Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Deafness-lymphedema-leukemia syndrome. Core disease mechanisms, molecular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] ‘Breast Cancer Resistance Likelihood and Personalized Treatment Through Integrated Multiomics’

• Authors: S. Mehmood, Muhammad Faheem, Hammad Ismail, S. M. Farhat, Mahwish Ali et al.
• Year: 2022
• Venue: Frontiers in Molecular Biosciences
• URL: https://www.semanticscholar.org/paper/c542ec176c594aeddb3790bb3d10767598b86ae4
• DOI: 10.3389/fmolb.2022.783494
• PMID: 35495618
• PMCID: 9048735
• Citations: 19
• Influential citations: 1
• Summary: This review has summarized therapeutic resistance associated with BC and the techniques used for its management, and identifies the biomarkers of disease progression and treatment progress by collective characterization and quantification of pools of biological molecules within and among the cancerous cells.
• Evidence snippets:
• Snippet 1 (score: 0.445) > Breast cancer is a very complex and heterogeneous disorder with unique molecular and morphological features relative to a disease which involves only a single gene or protein in a simple signaling pathway contributing toward the progression of disease in an independent and autonomous manner (Organization 2019). Various studies had represented BC heterogeneity through the differential response of the same type of BC patients to treatment and risk of developing side effects. One of the major clinical complications in the treatment of breast carcinoma patients is the development of therapeutic resistance (Luque-Bolivar et al., 2020). Recently drug resistance in BC treatment is not properly addressed, rather to focus on molecular pathways deeply; an alternative strategy of using a different drug is commonly applied. In order to reduce the adverse effects of BC treatment including drug resistance, a profound understanding of the molecular mechanism of the disease and the response to the drug is needed. Multidrug resistance (MDR) and consequent relapse on therapy are prevalent issues related to breast carcinoma as our understanding is incomplete related to the molecular mechanism of breast carcinoma disease (Waks and Winer, 2019a). Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. For the management of breast cancers, the treatment decision not only depends on the Treatment with exemestane alone or in combination with an mTOR inhibitor such as everolimus (Carlini et al., 2007Chin et al., 2007Geisler et al., 2008Bahrami et al. (2020) ER+/ HER2- assessment of prognosis factors but also on the evaluation of pathological and clinical factors. Integrated data assessments of these multiple factors of breast carcinoma through multiomics can provide significant insight and hope for making therapeutic decisions (Parsons and Francavilla 2020). Major BC treatment strategies rely on the tumor subtype, immunohistochemical evaluation of prognostic elements, and seek new genetic markers to improve the diagnostic strategies and to enhance treatment outcomes with minimal side effects.

[2] The Unresolved Pathophysiology of Lymphedema

• Authors: S. Azhar, H. Lim, B. Tan, V. Angeli
• Year: 2020
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/d2b9ac3662e78ba19bb12fda47767744e4297fc4
• DOI: 10.3389/fphys.2020.00137
• PMID: 32256375
• PMCID: 7090140
• Citations: 122
• Influential citations: 7
• Summary: It is suggested that more studies should be dedicated to enhancing the understanding of the human pathophysiology of lymphedema to pave the way for new diagnostic and therapeutic avenues for this condition.
• Evidence snippets:
• Snippet 1 (score: 0.411) > In addition, macrophages may play a role in lymphedema by controlling lymphangiogenesis through the production of vascular endothelia growth factor-C, since depletion of macrophage, in established lymphedema, decreases lymphatic transport activity and VEGF-C expression (Zampell et al., 2012b;Ghanta et al., 2015). Finally, macrophages may improve lymph stasis through the upregulation of lymphatic pumping activity by modulating the expression of inducible nitric oxide synthase (Liao et al., 2011;Scallan et al., 2016). Altogether, these findings suggest a complex role for macrophages in the pathophysiology of lymphedema. This diversity of functions may depend on the stage of the disease, its anatomical location (upper versus lower extremity), and the type of macrophage population. > Clinical and animal studies show that inflammatory genes are upregulated in lymphedema (Foldi et al., 2000;Lin et al., 2012;Leung et al., 2014). Importantly, the expression of pro-inflammatory genes, such as TNF-α and IFN-γ, were decreased after complete decongestive treatment. Transcriptional profiling of lymphedematous tissues in a mouse tail model revealed the upregulation of genes involved in acute inflammation, immune response, fibrosis, and wound healing (Tabibiazar et al., 2006). The authors hypothesize that leukotrienes produced by 5-lipoxygenase (5-LO) have a potential role in the pathogenesis of the disease. Human lymphedema patients exhibit increased levels of plasma leukotriene B4 (LTB4) (Tian et al., 2017). In mice treated with LTB4 antagonist, edema is reversed, together with improvement in lymphatic function and skin pathological changes (Tian et al., 2017). Ketoprofen is a NSAID drug with a dual anti-inflammatory mechanism of action, including inhibition of the 5-LO pathway (Rajic et al., 2010).

