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OBJECTIVES: According to importance and increasing application of nanoparticles and their toxicity, the identification effects of nanoparticles on physiological systems are essential. Some studies show magnesium has analgesic effect in some pain models but this evaluation was not carried on nano-magnesium oxide (MgO). Thus, present study was designed to evaluation effect of Mgo nanoparticles alone and in combination with ketamine on two pain and inflammation model in mice. MATERIALS AND METHODS: At this study, adult male mice was used which had 29±3 gram weight. Formalin and acetic acid tests were carried. Acetic acid (1%) was intraperitoneally injected 0.3ml and the abdominal writhing was counted from 10 to 30 minutes after it. Formalin (2.5%) was injected 0.04 ml/mouse subcutaneously in plantar site of mice. The time of licking was cumulatively measured 0-5 (acute phase) and 15-25 (chronic phase) minutes later. Control (negative control), ketamine (0.1 mg/kg), MgO nanoparticles (5 and 10 mg/kg), conventional MgO (5 and 10 mg/kg) and ketamine with conventional and nanoparticles MgO groups were studied in both tests. RESULTS: Mean of writhing was significantly decreased by all drugs with comparison to control group (p = 0.0001). This decreasing was significant between conventional and nanoparticle MgO. The time of licking at both acute and chronic phases of formalin test was significantly decreased by all drugs with comparison to control group. However, this mean had significant difference with MgO nanoparticles. CONCLUSIONS: It seems that the nano-MgO induces analgesic and anti-inflammatory effects through central and peripheral mechanisms at experimental formalin and acetic acid testes and potentiates effect of ketamine. [ABSTRACT FROM AUTHOR]

The objective of this study in first stage studies the value relevance of earnings and book value, and in second stage study effect of Free Cash Flow agency problem on the value relevance of earnings and book value. The value relevance of earnings and book value are tested by Ohlson’s Price model (1995). To test Hypotheses of This study used a sample of 97 listed companies on Tehran Stock Exchange over a seven-year period (2004-2011). The results show that Book value per share for firms have Agency Problem and other firms are irrelevance value.Moreover result show that earning per share in presence or absent of agency problem of FCF is value relevance. The amount of value relevance of earning per share in firms with agency problems is lower. Thus FCF Agency problem have a negative effect on the value relevance of earnings.

