WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.

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The functional role of long non-coding RNA in human carcinomas

Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.

Non-small-cell lung cancers: a heterogeneous set of diseases

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have become a major focus of current cancer research, in part because of their enhanced ability to initiate and drive tumour growth and their intrinsic resistance to conventional therapeutics. The discovery that activation of the epithelial-to-mesenchymal transition (EMT) programme in carcinoma cells can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presents a possible avenue for their therapeutic manipulation. Here we address recent developments in CSC research, focusing on carcinomas that are able to undergo EMT. We discuss the signalling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for selective elimination or induction of their differentiation, and the role of the tumour microenvironment in sustaining them. Finally, we propose ways to use our current knowledge of the complex biology of CSCs to design novel therapies to eliminate them.

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Tackling the cancer stem cells — what challenges do they pose?

Nucleic acid sequencing technologies have advanced significantly in recent years, allowing the development of liquid biopsies as new means to detect cancer biomarkers and cancer heterogenicity. Most of the assays available clinically focus on cell free DNA, however, cell free RNA (cfRNA) is also present and has the potential to complement and improve cancer detection especially in cancers like lung cancer, which are usually only diagnosed at late stages and therefore have poor long-term survival outcomes. Remnant EDTA plasma was collected from lung cancer patients and non-cancer individuals at the University of Maryland Medical Center. RNA was extracted and processed for next generation sequencing with a tagmentation-based library preparation approach. cfRNA was successfully extracted and sequenced from 52 EDTA-treated plasma samples with volumes as low as 1.5 mL. This quantity was sufficient to prepare libraries with the length of libraries averaging from 264bp to 381bp and resulted in over 2.2 to 3.6 million total sequence reads respectively. Sequential dilution of cfRNA samples from healthy individuals indicated that the starting cfRNA concentration influenced the detection of differentially expressed genes. This proof-of-concept study provides a framework for screening cfRNA for identifying biomarkers for early detection of lung cancer (and other cancers), using minimal amounts of samples (1.5 ml) from standard EDTA 3-mL collection tubes routinely used for patient care. Further studies in large populations are required to establish limit of detection and other parameters including precision, accuracy, sensitivity, and specificity, to standardize this method.

Proof of Concept: detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients

Abstract: Lung cancers are the leading cause of cancer-related deaths worldwide. Studies have shown that non-small cell lung cancer (NSCLC) which constitute majority of lung cancers, are significantly more re-sponsive to early-stage interventions. However, the early stages are often asymptomatic, and current diag-nostic methods are limited in their precision and safety. The cell-free RNAs (cfRNA) circulating in plasma (Liquid biopsies) offer non-invasive detection of spatial and temporal changes occurring in primary tumors since early stages. To address gaps in current cfRNA knowledge base, we conducted a pilot study for com-prehensive analysis of transcriptome-wide changes in plasma cfRNA in NSCLC patients. Total cfRNA was extracted from archived plasma collected from NSCLC patients (N=12; cases), cancer-free former smokers (N=12; control_smokers) and non-smoking healthy volunteers (N=12; control_healthy). Plasma cfRNA ex-pression levels in each sample were quantified by using a tagmentation-based library preparation and se-quencing. The comparisons of cfRNA expression levels between cases and the two control groups revealed a total of 2537 differentially expressed cfRNA enriched in 123 pathways in NSCLC patients. Of these, 222 tran-scripts were previously reported in primary NSCLCs. Our study provides a framework for developing a blood-based assay for early detection of NSCLC and warrants further validation.

