Evolution of Molecular Biology and Cancer: Crucial Turning Points and Startling Discoveries in a Continual Battle

Cancer is the leading cause of morbidity and mortality worldwide. Comprehensive understanding of the evolution of molecular cell biology and cancer, and their crucial turning points in a chronological order, is of enormous importance for researchers, physicians, medical students, & other health professionals. This would allow better recognition of what we currently do have and what we have to do next to beat cancer. It is also central to realize that, while the field of molecular cell biology of cancer strived to bare the etiology of cancer or to produce a cure, it had immensely increased the understanding of the molecular biology of mammalian cells. We thus also discuss in this article how the study of cancer cells helped us to develop many of the molecular techniques used nowadays in our laboratories and clinics. Despite the surplus capacity of our cells in accommodating defects, cancer has frighteningly become a disease of the genome, and genomics is thus now considered a “dissecting” tool and a major part of cancer care. Looking to the future, there is a need to generate “individual” comprehensive genomic-based signatures, and develop better information systems for collection and integration of multiple data to improve our understanding of malignancy processes and tackle the increasing complexity (intra-/inter-individual heterogeneity) of cancer patients. This would be another turning point in the history of cancer research, and inevitably pave the way for a successful translation into clinical application in precision cancer medicine

Targeted enrichment of genomic DNA regions for next-generation sequencing

In this review, we discuss the latest targeted enrichment methods and aspects of their utilization along with second-generation sequencing for complex genome analysis. In doing so, we provide an overview of issues involved in detecting genetic variation, for which targeted enrichment has become a powerful tool. We explain how targeted enrichment for next-generation sequencing has made great progress in terms of methodology, ease of use and applicability, but emphasize the remaining challenges such as the lack of even coverage across targeted regions. Costs are also considered versus the alternative of whole-genome sequencing which is becoming ever more affordable. We conclude that targeted enrichment is likely to be the most economical option for many years to come in a range of settings

Antifungal activity of silver nanoparticles green biosynthesis from the extract of Zygophyllum album (L.f.) on Fusarium wilt

This study illustrates the antifungal activity of green biosynthesis of a silver nanoparticle solution using one of Sinai’s natural plant extracts, namely Zygophyllum album which was used as a stabilizer and reducing agent to reduce Ag+ to metallic silver. In this study the plant extract was prepared by boiling in water for 10 min., 70% ethanol and wet autoclaving for 5 min. AgNPs were prepared using these three different extract methods. Transmission electron microscope (TEM) and zeta potential techniques were employed to characterize the synthesis of nanoparticles. The size of particles ranged from 6.28 nm to 28.89 nm at x100 and the zeta potential had one peak at –16.6 mean (mV) at area 100% for green synthesized AgNPs from Z. album prepared from boiling in water for 10 min. The size of particles ranged from 6.64 nm to 54.82nm at 100x and the zeta potential had one peak at – 12.9 mean (mV) at 100% area for green synthesized AgNPs from the plant ethanol extract. The size of particles ranged from 9.39 nm to 31.93 nm at 100x and the zeta potential had one peak – 19.8 mean (mV) at 100% area for green synthesized AgNPs from the wet autoclaved plant extract of Z. album for 5 min. All treatments of plant extract and AgNPs solutions, prepared from these plant extracts of Zygophyllum album, were compared with the positive control and Tachigaren – 30% W/P was conducted on the radial growth of F. oxysporium and caused antifungal activity with a high inhibition percent. There was a highly significant difference between the various extraction techniques. Increasing the concentration of treatments was accompanied with a significant effect on Fusarium wilt. Thus, this study may provide a good alternative approach to control Fusarium wilt disease in the field and under storage conditions of vegetables. Our study suggests that silver nanoparticles of plant extracts can be used for controlling Fusarium wilt

Visual histological assessment of morphological features reflects the underlying molecular profile in invasive breast cancer: a morphomolecular study

© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd Aims: Tumour genotype and phenotype are related and can predict outcome. In this study, we hypothesised that the visual assessment of breast cancer (BC) morphological features can provide valuable insight into underlying molecular profiles. Methods and results: The Cancer Genome Atlas (TCGA) BC cohort was used (n=743) and morphological features, including Nottingham grade and its components and nucleolar prominence, were assessed utilising whole-slide images (WSIs). Two independent scores were assigned, and discordant cases were utilised to represent cases with intermediate morphological features. Differentially expressed genes (DEGs) were identified for each feature, compared among concordant/discordant cases and tested for specific pathways. Concordant grading was observed in 467 of 743 (63%) of cases. Among concordant case groups, eight common DEGs (UGT8, DDC, RGR, RLBP1, SPRR1B, CXorf49B, PSAPL1 and SPRR2G) were associated with overall tumour grade and its components. These genes are related mainly to cellular proliferation, differentiation and metabolism. The number of DEGs in cases with discordant grading was larger than those identified in concordant cases. The largest number of DEGs was observed in discordant grade 1:3 cases (n=1185). DEGs were identified for each discordant component. Some DEGs were uniquely associated with well-defined specific morphological features, whereas expression/co-expression of other genes was identified across multiple features and underlined intermediate morphological features. Conclusion: Morphological features are probably related to distinct underlying molecular profiles that drive both morphology and behaviour. This study provides further evidence to support the use of image-based analysis of WSIs, including artificial intelligence algorithms, to predict tumour molecular profiles and outcome

Nucleolar protein 10 (NOP10) predicts poor prognosis in invasive breast cancer

PurposeNucleolar protein 10 (NOP10) is required for ribosome biogenesis and telomere maintenance and plays a key role in carcinogenesis. This study aims to evaluate the clinical and prognostic significance of NOP10 in breast cancer (BC).MethodsNOP10 expression was assessed at mRNA level employing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1980) and Cancer Genome Atlas (TCGA) BC cohorts (n = 854). Protein expression was evaluated on tissue microarray of a large BC cohort (n = 1081) using immunohistochemistry. The correlation between NOP10 expression, clinicopathological parameters and patient outcome was assessed.ResultsNOP10 expression was detected in the nucleus and nucleolus of the tumour cells. At the transcriptomic and proteomic levels, NOP10 was significantly associated with aggressive BC features including high tumour grade, high nucleolar score and poor Nottingham Prognostic Index. High NOP10 protein expression was an independent predictor of poor outcome in the whole cohort and in triple-negative BC (TNBC) class (p = 0.002 & p = 0.014, respectively). In chemotherapy- treated patients, high NOP10 protein expression was significantly associated with shorter survival (p = 0.03) and was predictive of higher risk of death (p = 0.028) and development of distant metastasis (p = 0.02) independent of tumour size, nodal stage and tumour grade.ConclusionHigh NOP10 expression is a poor prognostic biomarker in BC and its expression can help in predicting chemotherapy resistance. Functional assessments are necessary to decipher the underlying mechanisms and to reveal its potential therapeutic values in various BC subtypes especially in the aggressive TNBC class

Prognostic Significance of Nucleolar Assessment in Invasive Breast Cancer

Aims: Nucleolar morphometric features have a potential role in the assessment of aggressiveness of many cancers. However, the role of nucleoli in invasive breast cancer (IBC) is still unclear. This study aimed to investigate the optimal scoring method of nucleoli in IBC and their prognostic significance, and refine the grading of BC by incorporating the nucleolar score.Methods and results: Digital images acquired from hematoxylin and eosin (H&E) stained sections from a large IBC cohort were divided into training (n=400) and validation (n=1200) sets were used in this study. Four different assessment methods including 1) modified Helpap’s method, and counting prominent nucleoli (size ≥2.5μm) in 2) 10 field views (10 FVs), 3) 5 FVs and 4) 1 FV were evaluated in the training set to identify the optimal method associated with the best performance and significant prognostic value. The optimal method was applied to the validation set and to an external validation set the Cancer Genome Atlas (TCGA) data (n=743). Scoring prominent nucleoli in 5 FVs, showed the highest inter-observer concordance rate (intraclass correlation coefficient = 0.8) and significant association with breast cancer specific survival (BCSS) (

Mechanistic and Clinical Evidence Supports a Key Role for Cell Division Cycle Associated 5 (CDCA5) as an Independent Predictor of Outcome in Invasive Breast Cancer

