Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed ‘Aging Cascade’

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann–Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories ‘regulome’, ‘inflammaging’, ‘regeneration’, and ‘pharmacogenes’. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed ‘aging cascade’, wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.

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Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma

Cells ◽

10.3390/cells10020416 ◽

2021 ◽

Vol 10 (2) ◽

pp. 416

Author(s):

Lorena Landuzzi ◽

Maria Cristina Manara ◽

Pier-Luigi Lollini ◽

Katia Scotlandi

Keyword(s):

Clinical Trials ◽

Tumor Heterogeneity ◽

Functional Studies ◽

Ngs Data Analysis ◽

The Many ◽

Orthotopic Xenografts ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing ◽

Somatic Copy Number Alterations

Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone. It is characterized by a complex genotype, mainly due to the high frequency of chromothripsis, which leads to multiple somatic copy number alterations and structural rearrangements. Any effort to design genome-driven therapies must therefore consider such high inter- and intra-tumor heterogeneity. Therefore, many laboratories and international networks are developing and sharing OS patient-derived xenografts (OS PDX) to broaden the availability of models that reproduce OS complex clinical heterogeneity. OS PDXs, and new cell lines derived from PDXs, faithfully preserve tumor heterogeneity, genetic, and epigenetic features and are thus valuable tools for predicting drug responses. Here, we review recent achievements concerning OS PDXs, summarizing the methods used to obtain ectopic and orthotopic xenografts and to fully characterize these models. The availability of OS PDXs across the many international PDX platforms and their possible use in PDX clinical trials are also described. We recommend the coupling of next-generation sequencing (NGS) data analysis with functional studies in OS PDXs, as well as the setup of OS PDX clinical trials and co-clinical trials, to enhance the predictive power of experimental evidence and to accelerate the clinical translation of effective genome-guided therapies for this aggressive disease.

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Fighting Oxidative Stress with Sulfur: Hydrogen Sulfide in the Renal and Cardiovascular Systems

Antioxidants ◽

10.3390/antiox10030373 ◽

2021 ◽

Vol 10 (3) ◽

pp. 373

Author(s):

Joshua J. Scammahorn ◽

Isabel T. N. Nguyen ◽

Eelke M. Bos ◽

Harry Van Goor ◽

Jaap A. Joles

Keyword(s):

Oxidative Stress ◽

Hydrogen Sulfide ◽

Redox Status ◽

The Body ◽

Therapeutic Interventions ◽

Oxygen Species ◽

Enzymatic Production ◽

Age Related ◽

Anti Oxidant ◽

Enzymatic Pathways

Hydrogen sulfide (H2S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, H2S plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). H2S also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NFκB, and HIF-1α, thereby promoting anti-oxidant mechanisms. Depletion of H2S is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for H2S-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond H2S use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, H2S is a prime subject for further research with potential for clinical use.

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HGG-21. GERMLINE MUTATIONS IN MSH2 GENE IN PEDIATRIC PATIENTS WITH CONGENITAL AND SPORADIC GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.308 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii348-iii348

Author(s):

Maria Ejmont ◽

Małgorzata Rydzanicz ◽

Wiesława Grajkowska ◽

Marta Perek-Polnik ◽

Agnieszka Sowińska ◽

...

Keyword(s):

Germline Mutations ◽

Response To Therapy ◽

Msh2 Gene ◽

Illumina Hiseq ◽

Adult Type ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

New Treatment ◽

Next Generation Sequencing Ngs ◽

Ngs Data

Abstract INTRODUCTION Glioblastoma (GBM) remains one of the biggest therapeutic challenges in neuro-oncology. In spite of multimodal treatment approaches the prognosis of GBM is extremely poor, median survival is estimated about 12–16 months. Although GBM is one of the most common and malignant primary brain tumors, pediatric glioblastoma, including congenital is a very rare tumor, with an incidence of about 1.1–3.4 per million live births. Moreover, the mode of presentation, behavior, response to therapy and molecular background of pediatric glioblastomas differs from adult type of GBM. Until now, about ten patients with congenital glioblastoma have been described and in none of them germline markers were examined. Here we report two patients with GBM, one with congenital tumor with germline mutations in MSH2 gene. METHODS Targeted Next-Generation Sequencing (NGS) of the probands DNA extracted from leucocytes was performed using the TruSight One sequencing panel on an Illumina HiSeq 1500. Applied gene panel investigated the coding sequence and splice sites of 4813 genes associated with known disease phenotypes. The NGS data were analyzed using an in-house procedure. Identified variants were validated by Sanger sequencing. RESULTS NGS analysis of patients constitutional DNA revealed know, pathogenic variants c.940C>T and c.942 + 3A>T in MSH2 gene (NM_000251.3) associated with MMR-dependent hereditary cancer syndromes. CONCLUSION Molecular analysis are heavily needed for better understanding of pediatric GBM etiology and new treatment modality implementation. Identification of this oncogenic driver may provide insight into the pathogenesis of GBM, including congenital cases. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/NZ2/01785).

