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Duane-Radial Ray Syndrome

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Duane-Radial Ray Syndrome. Core disease mechanisms, molecular and cellular...

2026-05-10
Asta MONDO:0011812 Model: Asta Scientific Corpus Retrieval 19 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Duane-Radial Ray Syndrome. Core disease mechanisms, molecular and cellular...

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

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] A novel de novo nonsense mutation in SALL4 causing duane radial ray syndrome: a case report and expanding the phenotypic spectrum

  • Authors: Mobarakeh Ajam-Hosseini, Farshid Parvini, A. Angaji
  • Year: 2023
  • Venue: BMC Medical Genomics
  • URL: https://www.semanticscholar.org/paper/bfc3fc258851307680f6d2e56bbc7a78bc1d3ab2
  • DOI: 10.1186/s12920-023-01467-1
  • PMID: 36829172
  • PMCID: 9951407
  • Citations: 7
  • Summary: The findings could extend the pathogenic mutations and phenotypic spectrum of SALL4 related disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > At the present study we explored the molecular mechanism of pathogenesis in a patient suspected to duane radial ray syndrome. The nonconsanguineous pedigree with an affected girl was recruited (Fig. 1a). The studied family is of Iranian origin located in Semnan province (central Iran). As shown in Fig. 1, proband was a 4-yearold girl with clinical symptoms of DRRS who results from a non-consanguineous marriage. Clinical and physical examinations of the patient showed craniofacial deformity, mild microcephaly, cleft palate, thumb aplasia of left hand, thumb hopoplasia of right hand (Fig. 1c), mild syndactyly in right hand, bilateral club foot and short leg, kyphoscoliosis, barrel chest, deep presacral sinus, anorectal abnormality, anal stenosis, constipation, and fecal incontinence. > Echocardiography diagnosed the patient with atrial septal defect. Additionally, the patient underwent audiometric and ophthalmic evaluation. This assessment showed moderate and severe hearing impairment in the right and left ear (Fig. 1b), respectively, as well as type III duan anomaly as deep-set eyes with partial strabismus of right eye. Cleft palate was surgically repaired. She did not show any impairments in the ultrasound evaluation of the kidney, liver, gallbladder and bladder. Transfontanelle ultrasound showed no evidence of hydrocephalus, as well. In addition, Fig. 1c shows the phenotypes of craniofacial deformity, mild microcephaly, mild syndactyly and thumb abnormalities in patient III-1. On the other hands, the patient underwent MRI of the brain, which showed normal structure in the supra, infratentorial, and midline areas. The cortical and white matter signals of the brain, pituitary gland, parasellar regions, base of skull, orbits and 7-8th nerve complexes were also unchanged.

[2] Duane-Radial Ray syndrome a SALL4-Related Disorder. Report of a case in Chile

  • Authors: H. Jonathan, D. Catherine
  • Year: 2020
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/13a3ea72f06d595d1ae541972bed1532cdb7daf0
  • DOI: 10.17352/2640-7876.000024
  • Citations: 1
  • Summary: The Duane-Radial Ray syndrome or Okihiro syndrome belongs to the SALL4-Related Disorders, a phenotypic spectrum, that additionally includes, acrorenoocular syndrome and Holt-Oram syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > According to the clinical characteristics of the proband, radial alterations, agenesis of the right thumb, left preaxial polydactyly, Duane anomaly, ulnar shortening, syndactyly of the fi rst, and second fi nger, bilateral deviation of the hand, right talipes equinovarus, heart disease, hearing loss, imperforate anus, and facial asymmetry, made us suspecting of a disorder related to SALL4, specifi cally a Radial Ray Duane syndrome. Therefore, it was decided for sequence the gene, which resulted in a heterozygous pathogenic variant c.516_522del (p.Gly174Trpfs* 6), evidence a 7 bp deletion, which causes a change in the reading frame, generating a premature stop codon, leading to a nonsense-mediated mRNA decay [1,6], within the embryonic cells, affecting the translation of this gene, generating a smaller amount of the SALL4 protein, that has a fundamental role in the development of the limbs and other tissues such as the heart, mesodermal tissue, eye, and brain, explaining many of the symptoms. > The molecular study has been of substantial importance, in being able to relate different phenotypes such as acrorenoocular syndrome, Duane-Radial Ray syndrome, and some cases of Holt-Oram syndrome with a pathogenic variant in the SALL4 gene, demonstrating a continuous in phenotypes [1]. To date 20 pathogenic variants have been described, 19 of them generate a change in the reading frame and one affects the splicing site [8-10]. The variant of this patient c.516_522del is located in exon 2, although it is not reported on populations databases, it is classifi ed as pathogenic, since the frameshift mechanism, described in genes with loss of heterozygosity, on the other had this variant is not found in population databases like gnomAD or DGV, and computational evidence infers a deleterious effect on this gene, according to the 2015 ACMG guidelines [9,10].

