Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Nijmegen breakage syndrome. Core disease mechanisms, molecular and cellula...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Nijmegen breakage syndrome in pediatric practice (literature review and personal observation)

• Authors: A.D. Hubanov, V. S. Konoplitskyi, V. Pohorilyi, O. V. Tykholaz, A. Sasiuk et al.
• Year: 2025
• Venue: The Journal of V. N. Karazin Kharkiv National University, Series "Medicine"
• URL: https://www.semanticscholar.org/paper/f7a7bc20907d8c7e3d5c48a9f3f6382bc22fc79d
• DOI: 10.26565/2313-6693-2025-52-11
• Summary: The clinical case presented in this work demonstrates the importance of a comprehensive analysis and a thorough approach for the timely diagnosis and treatment of a rare disease, which may be an «incidental finding» in the practice of doctors of various specialties.
• Evidence snippets:
• Snippet 1 (score: 0.420) > Background. Nijmegen breakage syndrome is a rare autosomal recessive disease characterized by microcephaly, specific facial features, immunodeficiency, and an increased susceptibility to malignancies. > Purpose – is to highlight the importance of the pathology of Nijmegen breakage syndrome in pediatric practice, to demonstrate oneʼs own experience in a clinical case. > Materials and methods. An analysis and generalization of the results of scientific research for 1985–2025, selected on the basis of an information search in the scientometric databases Scopus, Web of Science, PubMed, MEDLINE, Google Scholar using the keywords «Nijmegen breakage syndrome», «immunodeficiency», «clinical features», «laboratory features», «genotype», «phenotype», was carried out. The majority of articles were represented by clinical studies and case presentations (73%). For the literature review, data were also obtained from sources containing literature reviews (27%). The most frequently cited sources in the article were from the years 2022–2024. > Results and discussion. Nijmegen breakage syndrome is caused by mutations in the NBN gene, which encodes the protein nibrin, which is important for the repair of double-stranded DNA breaks. The most common mutation is a 5-base pair deletion (657del5), which leads to genomic instability and increased sensitivity to ionizing radiation. Parents of children with this syndrome are heterozygous carriers of the mutation, and the risk of having an affected child is 25% if both parents are carriers of the defective gene. Chromosomal instability with characteristic rearrangements of peripheral T-lymphocytes in the form of inversions and translocations involving chromosomes 7 and 14, sensitivity of cells to ionizing radiation in vitro — all these are characteristic features of this disease that have important diagnostic value. Detection of mutations in both alleles of the nibrin gene is the final study in making the diagnosis. Most patients with Nijmegen breakage syndrome are of Slavic origin, so this mutation began to be called the «Slavic mutation». Our work presents a clinical case of Nijmegen breakage syndrome in a patient with bacterial destruction of the

[2] Contemporary Pediatric Hematology and Oncology

• Authors: M. Zakaria, T. Hassan
• Year: 2019
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/109d2f72206da6d06dbcc9394c6efcf66fa907e0
• DOI: 10.5772/INTECHOPEN.73875
• Citations: 1
• Summary: This book chapter aims to discuss the epidemiologic perspectives of nocturnal enuresis in SCA, as well as the current hypotheses on the etiopathogenesis of this complication.
• Evidence snippets:
• Snippet 1 (score: 0.405) > Nijmegen syndrome (NS) is named from the Dutch city Nijmegen where the condition was first described. It is also named Berlin breakage syndrome, Ataxia Telangiectasia variant 1. NS is an autosomal recessive inherited disease with a complex health problematic conditions typically characterized (NS) by short stature, microcephaly, distinctive facial feature, recurrent respiratory tract infections, mental development delay from infancy to childhood, dysfunctional immune deficiency in T cells and low level of immunoglobulin G and A and increased susceptibility to infections. Individuals with NS increased risk of cancer development (>50 times), commonly in Hodgkin lymphoma, brain tumor, rhabdomyosarcoma about 40% of the affected individuals and usual before age 15. Studies showed heterozygous mutation increase cancer occurrence as well [52]. > It is estimated that the prevalence of Nijmegen syndrome is in approximately 100,000 newborns although the exact data is still unknown [53]. Most individuals with NS have West Slavic origins and the largest number of them live in Poland. In the clinical presentation and laboratory diagnostic testing, Nijmegen syndrome and Fanconi anemia show biological overlap. A positive result of chromosomal breakage induced with clastogens such as MMC and DEB can be seen both in Fanconi anemia and Nijmegen syndrome. Translocations or inversions between chromosomes 7 and 14 can be seen its feature in Nijmegen syndrome [54]. > The genetic cause of NS is due to the mutation of NBN gene mutation with homozygous c.657_661del5 on chromosome 8q21.3, resulting in nibrin protein dysfunction which is involved in several critical cellular functions, including the repair of damaged DNA to maintain the stability of the genomic function when breaks of DNA strands happen in the stage where the genetic material in chromosomes exchanges for cell division. As a result, affected individuals are sensitive to radiation and other agent exposures [55,56]. The molecular tests to confirm the diagnosis of a suspected proband are the analysis of exon 6 to determine if the c.657_661 del5 allele and the analysis of entire NBN gene by the