Neuroblastoma is a paediatric malignancy of the sympathoadrenal or Schwann cells derived from the neural crest. Risk stratification in neuroblastoma is informed by MYCN amplification, age, stage, ploidy, and segmental chromosomal alterations. High-risk cases bear dismal overall survival. A panel of pathology and imaging modalities are utilised for diagnosis, while treatment strategies depend on the risk group. Despite this, relapse can occur in 50% of high-risk neuroblastoma patients in remission post-treatment. Liquid biopsies typically comprise the sampling of the peripheral blood and are attractive since they are less invasive than surgical tumour tissue biopsies. Liquid biopsies retrieve circulating tumour DNA and circulating tumour RNA released by tumours in addition to circulating tumour cells. These biological materials can be utilised to analyse tumour genetic alterations. Monitoring tumour-derived molecular information can assist diagnostics, targeted therapy selection, and treatment while reflecting minimal residual disease, relapse, and recurrence. This study aims to review the latest research on liquid biopsies for disease diagnosis, assessing treatment efficacy, minimal residual disease, relapse, and recurrence in neuroblastoma. A deeper understanding of the application of liquid biopsies could inform future prospective clinical trials, and in time, facilitate their routine implementation in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The nuclear pore complexes are essential for cellular and molecular processes such as trafficking between the cytoplasm and the nucleus, chromatin, transcriptional outputs, and DNA damage repair. Nucleoporins, components of nuclear pore complexes, have been linked to cancer through nucleo-cytoplasmic cargo trafficking, cell division, signalling pathways, chromatin-related processes, and protein stability and degradation. This study aims to understand how nucleoporins specifically contribute to cancer proliferation and progression across various cancer types. Accordingly, angles such as nuclear trafficking, fusion proteins, tumour suppressors, signalling pathways, tumour microenvironment, nucleosomes, and chromatin processes were found to bridge the function of nucleoporins and cancer progression, and the underlying mechanisms have been analysed in this study. A deep understanding of the function of nucleoporins in cancer progression will pave the way for the effective targeting of these molecules for therapeutic gain. Improved treatment responses can enhance the quality of life of cancer patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leila Jahangiri reports a relationship with Nottingham Trent University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paperThe author has no competing interests and is employed by Nottingham Trent University., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Moritella viscosa (M. viscosa) and sea lice (Lepeophtheirus salmonis) are severe pathogens that primarily infect the skin of Atlantic salmon (Salmo salar), which cause significant economic losses in the farming industry. However, the pathogenesis and molecular mechanisms underlying the host's immune defence at the post-transcriptional level remain unclear. Alternative splicing (AS) is an evolutionarily conserved post-transcriptional mechanism that can greatly increase the richness of the transcriptome and proteome. In this study, transcriptomic data derived from skin tissues of Atlantic salmon after M. viscosa and sea lice infections were used to examine the AS profiles and their differential expression patterns. In total, we identified 33,044 AS events (involving 13,718 genes) in the control (CON) group, 35,147 AS events (involving 14,340 genes) in the M. viscosa infection (MV) group, and 30,364 AS events (involving 13,142 genes) in the sea lice infection (LC) group, respectively. Among the five types of AS identified in our study (i.e., SE, A5SS, A3SS, MXE, and RI), SE was the most prevalent type in all three groups (i.e., CON, MV, and LC groups). Decreased percent-spliced-in (PSI) levels were observed in SE events under both MV- and LC-infected conditions, suggesting that MV or LC infection elevated exon-skipping isoforms and promoted the selection of shorter transcripts in numerous DAS genes. In addition, most of the differential AS genes were found to be associated with pathways related to mRNA regulation, epithelial or muscle development, and immune response. These findings provide novel insights into the role of AS in host-pathogen interactions and represent the first comparative analysis of AS in response to bacterial and parasitic infections in fish., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The E11 cell line, derived from striped snakehead fish (Channa striata), possesses a distinctive feature: it is persistently infected with a C-type retrovirus. Notably, it exhibits high permissiveness to piscine nodavirus and the emerging tilapia lake virus (TiLV). Despite its popularity in TiLV research, the absence of genome assembly for the E11 cell line and Channa striata has constrained research on host-virus interactions. This study aimed to fill this gap by sequencing, assembling, and annotating the E11 cell line genome. Our efforts yielded a 600.5 Mb genome including 24 chromosomes with a BUSCO score of 98.8%. In addition, the complete proviral DNA sequence of snakehead retrovirus (SnRV) was identified in the E11 cell genome. Comparative genomic analysis between the E11 cell line and another snakehead species Channa argus revealed the loss of many immune-related gene families in the E11 cell genome, indicating a compromised immune response. We also conducted transcriptome analysis of mock- and TiLV-infected E11 cells, unveiling new perspectives on virus-virus and host-virus interactions. The TiLV infection suppressed the high expression of SnRV in E11 cells, and activated some other endogenous retroviruses. The protein-coding gene comparison revealed a pronounced up-regulation of genes involved in immune response, alongside a down-regulation of genes associated with specific metabolic processes. In summary, the genome assembly and annotation of the E11 cell line provide valuable resources to understand the SnRV and facilitate further studies on nodavirus and TiLV. The RNA-seq profiles shed light on the cellular mechanisms employed by fish cells in response to viral challenges, potentially guiding the development of therapeutic strategies against TiLV in aquaculture. This study also provides the first insights into the viral transcriptome profiles of endogenous SnRV and evading TiLV, enhancing our understanding of host-virus interactions in fish., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Parkinson's disease is a neurodegenerative disease that results in patients exhibiting uncontrolled movements, changes in saliva production, and difficulty in swallowing and speech. Understanding the staging of the disease and the available therapies allows dentists to treat these patients safely and with compassion to meet their oral health care needs for an optimal quality of life. This appraisal discusses Parkinson's disease as it relates to clinically relevant facts to manage and treat the oral health care needs of these patients in the short and long term including general dental care recommendations. Important observations related to Parkinson's disease include disease causation,; stages, pharmacologic treatment, the effects on saliva, mastication, dysphagia, and aspiration pneumonia. Dental recommendations are made for the dentate, the partially edentulous, and the completely edentulous Parkinson's patients with a focus on late-stage concerns. Optimizing dental health will help maintain the quality of life as the disease progresses. In late stages of Parkinson's disease, dental treatment should focus on keeping the patient comfortable and out of pain.  While benign neglect is an often-used term, compassionate therapy in the late stages of Parkinson's disease is a more compelling term for defining the patient's needs.  Since dysphagia in Parkinson's patients has been underdiagnosed, neurologists must be aware of the important part that dentists play in the early diagnosis for these patients.  Early referral to a dentist is vital to mitigate the unfortunate consequence of the need for extensive dental care in late-stage patients., (© 2024 by the American College of Prosthodontists.)

