Asta Literature Retrieval: Pathophysiology and clinical mechanisms of CTLA4 Haploinsufficiency. Core disease mechanisms, molecular and cellular...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade

• Authors: Josselyn E Garcia-Perez, Ryan M. Baxter, D. Kong, R. Tobin, M. McCarter et al.
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/b4e3547d18e57d28d09ecb5698e011ff3fae6f59
• DOI: 10.3389/fimmu.2019.00998
• PMID: 31156616
• PMCID: 6532297
• Citations: 16
• Summary: Assessment of CTLA4 mRNA expression in CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients demonstrated an inverse correlation between theCTLA4 message and degree of CTla-4 pathway disruption, suggesting that CTLA2 mRNA levels may be a quantifiable surrogate for altered CTLA3 expression.
• Evidence snippets:
• Snippet 1 (score: 0.464) > CTLA-4 is an important immune checkpoint that modulates tolerance, in which CTLA-4 pathway engagement promotes Treg suppressive function, while its blockade enhances T cell activation. In the absence of a competently functioning CTLA-4 pathway, autoimmunity ensues. Despite differing in genetic origins, the irrevocably linked biology of CTLA-4 and LRBA leads CTLA-4 haploinsufficiency and LRBA deficiency patients to similar clinical ends. Although there have been many attempts to understand underlying disease mechanisms in CTLA-4 haploinsufficiency and LRBA deficiency and correlate genotype with phenotype, none have been successful thus far (13,29). Similarly, investigations into predictive parameters or disease biomarkers that might identify those patients at risk of developing autoimmune complications after CTLA-4 blockade have been unrevealing. In this perspective, we observe an apparent correlation between CTLA4 mRNA levels and the degree of CTLA-4 pathway disruption. In CTLA-4 haploinsufficient and LRBA deficient patients, those that are abatacept non-treated show higher levels of CTLA4 mRNA expression than abatacept-treated patients, who show CTLA4 mRNA expression levels similar to healthy controls. Consistent with this correlation of CTLA-4 pathway disruption, ipilimumab-treated patients demonstrate the highest CTLA4 mRNA expression levels compared to the monogenic patients or healthy controls; particularly, the ipilimumab-treated patients who developed autoimmunity were those who had the highest CTLA4 mRNA expression (most CTLA-4 pathway disruption). These findings represent the first study comparing genetic vs. therapeutic disruptions to the CTLA-4 pathway and suggest the evaluation of CTLA4 mRNA expression as a proxy for severity of CTLA-4 pathway disruption in patients receiving anti-CTLA-4 immunotherapy. Future studies evaluating larger patient cohorts are required to further expand this finding and potentially uncover a reliable biomarker for clinical management of these disorders.

[2] Non-infectious Complications of Common Variable Immunodeficiency: Updated Clinical Spectrum, Sequelae, and Insights to Pathogenesis

• Authors: Hsi-en Ho, C. Cunningham-Rundles
• Year: 2020
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/002847d6f73acda4dbf3e61275000d7b56b68496
• DOI: 10.3389/fimmu.2020.00149
• PMID: 32117289
• PMCID: 7025475
• Citations: 175
• Influential citations: 15
• Summary: Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.461) > osis, resulting in reduced APC-mediated T cell activation. CTLA4 is essential for the function of Treg cells, which are responsible for maintaining self-tolerance and immune homeostasis. Homozygous recessive LRBA mutations have mostly been identified in childhood onset disease, but compound heterozygous mutations have been identified in adult CVID cohorts (40)(41)(42). In LRBA deficient patients, there are concurrent B cell defects (disturbed development, defective activation, poor plasmablast formation) manifesting as hypogammaglobulinemia, and T cell dysregulation (decreased Treg cell markers, expansion of T follicular helper cells, contraction of T follicular regulatory cells) that may contribute to inflammatory complications (38,42). Clinically, these patients are affected by recurrent infections, autoimmunity, lymphoid hyperplasia, as well as severe inflammatory bowel disease in some (40)(41)(42). Heterozygous CTLA4 mutations, on the other hand, can lead to haploinsufficiency, impaired protein dimerization, or impaired ligand binding, causing an autosomal dominant syndrome with variable penetrance (43)(44)(45)(46). Clinically, this highly variable syndrome is marked by antibody deficiency (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), as well as lung (68%) and gastrointestinal (59%) diseases, amongst additional non-infectious complications, in a large cohort study (n = 133) (46). The elucidation of this molecular pathway and the availability of CTLA4 fusion proteins (abatacept, belatacept) have allowed for the potential for targeted treatment approach. In select cases, the loss of CTLA4 in LRBA deficiency has been successfully treated with abatacept (38). Similarly, some subjects with CTLA4 haploinsufficiency have had positive clinical response to abatacept or belatacept (11/14 subjects in one series) (46). Phosphoinositide 3-kinase (PI3