[3] Renal ciliopathies: promising drug targets and prospects for clinical trials

  • Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
  • Year: 2023
  • Venue: Expert Opinion on Therapeutic Targets
  • URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
  • DOI: 10.1080/14728222.2023.2218616
  • PMID: 37243567
  • Citations: 10
  • Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.414) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[4] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[5] 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: 38
  • 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: 0.383) > 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.

[6] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[7] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

  • Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
  • Year: 2019
  • Venue: Allergy
  • URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
  • DOI: 10.1111/all.13851
  • PMID: 31056763
  • PMCID: 6973012
  • Citations: 90
  • Influential citations: 3
  • Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[8] Cohesin mediates Esco2-dependent transcriptional regulation in a zebrafish regenerating fin model of Roberts Syndrome

  • Authors: Rajeswari Banerji, R. Skibbens, M. Iovine
  • Year: 2017
  • Venue: Biology Open
  • URL: https://www.semanticscholar.org/paper/95f5ef8c420feeac5752fd70f957c8130797cc3d
  • DOI: 10.1242/bio.026013
  • PMID: 29084713
  • PMCID: 5769645
  • Citations: 21
  • Influential citations: 2
  • Summary: An underlying mechanism of RBS is revealed in which ESCO2 mutation results in cohesin-dependent dysregulation of transcriptional programs that include the clinically relevant signaling molecule CX43, which has the potential to unify RBS and CdLS as transcription-based mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > RBS is a severe type of human developmental disorder characterized by craniofacial deformities, limb malformation and mental retardation. Currently the treatment options are very limited and not very beneficial. Thus, it is important to understand the molecular mechanisms underlying RBS if we are to identify relevant pharmacological targets for more effective treatments. In a previous study we developed a zebrafish regenerating fin vertebrate model to Zebrafish caudal fin stained with calcein examine the skeletal defects of RBS. We established a genetic link between the gene mutated in RBS -esco2and the clinically relevant gap junction gene cx43, which suggested a transcriptional role for Esco2 in Cx43 regulation. This is the first study to provide evidence that unifies RBS and similar birth defect maladies such as Cornelia de Lange syndrome (CdLS). > What, in your opinion, are some of the greatest achievements in your field and how has this influenced your research? > One of the greatest achievements in our field is the use of various model systems such as zebrafish, Drosophila and yeast to study mechanisms underlying human diseases. In particular zebrafish research plays a valuable role in developmental studies and also drug discovery. > What has surprised you the most while conducting your research? > Both RBS and CdLS are severe birth defects with overlapping phenotypes, and arise from mutation of genes that function in a common pathway, but surprisingly the etiologies of these syndromes are believed to be distinct. Though it is widely accepted that CdLS arises from transcriptional deregulation of a set of genes, the mechanism underlying RBS remains unknown. A popular model states that RBS is caused by mitotic failure and cell death that is completely distinct from CdLS. I was surprised that similar developmental diseases such as RBS and CdLS could have such distinct mechanisms and believed that this area needed further investigation.