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse., (© 2024. The Author(s).)

Neuroblastoma, a paediatric malignancy with high rates of cancer-related morbidity and mortality, is of significant interest to the field of paediatric cancers. High-risk NB tumours are usually metastatic and result in survival rates of less than 50%. Machine learning approaches have been applied to various neuroblastoma patient data to retrieve relevant clinical and biological information and develop predictive models. Given this background, this study will catalogue and summarise the literature that has used machine learning and statistical methods to analyse data such as multi-omics, histological sections, and medical images to make clinical predictions. Furthermore, the question will be turned on its head, and the use of machine learning to accurately stratify NB patients by risk groups and to predict outcomes, including survival and treatment response, will be summarised. Overall, this study aims to catalogue and summarise the important work conducted to date on the subject of expression-based predictor models and machine learning in neuroblastoma for risk stratification and patient outcomes including survival, and treatment response which may assist and direct future diagnostic and therapeutic efforts.

Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression and patient prognosis. This study aimed to dissect the ways in which neuroblastoma biology, treatment, prognosis, progression, and relapse are linked with the extracellular matrix, the dichotomous identities of neuroblastoma, various regulatory proteins and RNA, and extracellular vesicles within the backdrop of the tumour microenvironment. In addition, other aspects, such as immune cell infiltration, therapeutic options including monoclonal antibodies and small molecule inhibitors; and the ways in which these may affect disease progression and immunosuppression within the context of the neuroblastoma tumour microenvironment, are addressed. Such studies may shed light on useful therapeutic targets within the tumour microenvironment that may benefit groups of NB patients. Ultimately, a detailed understanding of these aspects will enable the neuroblastoma scientific community to improve treatment options, patient outcomes, and quality of life.

Background: Febrile convulsion (FC) is the most common and preventable seizure in children. This study aimed to assess the effectiveness of the diazepam and phenobarbital for preventing recurrent FC., Materials and Methods: In this systematic review study, literature published in English language were carefully searched in biological databases (Cochrane Library, Medline, Scopus, CINHAL, Psycoinfo, and Proquest) by February 2020.Randomized clinical trials (RCTs) and Quasi randomized trial were included in the review. Two researchers checked the literature independently. The quality of studies was assessed using the JADAD score. The potential risk for publication bias was assessed by Funnel plot and Egger's test. Meta regression test and sensitivity analysis were used to identify the reasons for heterogeneity. Given the results of assessing heterogeneity, the random effect model in RevMan5.1 software was used for meta analysis., Results: Four out of 17 studies had compared the effect of diazepam and phenobarbital in preventing recurrent FC. The result of the meta analysis showed that the use of diazepam in comparison with phenobarbital reduces the risk of recurrence FC by 34% (risk ratio = 0.66, 95% confidence interval [CI] = [0.36-1.21]), but the relationship was not statistically significant. In assessing the effect of diazepam or phenobarbital versus placebo, the results showed that the use of diazepam and phenobarbital has reduced the risk of recurrent FC by 49% (risk ratio = 0.51, 95% CI = [0.32-0.79]) and 37% (risk ratio = 0.63, 95% CI = [0.42-0.96)]), respectively, and these relationships were statistically significant ( P < 0.05). Results of the meta regression test showed that the follow up time can be a reason for the heterogeneity between trials with the comparison of diazepam versus phenobarbital ( r = 0.047, P = 0.049) and Phenobarbital versus placebo ( r = 0.022, P = 0.016). According to the results of Funnel plot and Egger's test, there was evidence of publication bias ( P = 0.0584 for comparison of diazepam vs. phenobarbital; P = 0.0421 for comparison of diazepam vs. placebo; P = 0.0402 for comparison of phenobarbital vs. placebo)., Conclusion: The results of this meta analysis indicated that preventive anticonvulsants can be useful in preventing recurrent convulsions in cases of febrile seizures., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Research in Medical Sciences.)