[3] Non-Celiac Villous Atrophy—A Problem Still Underestimated

• Authors: K. Napiórkowska-Baran, Paweł Treichel, Adam Wawrzeńczyk, Ewa Alska, Robert Zacniewski et al.
• Year: 2025
• Venue: Life
• URL: https://www.semanticscholar.org/paper/426f4a37580e1c18878b8d584ac0df940b949cb2
• DOI: 10.3390/life15071098
• PMID: 40724600
• PMCID: 12301050
• Citations: 2
• Summary: An in-depth understanding of the heterogeneous etiology of NCVA is critical to improving diagnostic accuracy and optimizing therapeutic strategies, and future research should prioritize the identification of specific biomarkers and the development of targeted interventions to address the unique mechanisms underlying NCVA, thereby improving patient management and outcomes.
• Evidence snippets:
• Snippet 1 (score: 0.453) > Genetic and environmental factors contribute significantly to the pathogenesis of NCVA. These factors act independently and synergistically to affect immune regulation, inflammatory responses, and intestinal health. Genetic predispositions, such as those in monogenic immune disorders, are fundamental to understanding NCVA. Conditions like CTLA4 haploinsufficiency and IL10RA mutations exemplify how specific genetic aberrations lead to immune dysregulation. CTLA4 haploinsufficiency is implicated in autoimmune enteropathy, primarily through dysregulated T-cell activity, culminating in sustained inflammation and tissue destruction in the small intestine. Similarly, mutations in the IL10RA gene, particularly prominent in early-onset inflammatory bowel disease (IBD), disrupt critical anti-inflammatory pathways, allowing unrestrained inflammatory responses that damage the intestinal villi. These findings underscore the importance of genetic analyses in identifying hereditary causes of NCVA, which not only aid in diagnosis but also highlight potential therapeutic targets, such as cytokine modulation or T-cell suppression, tailored to the specific genetic mechanism involved [5,27]. > Regional trends in genetic mutations, such as the prevalence of IL10RA mutations in Southeast Asia, point to the need for geographically specific screening programs. In endemic regions, the burden of NCVA resulting from these mutations underscores how local epidemiological factors must guide diagnostic strategies and public health interventions. For example, infections endemic to these areas may exacerbate genetically predisposed inflammation, illustrating a gene-environment interaction that warrants proactive regional genetic and clinical monitoring. Targeted genetic testing, combined with an understanding of local environmental influences, facilitates early identification and prevention of complications in high-risk populations [27]. > Genetic testing is crucial in identifying CTLA4 haploinsufficiency, which often underlies autoimmune enteropathies. Identifying inherited mutations allows early intervention through therapies such as immunomodulation, targeting specific genetic mechanisms re-sponsible for disease progression. Moreover, the findings argue for family screening, since relatives of affected individuals may share genetic susceptibilities.

[4] Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency

• Authors: Roos-Marijn Berbers, M. van der Wal, J. V. van Montfrans, P. Ellerbroek, Virgil A. S. H. Dalm et al.
• Year: 2021
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/1dc4de90022a3d4abaabc387e7674af8d7181a2d
• DOI: 10.1007/s10875-021-01084-6
• PMID: 34247288
• PMCID: 8452589
• Citations: 24
• Influential citations: 1
• Summary: CVIDid was characterized by chronic activation of peripheral T-cells with preserved inflammatory potential rather than functional exhaustion, and increased tissue migratory capacity, and combined studies of T-cell dysfunction and circulating inflammatory proteins may direct future treatment strategies.
• Evidence snippets:
• Snippet 1 (score: 0.442) > In addition to this chronically activated T-cell state, we observed a decreased ability of Tregs to upregulate CTLA4, while CTLA4 expression was increased in the whole CD4 + population. Expression of CTLA4 by Tregs is an important mechanism by which Tregs mediate their suppressive function [33]. Clinical CTLA4 haploinsufficiency often results in a CVIDid phenotype with hypogammaglobulinemia and autoimmune disease, and functional Treg dysfunction has been described [19]. In this study, the T-cell profile of the patient with CTLA4 haploinsufficiency was often not very different from the other non-genetic CVIDid patients. Therefore, the expression of CTLA4 in Tregs of non-genetic CVIDid patients may be relevant to the overall underlying pathophysiology of CVIDid and warrants further research. A recent study shows that abatacept, a CTLA4 fusion protein, was safe and effective in the treatment of CVIDid with interstitial lung disease [34]. As the population of CVIDid patients with low CTLA4 + CD27 + Tregs represented a mix of patients with pulmonary inflammation but also other organ-specific autoimmunity (data not shown), abatacept may be efficacious in other CVIDid patients as well. In addition, longitudinal monitoring of CTLA4 Treg expression in CVIDid may indicate whether it can be used as a biomarker for disease exacerbation and/or therapeutic response. > Despite these overall differences between CVIDid and CVIDio, the heterogeneity within the CVIDid group was substantial. Subgroup analyses of patients with organspecific autoimmunity did not yield insightful patterns, except that GLILD patients were often more extreme in all observed differences (data not shown). In addition, disease severity did not always reflect immune activation.

