scholarly journals The origins and functional effects of postzygotic mutations throughout the human lifespan

2021 ◽  
Author(s):  
Nicole Briana Rockweiler ◽  
Avinash Ramu ◽  
Liina Nagirnaja ◽  
Wing Hing Wong ◽  
Michiel J. Noordam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Phylogenetic Reconstruction ◽  
Tissue Expression ◽  
Prenatal Development ◽  
Tissue Samples ◽  
Human Lifespan ◽  
Specific Effects ◽  
Mutation Burden ◽  
Functional Consequences ◽  
Postzygotic Mutations

Postzygotic mutations (PZMs) begin to accrue in the human genome immediately after fertilization, but how and when PZMs affect development and lifetime health remains unclear. To study the origins and functional consequences of PZMs, we generated a multi-tissue atlas of PZMs from 948 donors using the final major release of the Genotype-Tissue Expression (GTEx) project. Nearly half the variation in mutation burden among tissue samples can be explained by measured technical and biological effects, while 9% can be attributed to donor-specific effects. Through phylogenetic reconstruction of PZMs, we find that their type and predicted functional impact varies during prenatal development, across tissues, and the germ cell lifecycle. Remarkably, a class of prenatal mutations was predicted to be more deleterious than any other category of genetic variation investigated and under positive selection as strong as somatic mutations in cancers. In total, the data indicate that PZMs can contribute to phenotypic variation throughout the human lifespan, and, to better understand the relationship between genotype and phenotype, we must broaden the long-held assumption of one genome per individual to multiple, dynamic genomes per individual.

scholarly journals A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden

2017 ◽  
Vol 242 (13) ◽  
pp. 1318-1324 ◽  
Author(s):  
Jan Vijg ◽  
Xiao Dong ◽  
Lei Zhang
Keyword(s):  
Single Cell ◽  
Somatic Mutations ◽  
Somatic Cells ◽  
Whole Genome ◽  
Tissue Samples ◽  
Amplification System ◽  
Functional Consequences ◽  
Postzygotic Mutations

Postzygotic mutations in somatic cells lead to genome mosaicism and can be the cause of cancer, possibly other human diseases and aging. Somatic mutations are difficult to detect in bulk tissue samples. Here, we review the available assays for measuring somatic mutations, with a focus on recent single-cell, whole genome sequencing methods. Impact statement Somatic mutations cause cancer, possibly other diseases and aging. Yet, very little is known about the frequency of such mutations in vivo, their distribution across the genome, and their possible functional consequences other than cancer. Even in cancer, we do not know the heterogeneity of mutations within a tumor and if seemingly normal cells in its surroundings already have elevated mutation frequencies. Here, we review a new, whole genome amplification system that allows accurate quantification and characterization of single-cell mutational landscapes in human cells and tissues in relation to disease.

scholarly journals Development and validation of an individualized immune prognostic model in stage I–III lung squamous cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi-Fan Yang ◽  
Di Wu ◽  
Jian Wang ◽  
Li Ba ◽  
Chen Tian ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Prognostic Model ◽  
Lung Squamous Cell Carcinoma ◽  
Risk Groups ◽  
Stage I ◽  
Tissue Samples ◽  
Mutation Burden

AbstractLung squamous cell carcinoma (LUSC) possesses a poor prognosis even for stages I–III resected patients. Reliable prognostic biomarkers that can stratify and predict clinical outcomes for stage I–III resected LUSC patients are urgently needed. Based on gene expression of LUSC tissue samples from five public datasets, consisting of 687 cases, we developed an immune-related prognostic model (IPM) according to immune genes from ImmPort database. Then, we comprehensively analyzed the immune microenvironment and mutation burden that are significantly associated with this model. According to the IPM, patients were stratified into high- and low-risk groups with markedly distinct survival benefits. We found that patients with high immune risk possessed a higher proportion of immunosuppressive cells such as macrophages M0, and presented higher expression of CD47, CD73, SIRPA, and TIM-3. Moreover, When further stratified based on the tumor mutation burden (TMB) and risk score, patients with high TMB and low immune risk had a remarkable prolonged overall survival compared to patients with low TMB and high immune risk. Finally, a nomogram combing the IPM with clinical factors was established to provide a more precise evaluation of prognosis. The proposed immune relevant model is a promising biomarker for predicting overall survival in stage I–III LUSC. Thus, it may shed light on identifying patient subset at high risk of adverse prognosis from an immunological perspective.