/pdf/a-pilot-analysis-of-circulating-cfrna-transcripts-for-the-2d9q6frv.pdf

A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer

Diagnosis and classification of aggressive mature B-cell lymphoma with atypical morphology remains a challenge. To identify factors that may contribute to the atypical morphology, we selected eight such cases and evaluated their morphologic, immunophenotypic and cytogenetic features and clinical outcomes. The neoplastic cells showed a diffuse monotonous infiltrating pattern with a spectrum of morphology including: 1) L1 lymphoblastic; 2) centroblastic; 3) immunoblastic; and 4) mixed centroblastic and immunoblastic. The lymphoma cells in most cases were positive for CD10 and/or BCL6, and showed BCL2 expression. 6 of 8 cases showed C- MYC rearrangements, and interestingly, all 6 cases demonstrated a proliferation index of <90%. 3 of the 6 cases also demonstrated t(14;18). Clinical follow-up indicated that aggressive mature B-cell lymphoma may benefit from more intensified chemotherapeutic regimens used for BL. Our study suggests that aggressive mature B-cell lymphoma with atypical morphology may be another "grey zone lymphoma" lying in the spectrum between Burkitt lymphoma and diffuse large B-cell lymphoma.

Original Article C-MYC Rearrangements are Frequent in Aggressive Mature B-Cell Lymphoma with Atypical Morphology

Abstract Lung cancers are the leading cause of cancer-related deaths worldwide. Studies have shown that non-small cell lung cancer (NSCLC) which constitutes majority of lung cancers, are significantly more responsive to early-stage interventions. However, the early stages are often asymptomatic, and current diagnostic methods are limited in their precision and safety. The cell-free RNAs (cfRNA) circulating in plasma (Liquid biopsies) offer non-invasive detection of spatial and temporal changes occurring in primary tumors since early stages. To address gaps in current cfRNA knowledgebase, we conducted a pilot study for comprehensive analysis of transcriptome-wide changes in plasma cfRNA in NSCLC patients. Total cfRNA was extracted from archived plasma collected from NSCLC patients (N=12), cancer-free former smokers (N=12) and non-smoking healthy volunteers (N=12). Plasma cfRNA expression levels were quantified by using a tagmentation-based library preparation and sequencing. The comparisons of cfRNA expression levels between patients and the two control groups revealed a total of 2357 differentially expressed cfRNA enriched in 123 pathways. Of these, 251 transcripts were previously reported in primary NSCLCs. A small subset of genes (N=5) was validated in an independent sample (N=50) using qRT-PCR. Our study provides a framework for developing blood-based assays for early detection of NSCLC and warrants further validation. 

A pilot analysis of circulating cfRNA transcripts for the detection of lung cancer

Non-small cell lung cancer (NSCLC) is a major contributor to cancer-related deaths, but early detection can reduce mortality. NSCLC comprises mainly adenocarcinoma (AC) and squamous cell carcinoma (SCC). Circulating microRNAs (miRNAs) in plasma have emerged as promising biomarkers for NSCLC. However, existing techniques for analyzing miRNAs have limitations, such as restricted target detection and time-consuming procedures. The MiSeqDx System has been shown to overcome these limitations, making it a promising tool for routine clinical settings. We investigated whether the MiSeqDx could profile cell-free circulating miRNAs in plasma and diagnose NSCLC. We sequenced RNA from the plasma of patients with AC and SCC and from cancer-free smokers using the MiSeqDx to profile and compare miRNA expressions. The MiSeqDx exhibits high speed and accuracy when globally analyzing plasma miRNAs. The entire workflow, encompassing RNA to data analysis, was completed in under three days. We also identified panels of plasma miRNA biomarkers that can diagnose NSCLC with 67% sensitivity and 68% specificity, and detect SCC with 90% sensitivity and 94% specificity, respectively. This study is the first to demonstrate that rapid profiling of plasma miRNAs using the MiSeqDx has the potential to offer a straightforward and effective method for the early detection and classification of NSCLC.

/pdf/utilizing-miseq-sequencing-to-detect-circulating-micrornas-2cbdl0tw.pdf

Sanford A. Stass

Papers

Proof of Concept: detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients

A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer

Original Article C-MYC Rearrangements are Frequent in Aggressive Mature B-Cell Lymphoma with Atypical Morphology

A pilot analysis of circulating cfRNA transcripts for the detection of lung cancer

Utilizing MiSeq Sequencing to Detect Circulating microRNAs in Plasma for Improved Lung Cancer Diagnosis