[3] 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: 0.408) > 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

[4] Role of estrogen receptor signaling pathway-related genes in diffuse large B-cell lymphoma and identification of key targets via integrated bioinformatics analysis and experimental validation

• Authors: Bo Chen, Tianjiao Mao, X. Qin, Wenqi Zhang, N. Watanabe et al.
• Year: 2022
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/580116a1e69f72bee6a7fa0aee9cef4312193b46
• DOI: 10.3389/fonc.2022.1029998
• PMID: 36531013
• PMCID: 9749266
• Citations: 4
• Summary: This study identified 81 overlapping DEGs and CDC6, CDC20, KIF20A, STIL, and TOP2A as novel biomarkers affecting the prognosis of DLBCL and identified the STAT and KRAS pathways as potential growth regulatory pathways.
• Evidence snippets:
• Snippet 1 (score: 0.386) > Currently, targeting DLBCL remains a major clinical challenge, with approximately 30% of patients unable to achieve clinical cure (23, 33). Understanding the molecular pathogenesis of DLBCL identifies druggable molecular pathways. New drugs for DLBCL are being studied and focusing on the optimal sequencing of emerging DLBCL drugs is necessary (34). DLBCL is a heterogeneous disease in terms of morphology, immunophenotype, and molecular features, and its pathogenesis reflects this (35)(36)(37). Studies have shown that the incidence of DLBCL in women is lower. Still, it increases after the age of 50, usually leading to menopause, suggesting that sex hormones may have a protective role for women in developing DLBCL (19,20,38). A previous study indicated that exposure to estrogen in oral contraceptives or postmenopausal hormone replacement during pregnancy reduces the risk of aggressive lymphoma (39). Females were an important favorable prognostic factor compared with males in NHL (23, 40). Yakimchuk K et al. showed that T-cell lymphomas grow faster in ovariectomized mice than in normal female mice (41). In addition, blocking estrogen synthesis by aromatase inhibitors can accelerate lymphoma progression (42). In ovariectomized mice, estradiol treatment slows lymphoma growth (26). Animallevel studies found that human DLBCL transplanted into female mice grew significantly slower than in male mice (43). These results suggest that sexually dimorphic mechanisms that influence tumorigenesis and progression in DLBCL are widespread, likely due to differences in physiological processes such as sex hormone signaling, especially estrogen. > To date, no functional test is capable of screening, and patients must be managed effectively once they are diagnosed. Therefore, identifying the characteristics and regulatory pathways of unique estrogen receptor genes relevant to their pathogenesis and prognosis is of interest. Here, we examined the gene expression profiling of GSE56315 to discover dysregulated hub genes and pathways to understand DLBCL pathogenesis further and provide potential biomarkers. > First, based on differential gene expression analysis and GSEA enrichment analysis, we identified

[5] Gap Junction Channelopathies and Calmodulinopathies. Do Disease-Causing Calmodulin Mutants Affect Direct Cell–Cell Communication?