scholarly journals Comparison of cutting and coagulation properties of 1.56 and 1.94 µm fiber lasers and a 0.98 µm semiconductor laser

2022 ◽  
Vol 20 (4) ◽  
pp. 56-62
Author(s):  
M. A. Ryabova ◽  
M. Yu. Ulupov ◽  
N. A. Shumilova ◽  
G. V. Portnov ◽  
E. K. Tikhomirova ◽  
...  
Keyword(s):  
Semiconductor Laser ◽  
Fiber Lasers ◽  
Radiation Power ◽  
Biological Effects ◽  
Laser Wavelength ◽  
Ablation Zone ◽  
Tissue Samples ◽  
Zone Depth ◽  
Laser Incision ◽  
Coagulation Zone

Aim of the study was to compare the cutting and coagulation properties of 1.56 and 1.94 μm fiber lasers with those of a 0.98 μm semiconductor laser.Materials and methods. A comparative study of the biological effects of 1.56 and 1.94 µm lasers and a 0.98 µm semiconductor laser used in a constant, continuous mode was carried out. The cutting properties of the lasers were evaluated on the chicken muscle tissue samples by the width and depth of the ablation zone formed via a linear laser incision at a speed of 2 mm/s, while the coagulation properties were assessed by the width of the lateral coagulation zone. The zones were measured using a surgical microscope and a calibration slide. For statistical analysis, power values of 3, 5, 7, 9, and 11 W were chosen for each laser wavelength.Results. Analysis of the findings confirmed that laser wavelength had a statistically significant effect on the linear dependence between incision parameters and laser power. It was found that the 1.56 μm fiber laser (water absorption) had a greater coagulation ability but a comparable cutting ability compared with the 0.98 μm laser (hemoglobin absorption). When used in the power mode of 7W or higher, the 1.94 µm laser provided superior cutting performance compared with the 0.98 µm semiconductor laser at the same exposure power. Elevating the power in any of the lasers primarily increased the width of the ablation zone, and to a lesser extent – the crater depth and the width of the lateral coagulation zone. Therefore, in comparison with the 0.98 μm semiconductor laser, higher radiation power in the 1.56 and 1.94 μm lasers mainly influences their cutting properties, expanding the width and depth of the ablation zone, and has a smaller effect on their coagulation ability.Conclusion. The findings of the study showed that the 1.56 and 1.94 μm fiber lasers have better coagulation properties in comparison with the 0.98 μm semiconductor laser. was statistically proven that all incision characteristics (width of the lateral coagulation zone, depth and width of the ablation zone) for the 1.56, 1.94, and 0.98 μm lasers depend on the power of laser radiation. The 1.94 µm laser is superior to the 0.98 µm laser in its cutting properties. 

scholarly journals Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3680
Author(s):  
Marco Cesati ◽  
Francesca Scatozza ◽  
Daniela D’Arcangelo ◽  
Gian Carlo Antonini-Cappellini ◽  
Stefania Rossi ◽  
...  
Keyword(s):  
Single Molecule ◽  
Learning Algorithm ◽  
Profile Analysis ◽  
Pearson Correlation ◽  
Tissue Expression ◽  
Support Vector ◽  
Expression Data ◽  
Serum Samples ◽  
Tissue Samples ◽  
Mortality And Morbidity

The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma- and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker.

scholarly journals Molecular Targets of Genistein and Its Related Flavonoids to Exert Anticancer Effects

2019 ◽  
Vol 20 (10) ◽  
pp. 2420 ◽  
Author(s):  
Hee-Sung Chae ◽  
Rong Xu ◽  
Jae-Yeon Won ◽  
Young-Won Chin ◽  
Hyungshin Yim
Keyword(s):  
Biological Effects ◽  
Survival Rates ◽  
Mitogen Activated Protein Kinase ◽  
Anticancer Activities ◽  
Biological Targets ◽  
Cycle Arrest ◽  
Specific Effects ◽  
Anticancer Effects ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Increased health awareness among the public has highlighted the health benefits of dietary supplements including flavonoids. As flavonoids target several critical factors to exert a variety of biological effects, studies to identify their target-specific effects have been conducted. Herein, we discuss the basic structures of flavonoids and their anticancer activities in relation to the specific biological targets acted upon by these flavonoids. Flavonoids target several signaling pathways involved in apoptosis, cell cycle arrest, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT kinase, and metastasis. Polo-like kinase 1 (PLK1) has been recognized as a valuable target in cancer treatment due to the prognostic implication of PLK1 in cancer patients and its clinical relevance between the overexpression of PLK1 and the reduced survival rates of several carcinoma patients. Recent studies suggest that several flavonoids, including genistein directly inhibit PLK1 inhibitory activity. Later, we focus on the anticancer effects of genistein through inhibition of PLK1.