[9] Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

  • Authors: J. Hansen, J. Galatioto, Cristina I. Caescu, P. Arnaud, R. C. Calizo et al.
  • Year: 2019
  • Venue: JCI insight
  • URL: https://www.semanticscholar.org/paper/261628418de4c8b21daeb694301dc1b8759b622d
  • DOI: 10.1172/jci.insight.127652
  • PMID: 31167969
  • Citations: 20
  • Summary: System pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy. Earlier studies of MFS mice with nondissecting TAA (Fbn1 C1039G/+ mice) have correlated aneurysm onset and progression with increased TGF-β signaling in the media stimulated by improper angiotensin II (AngII) type I receptor (AT1r) activity (6,7). More recent findings indicate a more complex disease mechanism involving the gradual stratification of stress-stimulated interactions among different cell types and multiple regulatory pathways, of which the AT1r and TGF-β signaling pathways are a critical subset (8)(9)(10)(11)(12)(13)(14). > An overview of regulatory pathways and networks associated with a given pathology can often be obtained by examining changes in gene expression during disease progression. Systems pharmacology approaches that consider drug targets as nodes within cellular regulatory networks can use differentially expressed genes (DEGs) to predict dysregulated SCPs that underlie cell-level mechanisms (1,3). Further, computational analyses of the pharmacologically induced perturbations of gene expression listed in the Connectivity Map (CMap) database can predict drugs to be repurposed to normalize dysregulated SCPs (15).

[10] 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: 0.369) > 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.

[11] Lateralized and Segmental Overgrowth in Children

  • Authors: A. Mussa, D. Carli, S. Cardaropoli, G. Ferrero, N. Resta
  • Year: 2021
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/1bf068188ceb52b6d570aedc7fc2b9bdfd8c7ca9
  • DOI: 10.3390/cancers13246166
  • PMID: 34944785
  • PMCID: 8699773
  • Citations: 19
  • Summary: Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Simple Summary Congenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO. Abstract Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

[12] The Role of Targeted Therapy in Metastatic Renal Cell Carcinoma

  • Authors: J. Unnithan, B. Rini
  • Year: 2007
  • Venue: The Scientific World Journal
  • URL: https://www.semanticscholar.org/paper/d5d6d3155431806aa44bbc5391b25cad4f4ed412
  • DOI: 10.1100/tsw.2007.149
  • PMID: 17619763
  • PMCID: 5901264
  • Citations: 6
  • Summary: The biological pathways involved in the development of RCC and the results of clinical trials using targeted therapy in metastatic RCC are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Renal cell carcinoma has historically been a treatment resistant tumor. Association of renal cell carcinoma with inherited VHL syndrome and the subsequent elucidation of relevant biological pathways in clear cell RCC have changed the approach to systemic therapy. Drugs targeting the VEGF and related pathways have robust clinical activity. Ongoing clinical trials are exploring multiple options such as combining molecular targets with cytokines and combining targeting agents directed against different proteins in the same or different molecular pathways. The emergence of active agents in RCC has generated several needs within the RCC clinical research arena. One pressing need is a pre-clinical model that can replicate the phenotype of disease and treatment with these drugs to better understand mechanisms of response and resistance. Predictive clinical and molecular markers also require investigation to most appropriately target these agents. In addition, standard CT scans and RECIST criteria are often inadequate to evaluate response and progression with VEGF-targeted therapy. Investigation of newer imaging modalities and evaluation criteria is warranted. A new era of treatment in metastatic RCC has emerged, however, where rational therapeutic targeting has lead to substantial clinical advances.

