The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition.

For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs).  Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development

Phosphatidylserine targeting for diagnosis and treatment of human diseases

Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface

Prognostic value of microRNAs in head and neck cancers: a systematic review and meta-analysis protocol

Abstract Background Head and neck cancers form a significant share of all cancer incidences worldwide. Though treatment modalities exist, post-treatment recurrence and survival rates in recurrent patients continue to be high. MiRNAs offer an effective method of estimating the probability of recurrence and survival of HNC patients, thereby allowing for effective treatment and better survival rates. Methods The systematic review protocol was prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) 2015 statement. Relevant studies will be identified by a rigorous search of multiple bibliographical databases, including MEDLINE, Scopus, PubMed, Web of Science, Embase and Science Direct, without any language restrictions (up to June 2018). The primary screening will be performed by a review team via analysis of titles and abstracts of published articles. Final selection of articles will be achieved by two independent reviewers, based on predefined selection criteria. Data will be extracted from eligible studies using a pre-piloted data extraction form. Statistical analysis will be performed on the basis of available data, extracted from eligible studies. Meta-analysis will be performed, and a forest plot will be generated, to determine pooled hazard ratios (HR) and 95% confidence interval (CI) using CMA. A fixed or random-effects model of meta-analysis will be used depending upon the between-study heterogeneity; publication bias will be determined by the Egger’s bias indicator test. A narrative synthesis will be undertaken where statistical data is found to be insufficient. Discussion There is a lack of highly sensitive and specific biomarkers for estimating the HNC patients’ prognostic outcomes, particularly in post-treatment conditions. This systematic review will identify and validate specific miRNA as prognostic biomarkers by utilising a collection of previously published data on miRNA expression and survival. Highlighting these prognostic specific miRNAs will have major clinical implications by allowing for better overall treatment strategies and patient survival estimates, by offering clinicians a method of quantitatively analysing prognosis via miRNA expression. Systematic review registration This review protocol was registered on PROSPERO and assigned the registration number CRD42017077411

Letter to the editor: is HIF-1α a viable prognostic indicator in OSCC? A critical review of a meta-analysis study

Abstract The study performed by Zhou et al. (World J Surg Oncol 15:104, 2017) titled “Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis” attempts to highlight hypoxia-inducible factor-1 alpha as a possible prognostic marker in oral squamous cell carcinoma (OSCC). We would like to underline a few points which may affect such a conclusion. The correlations between HIF-1α expression and tumour size as well as tumour stage are debatable. Further, the subgroup analysis incorporating Australia and Europe into a single subgroup limits the viability of the prognostic analysis of HIF-1α. We also suggest future studies in the same research area to analyse head and neck squamous cell carcinoma instead of OSCC, to ameliorate the limitations encountered by Zhou et al., due to the scarcity of relevant clinical data and a low number of studies about OSCC

Systematic review and meta-analysis of prognostic microRNA biomarkers for survival outcome in nasopharyngeal carcinoma.

BACKGROUND:Nasopharyngeal cancer (NPC), despite being one of the most malignant head and neck carcinomas (HNC), lacks comprehensive prognostic biomarkers that predict patient survival. Therefore, this systematic review and meta-analysis is aimed to evaluate the potential prognostic value of miRNAs as prognostic biomarkers in NPC. METHODS:PRISMA guidelines were used to conduct this systematic review and meta-analysis study. Permutations of multiple "search key-words" were used for the search strategy, which was limited to articles published between January 2012 and March 2018. The retrieved articles were meticulously searched with multi-level screening by two reviewers and confirmed by other reviewers. Meta-analysis was performed using Hazard Ratios (HR) and associated 95% Confidence Interval (CI) of survival obtained from previously published studies. Publication bias was assessed by Egger's bias indicator test and funnel plot symmetry. RESULTS:A total of 5069 patients across 21 studies were considered eligible for inclusion in the systematic review, with 65 miRNAs being evaluated in the subsequent meta-analysis. Most articles included in this study originated from China and one study from North Africa. The forest plot was generated using cumulated survival data, resulting in a pooled HR value of 1.196 (95% CI: 0.893-1.601) indicating that the upregulated miRNAs increased the likelihood of death of NPC patients by 19%. CONCLUSION:To our knowledge, this is the first meta-analysis that examines the prognostic effectiveness of miRNAs as biomarkers in NPC patients. We noted that the combined effect estimate of HR across multiple studies indicated that increased miRNA expression in NPC potentially leads to poor overall survival. However, further large-scale prospective studies on the clinical significance of the miRNAs, with sizable cohorts are necessary in order to obtain conclusive results

Downregulation of Notch4 – a prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma

Introduction: Oral verrucous carcinoma is a special form of well-differentiated squamous cell carcinoma which possesses specific clinical, morphologic and cytokinetic features that differ from other types of oral cancers and hence diagnosis requires immense experience in histopathology. Hence it is certainly important to distinguish such a lesion from other oral tumors as treatment strategies vary widely between them. Objective: In search of a critical diagnostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma, Notch4 receptor, one of the key regulatory molecules of the Notch signaling family has been aberrantly activated in the progression of several types of tumors. However its function in oral verrucous carcinoma remains unexplored. Thus the present study aims in determining the differential expression pattern of Notch4 in oral verrucous carcinoma and oral squamous cell carcinoma. Methods: Ten patients reported positive for oral cancer (5 patients with oral verrucous carcinoma and 5 patients with oral squamous cell carcinoma). Five normal tissue samples were also obtained and evaluated for clinicopathological parameters and immunohistochemistry, western blotting and real time polymerase chain reaction for Notch4 expression. Results: Our results reveal that the expression of Notch4 was considerably high in oral squamous cell carcinoma lesions compared to normal tissue, whereas in oral verrucous carcinoma, irrespective of the clinicopathological features, complete regulação descendente of Notch4 was observed. Conclusions: These preliminary findings strongly support the fact that Notch4 is downregulated in oral verrucous carcinoma and could be considered as a suitable prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. This distinguishing marker can help in improving therapeutic options in patients diagnosed with oral verrucous carcinoma. Resumo: Introdução: O carcinoma verrucoso de cavidade oral é uma forma especial de carcinoma de células escamosas bem diferenciada que tem características clínicas, morfológicas e citocinéticas específicas que diferem de outros tipos de cânceres orais. Por essa razão, o diagnóstico requer grande experiência em histopatologia. Portanto, é certamente importante distingui-lo de outros tumores orais, pois as respectivas estratégias de tratamento variam muito. Objetivo: Em busca de um marcador de diagnóstico crítico na distinção entre o carcinoma verrucoso e o carcinoma de células escamosas de cavidade oral, o receptor Notch4, uma das principais moléculas reguladoras da família de sinalizadores Notch, foi ativado de maneira anormal na progressão de vários tipos de tumores. No entanto, sua função no carcinoma verrucoso permanece inexplorada. Assim, o presente estudo tem como objetivo determinar o padrão de expressão diferencial de Notch4 no carcinoma verrucoso e de células escamosas de cavidade oral. Método: Dez pacientes tiveram resultado positivo para câncer oral (cinco pacientes com carcinoma verrucoso e cinco pacientes com carcinoma de células escamosas) e cinco amostras normais foram também obtidas. Além da avaliação dos parâmetros clínico-patológicos, foram feitos análise imuno-histoquímica, Western Blot e reação de polimerase em cadeia em tempo real para a expressão de Notch4. Resultados: Nossos resultados revelam que a expressão de Notch4 foi consideravelmente alta em carcinomas de células escamosas em comparação com os tecidos normais, enquanto que no carcinoma verrucoso, independentemente das características clínico-patológicas, observou-se regulação descendente completa de Notch4. Conclusão: Esses achados preliminares apoiam fortemente o fato de que Notch4 estava regulado para baixo no carcinoma verrucoso oral e poderia ser considerado um marcador prognóstico adequado para distinguir entre carcinoma verrucoso e carcinoma de células escamosas de cavidade oral. Esse marcador distintivo pode ajudar a melhorar as opções terapêuticas em pacientes com diagnóstico de carcinoma verrucoso oral. Keywords: Oral verrucous carcinoma, Oral squamous cell carcinoma, Notch4, Prognostic marker, Palavras-chave: Carcinoma verrucoso oral, Carcinoma de células escamosas oral, Notch4, Marcador prognóstic

Exosome DNA: An untold story of cancer

Abstract Exosome is nanosized tiny membrane‐bound vesicles and is a subpopulation of extracellular vesicles (EVs). In general, it participates in intercellular communication and acts as a messenger of several pathological complications. Exosome and cancer interlink is the most exciting domain of current cancer research. The internal molecular cargos (proteins, lipids, metabolites, miRNA, and DNA) of tumor derived exosomes (TEXs) are capable of transforming normal cells into tumor phenotypes. Exosome DNA is the less explored area of EVs research. It is involved in several events in cancer progression such as uncontrol cell growth, reprogramming of immune cells, metastasis, and therapeutic resistance. Exo‐DNA is also involved in epigenetic alteration, which promotes cancer. It has a great impact on cancer theranostics (biomarker and therapeutics) research. Exo‐DNA‐based cancer examination supports more detailed cancer research

Detection of embryonic stem cell markers in adult human adipose tissue-derived stem cells

Background: Bone marrow transplantation is already an established therapy, which is now widely used in medicine to treat leukemia, lymphoma, and several inherited blood disorders. The culture of multilineage cells from easily available adipose tissue is another source of multipotent mesenchymal stem cells, and is referred to as adipose tissue-derived stem cells (ADSCs). While ADSCs are being used to treat various conditions, some lacuna exists regarding the specific proteins in these. It was therefore decided to analyze the specific proteins of embryonic cells in ADSCs. Aims: To analyze the specific protein of embryonic stem cells (ESCs) in ADSCs. Materials and Methods: Adult human adipose tissue-derived stem cells (ADSCs) were harvested from 13 patients after obtaining patients′ consent. The specific markers of ESCs included surface proteins CD10, CD13, CD44, CD59, CD105, and CD166, and further nucleostemin,(NS) NANOG, peroxisome proliferator-activated receptor-gγ, collagen type 1 (Coll1), alkaline phosphate, (ALP) osteocalcin (OC), and core binding factor 1 (Cbfa1) were analyzed using by reverse transcription-polymerase chain reaction, (RT-PCR) immunofluorescence (IF), and western blot. Results: All the proteins were expressed distinctly, except CD13 and OC. CD13 was found individually with different expressions, and OC expression was discernable. Conclusions: Although the ESC with its proven self-renewal capacity and pluripotency seems appropriate for clinical use, the recent work on ADSCs suggests that these adult stem cells would be a valuable source for future biotechnology, especially since there is a relative ease of procurement

Exosome: A megastar of future cancer personalized and precision medicine

Abstract Extracellular vesicles (EVs) are an innovative orientation of next‐generation cancer medicine. In EVs, the exosome is the most exciting domain associated with cancer research current decade.Exosomes have both cancer progression related and cancer healing capabilities depending on the source. It develops a new platform for cancer personalized and precision medicine visionary project to come to reality