[5] Anti-CTLA-4 Induced Inflammatory Bowel Disease: Is There A More Etiological Treatment? Lessons From CTLA-4 Haploinsufficiency

• Authors: Athina Theocharidou, Georgios Germanidis
• Year: 2018
• Venue: Gastroenterology: Medicine & Research
• URL: https://www.semanticscholar.org/paper/d5d6f885c8265794ece2edfa012aec3a0fa4fce7
• DOI: 10.31031/GMR.2018.01.000525
• Summary: The immunological characteristics of anti-CTLA-4 and anti-PD-1-related colitis have been up to now poorly described and may need to be better described.
• Evidence snippets:
• Snippet 1 (score: 0.433) > Although the frequency of FoxP3+ Treg cells within the CD4+ T cell compartment was increased in individuals with a heterozygous CTLA4 mutation compared to healthy CTLA4+/+ controls, affected patients had reduced CTLA-4 protein (similarly as to use a neutralizing CTLA-4 antibody) and mRNA expression in sorted Treg cells relative to healthy donors; this reduction persisted, and deficit was even more pronounced after T cell activation [3]. These results demonstrate the complex spectrum of clinical complications that can be anticipated from CTLA-4-blocking drugs. Consistent with these findings, treatment with the CTLA-4 mimetic, CTLA-4-Ig (abatacept), suppressed patients T cell hyperproliferation in vitro and could be a potential therapeutic intervention for CTLA-4deficient patients [3]. Therefore, human CTLA-4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis [3]. CTLA-4 can function by removal of its ligands (CD80 and CD86) from antigen presenting cells via transendocytosis. > These CTLA-4 ligands are shared with the stimulatory receptor CD28, whose engagement drives T cell activation, cytokine production and memory T cell differentiation. Depletion of the costimulatory ligands CD80 and CD86 by CTLA-4 reduces antigen presenting cell-mediated activation of conventional T cells via CD28, resulting in dominant suppression of T cell activation [4]. Treg cells from individuals with CTLA4 heterozygous mutations were unable to suppress CD4+ T cell proliferation as compared to healthy CTLA4+/+ controls. > Taken together, these data indicate that two functional CTLA4 alleles appear necessary to drive the high levels of protein required in activated Treg cells, and in this condition their overall suppressive activity is impaired by CTLA-4 mutations. The relative role of CTLA-4 in Treg cells versus conventional T cells remains unexplained and additional work is needed to interprete the T cell-intrinsic hyperproliferation in these patients bearing CTLA4 mutations.

[6] Cytotoxic T Lymphocyte Antigen 4 Haploinsufficiency Presenting As Refractory Celiac-Like Disease: Case Report