Neuroblastoma is a paediatric malignancy originating from the neural crest that commonly occurs in the abdomen and adrenal gland, leading to cancer-related deaths in children. Distant metastasis can be encountered at diagnosis in greater than half of these neuroblastoma patients. Autophagy, a self-degradative process, plays a key role in stress-related responses and the survival of cells and has been studied in neuroblastoma. Accordingly, in the early stages of metastasis, autophagy may suppress cancer cell invasion and migration, while its role may be reversed in later stages, and it may facilitate metastasis by enhancing cancer cell survival. To that end, a body of literature has revealed the mechanistic link between autophagy and metastasis in neuroblastoma in multiple steps of the metastatic cascade, including cancer cell invasion and migration, anoikis resistance, cancer cell dormancy, micrometastasis, and metastatic outbreak. This review aims to take a step forward and discuss the significance of multiple molecular players and compounds that may link autophagy to metastasis and map their function to various metastatic steps in neuroblastoma.

Neuroblastoma is an extracranial solid tumour of the developing sympathetic nervous system accounting for circa 15% of deaths due to cancer in paediatric patients. The clinical course of this cancer may be variable, ranging from aggressive progression to regression, while the amplification of MYCN in this cancer is linked to poor patient prognosis. Extracellular vesicles are a double membrane encapsulating various cellular components including proteins and nucleic acids and comprise exosomes, apoptotic bodies, and microvesicles. The former can act as mediators between cancer, stromal and immune cells and thereby influence the tumour microenvironment by the delivery of their molecular cargo. In this study, the contribution of extracellular vesicles including exosomes to the biology, prognosis, diagnosis and treatment of neuroblastoma was catalogued, summarised and discussed. The understanding of these processes may facilitate the in-depth dissection of the complexity of neuroblastoma biology, mechanisms of regression or progression, and potential diagnostic and treatment options for this paediatric cancer which will ultimately improve the quality of life of neuroblastoma patients.

Background: The prevalence of childhood obesity has increased worldwide and has reached alarming proportions. Contradictive results from studies and reviews have fuelled an endless debate on the role of SSBs in the development of childhood obesity., Objective: This study aimed to assess the impact of sugar-sweetened beverages (SSBs) intake on body mass index (BMI), body fat percentage (BFP), and waist circumference (WC) among children., Methods: Databases including PubMed/MEDLINE, Scopus, Cochrane Library, EMBASE, and Web of Science were searched up to August 2021. Observational studies reporting the relation between SSBs intake and BMI, BFP, and WC were included. STATA version 15 was used to analyse the data., Results: In this meta-analysis, 33 studies with 121 282 subjects were included. Excessive SSBs intake was associated with 0.75 kg/m 2 increase in BMI in children and adolescents (WMD: 0.75; CI 0.35-1.15; p < 0.001). In addition, high SSBs intake was significantly associated with higher WC (WMD: 2.35 cm; 95% CI, 1.34, 3.37; p = 0.016) and BFP (WMD: 2.81; CI 2.21-3.41; p < 0.001). No departure from linearity was detected in dose-response meta-analysis between SSBs consumption and changes in BMI, WC, and BFP., Conclusion: High SSBs consumption was associated with increased BMI, WC, and BFP among children and adolescents. Further large prospective long-term interventions are recommended to confirm the observed relationships., (© 2022 World Obesity Federation.)

Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their "awakening" is still controversial. This review will focus on cancer cells' microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response.

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.