[3] Inherited Bone Marrow Failure and Chromosome Instability Syndromes and their Cancer Predisposition

• Authors: Zhangyi Wu
• Year: 2018
• Venue: Contemporary Pediatric Hematology and Oncology
• URL: https://www.semanticscholar.org/paper/b10935f8113f634d301c47716dd98f5f677a71f7
• DOI: 10.5772/INTECHOPEN.81546
• Citations: 2
• Summary: Identification of the IBMFS and CIS has led to important advances in the understanding of the genotypes, guiding the clinical practice of the phenotypes and such studies provided insights into the function of the various DNA repair pathways.
• Evidence snippets:
• Snippet 1 (score: 0.405) > Nijmegen syndrome (NS) is named from the Dutch city Nijmegen where the condition was first described. It is also named Berlin breakage syndrome, Ataxia Telangiectasia variant 1. NS is an autosomal recessive inherited disease with a complex health problematic conditions typically characterized (NS) by short stature, microcephaly, distinctive facial feature, recurrent respiratory tract infections, mental development delay from infancy to childhood, dysfunctional immune deficiency in T cells and low level of immunoglobulin G and A and increased susceptibility to infections. Individuals with NS increased risk of cancer development (>50 times), commonly in Hodgkin lymphoma, brain tumor, rhabdomyosarcoma about 40% of the affected individuals and usual before age 15. Studies showed heterozygous mutation increase cancer occurrence as well [52]. > It is estimated that the prevalence of Nijmegen syndrome is in approximately 100,000 newborns although the exact data is still unknown [53]. Most individuals with NS have West Slavic origins and the largest number of them live in Poland. In the clinical presentation and laboratory diagnostic testing, Nijmegen syndrome and Fanconi anemia show biological overlap. A positive result of chromosomal breakage induced with clastogens such as MMC and DEB can be seen both in Fanconi anemia and Nijmegen syndrome. Translocations or inversions between chromosomes 7 and 14 can be seen its feature in Nijmegen syndrome [54]. > The genetic cause of NS is due to the mutation of NBN gene mutation with homozygous c.657_661del5 on chromosome 8q21.3, resulting in nibrin protein dysfunction which is involved in several critical cellular functions, including the repair of damaged DNA to maintain the stability of the genomic function when breaks of DNA strands happen in the stage where the genetic material in chromosomes exchanges for cell division. As a result, affected individuals are sensitive to radiation and other agent exposures [55,56]. The molecular tests to confirm the diagnosis of a suspected proband are the analysis of exon 6 to determine if the c.657_661 del5 allele and the analysis of entire NBN gene by the

[4] Nijmegen breakage syndrome in two half sibs with peripheral T-cell lymphoma and cortical T-cell acute lymphoid leukemia

• Authors: S. Sharapova, E. I. Golovataya, E. V. Shepelevich, Yuliya E. Mareika, I. Guryanova et al.
• Year: 2021
• Venue: Central-European Journal of Immunology
• URL: https://www.semanticscholar.org/paper/4990dafa4db25133487d983841a927541a00cefc
• DOI: 10.5114/ceji.2020.103387
• PMID: 33658897
• PMCID: 7882413
• Citations: 2
• Summary: This case highlights the value of checking NBN carrier in Belarusian families during genetic counselling and describes the first time to describe the repeated cases of two patients born with Nijmegen breakage syndrome from one mother and two different fathers.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosome instability disorder, characterized by growth and developmental defects (growth retardation, severe and progressive microcephaly, craniofacial features), immunodeficiency, high susceptibility to lymphoid malignancies, hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control. The disease is caused by mutations in the nBn gene, which encodes nibrin, a component of the complex involved in cellular response to DNA double-strand breaks [1][2][3]. > Most of described patients are homozygous for a founder mutation in nBn gene (c.657del5), which leads to protein truncation. The disease is most common in people of Eastern European or Slavic background, specifically those from Poland, Southeast Germany, Czech Republic, and the Ukraine [3][4][5][6]. > Herein, a repeated Nijmegen breakage syndrome is reported in two males from one mother after two marriages (Figure 1A) from the western part of Belarus and we describe the clinical data, cytogenetic, and molecular findings of a prenatally diagnosed fetus and his brothers with NBS. These data confirm the importance of genetic counseling of Slavic families and may substantiate the nBn carrier detection in some regions of Eastern Europe.