• Authors: Lauren V Collen, C. Salgado, B. Bao, E. Janssen, D. Weir et al.
• Year: 2022
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/6069ef76f4203c38aa8a45e4d9e13bd2918981b6
• DOI: 10.3389/fimmu.2022.894648
• PMID: 35935971
• PMCID: 9352891
• Citations: 6
• Summary: Two patients with celiac/celiac-like disease diagnosed in early childhood and refractory to the gluten-free diet are presented and diagnosed with cytotoxic T lymphocyte antigen 4 (CTLA4) haploinsufficiency, which has incomplete penetrance and significant phenotypic heterogeneity.
• Evidence snippets:
• Snippet 1 (score: 0.420) > To our knowledge, this is the first detailed report of CTLA4 haploinsufficiency presenting with refractory celiac-like disease as the primary manifestation. These cases highlight the value of keeping a high index of suspicion for CTLA4 haploinsufficiency in patients with refractory celiac disease, especially when multiple autoimmune diseases or a suggestive family history are present. Importantly, case 2 highlights that CTLA4 haploinsufficiency can mimic refractory celiac disease, even in the absence of other features suggestive of immunodeficiency or autoimmunity. > Identification of CTLA4 haploinsufficiency has important implications for therapeutics and cancer risk. From a therapeutic standpoint, both cases are examples of lifechanging responses to abatacept, a fusion protein that binds to CD80 and CD86 receptors on antigen-presenting cells (APCs), blocking interactions with CD28 and thereby inhibiting T cell activation. This precision medicine approach directly addresses the mechanism by which CTLA4 haploinsufficiency results in immune dysregulation. Abatacept is currently approved only for use in rheumatoid arthritis (RA) and, notably, both patients 1 and 2 required higher dosing than is typically used in RA to achieve a complete response. The largest report on therapeutic approaches to CTLA4 haploinsufficiency, which includes 123 patients, comments on responses to systemic and topical corticosteroids, abatacept, azathioprine, sirolimus, and tumor necrosis factor-a inhibitors in the subset of 74 patients (60%) with gastrointestinal involvement. Of these patients, nine of 74 used abatacept, and all nine had an initial clinical response, although two ultimately discontinued abatacept after diarrhea recurred. These nine patients notably used different dosing than reported in our patients (subcutaneous weekly dosing versus higher, less frequent intravenous dosing), and none of the nine patients who used abatacept were reported to have presented with celiac-like disease (11).

[7] Primary immune regulatory disorders: Undiagnosed needles in the haystack?

• Authors: A. Flinn, A. Gennery
• Year: 2022
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/14a105e193d6ba770039349397c083d49b466f0f
• DOI: 10.1186/s13023-022-02249-1
• PMID: 35241125
• PMCID: 8895571
• Citations: 20
• Influential citations: 2
• Summary: Due to the rarity of these conditions, worldwide collaboration and data-sharing is essential to improve knowledge of the clinical spectrum and disease course in PIRD, and to optimize therapeutic strategies including identification of which patients can benefit from hematopoietic stem cell transplant.
• Evidence snippets:
• Snippet 1 (score: 0.412) > LRBA deficiency is caused by biallelic mutations in LRBA gene, resulting in loss of or reduced expression of LRBA protein. LRBA deficiency and CTLA haploinsufficiency share a similar underlying pathophysiology; LRBA plays an essential role in recycling CTLA4 from intracellular vesicles to the cell surface and therefore impairs the availability of CTLA4 in Treg-mediated immune regulation [30]. Like other PIRDs, there is significant variability in the clinical phenotype and a lack of genotype-phenotype correlation [30][31][32][33][34]. Patients with residual protein expression exhibit a less severe clinical course compared to those with absent LRBA protein [34]. LRBA deficiency typically presents in the first two decades of life, although the timing of onset varies widely during this period [32]. Autoimmunity is the most common clinical manifestation, with splenomegaly, pneumonia, lymphoproliferation and enteropathy being other common clinical features [31][32][33]35]. Autoimmune cytopenias are a prominent feature, but a wide spectrum of autoimmune diseases including type 1 diabetes mellitus, hepatitis, thyroid disease, and arthritis are reported and patients often exhibit polyautoimmunity [32,33,36]. Reduced class-switched memory B-lymphocytes, Tregs and immunoglobulin levels are the most common abnormalities in immune parameters [35]. As expected, due to the shared pathogenetic mechanisms, the phenotype of LRBA deficiency overlaps significantly with that of CTLA haploinsufficiency, although severe infections appear to be a more prominent feature in LRBA deficiency [34,37]. A recent analysis of long-term outcomes in a large cohort of patients with LRBA deficiency demonstrated the superior effect of targeted therapy with abatacept or sirolimus with decreased disease activity scores compared to conventional immune suppression [34]. Treatment with allogeneic HSCT can result in complete disease remission, but higher disease burden pre HSCT is associated with a worse outcome [34].

[8] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.404) > 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.