scholarly journals Mammaglobin-A, VEGFR3, and Ki67 in Human Breast Cancer Pathology and Five Year Survival

2019 ◽  
Vol 13 ◽  
pp. 117822341985895 ◽  
Author(s):  
Elizabeth Baker ◽  
Naomi Whiteoak ◽  
Louise Hall ◽  
James France ◽  
Deborah Wilson ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Breast Tumour ◽  
Tissue Expression ◽  
Tissue Samples ◽  
Ki67 Expression ◽  
Cancer Pathology ◽  
Kaplan Meier ◽  
Breast Cancer Pathology ◽  
Endothelial Growth Factor

Background/Methods: This study determines the co-expression of mammaglobin-A, vascular endothelial growth factor receptor-3 (VEGFR3) and Ki67 by immunohistochemistry (IHC) in tissue samples from 80 patients undergoing breast surgery (cancer or benign disease). The tissue expression was compared with the tumour histopathology and Kaplan Meier 5-year survival analysis was performed. Results: Positive breast tissue expression was observed in 53% samples for mammaglobin, 41% Ki67 and 65% VEGFR3 with a significant positive correlation between Ki67 and VEGFR3 co-expression. Ki67 and VEGFR3 expression correlated with the breast tumour grade and Ki67 expression also correlated with oestrogen receptor (ER) status. At 5 years post-operatively, 6/80 patients had died and 3 patients were alive but had cancer recurrence. High Ki67 expression significantly correlated with poor survival (disease-free and overall). Conclusions: In this study, VEGFR3 and Ki67 expression but not mammaglobin-A correlated with breast tumour pathology. Positive Ki67 expression was also associated with a poor 5-year survival outcome.

scholarly journals Major hyperghrelinemia in advanced well-differentiated neuroendocrine carcinomas: report of three cases

2009 ◽  
Vol 161 (4) ◽  
pp. 639-645 ◽  
Author(s):  
Thomas Walter ◽  
Laurence Chardon ◽  
Valérie Hervieu ◽  
Richard Cohen ◽  
Jean-Alain Chayvialle ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Tissue Expression ◽  
Primary Tumors ◽  
Disease Characteristics ◽  
Total Ghrelin ◽  
Functional Consequences ◽  
Acyl Ghrelin ◽  
Well Differentiated ◽  
Serum Ghrelin ◽  
Neuroendocrine Carcinomas

ObjectiveWe aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution.DesignWe retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin.MethodsBetween February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (n=72). Three patients were found to have circulating ghrelin levels >10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry.ResultsThe three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with <10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia.ConclusionWell-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.

RNA sequencing analysis for profiling activation of cancer-associated molecular pathways.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13032-e13032 ◽  
Author(s):  
Anton Buzdin ◽  
Andrew Garazha ◽  
Maxim Sorokin ◽  
Alex Glusker ◽  
Alexey Aleshin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Original Data ◽  
Tissue Expression ◽  
Molecular Pathways ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Sequencing Data ◽  
Healthy Human ◽  
Tissue Samples ◽  
Normal Tissues

e13032 Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is essential for understanding mechanisms of molecular pathogenesis in oncology. Profiling IMPs requires RNA-seq data for tumors and for a collection of reference normal tissues. However, there is a shortage now in such profiles for normal tissues from healthy human donors, uniformly profiled in a single series of experiments. Access to the largest dataset of normal profiles GTEx is only partly available through the dbGaP. In TCGA database, norms are adjacent to surgically removed tumors and may be affected by tumor-linked growth factors, inflammation and altered vascularization. ENCODE datasets were for the autopsies of normal tissues, but they can’t form statistically significant reference groups. Methods: Tissue samples representing 20 organs were taken from post-mortal human healthy donors killed in road accidents no later than 36 hours after death, blood samples were taken from healthy volunteers. Gene expression was profiled in RNA-seq experiments using the same reagents, equipment and protocols. Bioinformatic algorithms for IMP analysis were developed and validated using experimental and public gene expression datasets. Results: From original sequencing data we constructed the biggest fully open reference expression database of normal human tissues including 465 profiles termed Oncobox Atlas of Normal Tissue Expression (ANTE, original data: GSE120795). We next developed a method termed Oncobox for interrogating activation of IMPs in human cancers. It includes modules of expression data harmonization and comparison and an algorithm for automatic annotation of molecular pathways. The Oncobox system enables accurate scoring of thousands molecular pathways using RNA-seq data. Oncobox pathway analysis is also applicable for quantitative proteomics and microRNA data in oncology. Conclusions: The Oncobox system can be used for a plethora of applications in cancer research including finding differentially regulated genes and IMPs, and for discovery of new pathway-related diagnostic and prognostic biomarkers.