[5] DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation

• Authors: Benilde García-de Teresa, M. Hernández-Gómez, S. Frías
• Year: 2017
• Venue: BioMed Research International
• URL: https://www.semanticscholar.org/paper/949ddbbadc5c1e6a389130cd3544b61d024c293d
• DOI: 10.1155/2017/8193892
• PMID: 29238724
• PMCID: 5702399
• Citations: 27
• Summary: The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature.
• Evidence snippets:
• Snippet 1 (score: 0.378) > Nijmegen breakage syndrome (NBS) is an autosomal recessive disease caused by biallelic mutations in NBN, a gene that encodes nibrin, a protein involved in DNA repair and cell cycle checkpoint regulation. It participates in the former by sensing doublestrand breaks as part of the trimeric complex MRN, alongside MRE11 and RAD50. Meanwhile, for the latter, it contributes to the appropriate activation of ATM and ATR which are central transductors of the DNA damage response (DDR) [55]. The malfunction of nibrin translates in a cellular phenotype marked by chromosomal instability, radiosensitivity, reduced phosphorylation of ATM substrates, and S and G2/M cell cycle defects [56]. Chromosome instability is evidenced by cytogenetic methods in 10-60% of cells in the form of breaks and numeric and structural aberrations: translocations and inversions affecting chromosomes 7 and 14 are found in the majority of NBS patients and are considered a cytogenetic characteristic of this syndrome ( Figure 6) [57]. > The clinical impact of these alterations is a phenotype characterized by microcephaly, a distinctive facial appearance consisting of receding forehead and mandible and a prominent mid face with a long nose and philtrum, as well as immunodeficiency that leads to recurrent infections and an increased risk for the development of neoplasia, particularly leukemia and lymphoma. According to the international Nijmegen breakage syndrome study group, growth retardation is also a hallmark of this disease [58], although there is not many details about this feature in the literature. > Most of the information on the natural history of NBS available today comes from patients participating in registries, in which fairly large cohorts of NBS patients are included. There is a large representation of Slavic patients in these cohorts which correlates with the high carrier frequency of a founder mutation of NBN in this population. From these studies, it is evident that the most severely affected anthropometric measure in NBS patients is head circumference since all participants display microcephaly, even though only 75% display this feature at birth. When it comes to

[6] Nijmegen breakage syndrome (NBS)

• Authors: K. Chrzanowska, H. Gregorek, B. Dembowska-Bagińska, M. Kalina, M. Digweed
• Year: 2012
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/0f4e49fbcdbab075cae779b63d0f2b5ffc397f59
• DOI: 10.1186/1750-1172-7-13
• PMID: 22373003
• PMCID: 3314554
• Citations: 228
• Influential citations: 18
• Summary: No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients and genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected.
• Evidence snippets:
• Snippet 1 (score: 0.375) > The first description was in 1979 of a Dutch boy with microcephaly, growth and developmental retardation, IgA deficiency and chromosomal rearrangements resembling those observed in ataxia telangiectasia (A-T), i.e. affecting chromosomes 7 and 14 with breakpoints in four sites (7p13, 7q35, 14q11 and 14q32) [1]. > The discovery that a deceased brother of this patient had presented with similar clinical features led in 1981 to the formal description of this genetic disease by researchers at the University of Nijmegen in the Netherlands, who named it, Nijmegen breakage syndrome [2]. Patients manifesting microcephaly with normal intelligence, immunodeficiency, and an unprecedentedly strong predisposition to lymphoreticular malignancies were reported in 1985 as the Seemanova Syndrome II [3] but it was subsequently confirmed that they were actually affected with the same disease [4]. > In addition to chromosomal instability, intensive studies of NBS cells in vitro showed other cellular features similar to those found in ataxia-telangiectasia, such as sensitivity to IR and radioresistant DNA synthesis (RDS) [4][5][6]. For these reasons, NBS was considered to be a variant of A-T, even though the neurological symptoms are clearly different and neither ataxia nor telangiectasia are observed in NBS [7]. Complementation studies of different NBS cell lines suggested genetic heterogeneity and two groups were distinguished: A-T variant 1 (AT-V1) or Nijmegen breakage syndrome and A-T variant 2 (AT-V2) or Berlin breakage syndrome [5,8]. > In 1998 the gene responsible for NBS, originally designated as NBS1 but now renamed as NBN, was cloned and the gene product, nibrin, was identified [9][10][11]. Nibrin, together with MRE11 and RAD50 forms a trimeric protein complex (MRN) involved in repairing DNA double strand breaks (DSBs).