• Authors: C. Peracchia
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/a90237be940aede218934b765ca0ccc3375481eb
• DOI: 10.3390/ijms22179169
• PMID: 34502077
• PMCID: 8431743
• Citations: 5
• Summary: The studies have demonstrated that certain CaM mutants affect gap junction channel gating or expression, so it would not be surprising to learn that CaM mutations known to cause diseases also affect cell communication mediated by gap junction channels.
• Evidence snippets:
• Snippet 1 (score: 0.383) > Additional symptoms such as peripheral neuropathy, muscle wasting (amyotrophy), ataxia, seizures and dementia may also occur. > Hereditary Lymphedema type 1C (LMPH1C) [27] is caused by autosomal dominant mutations that damage the lymphatic system. The major consequence of this disease is chronic leg swelling, but occasionally swelling also affects the arms, face, chest and genitals. Often, lymphedema is associated with skin disorders (nail dysplasia or papillomatosis). Cx26 is expressed in the epithelium and connective tissue of the organ of Corti in the cochlea, where it regulates the removal of potassium ions and the intracellular pH. Indeed, the release of ATP from connexin hemichannels in cochlear non-sensory cells has been proposed to be the main trigger for action potential activity in immature sensory inner hair cells (IHCs), which is crucial for the refinement of the developing auditory circuitry [28]. Among non-syndromic deafness diseases, the Autosomal Recessive Deafness (1A) [29,30] is the most frequent, while ~20% result from the Autosomal Dominant type (3A). Cx26 truncation or missense mutations are the cause of deafness. Most mutations result in complete loss of hearing, while the N206S mutation results in only moderate hearing loss. The V84L mutation results in total deafness as it inhibits channel permeability to inositol 1,4,5-trisphosphate (IP 3 ) and blocks Ca 2+ waves. Autosomal Dominant Deafness (3A) is also caused by mutations in the transmembrane (TM1) domain or the extracellular loop (EL1) [29,30]. > Autosomal Dominant Deafness-2B (DFNA2B) [31], resulting in the progressive loss of high-frequency hearing, is more severe in males and caused by missense, nonsense and deletion mutations in the GJB3 (Cx31).

[6] Role of Transcriptomics in Precision Oncology

• Authors: Ruby Srivastava
• Year: 2024
• Venue: Reports of Radiotherapy and Oncology
• URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
• DOI: 10.5812/rro-142195
• Citations: 4
• Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
• Evidence snippets:
• Snippet 1 (score: 0.382) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[7] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 27
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.381) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[8] Seven Novel Genes Related to Cell Proliferation and Migration of VHL-Mutated Pheochromocytoma

• Authors: Shuai Gao, Longfei Liu, Zhuolin Li, Y. Pang, Jiaqi Shi et al.
• Year: 2021
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/87ed1b2552635a2a8a8af7056c578bcae1f80180
• DOI: 10.3389/fendo.2021.598656
• PMID: 33828526
• PMCID: 8021008
• Citations: 11
• Summary: It is indicated that inhibition of VHL expression could promote the development of pheochromocytoma by activating the expression of cell proliferation and migration associated genes.
• Evidence snippets:
• Snippet 1 (score: 0.381) > As a rare neuroendocrine tumor, PPGL were mostly benign and could be cured by surgery (47). However, due to the limitations of precise diagnostic tools and effective treatment methods, metastatic PPGL had become a major challenge in the medical field (48,49). Nowadays, more and more attention had been paid to the targeted therapy of PPGL (50). Therefore, optimizing the diagnostic efficiency of metastatic PPGL and finding more effective biological target molecules had gradually become the trend of clinical and basic research (51). In this study, the most relevant tumor malignant indicators and essential biological characteristics were used as screening criteria, and highthroughput technology was used to comprehensively evaluate the molecular mechanism of tumor pathogenesis. As we know, targeted therapy needs long-term and painstaking exploration to obtain more effective treatments (52). > As the key protein of VHL syndrome, pVHL regulated the expression of different tumor genes (53). The patients with VHL germline mutations were susceptible to VHL disease, which was an autosomal dominant syndrome (54). The multiple subtypes of VHL disease indicated that pVHL had multiple cellular functions (55). Other related studies also showed that VHL was involved in other functions besides the regulation mechanism of HIF1amediated proteasome degradation induced by hypoxia (19). > Chitrakar et al. found that in Th17 cells, VHL was involved in the regulation of a variety of cellular pathways (56), including glycolytic pathways that were indirectly or directly inhibited by protein-coding genes (57). Furthermore, the VHL also controlled the function of innate immune cells (58), and the interleukin 33 receptor directly interacted with VHL (59). Our results suggested that pVHL was related to interleukin-related proteins. In order to study the role of pVHL in hypoxia induced pathway, we carried out the whole protein quantitative analysis. Our study showed that the differentially expressed proteins caused by VHL inactivation were mainly concentrated in clusters related to proliferation and migration.