[9] Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions

• Authors: H. Su
• Year: 2017
• Venue: F1000Research
• URL: https://www.semanticscholar.org/paper/a0f21f92e996a7ed4bc95bf85a5648a07127fc33
• DOI: 10.12688/f1000research.10594.1
• PMID: 28408979
• PMCID: 5373415
• Citations: 1
• Summary: Immunodeficiencies reveal the crucial role of the immune system in defending the body against microbial pathogens and have provided insights into how gene products normally function in the natural environment.
• Evidence snippets:
• Snippet 1 (score: 0.402) > B cell memory generation, concurrent lymphoproliferation and hypogammaglobulinemia, and increased infections including poor control of EBV and cytomegalovirus infections. With the knowledge of the signaling pathway affected, the mTOR inhibitor sirolimus has been used in these patients and clinical improvement observed. Fortuitously, targeted therapy using small molecular inhibitors of PI3Kδ are being developed for the treatment of cancers, in which somatic gain-of-function mutations of PIK3CD are sometimes found. Thus, PASLI as an orphan disease provides the perfect opportunity to demonstrate precision medicine in action by using the same drugs designed for another purpose. Clinical trials are ongoing to test their efficacy in this disease. > A second example comes from recent work elucidating the molecular mechanism by which LATAIE disease (for "LRBA deficiency with autoantibodies, regulatory T [Treg] cell defects, autoimmune infiltration, and enteropathy"), due to genetic deficiency of the LRBA adaptor protein, causes a mixed picture of autoimmunity and humoral immunodeficiency and responds to CTLA4-Ig (abatacept) treatment 45 . This therapeutic intervention helped to establish the mechanism by which LRBA deficiency phenocopies CHAI disease (for "CTLA4 haploinsufficiency with autoimmune infiltration") 23,24 . Both molecules are interconnected in the same pathway whereby LRBA normally regulates the intracellular vesicle trafficking of, and is required for, cell surface expression of CTLA4. CTLA4 expression, especially on Treg cells, in turn restrains lymphocyte responses and indirectly regulates B cell responses. Furthermore, by defining that LRBA normally helps prevent CTLA4 deposition and degradation in lysosomes, treatment with hydroxychloroquine, a lysosome blocker that is already clinically used for the treatment of lupus, could also be helpful in the treatment of LRBA deficiency. > Together, these two examples illustrate that the unbiased identification of causative gene mutations in human patients leads to knowledge of potential mechanistic targets with immediate clinical implications. Translation of this knowledge has sped up because of the increased development of new biological immun

[10] 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: 8
• 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: 0.396) > 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.

[11] 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: 0.385) > 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

[12] Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications

• Authors: Jianan Zhao, Shicheng Guo, Steven J. Schrodi, D. He
• Year: 2021
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/c94ff7b93e79668e765719486b267d8485231fe6
• DOI: 10.3389/fimmu.2021.790122
• PMID: 34899757
• PMCID: 8660630
• Citations: 123
• Influential citations: 3
• Summary: This review discusses the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis and provides a suggestive framework for implementing preclinical and clinical experimental results into clinical practice.
• Evidence snippets:
• Snippet 1 (score: 0.384) > RA is a heritable autoimmnune disease mediated by genetic (15), epigenetic (11,16), genetic-epigenetic (17) and genetic-environment (18) interactions while treatment usually take epigenetics and immnue factors as therapeutic targets (19). These inherited factors influence the heterogeneity of disease progression and determine the underlying set of cellular and molecular mechanisms. The role of heritability has been dissected in linkage and association studies, revealing the molecular variation underlying RA risk variability. The most evident aspects include (i) class II HLA genes, primarily HLA-DRB1, segregate variants that elevate RA risk 2-3-fold through aberrant antigen presentation (20)(21)(22); (ii) the 620W allele of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which generates various effects across numerous immune cell types and confers elevated risk of autoimmunity (15,23); (iii) chemokine receptor genes, including C-C chemokine receptor 6 (CCR6) (15,24,25); (iv) peptidyl arginine deiminase type IV (PADI4), which encodes peptidylarginine deiminase type 4 (involved in protein citrullination) (26,27); (v) the transcription factor-encoding gene signal transducer and activator of transcription 4 protein (STAT4) (15,25), (vi) cytotoxic T-lymphocyte antigen 4 (CTLA4), encoding for the cytotoxic T-cell associated protein (25,28), and (vii) the B-cell cell surface receptor gene, CD40 (29,30). Although these genetic factors predispose individuals to RA, patients exhibit a wide variety of combinations of these variants. This genetic variation across patients is considered to partially drive the heterogeneity in RA pathophysiology, clinical presentation, and response to therapies (31) (See Table 1).