[7] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.363) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[8] Nijmegen breakage syndrome: case report and review of literature

• Authors: Brahim El Hasbaoui, A. Elyajouri, R. Abilkassem, A. Agadr
• Year: 2020
• Venue: The Pan African Medical Journal
• URL: https://www.semanticscholar.org/paper/5500d49e80568ba393629dc4705a149e15e1a0a5
• DOI: 10.11604/pamj.2020.35.85.14746
• PMID: 32537088
• PMCID: 7250236
• Citations: 17
• Summary: A case of Nijmegen breakage syndrome associated with Hodgkin lymphomas and Combined variable immunodeficiency is presented here and prognosis is generally poor due to the extremely high rate of malignancies.
• Evidence snippets:
• Snippet 1 (score: 0.359) > Nijmegen Breakage Syndrome (NBS) is a rare autosomalrecessive DNA repair disorder characterized by genomic instability andincreased risk of haematopoietic malignancies observed in morethan 40% of the patients by the time they are 20 years old. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a frame shift and protein truncation. Nibrin (NBN) plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signalling pathway in apoptosis and senescence. Cardinal symptoms of Nijmegen breakage syndrome are characteristic: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS; however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. We present here a case of Nijmegen breakage syndrome associated with Hodgkin lymphomas and Combined variable immunodeficiency.

[9] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.352) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[10] Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

• Authors: Dido Carrero, C. Soria-Valles, C. López-Otín
• Year: 2016
• Venue: Disease Models & Mechanisms
• URL: https://www.semanticscholar.org/paper/ec1ed5c2e45d4aeb1fcd088517438dc345058b88
• DOI: 10.1242/dmm.024711
• PMID: 27482812
• PMCID: 4958309
• Citations: 137
• Influential citations: 8
• Summary: A series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing are defined and the therapeutic strategies developed to date are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.343) > characteristics of progeroid syndromes and define the mechanisms underlying their pathogenesis, which could provide ideas for future studies on both physiological and pathological ageing. Finally, we review different therapeutic strategies developed for the treatment of these rare but devastating diseases. > A classification system for human progeroid syndromes All progeroid syndromes are characterized by similar clinical features (Table 1), but their underlying mechanisms can vary depending on the mutated gene and the pathway that is consequently altered. Below, we have classified progeroid syndromes into two general categories based on the molecular pathway involved. The first group includes those syndromes caused by alterations in components of the nuclear envelope, such as Hutchinson-Gilford progeria syndrome (HGPS), Néstor-Guillermo progeria syndrome (NGPS), atypical progeria syndromes (APSs), restrictive dermopathy (RD) and mandibuloacral dysplasia (MAD). The second group consists of progeroid syndromes induced by mutations in genes involved in DNA-repair pathways, such as Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndrome (RTS), Cockayne syndrome (CS), xeroderma pigmentosum (XP), trichothiodystrophy (TTD), Fanconi anaemia (FA), Seckel syndrome (SS), ataxia telangiectasia (AT), ataxia telangiectasia-like disorder (ATLD), cerebroretinal microangiopathy with calcifications and cysts (CRMCC), and Nijmegen breakage syndrome (NBN). A subcategory of this group comprises dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson syndrome (HHS), linked to mutations in components of the telomerase complex (see Box 1 for a glossary of terms) that cause telomere attrition.

