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Head and Neck Pathology Mar 2022The 5 edition of the World Health Organization (WHO) Classification of Head and Neck Tumours (2022) comes out only five years after the previous edition, however it...
The 5 edition of the World Health Organization (WHO) Classification of Head and Neck Tumours (2022) comes out only five years after the previous edition, however it presents important updates that run in parallel with the rapid progression involving the increasingly sophisticated molecular investigation and its interpretation, some of which already have therapy-related impact. This manuscript provides an overview of the leading changes introduced in the classification of Odontogenic and Maxillofacial Bone Tumours that encompasses cysts of the jaws, odontogenic tumours, giant cell lesions and bone cysts, and bone and cartilage tumours. This is the first edition that Essential and Desirable Diagnostic Features were added for each entity, so that the most important clinical, microscopic and/or radiologic features were encapsulated and briefly highlighted. Surgical ciliated cyst was added to the group of odontogenic cysts, adenoid ameloblastoma was a newly recognized benign epithelial odontogenic tumour, and segmental odontomaxillary dysplasia was introduced in the group of fibro-osseous tumours and dysplasia. In addition, rhabdomyosarcoma with TFCP2 rearrangement, was introduced into the group of malignant jawbone tumours. The unique genetic aberrations distinguish it from other types of rhabdomyosarcomas. On the other hand, melanotic neuroectodermal tumour of infancy and osteoid osteoma were deleted from the benign bone and cartilageneous tumours, as was the hematolymphoid tumour of solitary plasmacytoma of bone. We systematically reviewed each entity in this chapter and provided important updated findings for selected topics that can further aid in the diagnostic process for challenging cases, broaden insights on the logic of the present classification, and finally, emphasize the potential that some of the molecular results may have in the near future to set new treatment approaches.
Topics: Bone Neoplasms; DNA-Binding Proteins; Head and Neck Neoplasms; Humans; Odontogenic Cysts; Odontogenic Tumors; Transcription Factors; World Health Organization
PubMed: 35312978
DOI: 10.1007/s12105-021-01404-7 -
Frontiers in Immunology 2021Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical...
Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.
Topics: Animals; Antibodies, Bispecific; Antibody Specificity; Binding Sites, Antibody; Biotechnology; Drug Design; Epitopes; Humans; Immunotherapy; Protein Engineering; Recombinant Proteins; Translational Research, Biomedical
PubMed: 34025638
DOI: 10.3389/fimmu.2021.626616 -
Frontiers in Immunology 2021The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different...
INTRODUCTION
The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different technologies: viral vectors and mRNA. Thrombosis is one of the most severe and atypical adverse effects of vaccines. This study aimed to analyze published cases of thrombosis after COVID-19 vaccinations to identify patients' features, potential pathophysiological mechanisms, timing of appearance of the adverse events, and other critical issues.
MATERIALS AND METHODS
We performed a systematic electronic search of scientific articles regarding COVID-19 vaccine-related thrombosis and its complications on the PubMed (MEDLINE) database and through manual searches. We selected 10 out of 50 articles from February 1 to May 5, 2021 and performed a descriptive analysis of the adverse events caused by the mRNA-based Pfizer and Moderna vaccines and the adenovirus-based AstraZeneca vaccine.
RESULTS
In the articles on the Pfizer and Moderna vaccines, the sample consisted of three male patients with age heterogeneity. The time from vaccination to admission was ≤3 days in all cases; all patients presented signs of petechiae/purpura at admission, with a low platelet count. In the studies on the AstraZeneca vaccine, the sample consisted of 58 individuals with a high age heterogeneity and a high female prevalence. Symptoms appeared around the ninth day, and headache was the most common symptom. The platelet count was below the lower limit of the normal range. All patients except one were positive for PF4 antibodies. The cerebral venous sinus was the most affected site. Death was the most prevalent outcome in all studies, except for one study in which most of the patients remained alive.