[13] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[14] The Role of De Novo Variants in Formation of Human Anorectal Malformations

  • Authors: G. Dworschak, I. V. van Rooij, H. Reutter
  • Year: 2021
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/797971808f29591fc8f276c174b34568ba9bbfa5
  • DOI: 10.3390/genes12091298
  • PMID: 34573284
  • PMCID: 8466114
  • Citations: 3
  • Summary: The implicated mortality and reduced fecundity in patients with ARM would lead to allele loss, however, mutational de novo events among the affected individuals could compensate for the evolutionary pressure.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > The Duane-radial ray syndrome (OMIM #607323) is an autosomal dominant disorder characterized by upper limb, ocular, and renal anomalies caused by variants in SALL4. Less common features comprise sensorineural hearing loss and gastrointestinal anomalies, such as ARM. Pathogenic variants in SALL4 occur in 40%-50% de novo [14].
  • Snippet 2 (score: 0.365) > The Duane-radial ray syndrome (OMIM #607323) is an autosomal dominant disorder characterized by upper limb, ocular, and renal anomalies caused by variants in SALL4. Less common features comprise sensorineural hearing loss and gastrointestinal anomalies, such as ARM. Pathogenic variants in SALL4 occur in 40%-50% de novo [14].

[15] 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: 0.365) > 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.

[16] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

  • Authors: I. Condò
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
  • DOI: 10.3390/ijms23126525
  • PMID: 35742964
  • PMCID: 9223693
  • Citations: 18
  • Influential citations: 2
  • Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[17] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 4
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.363) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[18] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 10
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[19] Non-Invasive Prenatal Screening for Down Syndrome: A Review of Mass-Spectrometry-Based Approaches

  • Authors: Răzvan Lucian Jurca, I. Pralea, M. Iacobescu, I. Rus, C. Iuga et al.
  • Year: 2025
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/77585fbeddaee796b0d9030dfccee9713f2d3e52
  • DOI: 10.3390/life15050695
  • PMID: 40430124
  • PMCID: 12112985
  • Citations: 1
  • Summary: A comprehensive examination of the differentially expressed proteins (DEPs) and metabolites (DEMs) reported in the literature in T21 prenatal screening aims to guide future research in the field and foster the development of more advanced, less invasive prenatal screening techniques for T21.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Additionally, CS and DS are commonly associated with atherosclerosis, nerve development and repair, inflammation, tumor growth, and metastasis [80]. Modifications of the enzymes involved in the biosynthesis of glycosaminoglycans are important in Ehlers-Danlos syndrome, joint dislocations, short stature, spondyloepiphyseal dysplasia with congenital joint dislocations, spondyloepimetaphyseal dysplasia with joint laxity type 1, congenital heart defects, and Temtamy preaxial brachydactyly syndrome. While congenital heart defects and joint laxity are common in T21 patients, the co-occurrence of T21 and Ehlers-Danlos syndrome is rare, and no established correlation exists between the two conditions [104]. > Pathways associated with diseases of hemostasis were predominantly observed in maternal plasma, along with pathways related to signal transduction mediated by growth factors and second messengers-specifically, oncogenic MAPK signaling. MAPKs are protein kinases that control intracellular processes, such as gene expression, metabolism, proliferation, differentiation, and apoptosis, as part of normal physiology, being mainly studied in the context of oncogenesis, tumor progression, and drug resistance [105]. MAPK pathways in T21 patients have been primarily studied to enhance antitumor treatment efficacy in patients with B cell acute lymphoblastic leukemia [106] or to assess MAPK activity in the brains of T21 and Alzheimer's disease patients [107]. > Table 2 summarizes the key molecular pathways implicated in Down syndrome (T21), emphasizing their normal biological functions and the observed or potential alterations in T21. While direct evidence for some pathways remains limited, numerous pathways-particularly those involved in signaling, immune functions, extracellular matrix organization, and metabolic processes-show promising associations with the clinical features of T21. Regarding the metabolomic pathways of significant differentially expressed metabolites (DEMs) in T21, brief discussions on this topic are included in the description of each metabolomic study outlined in the previous section.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.