[11] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.342) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[12] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

• Authors: Christine Péladeau, J. Sandhu
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
• DOI: 10.3390/ijms22116068
• PMID: 34199845
• PMCID: 8200055
• Citations: 18
• Influential citations: 1
• Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
• Evidence snippets:
• Snippet 1 (score: 0.342) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[13] Chemotherapy and Mechanisms of Resistance in Breast Cancer

• Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
• DOI: 10.5772/24629
• Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
• Evidence snippets:
• Snippet 1 (score: 0.341) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[14] Hematopoietic Stem Cell Transplantation for DNA Double Strand Breakage Repair Disorders

• Authors: B. Wolska-Kuśnierz, A. Gennery
• Year: 2020
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/8cf7b82b027e0dc1a057877bf76e56124c22853c
• DOI: 10.3389/fped.2019.00557
• PMID: 32010653
• PMCID: 6974535
• Citations: 14
• Summary: Increasing numbers of patients with Nijmegen Breakage syndrome, Ligase 4 deficiency and Cernunnos-XLF deficiency have been successfully transplanted and best results are obtained with the use of reduced intensity conditioning.
• Evidence snippets:
• Snippet 1 (score: 0.339) > Nijmegen breakage syndrome (NBS) is an autosomal-recessive disease caused by mutations of the NBN gene on chromosome 8q21. The disease occurs worldwide, but has a high prevalence among Central and Eastern European Slavic populations due to a founder mutation effect. The largest cohort has been diagnosed in Poland (n = 118), where all patients carry the same homozygous deletion of five nucleotides (657_661del5) (22). > The Slavic hypomorhic mutation in NBN encodes partially functional, truncated p70-nibrin protein, which is a crucial component of the MRN complex involved in DNA double and single-strand breaks repair and in the activation of cell cycle checkpoints. > Almost all patients demonstrate microcephaly at birth, a distinct, dysmorphic facial appearance, becoming more noticeable with age (a prominent midface emphasized by a sloping forehead and receding mandible). Short stature, mild mental retardation, congenital skeletal (clinodactyly, syndactyly), renal, or other abnormalities are also found. In females, premature ovarian insufficiency is observed. > All affected individuals demonstrate a combined immunodeficiency, but of wide severity and clinical manifestation: from "clinically-silent" abnormalities only (disturbed lymphocyte subsets in peripheral blood) to clinically relevant immunodeficiency with hypogammaglobulinaemia. The humoral defect is associated with recurrent, chronic infections, mainly of respiratory tract, leading in some patients to bronchiectasis. About 68 %of patients require immunoglobulin substitution therapy. Surprisingly, there is no correlation between the degree of cellular deficiency (usually decreased number of CD4, CD8 lymphocytes, thymic emigrants, low percentage of naïve cells, increased memory cells, TCRγδ lymphocytes), and severity of infections. Predisposition to opportunistic infections is relatively low and patients do not use routinely antimicrobial prophylaxis. Some patients may be detected on newborn screening for SCID with very low TRECs (23).

[15] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

• Authors: M. Saporta
• Year: 2015
• Venue: Neural Regeneration Research
• URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
• DOI: 10.4103/1673-5374.158345
• PMID: 26199602
• PMCID: 4498347
• Citations: 4
• Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
• Evidence snippets:
• Snippet 1 (score: 0.338) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[16] Clinical Phenotypes of Cardiovascular and Heart Failure Diseases Can Be Reversed? The Holistic Principle of Systems Biology in Multifaceted Heart Diseases

• Authors: K. Lourida, G. Louridas
• Year: 2022
• Venue: Cardiogenetics
• URL: https://www.semanticscholar.org/paper/3960806730c4c1115f527e22d6d0a76536570ec5
• DOI: 10.3390/cardiogenetics12020015
• Citations: 4
• Influential citations: 1
• Summary: Only by understanding the complexity of chronic heart diseases and explaining the interrelationship between different interconnected biological networks can the probability for clinical phenotypes reversal be increased.
• Evidence snippets:
• Snippet 1 (score: 0.337) > Treatment with ACEIs, ARBs, and β-blockers impedes deterioration of myocardial function as well as clinical deterioration caused by the deleterious impact of the compensatory systems [58,59]. Therefore, the therapy with ACEIs, ARBs, and β-blockers is the appropriate therapy to block LV remodeling and HF progression and reduce symptoms and/or mortality [55]. > In general, the HF syndrome demonstrates a modular construction with predictable behavior of functional clinical phenotypes having a strong impact on biological networks from epigenetic, cellular to regulatory systems [18]. The importance of individual genes for the pathogenesis and clinical progression of the HF syndrome is restricted to the hypertrophic and dilated cardiomyopathies. It seems that some HF patients have a complex multigenic inheritance, but the importance of individual genes is limited. In contrast, the significant role of epigenetics, proteomics, and metabolomics is increased; but, the complete genetic network system and the interactions between multiomics systems are still uncertain [60]. Multimodal systems that include genetic networks, multiomics, metabolic pathways, environmental factors, and sophisticated disease-related clinical networks are required to be integrated and provide a new holistic and realistic picture. > Significant breakthroughs have been made to understand many of the pathophysiological mechanisms of HFrEF but the natural pathophysiological history and clinical progression of HFpEF still remains inadequately defined [39]. The subclinical progression of pre-clinical diastolic dysfunction (PDD) of LV "to clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement . . . continue to be poorly understood" [40]. Prospective studies are expected to clarify the natural history and clinical progression of HFpEF and define the LV remodeling mechanisms involved. The pathophysiology of LV systolic dysfunction is different to the diastolic dysfunction, as systolic dysfunction is considered a disease of calcium handling and diastolic dysfunction is regarded as a disease of increased myofilament sensitivity to calcium [61][62][63].