[9] 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: 0.380) > 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.

[10] Characteristics and advances in signaling pathways, cellular communication, cell junctions, and oxidative stress in lymphedema

• Authors: Qiancheng Zhao, Zhipu Niu, Ying Pan, Yongqi Hao, Yuan Ma et al.
• Year: 2025
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/afed566ddc9a8e2479a25cea50484d41d83e0622
• DOI: 10.3389/fcell.2025.1521320
• PMID: 40766782
• PMCID: 12321895
• Citations: 1
• Summary: This review provides a conceptual framework for developing multitarget therapeutic strategies to restore lymphatic homeostasis and develop potential therapies for treating lymphedema by integrating current findings on signaling dysregulation, cell junctions, and cellular crosstalk.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Traditional core therapy Complete CDT (Senger et al., (Szuba et al., 2002;Tammela et al., 2007;Leppäpuska et al., 2022) Promotes understanding of the immunopathological mechanisms underlying lymphedema and establish a theoretical foundation for targeted immunomodulation as a therapeutic approach for this condition. > The existing therapeutic interventions for lymphedema and the current state of research in this domain are inherently limited and encumbered by significant challenges. Clinical interventions, including compression therapy and surgical procedures, are effective in mitigating symptoms. However, they do not address the underlying pathophysiology. Furthermore, there is a paucity of precise treatment regimens that are tailored to specific molecular typing profiles, which is crucial for the management of this condition. In the context of individual signaling pathways, single-target interventions may be inadequate for reversing the pathological process. Consequently, there is an imperative need to explore synergistic regulatory strategies that involve multiple pathways. However, notably, the majority of signaling pathways exhibit cross-talk, a phenomenon exemplified by PI3K/AKT and RAS/MAPK. This observation underscores the existence of substantial research potential and a notable gap in the existing knowledge. Moreover, the majority of extant studies are predicated on animal models, and the heterogeneity of primary versus secondary lymphedema may limit the generalizability of therapeutic strategies. By simulating lymphatic vessel-immune cell interactions, targeting antioxidant-promoting lymphatic regeneration, and remodeling the intralymphatic immune-metabolic microenvironment, further research into the mechanism of lymphedema and exploring therapeutic strategies are highly important. It is anticipated that this study will generate novel research concepts and insights relevant to targeted therapy for lymphedema. > In conclusion, it is imperative that research on lymphedema integrate the exploration of molecular mechanisms with the innovation of therapeutic modalities. In the future, the therapeutic bottlenecks currently experienced by lymphedema patients may be overcome through targeted regulation of oxidative stress, multipathway interventions, and precision medicine strategies. Such strategies may improve lymphatic function and reverse the

[11] 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: 0.375) > 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.