Aim: Neuroblastoma is a heterogeneous childhood cancer derived from the neural crest. The dual cell identities of neuroblastoma include Mesenchymal (MES) and Adrenergic (ADRN). These identities are conferred by a small set of tightly-regulated transcription factors (TFs) binding super enhancers, collectively forming core regulatory circuitries (CRCs). The purpose of this study was to gain a deep understanding of the role of MES and ADRN TFs in neuroblastoma and other cancers as potential indicators of disease prognosis, progression, and relapse., Methods: To that end, we first investigated the expression and mutational profile of MES and ADRN TFs in neuroblastoma. Moreover, we established their correlation with neuroblastoma risk groups and overall survival while establishing their extended networks with long non-coding RNAs (lncRNAs). Furthermore, we analysed the pan-cancer expression and mutational profile of these TFs and their correlation with patient survival and finally their network connectivity, using a panel of bioinformatic tools including GEPIA2, human pathology atlas, TIMER2, Omicsnet, and Cytoscape., Results: We show the association of multiple MES and ADRN TFs with neuroblastoma risk groups and overall survival and find significantly higher expression of various MES and ADRN TFs compared to normal tissues and their association with overall survival and disease-free survival in multiple cancers. Moreover, we report the strong correlation of the expression of these TFs with the infiltration of stromal and immune cells in the tumour microenvironment and with stemness and metastasis-related genes. Furthermore, we reveal extended pan-cancer networks comprising these TFs that influence the tumour microenvironment and metastasis and may be useful indicators of cancer prognosis and patient survival., Conclusion: Our meta-analysis shows the significance of MES and ADRN TFs as indicators of patient prognosis and the putative utility of these TFs as potential novel biomarkers., (© 2021. The Author(s).)

MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

Burkitt lymphoma (BL) accounts for almost two-thirds of all B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents and is characterised by a MYC translocation and rapid cell turnover. Intensive chemotherapeutic regimens have been developed in recent decades, including the lymphomes malins B (LMB) protocol, which have resulted in a survival rate in excess of 90%. Recent clinical trials have focused on immunochemotherapy, with the addition of rituximab to chemotherapeutic backbones, showing encouraging results. Despite these advances, relapse and refractory disease occurs in up to 10% of patients and salvage options for these carry a dismal prognosis. Efforts to better understand the molecular and functional characteristics driving relapse and refractory disease may help improve this prognosis. This study has established a paediatric BL patient-derived xenograft (PDX) resource which captures and maintains tumour heterogeneity, may be used to better characterise tumours and identify cell populations responsible for therapy resistance., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The purpose of this article is to detail the primary challenges faced by large dental institutions as they incorporate digital dentistry into their mainstream workflow. Integration of digital technology is easier in private practices with smaller patient volumes and fewer trained staff required. Additionally, in private practices, scanning, designing and milling frequently occur in a single location, which does not require an external digital data transfer. However, large dental institutions must overcome several barriers which are uniquely generated by their large-scale operation. Numerous individuals must be comprehensively and efficiently trained to operate the advanced technologies. The digital software must seamlessly integrate with existing software and an internal infrastructure must be established capable of handling massive data inputs. High-volume production in large dental institutions requires the involvement of external laboratories to meet demand. This outsourcing presents a new challenge of safe digital data transfer in accordance with patient privacy and protection regulations set forth by governing agencies. It is vital for large dental institutions to recognise the unique challenges thrust upon them as they attempt to incorporate a digital workflow. With proper forethought and planning an appropriate infrastructure may be established allowing for a smooth and safe transition to the digital era.

Gene expression programmes driving cell identity are established by tightly regulated transcription factors that auto- and cross-regulate in a feed-forward manner, forming core regulatory circuitries (CRCs). CRC transcription factors create and engage super-enhancers by recruiting acetylation writers depositing permissive H3K27ac chromatin marks. These super-enhancers are largely associated with BET proteins, including BRD4, that influence higher-order chromatin structure. The orchestration of these events triggers accessibility of RNA polymerase machinery and the imposition of lineage-specific gene expression. In cancers, CRCs drive cell identity by superimposing developmental programmes on a background of genetic alterations. Further, the establishment and maintenance of oncogenic states are reliant on CRCs that drive factors involved in tumour development. Hence, the molecular dissection of CRC components driving cell identity and cancer state can contribute to elucidating mechanisms of diversion from pre-determined developmental programmes and highlight cancer dependencies. These insights can provide valuable opportunities for identifying and re-purposing drug targets. In this article, we review the current understanding of CRCs across solid and liquid malignancies and avenues of investigation for drug development efforts. We also review techniques used to understand CRCs and elaborate the indication of discussed CRC transcription factors in the wider context of cancer CRC models.