[13] 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: 0.383) > 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

[14] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.382) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[15] LifeTime and improving European healthcare through cell-based interceptive medicine

• Authors: N. Rajewsky, G. Almouzni, S. Gorski, S. Aerts, I. Amit et al.
• Year: 2020
• Venue: Nature
• URL: https://www.semanticscholar.org/paper/d626a4acb560c1ef16ea394cb4dccf277882d119
• DOI: 10.1038/s41586-020-2715-9
• PMID: 32894860
• PMCID: 7656507
• Citations: 138
• Influential citations: 2
• Summary: The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe over the next decade.
• Evidence snippets:
• Snippet 1 (score: 0.380) > , a major challenge is a lack of understanding of the early events in disease onset to enable the development of disease-modifying therapies. The lack of access to longitudinal samples from patients necessitates the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. The discovery of pathways and biomarkers that will allow the stratification of patients on the basis of the cellular mechanisms that drive a disease will make it possible to design new clinical trials to reevaluate drugs that were previously tested without such stratification, and to broaden the drug target portfolio. > As seen during the coronavirus disease 2019 (COVID-19) pandemic, it is important to be able to understand infection mechanisms and the host response in order to rapidly identify the most likely effective treatment for an infection. At the same time, the continuous rise of antimicrobial resistance requires the discovery of new therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and to develop precision, immune-based therapeutic strategies to combat infections. > Chronic inflammatory diseases impose a high burden owing to their long-term debilitating consequences, which result from the structural destruction of affected organs or tissues. Current therapies treat the symptoms but do not cure or fully control the chronic inflammatory pathophysiology. While different targeted therapies exist, they are expensive and their success is limited by high rates of non-response to treatment. Consequently, there is an urgent need to explore and understand how cellular heterogeneity contributes to the pathology of inflammatory diseases 61 and how this relates to the predicted course of disease and the response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies owing to a lack of knowledge of their underlying causes and the link between abnormal cardiac cell structure or function and pathophysiology. The identified medical priority is to understand the cellular and molecular mechanisms involved, in order to enable early diagnosis and the design of new mechanism-based therapies for precise clinical treatment. > The LifeTime disease roadmaps can be divided broadly into three phases 7 : first, immediate research into the identified medical challenges using established, scaled single-cell technologies, computational tools and disease models; second, the development of new technologies that are required

[16] 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: 0.380) > 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.

[17] 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: 24
• 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: 0.379) > 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].

[18] 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: 0.376) > 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.

[19] Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

• Authors: S. Tangye, W. Al-Herz, A. Bousfiha, C. Cunningham-Rundles, J. Franco et al.
• Year: 2022
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/ac4b6624d4dce3dfcad27f1114ce4a63eda1b45d
• DOI: 10.1007/s10875-022-01289-3
• PMID: 35748970
• PMCID: 9244088
• Citations: 855
• Influential citations: 56
• Summary: This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update or were characterized earlier but have since been confirmed or expanded in subsequent studies.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Inborn errors of immunity (IEI) are caused by damaging germline variants in single genes. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. While individually rare, the aggregated number of individuals with an IEI represents a significant health burden [1]. Genetic variants cause disease by altering the encoded gene product, such as by abolishing or reducing protein expression and function (null/hypomorphic) or modifying the protein to acquire gain-of-function (GOF) [2][3][4][5]. Mechanisms of disease in IEI depend on the nature of the variant as well as the mode of inheritance. Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, loss of function (LOF), GOF, or even neomorphic function of the encoded protein, while X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males, or homozygous state in females. > The fact that some monogenic variants are pathogenic clearly highlights the non-redundant and fundamental roles of individual genes and proteins, and associated pathways and cell types, in the development and function of leukocytes and non-hematopoietic cells that contribute to immune homeostasis and host defense [6,7]. Thus, IEI represent an elegant model linking defined monogenic defects with clinical phenotypes of immune dysregulation. IEI have also revealed mechanisms of disease pathogenesis in, and enabled the implementation of gene-or pathway-specific therapies for the treatment of, rare and common conditions and established fundamental aspects of human immunology [8][9][10]. Thus, the study of IEI has enabled profound advances in molecular medicine and human biology. > Since 1970, an international expert committee comprising pediatric and adult clinical immunologists, clinician/scientists and researchers in basic immunology -initially

[20] 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: 0.375) > 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.

Notes

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