DISCUSSION
Vaccine-induced thrombotic thrombocytopenia (VITT) is an unknown nosological phenomenon secondary to inoculation with the COVID-19 vaccine. Several hypotheses have been formulated regarding its physiopathological mechanism. Recent studies have assumed a mechanism that is assimilable to heparin-induced thrombocytopenia, with protagonist antibodies against the PF4-polyanion complex. Viral DNA has a negative charge and can bind to PF4, causing VITT. New experimental studies have assumed that thrombosis is related to a soluble adenoviral protein spike variant, originating from splicing events, which cause important endothelial inflammatory events, and binding to endothelial cells expressing ACE2.
CONCLUSION
Further studies are needed to better identify VITT's pathophysiological mechanisms and genetic, demographic, or clinical predisposition of high-risk patients, to investigate the correlation of VITT with the different vaccine types, and to test the significance of the findings.
Topics: 2019-nCoV Vaccine mRNA-1273; Antigen-Antibody Complex; BNT162 Vaccine; COVID-19; Cerebral Veins; ChAdOx1 nCoV-19; Female; Headache; Humans; Mass Vaccination; Platelet Factor 4; SARS-CoV-2; Sex Factors; Survival Analysis; Thrombosis
PubMed: 34912330
DOI: 10.3389/fimmu.2021.729251 -
Redox Report : Communications in Free... Dec 2018p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative... (Review)
Review
BACKGROUND
p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis.
METHODS
A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases. Articles published in the English language between January 1, 1990 and March 1, 2017 were identified and isolated based on the analysis of p53 in skeletal muscle in both animal and cell culture models.
RESULTS
Literature was categorized according to the modality of imposed oxidative stress including exercise, diet modification, exogenous oxidizing agents, tissue manipulation, irradiation, and hypoxia. With low to moderate levels of oxidative stress, p53 is involved in activating pathways that increase time for cell repair, such as cell cycle arrest and autophagy, to enhance cell survival. However, with greater levels of stress intensity and duration, such as with irradiation, hypoxia, and oxidizing agents, the role of p53 switches to facilitate increased cellular stress levels by initiating DNA fragmentation to induce apoptosis, thereby preventing aberrant cell proliferation.
CONCLUSION
Current evidence confirms that p53 acts as a threshold regulator of cellular homeostasis. Therefore, within each modality, the intensity and duration are parameters of the oxidative stressor that must be analyzed to determine the role p53 plays in regulating signaling pathways to maintain cellular health and function in skeletal muscle.
ABBREVIATIONS
Acadl: acyl-CoA dehydrogenase, long chain; Acadm: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; AIF: apoptosis-inducing factor; Akt: protein kinase B (PKB); AMPK: AMP-activated protein kinase; ATF-4: activating transcription factor 4; ATM: ATM serine/threonine kinase; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell Leukemia/Lymphoma 2 apoptosis regulator; Bhlhe40: basic helix-loop-helix family member e40; BH3: Borane; Bim: bcl-2 interacting mediator of cell death; Bok: Bcl-2 related ovarian killer; COX-IV: cytochrome c oxidase IV; cGMP: Cyclic guanosine monophosphate; c-myc: proto-oncogene protein; Cpt1b: carnitine palmitoyltransferase 1B; Dr5: death receptor 5; eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated MAP kinase; Fas: Fas Cell surface death receptor; FDXR: Ferredoxin Reductase; FOXO3a: forkhead box O3; Gadd45a: growth arrest and DNA damage-inducible 45 alpha; GLS2: glutaminase 2; GLUT 1 and 4: glucose transporter 1(endothelial) and 4 (skeletal muscle); GSH: Glutathione; Hes1: hes family bHLH transcription factor 1; Hey1: hes related family bHLH transcription factor with YRPW motif 1; HIFI-α: hypoxia-inducible factor 1, α-subunit; HK2: Hexokinase 2; HSP70: Heat Shock Protein 70; HO: Hydrogen Peroxide; Id2: inhibitor of DNA-binding 2; IGF-1-BP3: Insulin-like growth factor binding protein 3; IL-1β: Interleukin 1 beta; iNOS: inducible nitric oxide synthase; IRS-1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LY-83583: 6-anilino-5,8-quinolinedione; inhibitor of soluble guanylate cyclase and of cGMP production; Mdm 2/ 4: Mouse double minute 2 homolog (mouse) Mdm4 (humans); mtDNA: mitochondrial DNA; MURF1: Muscle RING-finger protein-1; MyoD: Myogenic differentiation 1; MyoG: myogenin; Nanog: Nanog homeobox; NF-kB: Nuclear factor-κB; NO: nitric oxide; NoxA: phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1); NRF-1: nuclear respiratory factor 1; Nrf2: Nuclear factor erythroid 2-related factor 2; P21: Cdkn1a cyclin-dependent kinase inhibitor 1A (P21); P38 MAPK: mitogen-activated protein kinases; p53R2: p53 inducible ribonucleotide reductase gene; P66Shc: src homology 2 domain-containing transforming protein C1; PERP: p53 apoptosis effector related to PMP-22; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGM: phosphoglucomutase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCβ: protein kinase c beta; PTEN: phosphatase and tensin homolog; PTIO: 2-phenyl-4, 4, 5, 5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) has been used as a nitric oxide (NO) scavenger; Puma: The p53 upregulated modulator of apoptosis; PW1: paternally expressed 3 (Peg3); RNS: Reactive nitrogen species; SIRT1: sirtuin 1; SCO2: cytochrome c oxidase assembly protein; SOD2: superoxide dismutase 2; Tfam: transcription factor A mitochondrial; TIGAR: Trp53 induced glycolysis repulatory phosphatase; TNF-a: tumor necrosis factor a; TRAF2: TNF receptor associated factor 2; TRAIL: type II transmembrane protein.
Topics: Animals; Diet; Exercise; Humans; Muscle, Skeletal; Oxidative Stress; Oxygen; Proto-Oncogene Mas; Radiation Injuries; Tumor Suppressor Protein p53
PubMed: 29298131
DOI: 10.1080/13510002.2017.1416773 -
Rheumatology (Oxford, England) Jun 2021To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening.
METHODS
A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review.
RESULTS
Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers.
CONCLUSION
Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.
Topics: Adenosine Triphosphatases; Age Factors; Antibodies, Antinuclear; Creatine Kinase; DNA-Binding Proteins; Deglutition Disorders; Dermatomyositis; Female; Guidelines as Topic; Humans; L-Lactate Dehydrogenase; Lung Diseases, Interstitial; Male; Myositis; Neoplasms; Publication Bias; Raynaud Disease; Risk; Sex Factors; Skin Ulcer; Tomography, X-Ray Computed; Transcription Factors
PubMed: 33599244
DOI: 10.1093/rheumatology/keab166 -
Clinical Epigenetics Mar 2023Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in... (Review)
Review
BACKGROUND
Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking.
RESULTS
A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10) and biological processes "skeletal system development" (q = 1.89 × 10). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10) and atherosclerosis (p = 4.9 × 10).
CONCLUSION
This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.
Topics: Humans; DNA Methylation; Cardiovascular Diseases; CpG Islands; Smoking; Air Pollution; Epigenesis, Genetic
PubMed: 36991458
DOI: 10.1186/s13148-023-01468-y -
Diagnostics (Basel, Switzerland) Jan 2023TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly... (Review)
Review
BACKGROUND
TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS.
METHODS
Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to 8 April 2022.
RESULTS
Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups.
CONCLUSIONS
CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.
PubMed: 36766521
DOI: 10.3390/diagnostics13030416 -
Cancers Aug 2020Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median... (Review)
Review
Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very attractive areas of study. Aptamers are short three-dimensional structures of single-stranded nucleic acids (RNA or DNA), identified by an in vitro process, named systematic evolution of ligands by exponential enrichment (SELEX), starting from a partially random oligonucleotide library. They bind to a molecular target with high affinity and specificity and can be easily modified to optimize binding affinity and selectivity. Thanks to their properties (low immunogenicity and toxicity, long stability, and low production variability), a large number of aptamers have been selected against GBM biomarkers and provide specific imaging agents and therapeutics to improve the diagnosis and treatment of GBM. However, the use of aptamers in GBM diagnosis and treatment still represents an underdeveloped topic, mainly due to limited literature in the research world. On these bases, we performed a systematic review aimed at summarizing current knowledge on the new promising DNA and RNA aptamer-based molecules for GBM diagnosis and treatment. Thirty-eight studies from 2000 were included and investigated. Seventeen involved the use of aptamers for GBM diagnosis and 21 for GBM therapy. Our findings showed that a number of DNA and RNA aptamers are promising diagnostic and therapeutic tools for GBM management.