Background: The importance of teaching the skills and practice of evidence-based medicine (EBM) for medical professionals has steadily grown in recent years. Alongside this growth is a need to evaluate the effectiveness of EBM curriculum as assessed by competency in the five 'A's': asking, acquiring, appraising, applying and assessing (impact and performance). EBM educators in medical education will benefit from a compendium of existing assessment tools for assessing EBM competencies in their settings. The purpose of this review is to provide a systematic review and taxonomy of validated tools that evaluate EBM teaching in medical education., Methods: We searched MEDLINE, EMBASE, Cochrane library, Educational Resources Information Centre (ERIC), Best Evidence Medical Education (BEME) databases and references of retrieved articles published between January 2005 and March 2019. We have presented the identified tools along with their psychometric properties including validity, reliability and relevance to the five domains of EBM practice and dimensions of EBM learning. We also assessed the quality of the tools to identify high quality tools as those supported by established interrater reliability (if applicable), objective (non-self-reported) outcome measures and achieved ≥ 3 types of established validity evidence. We have reported our study in accordance with the PRISMA guidelines., Results: We identified 1719 potentially relevant articles of which 63 full text articles were assessed for eligibility against inclusion and exclusion criteria. Twelve articles each with a unique and newly identified tool were included in the final analysis. Of the twelve tools, all of them assessed the third step of EBM practice (appraise) and four assessed just that one step. None of the twelve tools assessed the last step of EBM practice (assess). Of the seven domains of EBM learning, ten tools assessed knowledge gain, nine assessed skills and-one assessed attitude. None addressed reaction to EBM teaching, self-efficacy, behaviours or patient benefit. Of the twelve tools identified, six were high quality. We have also provided a taxonomy of tools using the CREATE framework, for EBM teachers in medical education., Conclusions: Six tools of reasonable validity are available for evaluating most steps of EBM and some domains of EBM learning. Further development and validation of tools that evaluate all the steps in EBM and all educational outcome domains are needed., Systematic Review Registration: PROSPERO CRD42018116203.

Background: MYCN amplification (MNA) is the strongest indicator of poor prognosis in neuroblastoma (NB). This meta-analysis aims to determine the diagnostic accuracy of MNA analysis in circulating-free DNA (cfDNA) from advanced-stage NB patients., Methods: A systematic review of electronic databases was conducted to identify studies exploring the detection of MNA in plasma/serum cfDNA from NB patients at diagnosis using PCR methodology. Pooled estimates for sensitivity, specificity and diagnostic odds ratio (DOR) were calculated by conducting a bivariate/HSROC random-effects meta-analysis., Results: Seven studies, with a total of 529 advanced-stage patients, were eligible. The pooled sensitivity of cfDNA-based MNA analysis was 0.908 (95% CI, 0.818-0.956), the pooled specificity was 0.976 (0.940-0.991) and the DOR was 410.0 (-103.6 to 923.7). Sub-grouped by INSS stage, the sensitivity for stage 3 and 4 patients was 0.832 (0.677-0.921) and 0.930 (0.834-0.972), respectively. The specificity was 0.999 (0.109-1.000) and 0.974 (0.937-0.990), respectively, and the DOR was 7855.2 (-66267.0 to 81977.4) and 508.7 (-85.8 to 1103.2), respectively., Conclusions: MNA analysis in cfDNA using PCR methodology represents a non-invasive approach to rapidly and accurately determine MNA status in patients with advanced-stage NB. Standardised methodology must be developed before this diagnostic test can enter the clinic.