scholarly journals Identification of Somatic Mutations From Bulk and Single-Cell Sequencing Data

2022 ◽  
Vol 2 ◽  
Author(s):  
August Yue Huang ◽  
Eunjung Alice Lee
Keyword(s):  
Single Cell ◽  
Somatic Mutations ◽  
Sequencing Data ◽  
Tissue Samples ◽  
Genome Amplification ◽  
Bioinformatic Tools ◽  
Base Calling ◽  
Human Lifespan ◽  
Dna Variants ◽  
Underlying Mechanisms

Somatic mutations are DNA variants that occur after the fertilization of zygotes and accumulate during the developmental and aging processes in the human lifespan. Somatic mutations have long been known to cause cancer, and more recently have been implicated in a variety of non-cancer diseases. The patterns of somatic mutations, or mutational signatures, also shed light on the underlying mechanisms of the mutational process. Advances in next-generation sequencing over the decades have enabled genome-wide profiling of DNA variants in a high-throughput manner; however, unlike germline mutations, somatic mutations are carried only by a subset of the cell population. Thus, sensitive bioinformatic methods are required to distinguish mutant alleles from sequencing and base calling errors in bulk tissue samples. An alternative way to study somatic mutations, especially those present in an extremely small number of cells or even in a single cell, is to sequence single-cell genomes after whole-genome amplification (WGA); however, it is critical and technically challenging to exclude numerous technical artifacts arising during error-prone and uneven genome amplification in current WGA methods. To address these challenges, multiple bioinformatic tools have been developed. In this review, we summarize the latest progress in methods for identification of somatic mutations and the challenges that remain to be addressed in the future.

scholarly journals Down-regulation of LAMP3 inhibits the proliferation and migration of HSCC

2021 ◽  
Author(s):  
Xiaoxia Qiu ◽  
Juanjuan Li ◽  
Keke Yang ◽  
Song Jiang ◽  
Yong Yin ◽  
...  
Keyword(s):  
Biological Effects ◽  
Hypopharyngeal Cancer ◽  
Down Regulation ◽  
Tissue Samples ◽  
Protein Levels ◽  
Fadu Cells ◽  
And Migration ◽  
Proliferation Assays

Abstract BackgroundLysosomal-associated membrane glycoprotein 3 (LAMP3) has been shown to be highly expressed in various types of tumors. It is associated with their poor prognosis, proliferation, invasion, and metastasis, respectively. However, the role of LAMP3 in hypopharyngeal squamous cell carcinoma (HSCC) is unclear.ObjectiveThis article aims to investigate the role of LAMP3 in the proliferation and metastasis of HSCC.MethodDetection of the expression of LAMP3 in clinical HSCC and paired adjacent healthy tissue samples by using immunohistochemistry. Furthermore, LAMP3 was knocked out of the HSCC cell line, FaDu, using a lentivirus vector and the in vitro biological effects of LAMP3 knockdown in FaDu cells were studied.ResultsImmunohistochemistry results showed that LAMP3 was highly expressed in HSCC. Additionally, it was verified at the mRNA and protein levels that lentiviral transduction effectively down-regulated the expression of LAMP3 in FaDu cells. Cell colony formation assays and CCK8 proliferation assays showed that down-regulation of LAMP3 on FaDu cells inhibited cell proliferation and growth rate. Wound healing experiments and transwell experiments showed that significant down-regulation of LAMP3 on FaDu cells inhibited cell migration.ConclusionCollectively, our results suggest that LAMP3 is a useful therapeutic target for the treatment of hypopharyngeal cancer.

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