[12] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

• Authors: Michael Harris, K. Bhuvaneshwar, Thanemozhi Natarajan, L. Sheahan, Difei Wang et al.
• Year: 2013
• Venue: Pharmacogenetics and Genomics
• URL: https://www.semanticscholar.org/paper/1382ddf84b87736a73c2f2f81164ca876c29f4c4
• DOI: 10.1097/FPC.0000000000000015
• PMID: 24401833
• PMCID: 3888473
• Citations: 16
• Summary: This in-silico study identified gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic and gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Understanding the genetic and molecular mechanisms underlying complex diseases such as cancer is extremely challenging. Genome-wide association studies (GWAS) have been extensively used in the past decade to discover important genetic variants. However, the identified SNPs explain only a small proportion of the phenotypic variation, and the predictive power of these SNPs remains low for many complex diseases [10]. To fully elucidate genetic underpinnings of disease a systems biology approach is necessary to characterize variants, mRNA, copy number, proteins, and metabolites, as well as their cellular interactions [11]. Gene set and pathway association analyses are playing an increasingly important role in explaining disease mechanisms through the identification of functional genetic interactions [12]. Many gene-disease association analyses are based on SNP genotype profiling or gene expression studies. However, SNPs can influence many downstream processes including the expression levels of multiple genes and/or protein levels, and variations in expression levels can directly or indirectly impact disease progression and even drug response [13]. An integrative approach combining multiple data types can more accurately capture pathway associations [12] for discovery of clinically actionable variants. > Statistical approaches commonly used to associate variants with disease and/or drug response Fisher's exact test (FET) is commonly used in the association of germline polymorphisms with drug response [14]. The use of probabilistic networks in conjunction with traditional statistical models for mining relationships and associations from genotype-phenotype data is well established [15]. Probabilistic network methods for pharmacogenomics and newer methods such as the Markov Blanket concept may be helpful to better analyze these complex genotype-phenotype associations [16]. Considering the complexity of both cancer prognosis and individual drug response to chemotherapeutics, application of these association methods in conjunction with novel informatics and data integration approaches is necessary to identify clinically relevant variants for validation studies and ultimately testing in the clinic for pharmacogenomics applications.

[13] Reverse Phase Protein Array Reveals Correlation of Retinoic Acid Metabolism With Cardiomyopathy in Friedreich's Ataxia

• Authors: Jill S. Napierala, K. Rajapakshe, Amanda D. Clark, Yu-Yun Chen, Shixia Huang et al.
• Year: 2021
• Venue: Molecular & Cellular Proteomics : MCP
• URL: https://www.semanticscholar.org/paper/b777b877ec20159f635445027db505f7596d558f
• DOI: 10.1016/j.mcpro.2021.100094
• PMID: 33991687
• PMCID: 8214145
• Citations: 8
• Summary: expression of aldehyde dehydrogenase family 1 member A3 differed significantly between cardiomyopathy-positive and cardiopathy-negative FRDA cohorts, demonstrating that metabolites such as retinol, retinal, or retinoic acid could become potential predictive biomarkers of cardiac presentation in FRDA.
• Evidence snippets:
• Snippet 1 (score: 0.373) > ly involved in DNA/chromatin metabolism. Interestingly, RRM2, CHAF1A, and EZH2 were all downregulated in the FRDA cohort. Although chromatin changes reported in FRDA were localized to the FXN gene, specifically proximal to the GAA repeats (60-64) without spreading toward neighboring upstream or downstream genes (26), transcriptome profiling of FRDA cells indicates significant global effects on pathways governing gene expression (14,65). Chromatin modifiers such as histone methyltransferases (EZH2) or chromatin assembly proteins (CHAF1) may represent the effectors responsible for global changes of the chromatin environment in FRDA cells contributing to the subsequent transcriptome remodeling observed in FRDA cells. > Hearing impairment observed in patients with FRDA has been studied from a clinical perspective (10,(66)(67)(68)(69). A consensus exists that the ability to detect sound is relatively unaffected in FRDA while auditory processing is compromised as a consequence of auditory neuropathy (10,67). On the other hand, no data exist related to the molecular mechanisms or pathways contributing to the development of hearing deficits in FRDA. Also, it is unclear why this symptom affects only a small subset of the patients. Here, we identified four proteins: HER2/c-ERBB2, CTBP2, integrin b3, and integrin a5 that were significantly downregulated in patients with FRDA diagnosed with HL. > The downregulation of integrins in this cohort of patients with FRDA is especially interesting as integrin b3 has been associated with differentiation of inner ear cells (70). Also, appropriate expression of integrins is necessary for organization and function of hair cells in the mammalian inner ear (71,72), and several members of this protein family are connected to genetic causes of HL (73). Further studies on molecular mechanisms will be necessary to evaluate specific contributions of integrins to FRDA-related HL. Finally, in the context of general FRDA pathophysiology and progression, it is important to consider that integrins are transmembrane receptor proteins

