Mohammed H. Al-Qahtani

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies

Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

The crossroads between cancer stem cells and aging

The cancer stem cell (CSC) hypothesis suggests that only a subpopulation of cells within a tumour is responsible for the initiation and progression of neoplasia. The original and best evidence for the existence of CSCs came from advances in the field of haematological malignancies. Thus far, putative CSCs have been isolated from various solid and non-solid tumours and shown to possess self-renewal, differentiation, and cancer regeneration properties. Although research in the field is progressing extremely fast, proof of concept for the CSC hypothesis is still lacking and key questions remain unanswered, e.g. the cell of origin for these cells. Nevertheless, it is undisputed that neoplastic transformation is associated with genetic and epigenetic alterations of normal cells, and a better understanding of these complex processes is of utmost importance for developing new anti-cancer therapies. In the present review, we discuss the CSC hypothesis with special emphasis on age-associated alterations that govern carcinogenesis, at least in some types of tumours. We present evidence from the scientific literature for age-related genetic and epigenetic alterations leading to cancer and discuss the main challenges in the field.

Specific nutrient combination effects on tax, NF- κB and MMP-9 in human T-cell lymphotropic virus -1 positive malignant T-lymphocytes

BackgroundAdult T-cell Leukemia (ATL) is a disease with no known cure. The disease manifests itself as an aggressive proliferation of CD4+ cells with the human T-cell Lymphotropic virus type 1 (HTLV-1). The leukemogenesis of the virus is mainly attributed to the viral oncoprotein. Tax activates the Nuclear Factor kappa B (NF-κB) which stimulates the activity and expression of the matrix metalloproteinase-9 (MMP-9). The objective of this study was to investigate the efficacy of a specific nutrient synergy (SNS) on proliferation, Tax expression, NF-κB levels as well as on MMP-9 activity and expression both at the transcriptional and translational levels in two HTLV-1 positive cell lines, HuT-102 and C91-PL at 48h and 96h of incubation. Cytotoxicity of Epigallocatechin-3-gallate (EGCG) was assayed using CytoTox 96 Non-radioactive and proliferation was measured using Cell Titer96TM Nonradioactive Cell Proliferation kit (MTT- based assay). Enzyme linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA) were used to assess the effect of SNS on NF-κB mobility. Zymography was used to determine the effects of SNS on the activity and secretion of MMP-9. The expression of MMP-9 was done using RT-PCR at the translational level and Immunoblotting at the transcriptional level.ResultsA significant inhibition of proliferation was seen in both cell lines starting at a concentration of 200μg/ml and in a dose dependent manner. SNS induced a dose dependent decrease in Tax expression, which was paralleled by a down-regulation of the nuclearization of NF-κB. This culminated in the inhibition of the activity of MMP-9 and their expression both at the transcriptional and translational levels.ConclusionsThe results of this study indicate that a specific nutrient synergy targeted multiple levels pertinent to the progression of ATL. Its activity was mediated through the NF-κB pathway, and hence has the potential to be integrated in the treatment of this disease as a natural potent anticancer agent.

Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis

Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte death/survival in the pathogenesis of OA. Identification of biomarkers of chondrocyte apoptosis may facilitate the development of novel therapies that may eliminate the cause or, at least, slow down the degenerative processes in OA. The aim of this review was to explore the molecular markers and signals that induce chondrocyte apoptosis in OA. A literature search was conducted in PubMed, Scopus, Web of Science and Google Scholar using the keywords chondrocyte death, apoptosis, osteoarthritis, autophagy and biomarker. Several molecules considered to be markers of chondrocyte apoptosis will be discussed in this brief review. Molecular markers and signalling pathways associated with chondroycte apoptosis may turn out to be therapeutic targets in OA and approaches aimed at neutralizing apoptosis-inducing molecules may at least delay the progression of cartilage degeneration in OA.

Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimers disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Nitric Oxide–Induced Regulatory T Cells Inhibit Th17 but Not Th1 Cell Differentiation and Function

NO is a free radical with pleiotropic functions. We have shown earlier that NO induces a population of CD4+CD25+Foxp3− regulatory T cells (NO-Tregs) that suppress the functions of CD4+CD25− effector T cells in vitro and in vivo. We report in this study an unexpected finding that NO-Tregs suppressed Th17 but not Th1 cell differentiation and function. In contrast, natural Tregs (nTregs), which suppressed Th1 cells, failed to suppress Th17 cells. Consistent with this observation, NO-Tregs inhibited the expression of retinoic acid–related orphan receptor γt but not T-bet, whereas nTregs suppressed T-bet but not retinoic acid–related orphan receptor γt expression. The NO-Treg–mediated suppression of Th17 was partially cell contact–dependent and was associated with IL-10. In vivo, adoptively transferred NO-Tregs potently attenuated experimental autoimmune encephalomyelitis. The disease suppression was accompanied by a reduction of Th17, but not Th1 cells in the draining lymph nodes, and a decrease in the production of IL-17, but an increase in IL-10 synthesis. Our results therefore demonstrate the differential suppressive function between NO-Tregs and nTregs and indicate specialization of the regulatory mechanism of the immune system.