The clinician's selection of an implant system is influenced by many variables. Ideally, the decision should be based on scientific evidence, but often these decisions are based on economic considerations or influenced by the experience of a trusted peer. The purpose of this paper is to describe the influence of implant neck features (shape and surface) and abutment connection (diameter that matches or is smaller than the implant's platform) on hard and soft tissues around single-tooth implants placed into healed ridges with adequate hard and soft tissue thickness. In an effort to reduce the number of variables, only two-piece implants fully placed at bone level or beneath were taken into consideration. The goal is to provide additional guidance for clinicians on the decision-making and implant-selection processes.

Somatic alterations to the genomes of solid tumours, which in some cases represent actionable drivers, provide diagnostic and prognostic insight into these complex diseases. Spatial and longitudinal tracking of somatic genomic alterations (SGAs) in patient tumours has emerged as a new avenue of investigation, not only as a disease monitoring strategy, but also to improve our understanding of heterogeneity and clonal evolution from diagnosis through disease progression. Furthermore, analysis of circulating-free DNA (cfDNA) in the so-called "liquid biopsy" has emerged as a non-invasive method to identify genomic information to inform targeted therapy and may also capture the heterogeneity of the primary and metastatic tumours. Considering the potential of cfDNA analysis as a translational laboratory tool in clinical practice, establishing the extent to which cfDNA represents the SGAs of tumours, particularly actionable driver alterations, becomes a matter of importance, warranting standardisation of methods and practices. Here, we assess the utilisation of cfDNA for molecular profiling of SGAs in tumour tissue across a broad range of solid tumours. Moreover, we examine the underlying factors contributing to discordance of detected SGAs between cfDNA and tumour tissue.

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

The oral rehabilitation of adolescent patients with amelogenesis imperfecta (AI) is complex due to the presence of mixed dentition with altered eruption sequence. In this article, the interdisciplinary treatment approach for adolescent patients with AI is discussed. The types and timing of treatments at various stages of growth are described through a literature review on this topic. AI is an inherited condition that disturbs the development of the enamel structure. Because of the presence of mixed dentition, definitive treatment options often have to be delayed until eruption of permanent dentition is complete, requiring careful treatment coordination and proper sequencing between different dental disciplines starting at a young age. Adolescent patients require prosthodontic treatment design that can be adapted to the changes in arch shapes, sizes, interarch relationship, and esthetic needs. AI patients are often challenged with both excessive and limited restorative spaces within the same arch due to the abnormal growth patterns, enamel structure, tooth size, and tooth shape. Therefore, careful determination of the required restorative space is critical to ensure optimal prognosis. This clinical report discusses treatment recommendations, timing of various treatment modalities, and involvement of appropriate interdisciplinary teams for managing adolescent patients., (© 2019 by the American College of Prosthodontists.)

Aim: The aim of this study is to assess the influence of e-learning on dental education as perceived by predoctoral dental students., Materials and Methods: In an institutional review board (IRB) approved protocol, a 14-question survey was created and electronically distributed to second-, third-, and fourth-year dental students. The participation was considered voluntary and all responses were anonymous., Results: The survey targeted 1,130 predoctoral students, of which 255 (22.6%) responded. Of the respondents, 124 students (48.6%) preferred traditional lecture mixed with online learning, while 46 students (18%) preferred only the traditional lecture style. The top three electronic resources/applications, which students perceived as having the greatest impact on their learning, were: YouTube, Bone Box, and Google. The responses also indicated that 76.5% of the students gave high credibility (scores of 4 and 5) to electronic resources recommended by faculties. Sixty percent of students spent 1 to more than 4 hours per day on electronic resources for academic performance. The most important factor for online applications influencing academic performance was "organization and logic of content" (54%). E-learning had a significant perceived effect (scores of 4/5) on didactic understanding (65.1%) and on clinical understanding (71.4%). Students observed that faculties estimated to be under 50 years of age were more likely to incorporate e-learning into courses (52.6%) and more likely to use social media for communication (41.6%)., Conclusion: The results indicate that e-learning may successfully be used in a dental school's curriculum to enhance students' perceptions of fundamental concepts and to enable students to apply this knowledge to clinical cases., Clinical Significance: E-learning has recently been proposed as a basic supplementary tool to enhance medical and dental education. It is crucial to determine dental students' preferences regarding social media, online applications, and databases in order to incorporate e-learning into dental school courses.