Genome-wide copy number variation study in anorectal malformations

Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2-5/10 000 live-births) and carry significant chronic morbidity. ARMs present either as isolated or as part of the phenotypic spectrum of some chromosomal abnormalities or monogenic syndromes. The etiology is unknown. To assess the genetic contribution to ARMs, we investigated single-nucleotide polymorphisms and copy number variations (CNVs) at genome-wide scale. A total of 363 Han Chinese sporadic ARM patients and 4006 Han Chinese controls were included. Overall, we detected a 1.3-fold significant excess of rare CNVs in patients. Stratification of patients by presence/absence of other congenital anomalies showed that while syndromic ARM patients carried significantly longer rare duplications than controls (P = 0.049), non-syndromic patients were enriched with both rare deletions and duplications when compared with controls (P = 0.00031). Twelve chromosomal aberrations and 114 rare CNVs were observed in patients but not in 868 controls nor 11 943 healthy individuals from the Database of Genomic Variants. Importantly, these aberrations were observed in isolated ARM patients. Gene-based analysis revealed 79 genes interfered by CNVs in patients only. In particular, we identified a de novo DKK4 duplication. DKK4 is a member of the WNT signaling pathway which is involved in the development of the anorectal region. In mice, Wnt disruption results in ARMs. Our data suggest a role for rare CNVs not only in syndromic but also in isolated ARM patients and provide a list of plausible candidate genes for the disorder.postprin

Deciphering the pathogenesis of tendinopathy: a three-stages process

Our understanding of the pathogenesis of "tendinopathy" is based on fragmented evidences like pieces of a jigsaw puzzle. We propose a "failed healing theory" to knit these fragments together, which can explain previous observations. We also propose that albeit "overuse injury" and other insidious "micro trauma" may well be primary triggers of the process, "tendinopathy" is not an "overuse injury" per se. The typical clinical, histological and biochemical presentation relates to a localized chronic pain condition which may lead to tendon rupture, the latter attributed to mechanical weakness. Characterization of pathological "tendinotic" tissues revealed coexistence of collagenolytic injuries and an active healing process, focal hypervascularity and tissue metaplasia. These observations suggest a failed healing process as response to a triggering injury. The pathogenesis of tendinopathy can be described as a three stage process: injury, failed healing and clinical presentation. It is likely that some of these "initial injuries" heal well and we speculate that predisposing intrinsic or extrinsic factors may be involved. The injury stage involves a progressive collagenolytic tendon injury. The failed healing stage mainly refers to prolonged activation and failed resolution of the normal healing process. Finally, the matrix disturbances, increased focal vascularity and abnormal cytokine profiles contribute to the clinical presentations of chronic tendon pain or rupture. With this integrative pathogenesis theory, we can relate the known manifestations of tendinopathy and point to the "missing links". This model may guide future research on tendinopathy, until we could ultimately decipher the complete pathogenesis process and provide better treatments

Network capitalism and the role of strategy, contracts and performance expectations for Asia-Pacific innovation partnerships

© Springer Nature Singapore Pte Ltd. 2018. With the growth of emerging economies in Asia-Pacific over the last three decades collaboration with the aim of innovation between firms within and with partners outside the region have developed substantially. Not always have such partnerships fulfilled their anticipated strategic objectives. The literature suggests that the nature of market arrangements and the role of government within that system play a role, but also innate contracting practices and governance of innovation partnerships are related. Yet, our understanding about the specific relationships between these factors and the emerging partnership innovation culture that facilitates joint business activities in an Asia-Pacific context remains vague. In this conceptual chapter we suggest how characteristics of so called network capitalism in conjunction with the nature of contractual agreements between partners, the alignment of their innovation objectives and the ambiguity inherent in their mutual contributions to the partnership can be interpreted as indicators of joint innovation culture. However, while innovation partnerships generally may result to be bureaucratic, market, clan, or adhocracy, we discuss how in an Asia Pacific context, innovation partnerships are limited by the extent of codification and diffusion of information and the social embeddedness of economic transactions

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders

BACKGROUND: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC). METHODS: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression. RESULTS: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain. CONCLUSIONS: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-015-0029-9) contains supplementary material, which is available to authorized users