[17] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

• Authors: O. Tsukamoto
• Year: 2019
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
• DOI: 10.3390/ijms21010226
• PMID: 31905684
• PMCID: 6982115
• Citations: 16
• Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
• Evidence snippets:
• Snippet 1 (score: 0.335) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[18] Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

• Authors: T. Nakajima, S. Tamura, M. Kurabayashi, Y. Kaneko
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/3d299f57f344d42eff9d3565d1581dae7fb87a54
• DOI: 10.3390/ijms22083930
• PMID: 33920294
• PMCID: 8069124
• Citations: 6
• Influential citations: 1
• Summary: Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy.
• Evidence snippets:
• Snippet 1 (score: 0.331) > Recent advances in molecular genetics have identified many causal genes for inherited arrhythmia syndromes (IASs) such as long QT syndrome (LQTS) [1], short QT syndrome (SQTS) [2], Brugada syndrome (BrS) [3,4] and early repolarization (ER) syndrome (ERS) [3,5]. Most causal genes for IASs encode cardiac ion channels or their related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and experimental animal models, have revealed the pathophysiology of IASs and enabled the establishment of causal gene-specific precision medicine [6][7][8]. Furthermore, analyses of patient-specific and/or genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies for IASs, although there are still some limitations of using iPSC-CMs, such as immature structure and function and mixed population of atrial, ventricular, and nodal cells, as a standard technology [9]. > The altered function of causal genes that encode cardiac ion channels is caused by multiple mechanisms, including trafficking defects, producing non-functional channels, altered channel gating properties, and a combination thereof. These altered functions of mutant channels underly the clinical phenotypes of IASs [10][11][12]. Particularly, unique electrophysiological properties of mutant channels have been shown to be associated with the atypical clinical phenotypes of IASs [10,13]. Furthermore, the elucidation of the mechanisms underlying the atypical clinical phenotypes of IASs has raised the possibility of mutation-specific precision medicine. > We herein review the current knowledge of genotype-phenotype relationships, underlying molecular and cellular mechanisms, and established pharmacological therapies of IASs, including LQTS, SQTS, and J wave syndrome (BrS and ERS).

[19] Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

• Authors: Esmeralda Alonso-Barroso, B. Pérez, L. Desviat, E. Richard
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/da649a0f04477c53b448c5ac5f873f8762235290
• DOI: 10.3390/ijms22031161
• PMID: 33503868
• PMCID: 7865492
• Citations: 16
• Influential citations: 1
• Summary: The novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.
• Evidence snippets:
• Snippet 1 (score: 0.330) > The study of the mechanisms involved in disease physiopathology has been mainly performed using the hypomorphic PA mouse model that mimics the biochemical and clinical phenotype [5]. Using this model, bioenergetic failure, oxidative damage and deregulation of miRNAs induced by accumulating propionyl-CoA have been described as potential mechanisms contributing to PA physiopathology [6][7][8]. The limitations of animal models for the study of cardiac energy metabolism [9] and of the commonly available cellular human models such as fibroblasts, underline the importance of generating new relevant cell models to provide deeper insight into the underlying mechanisms of disease. The use of in vitro models with human cellular context is highly recommended and, in this sense, induced pluripotent stem cells (iPSCs) have certain advantages since they provide the genetic background of the patient and represent an unlimited source of biological material for the study of pathophysiology and treatment effectiveness [10]. We have previously generated an iPSC line from a PA patient with defects in the PCCA gene that showed full pluripotency, differentiation capacity and genetic stability [11]. > In the present study, we aimed to establish a platform that served as a disease model to study the cellular and molecular alterations operating in cardiac tissue affected by PA disease. We described the characterization of cardiomyocytes derived from the PCCA iPSC line (PCCA iPSC-CMs) and the analysis of specific pathways potentially involved in cardiac PA physiopathology.

[20] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.326) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

Notes

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