[14] Deciphering cellular states of innate tumor drug responses

• Authors: Esther Graudens, V. Boulanger, Cindy Mollard, R. Mariage-Samson, Xavier Barlet et al.
• Year: 2006
• Venue: Genome Biology
• URL: https://www.semanticscholar.org/paper/c79e62f4751e287a9527444fdeae83162022d48a
• DOI: 10.1186/gb-2006-7-3-r19
• PMID: 16542501
• PMCID: 1557757
• Citations: 135
• Influential citations: 7
• Summary: Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses, and represent a starting point from which by-pass chemotherapy schemes may be developed for critical therapeutic intervention in CRC patients.
• Evidence snippets:
• Snippet 1 (score: 0.372) > to TOP1 inhibitors [20,22]. > Our current understanding of mechanisms associated with drug resistance has been furthered by investigating drugresistant cellular models created by exposing a parental population (yeast, bacteria, mammalian cell lines) to increasing concentrations of a cytotoxic agent [23][24][25][26]. It has been difficult, however, to translate these insights into clinically meaningful improvements in cancer treatment, suggesting that in vitro unicellular models may not be applicable to the in vivo situation or represent the disease in its entirety. For instance, in CRC, TOP1 mutations that decrease the formation of DNA cleavage complexes were identified [27], but their implication in clinical resistance was not confirmed. > Since the introduction of molecular genetics methods in clinical oncology, examination of individual mRNA/protein expression levels of drug target molecules provided complementary indications on the mechanisms involved. Thus far, however, only a limited number of clinical studies of drug resistance have focused on individual candidate genes and these used clinical samples exclusively derived from patients that were already treated with drugs. In CRC, such gene-bygene molecular biology studies have highlighted only a partial list of candidate genes [28][29][30][31][32][33]; some of these genes were shown to be involved in mechanisms altering drug metabolite potency, others are known to participate in increase of drug efflux or decrease of drug toxicity, or to participate in inhibition of apoptosis (for an overview, see [32][33][34][35][36][37]). It is unclear at present whether these mechanisms play a causative role in clinical drug resistance, and no comprehensive analysis of entire drug resistance pathways has been conducted. > Pharmacogenetics and pharmacogenomics approaches have been initiated to study the relationship between individual variations and drug response rates [38,39]. Genetic polymorphisms of specific genes were found to be associated with clinical outcomes in patients treated through chemotherapy, and amplification of genes encoding drug targets or transporters was shown to alter the sensitivity of cancer cells to a particular chemotherapy [40,41]. Finally, loss of heterozygosity at specific regions of chromosomes was identified in specific carcinoma, although its consequence in treatment outcome remains

[15] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

• Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
• Year: 2014
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
• DOI: 10.3389/fcell.2014.00037
• PMID: 25364744
• PMCID: 4207010
• Citations: 23
• Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.371) > In such scenario a biomarker needs to serve as proxy of key mechanistic factors characterizing and driving a disease on a patient-specific level, combined with educating on the specific interference of disease mechanism with drug mechanism of action. For capturing these constraints a detailed molecular map of a clinical phenotype and its interference with a drug mechanism of action is needed, and here integration of Omics profiling adds to identifying such mechanisms (Fechete et al., 2011;Mühlberger et al., 2012). > An a priori stratification of patients based on an appropriately chosen biomarker panel reflecting the pathophysiology of a given patient (group) allowing to determine a match with a specific drug's mechanism of action appears as promising approach. As recently discussed by Himmelfarb et al. fresh approaches are critical in finding therapies to kidney disease benefiting patients, outlining the importance of improving the translational aspect in clinical research (Himmelfarb and Tuttle, 2013). Here, omics technologies have added significantly to the data landscape characterizing chronic kidney disease, however, in a first instance mainly expanding the candidate set of apparently relevant processes and pathways, going in hand with a large number of biomarker candidates, which individually hamper clinically relevant assessment on disease progression (Fechete et al., 2011;Hellemons et al., 2012). > Integrative approaches in the realm of Systems Biology have been proposed for reaching a consensus description of chronic kidney disease pathophysiology, including molecular models of DN as well as of the reno-cardial axis (He et al., 2012;Komorowsky et al., 2012;Mayer et al., 2012;Heinzel et al., 2013). Still, a translation process needs to be followed, joining disease pathophysiology, stratification markers allowing enrichment strategies, combined with on a molecular mechanistic level matching drugs for allowing precision medicine (Mirnezami et al., 2012). In this work we exemplify such procedure on DN being the major clinical presentation leading to end stage renal disease.