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Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease

Gerontology ◽

10.1159/000452972 ◽

2016 ◽

Vol 63 (2) ◽

pp. 103-117 ◽

Cited By ~ 7

Author(s):

Cia-Hin Lau ◽

Yousin Suh

Keyword(s):

Animal Models ◽

Genetic Manipulation ◽

Logic Gate ◽

Therapeutic Interventions ◽

Human Aging ◽

Aging Research ◽

Epigenome Editing ◽

Related Disease ◽

Age Related

The recent advent of genome and epigenome editing technologies has provided a new paradigm in which the landscape of the human genome and epigenome can be precisely manipulated in their native context. Genome and epigenome editing technologies can be applied to many aspects of aging research and offer the potential to develop novel therapeutics against age-related diseases. Here, we discuss the latest technological advances in the CRISPR-based genome and epigenome editing toolbox, and provide insight into how these synthetic biology tools could facilitate aging research by establishing in vitro cell and in vivo animal models to dissect genetic and epigenetic mechanisms underlying aging and age-related diseases. We discuss recent developments in the field with the aims to precisely modulate gene expression and dynamic epigenetic landscapes in a spatial and temporal manner in cellular and animal models, by complementing the CRISPR-based editing capability with conditional genetic manipulation tools including chemically inducible expression systems, optogenetics, logic gate genetic circuits, tissue-specific promoters, and the serotype-specific adeno-associated virus. We also discuss how the combined use of genome and epigenome editing tools permits investigators to uncover novel molecular pathways involved in the pathophysiology and etiology conferred by risk variants associated with aging and aging-related disease. A better understanding of the genetic and epigenetic regulatory mechanisms underlying human aging and age-related disease will significantly contribute to the developments of new therapeutic interventions for extending health span and life span, ultimately improving the quality of life in the elderly populations.

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Age-related increase in methylation of ribosomal genes and inactivation of chromosome-specific rRNA gene clusters in mouse

Mutation Research/DNAging ◽

10.1016/0921-8734(90)90019-n ◽

1990 ◽

Vol 237 (3-4) ◽

pp. 131-146 ◽

Cited By ~ 54

Author(s):

Karen Swisshelm ◽

Christine M. Disteche ◽

Joanne Thorvaldsen ◽

Andrew Nelson ◽

Darrell Salk

Keyword(s):

Gene Clusters ◽

Ribosomal Genes ◽

Rrna Gene ◽

Age Related ◽

Related Increase

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Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters

Journal of Endocrinology ◽

10.1677/joe.0.1490117 ◽

1996 ◽

Vol 149 (1) ◽

pp. 117-124 ◽

Cited By ~ 41

Author(s):

X Li ◽

H Cui ◽

B Sandstedt ◽

H Nordlinder ◽

E Larsson ◽

...

Keyword(s):

Growth Factor ◽

Human Liver ◽

Fetal Liver ◽

Adult Life ◽

Absolute Amount ◽

Insulin Like Growth Factor ◽

Rnase Protection ◽

Highly Active ◽

Age Related ◽

Factor Ii

Abstract We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The PI promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts. Journal of Endocrinology (1996) 149, 117–124

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Mining and Development of Novel SSR Markers Using Next Generation Sequencing (NGS) Data in Plants

Molecules ◽

10.3390/molecules23020399 ◽

2018 ◽

Vol 23 (2) ◽

pp. 399 ◽

Cited By ~ 41

Author(s):

Sima Taheri ◽

Thohirah Lee Abdullah ◽

Mohd Yusop ◽

Mohamed Hanafi ◽

Mahbod Sahebi ◽

...

Keyword(s):

Next Generation Sequencing ◽

Ssr Markers ◽

Next Generation ◽

Next Generation Sequencing Ngs ◽

Ngs Data ◽

Generation Sequencing

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Detection of a Microsomal Antigen and Its Antibody in Human Liver Diseases

International Archives of Allergy and Immunology ◽

10.1159/000232296 ◽

1979 ◽

Vol 59 (4) ◽

pp. 459-464 ◽

Cited By ~ 1

Author(s):

E. Penner ◽

S.O. Emejuaiwe ◽

F. Milgrom

Keyword(s):

Liver Diseases ◽

Human Liver ◽

Microsomal Antigen

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The microbiome and ophthalmic disease

Experimental Biology and Medicine ◽

10.1177/1535370218813616 ◽

2018 ◽

Vol 244 (6) ◽

pp. 419-429 ◽

Cited By ~ 13

Author(s):

Adam D Baim ◽

Asadolah Movahedan ◽

Asim V Farooq ◽

Dimitra Skondra

Keyword(s):

Ocular Surface ◽

Open Angle Glaucoma ◽

Age Related Macular Degeneration ◽

Therapeutic Interventions ◽

Gastrointestinal Microbiota ◽

Treatment And Prevention ◽

Age Related ◽

Microbiome Research ◽

Ophthalmic Diseases ◽

Ophthalmic Disease

Progress in microbiome research has accelerated in recent years. Through the use of 16S rRNA assays and other genomic sequencing techniques, researchers have provided new insights about the communities of microorganisms that inhabit human and animal hosts. There is mounting evidence about the importance of these ‘microbiotas’ in a wide variety of disease states, suggesting potential targets for preventative and therapeutic interventions. Until recently, however, the microbiome received relatively little attention in ophthalmology. This review explores emerging research on the roles that ocular and extraocular microbiotas may play in the pathogenesis and treatment of ophthalmic diseases. These include diseases of the ocular surface as well as autoimmune uveitis, age-related macular degeneration, and primary open angle glaucoma. Many questions remain about the potential impacts of microbiome research on the diagnosis, treatment, and prevention of ophthalmic disease. In light of current findings, we suggest directions for future study as this exciting area of research continues to expand. Impact statement This review describes a growing body of research on relationships between the microbiome and eye disease. Several groups have investigated the microbiota of the ocular surface; dysregulation of this delicate ecosystem has been associated with a variety of pro-inflammatory states. Other research has explored the effects of the gastrointestinal microbiota on ophthalmic diseases. Characterizing the ways these microbiotas influence ophthalmic homeostasis and pathogenesis may lead to research on new techniques for managing ophthalmic disease.

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