PubMed: 32764266
DOI: 10.3390/cancers12082173 -
Public Health Genomics 2020The complex genetic diversity among human populations results from an assortment of factors acting at various sequential levels, including mutations, population...
SNPs in Sites for DNA Methylation, Transcription Factor Binding, and miRNA Targets Leading to Allele-Specific Gene Expression and Contributing to Complex Disease Risk: A Systematic Review.
INTRODUCTION
The complex genetic diversity among human populations results from an assortment of factors acting at various sequential levels, including mutations, population migrations, genetic drift, and selection. Although there are a plethora of DNA sequence variations identified through genome-wide association studies (GWAS), the challenge remains to explain the mechanisms underlying interindividual phenotypic disparity accounting for disease susceptibility. Single nucleotide polymorphisms (SNPs) present in the sites for DNA methylation, transcription factor (TF) binding, or miRNA targets can alter the gene expression. The systematic review aimed to evaluate the complex crosstalk among SNPs, miRNAs, DNA methylation, and TFs for complex multifactorial disease risk.
METHODS
PubMed and Scopus databases were used from inception until May 15, 2019. Initially, screening of articles involved studies assessing the interaction of SNPs with TFs, DNA methylation, or miRNAs resulting in allele-specific gene expression in complex multifactorial diseases. We also included the studies which provided experimental validation of the interaction of SNPs with each of these factors. The results from various studies on multifactorial diseases were assessed.
RESULTS
A total of 11 articles for SNPs interacting with DNA methylation, 30 articles for SNPs interacting with TFs, and 11 articles for SNPs in miRNA binding sites were selected. The interactions of SNPs with epigenetic factors were found to be implicated in different types of cancers, autoimmune diseases, cardiovascular diseases, diabetes, and asthma.
CONCLUSION
The systematic review provides evidence for the interplay between genetic and epigenetic risk factors through allele-specific gene expression in various complex multifactorial diseases.
Topics: Alleles; Binding Sites; DNA Methylation; Epigenesis, Genetic; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; MicroRNAs; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Transcription Factors
PubMed: 32966991
DOI: 10.1159/000510253 -
The Japanese Dental Science Review Dec 2023Mutations in are the most common genetic cause of tooth agenesis (TA). The aim of this study was to systematically review the profiles of the TA and variants and... (Review)
Review
Mutations in are the most common genetic cause of tooth agenesis (TA). The aim of this study was to systematically review the profiles of the TA and variants and establish their genotype-phenotype correlation. Forty articles were eligible for 178 patients and 61 mutations (26 in frame and 32 null mutations). mutations predominantly affected molars, mostly the second molar, and the mandibular first premolar was the least affected. More missing teeth were found in the maxilla than the mandible, and with null mutations than in-frame mutations. The number of missing teeth was correlated with the locations of the in-frame mutations with the C-terminus mutations demonstrating the fewest missing teeth. The null mutation location did not influence the number of missing teeth. Null mutations in all locations predominantly affected molars. For the in-frame mutations, a missing second molar was commonly associated with mutations in the highly conserved paired DNA-binding domain, particularly the linking peptide (100% prevalence). In contrast, C-terminus mutations were rarely associated with missing second molars and anterior teeth, but were commonly related to an absent second premolar. These finding indicate that the mutation type and position contribute to different degrees of loss of function that further differentially influences the manifestations of TA. This study provides novel information on the correlation of the genotype-phenotype, aiding in the genetic counseling for TA.
PubMed: 37159578
DOI: 10.1016/j.jdsr.2023.04.001