Background: Cell Division Cycle Associated 5 (CDCA5) plays a role in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signalling pathway involving cell division, cancer cell migration and apoptosis. This study aims to assess the prognostic and biological value of CDCA5 in breast cancer (BC). Methods: The biological and prognostic value of CDCA5 were evaluated at mRNA (n = 5109) and protein levels (n = 614) utilizing multiple well-characterized early stage BC cohorts. The effects of CDCA5 knockdown (KD) on multiple oncogenic assays were assessed in vitro using a panel of BC cell lines. Results: this study examined cohorts showed that high CDCA5 expression was correlated with features characteristic of aggressive behavior and poor prognosis, including the presence of high grade, large tumor size, lymphovascular invasion (LVI), hormone receptor negativity and HER2 positivity. High CDCA5 expression, at both mRNA and protein levels, was associated with shorter BC-specific survival independent of other variables (p = 0.034, Hazard ratio (HR) = 1.6, 95% CI; 1.1–2.3). In line with the clinical data, in vitro models indicated that CDCA5 depletion results in a marked decrease in BC cell invasion and migration abilities and a significant accumulation of the BC cells in the G2/M-phase. Conclusions: These results provide evidence that CDCA5 plays an important role in BC development and metastasis and could be used as a potential biomarker to predict disease progression in BC

The nucleolar related protein Dyskerin pseudouridine 1 synthase 1 (DKC1) predicts poor prognosis in breast cancer

BackgroundHypertrophy of the nucleolus is a distinctive cytological feature of malignant cells and corresponds to aggressive behaviour. This study aimed to identify the key gene associated with nucleolar prominence (NP) in breast cancer (BC) and determine its prognostic significance.MethodsFrom The Cancer Genome Atlas (TCGA) cohort, digital whole slide images identified cancers having NP served as label and an information theory algorithm was applied to find which mRNA gene best explained NP. Dyskerin Pseudouridine Synthase 1 (DKC1) was identified. DKC1 expression was assessed using mRNA data of Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1980) and TCGA (n = 855). DKC1 protein expression was assessed using immunohistochemistry in Nottingham BC cohort (n = 943).ResultsNuclear and nucleolar expressions of DKC1 protein were significantly associated with higher tumour grade (p [less than] 0.0001), high nucleolar score (p [less than] 0.001) and poor Nottingham Prognostic Index (p [less than] 0.0001). High DKC1 expression was associated with shorter BC-specific survival (BCSS). In multivariate analysis, DKC1 mRNA and protein expressions were independent risk factors for BCSS (p [less than] 0.01).ConclusionDKC1 expression is strongly correlated with NP and its overexpression in BC is associated with unfavourable clinicopathological characteristics and poor outcome. This has been a detailed example in the correlation of phenotype with genotype

Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans

BACKGROUND: In eukaryotes mRNA transcripts of protein-coding genes in which an intron has been retained in the coding region normally result in premature stop codons and are therefore degraded through the nonsense-mediated mRNA decay (NMD) pathway. There is evidence in the form of selective pressure for in-frame stop codons in introns and a depletion of length three introns that this is an important and conserved quality-control mechanism. Yet recent reports have revealed that the efficiency of NMD varies across tissues and between individuals, with important clinical consequences. PRINCIPAL FINDINGS: Using previously published Affymetrix exon microarray data from cell lines genotyped as part of the International HapMap project, we investigated whether there are heritable, inter-individual differences in the abundance of intron-containing transcripts, potentially reflecting differences in the efficiency of NMD. We identified intronic probesets using EST data and report evidence of heritability in the extent of intron expression in 56 HapMap trios. We also used a genome-wide association approach to identify genetic markers associated with intron expression. Among the top candidates was a SNP in the DCP1A gene, which forms part of the decapping complex, involved in NMD. CONCLUSIONS: While we caution that some of the apparent inter-individual difference in intron expression may be attributable to different handling or treatments of cell lines, we hypothesize that there is significant polymorphism in the process of NMD, resulting in heritable differences in the abundance of intronic mRNA. Part of this phenotype is likely to be due to a polymorphism in a decapping enzyme on human chromosome 3