Individualized medicine enabled by genomics in Saudi Arabia

The biomedical research sector in Saudi Arabia has recently received special attention from the government, which is currently supporting research aimed at improving the understanding and treatment of common diseases afflicting Saudi Arabian society. To build capacity for research and training, a number of centres of excellence were established in different areas of the country. Among these, is the Centre of Excellence in Genomic Medicine Research (CEGMR) at King Abdulaziz University, Jeddah, with its internationally ranked and highly productive team performing translational research in the area of individualized medicine. Here, we present a panorama of the recent trends in different areas of biomedical research in Saudi Arabia drawing from our vision of where genomics will have maximal impact in the Kingdom of Saudi Arabia. We describe advances in a number of research areas including; congenital malformations, infertility, consanguinity and pre-implantation genetic diagnosis, cancer and genomic classifications in Saudi Arabia, epigenetic explanations of idiopathic disease, and pharmacogenomics and personalized medicine. We conclude that CEGMR will continue to play a pivotal role in advances in the field of genomics and research in this area is facing a number of challenges including generating high quality control data from Saudi population and policies for using these data need to comply with the international set up.

BRAF mutations in thyroid tumors from an ethnically diverse group

BackgroundThe molecular etiology of thyroid carcinoma (TC) and other thyroid diseases which may present malignant precursor lesions is not fully explored yet. The purpose of this study was to estimate frequency, type and clinicopathological value of BRAF exon 15 mutations in different types of cancerous and non-cancerous thyroid lesions originating in an ethnically diverse population.MethodsBRAF exon 15 was sequenced in 381 cases of thyroid lesions including Hashimoto´s thyroiditis, nodular goiters, hyperplastic nodules, follicular adenomas (FA), papillary TC (PTC), follicular variant PTC (FVPTC), microcarcinomas of PTC (micro PTC; tumor size ≤ 1 cm), follicular TC (FTC), and non-well differentiated TC (non-WDTC).ResultsWe identified BRAF mutations in one of 69 FA, 72 of 115 (63%) PTC, seven of 42 (17%) FVPTC, 10 of 56 (18%) micro PTC, one of 17 (6%) FTC, and one of eight (13%) non-WDTC. Most of the cases showed the common V600E mutation. One case each of PTC, FVPTC, and FTC harbored a K601E mutation. A novel BRAF mutation was identified in a FA leading to deletion of threonine at codon 599 (p.T599del). A rare 3-base pair insertion was detected in a stage III PTC resulting in duplication of threonine at codon 599 (p.T599dup). Patients with PTC harboring no BRAF mutation (BRAFwt) were on average younger than those with a BRAF mutation (BRAFmut) in the PTC (36.6 years vs. 43.8 years). Older age (≥ 45 years) in patients with PTC was significantly associated with tumor size ≥ 4 cm (P = 0.018), vessel invasion (P = 0.004), and distant metastasis (P = 0.001). Lymph node (LN) involvement in PTC significantly correlated with tumor size (P = 0.044), and vessel invasion (P = 0.013). Of notice, taken the whole TC group, family history of thyroid disease positively correlated with capsular invasion (P = 0.025).ConclusionsOlder age is manifold associated with unfavorable tumor markers in our series. The K601E identified in a PTC, FVPTC, and FTC seems to be more distributed among different histological types of TC than previously thought. The T599del is a yet undescribed mutation and the rare T599dup has not been reported as a mutation in PTC so far.

A machine learning heuristic to identify biologically relevant and minimal biomarker panels from omics data

BackgroundInvestigations into novel biomarkers using omics techniques generate large amounts of data. Due to their size and numbers of attributes, these data are suitable for analysis with machine learning methods. A key component of typical machine learning pipelines for omics data is feature selection, which is used to reduce the raw high-dimensional data into a tractable number of features. Feature selection needs to balance the objective of using as few features as possible, while maintaining high predictive power. This balance is crucial when the goal of data analysis is the identification of highly accurate but small panels of biomarkers with potential clinical utility. In this paper we propose a heuristic for the selection of very small feature subsets, via an iterative feature elimination process that is guided by rule-based machine learning, called RGIFE (Rule-guided Iterative Feature Elimination). We use this heuristic to identify putative biomarkers of osteoarthritis (OA), articular cartilage degradation and synovial inflammation, using both proteomic and transcriptomic datasets.Results and discussionOur RGIFE heuristic increased the classification accuracies achieved for all datasets when no feature selection is used, and performed well in a comparison with other feature selection methods. Using this method the datasets were reduced to a smaller number of genes or proteins, including those known to be relevant to OA, cartilage degradation and joint inflammation. The results have shown the RGIFE feature reduction method to be suitable for analysing both proteomic and transcriptomics data. Methods that generate large ‘omics’ datasets are increasingly being used in the area of rheumatology.ConclusionsFeature reduction methods are advantageous for the analysis of omics data in the field of rheumatology, as the applications of such techniques are likely to result in improvements in diagnosis, treatment and drug discovery.

Role of miRNAs in human cancer metastasis: Implications for therapeutic intervention

Metastasis is the spread and growth of localized cancer to new locations in the body and is considered the main cause of cancer-related deaths. Metastatic cancer cells display distinct genomic and epigenomic profiles and almost universally an aggressive pathophysiology. A better understanding of the molecular mechanisms and regulation of metastasis, including how metastatic tumors grow and survive in the nascent niche and the interactions of the emergent metastatic cancer cells within the local microenvironment may provide tools to design strategies to restrict metastatic dissemination. Aberrant microRNAs (miRNA) expression has been reported in metastatic cancer cells. MicroRNAs are known to regulate divergent and/or convergent metastatic gene pathways including activation of reprogramming switches during metastasis. An in-depth understanding of role of miRNAs in the metastatic cascade may lead to the identification of novel targets for anti-metastatic therapeutics as well as potential candidate miRNAs for cancer treatment. This review primarily focuses on the role of miRNAs in the mechanisms of cancer metastasis as well as implications for metastatic cancer treatment.