[16] Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

• Authors: C. Çubuk, F. Can, M. Peña-Chilet, J. Dopazo
• Year: 2020
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/e40f7a3b8f72ba01374ba00fbf308a47a3fa5dd4
• DOI: 10.3390/cells9071579
• PMID: 32610626
• PMCID: 7408716
• Citations: 9
• Summary: Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-s...
• Evidence snippets:
• Snippet 1 (score: 0.371) > Therefore, a proper interpretation of the effect that differences in gene expression have over phenotypes, such as drug response or disease progression, involves understanding the mechanisms of the disease or the mode of action of drugs, which can be interpreted through mechanistic models of cell signaling [12] or cell metabolism [13]. Mechanistic models have helped to understand the disease mechanisms behind different cancers [14,15], including neuroblastoma [16,17], breast cancer [18], rare diseases [19], complex diseases [20], the mechanisms of action of drugs [21,22], and other biologically interesting scenarios such as the molecular mechanisms that explain how stress-induced activation of brown adipose tissue prevents obesity [23] or the molecular mechanisms of death and the post-mortem ischemia of a tissue [24]. Among the few available proposals of mechanistic modeling algorithms that model different aspects of signaling pathway activity, Hipathia has demonstrated having superior sensitivity and specificity [12]. > Here, we propose the use of mechanistic models [13,14] of signaling activity related with cancer hallmarks [25], other cancer-related signaling pathways, and some extra relevant cellular functions to understand the functional consequences of the gender bias in gene expression. Such mechanistic models use gene expression data to produce an estimation of profiles of signaling or metabolic circuit activity within pathways [13,14]. An interesting property of mechanistic models is that they can be used not only to understand molecular mechanisms of disease or of drug action but also to predict the potential consequences of gene perturbations over the circuit activity in a given condition [26]. Actually, in a recent work, our group has successfully predicted therapeutic targets in cancer cell lines with a precision over 60% [15]. Therefore, we will use this mechanistic framework to understand what is the molecular basis of the different effects of cancer drugs by directly simulating their effect in the patients. This approach has recently been used by us to understand the generation of resistances in cancer at the single cell level in glioblastoma [27].

[17] 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.

[18] Notch1 siRNA and AMD3100 Ameliorate Metabolic Dysfunction-Associated Steatotic Liver Disease

• Authors: Chunli Zhu, Yiheng Cheng, Lei Yang, Yifu Lyu, Jingjing Li et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/f3a6939b33db32d6c141825ae843fbc27c1d1ad8
• DOI: 10.3390/biomedicines13020486
• PMID: 40002899
• PMCID: 11853639
• Citations: 2
• Summary: This work demonstrated that in liver cells, siNotch1 combined with AMD3100 not only directly modulated macrophages by downregulating multiple pathways downstream of Notch, exerting anti-inflammatory, anti-migration, and switch of macrophage phenotype, but also modulated macrophage phenotypes through inhibiting NET release.
• Evidence snippets:
• Snippet 1 (score: 0.367) > Metabolic dysfunction-associated steatotic liver disease (MASLD), renamed from non-alcoholic liver disease (NAFLD), is considered one of the most common causes of chronic liver diseases, including progression of hepatic steatosis, metabolic dysfunctionassociated steatohepatitis (MASH), fibrosis, and hepatocellular carcinoma (HCC) [1,2]. Meanwhile, MASLD is a multisystem disease with some extrahepatic complications like cardiovascular disease (CVD), type 2 diabetes mellitus, and chronic kidney disease [3]. MASLD represents a significant and progressively increasing global health and economic burden, while prevalence of MASLD continues to increase substantially worldwide [4]. The good news is that the FDA approved the first drug for the treatment of MASH, Rezdiffra, in 2024, but the long-term efficacy of the drug is still being studied and evaluated [5]. Moreover, other promising drugs targeting mechanisms of MASLD are still under clinical trials. Apart from developing new drugs, considering the complex pathogenesis of MASLD, it is necessary to propose more clinical protocols for drug combination to treat MASLD, as efficacy can be increased and side effects can be reduced in this way [6]. > The Notch signaling pathway is extremely evolutionarily conserved and is extensively involved in various diseases of the nervous, immune, and cardiovascular systems [7]. In MASLD progression, the Notch signaling pathway is associated with hepatic lipid accumulation, insulin resistance (IR), oxidative stress (OS), fibrogenesis, and autophagy progression in MASLD [8]. Specifically, the Notch signaling pathway is involved in the activation and effect of pro-inflammatory macrophages, and it directly regulates the transcription of pro-inflammatory signature genes, such as Il6, Il12b, and Nos2 [9]. In monocytes, the Notch signaling pathway plays a crucial role in cell migration and differentiation [10], and it also mediates the transition between the Ly6C high inflammatory phenotype and the Ly6C low circulating surveillance phenotype through mechanisms similar to those in macrophages [11].

[19] 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: 3
• 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: 0.367) > 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.

[20] Use of the traditional Chinese medicine “compound healthy ear agent” to protect against age-related hearing loss in mice: A proteomics study

• Authors: Weijun Xuan, Liyi Huang, Y. Xuan, Sizhong Chen, Junbo Tang et al.
• Year: 2024
• Venue: Heliyon
• URL: https://www.semanticscholar.org/paper/70b8e88e73e62a97fbaddec36d97978d9872b909
• DOI: 10.1016/j.heliyon.2024.e26914
• PMID: 38434421
• PMCID: 10907787
• Citations: 2
• Summary: The TCM CHEA played a protective role against AHL in mice by regulating the expression of specific proteins and genes in cochlear hair cells and spiral ganglion neurons.
• Evidence snippets:
• Snippet 1 (score: 0.367) > To sum up, we found that CHEA could regulate several proteins and genes related to various pathways, including synaptic molecular transmission, cellular energy metabolism, immune defenses, anti-oxidant defenses, anti-apoptosis, etc. The findings provide strong evidence to explain the mechanisms of CHEA, which had already been clinically proven to prevent and treat AHL and other types of sensorineural hearing loss. Among these mechanisms, stimulating an improvement in immune defense is a new highlight of this study. > It is known that AHL mechanisms are quite complex, including contributions from oxidative stress, ROS damage, gene variations and inheritance, microcirculatory disorders in the inner ear, immune dysfunction, arteriosclerosis, hypertension, diabetes, aging and degeneration of inner ear organs, environmental noise, ototoxic drugs, infection and inflammation [44]. This proteomics study found that there were many different proteins with statistically significant differences between each group, which involved multiple and complex regulatory pathways. It is impossible to explain them all clearly and in detail in only one publication, so they remain to be investigated one by one in the future. This article is a preliminary summary of the results, with a focus on new discoveries about which proteins were upregulated by CHEA. In addition to discussing various proteins related to AHL mechanisms such as promoting neural growth, eliminating ROS, anti-apoptosis, we also highlight newly discovered proteins affected by CHEA which regulate and enhance immune function, improve cardiovascular function, and reverse age-related disorders. We suggest that not only has CHEA been proven over the past decade to prevent and treat AHL and regulate AHL-related mechanisms, but it also could prevent and treat other diseases related to aging.

Notes

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