Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Cold Agglutinin Disease. Core disease mechanisms, molecular and cellular p...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] 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: 39
• 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: 0.422) > 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.

[2] 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: 27
• 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: 0.406) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify 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. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.

[3] Differential Regulation of Interferon Signaling Pathways in CD4+ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype

• Authors: F. Alhamdan, L. Marsh, F. Pedersen, B. A. Alhamwe, C. Thölken et al.
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/64e368bc44d989aa672152b1812fa77c44e3189c
• DOI: 10.3390/ijms221810144
• PMID: 34576307
• PMCID: 8469911
• Citations: 25
• Summary: The specific activation of interferon (IFN)-stimulated genes associated with IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in theDevelopment of new stratified therapeutic approaches.
• Evidence snippets:
• Snippet 1 (score: 0.405) > Over the last decades, non-communicable diseases (NCDs) have become the major cause of death worldwide, especially after the development of effective anti-infectious measures of prevention (vaccines) and treatment (antibiotics) [1][2][3]. Moreover, they represent a huge burden on the healthcare system and economic situation [4,5]. Prevalence and incidence of NCDs are still further increasing along with ongoing urbanization, industrialization, and globalization of unhealthy diet and lifestyles [6,7]. According to the World Health Organization (WHO), the rapid increase in the NCDs is mainly driven by various risk factors including tobacco, harmful use of alcohol, and obesity [8]. Furthermore, different NCDs and their major risk factors seem to have substantially overlapping underlying mechanisms, often involving immunometabolic alterations [9,10]. Combinations of certain NCDs and associated risk factors can create separate specific disease entities, classified as a clinical subtype or phenotype [11]. > Obesity is a key risk factor underlying a variety of major NCDs, including asthma [10,12]. The comorbidity of obesity and asthma is referred to as obesity-associated asthma [13,14]. Various associated clinical characteristics of obesity and asthma have been described. The major obesity-associated asthma phenotype is characterized as "late-onset, severe and difficult to treat, type-2 low inflammation disease and presenting mostly in women" [15][16][17]. While these detailed clinical characteristics strictly define this particular phenotype of asthma, the specific underlying cellular and molecular mechanisms of this phenotype are still only poorly understood. > Gene expression alterations, especially in cells critically involved in disease development, represent a major molecular contributor to the pathophysiology of chronic inflammatory diseases such as asthma. Subsets of CD4 + T cells, such as Th1, Th2, and Th17 have been shown to differentially contribute to the initiation and perpetuation of specific asthma phenotypes [18,19]. Certain biological pathways and cellular processes play an essential role in the polarization of the CD4 + T cells subtypes [20].

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

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Citations: 2
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.403) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[5] Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

• Authors: S. Berentsen, S. D’Sa, U. Randen, A. Małecka, J. Vos
• Year: 2022
• Venue: Hemato
• URL: https://www.semanticscholar.org/paper/0a9973643451f4e4ac195138b5cf79863746d004
• DOI: 10.3390/hemato3040040
• Citations: 19
• Influential citations: 2
• Summary: This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification.
• Evidence snippets:
• Snippet 1 (score: 0.399) > Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

[6] The impact of individual clinical features in cold agglutinin disease: hemolytic versus non-hemolytic symptoms

• Authors: S. Berentsen, Josephine M. I. Vos, A. Małecka, G. E. Tjønnfjord, S. D'Sa
• Year: 2024
• Venue: Expert Review of Hematology
• URL: https://www.semanticscholar.org/paper/f9216132beb054361674d5f2eefc3a9dc055eea3
• DOI: 10.1080/17474086.2024.2372333
• PMID: 38938203
• Citations: 5
• Summary: This review addresses each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation.
• Evidence snippets:
• Snippet 1 (score: 0.395) > ABSTRACT Introduction During the last decades, the pathogenesis of cold agglutinin disease (CAD) has been well elucidated and shown to be complex. Several documented or investigational therapies have been made available. This development has resulted in major therapeutic advances, but also in challenges in choice of therapy. Areas covered In this review, we address each step in pathogenesis: bone marrow clonal lymphoproliferation, composition and effects of monoclonal cold agglutinin, non-complement mediated erythrocyte agglutination, complement-dependent hemolysis, and other effects of complement activation. We also discuss the heterogeneous clinical features and their relation to specific steps in pathogenesis, in particular with respect to the impact of complement involvement. CAD can be classified into three clinical phenotypes with consequences for established treatments as well as development of new therapies. Some promising future treatment approaches – beyond chemoimmunotherapy and complement inhibition – are reviewed. Expert opinion The patient’s individual clinical profile regarding complement involvement and hemolytic versus non-hemolytic features is important for the choice of treatment. Further development of treatment approaches is encouraged, and some candidate drugs are promising irrespective of clinical phenotype. Patients with CAD requiring therapy should be considered for inclusion in clinical trials.

[7] 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: 139
• 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: 0.392) > The lack of access to longitudinal samples from patients requires the establishment of cohorts of patient-derived disease models to understand the cellular heterogeneity associated with disease. Discovering pathways and biomarkers for the stratification of patients based on the cellular mechanisms driving the disease will enable new design of clinical trials to reevaluate drugs previously tested without such stratification and broaden the drug target portfolio. > As seen during the COVID-19 pandemic it is important to be able to understand infection mechanisms and the host response to rapidly identify the most likely effective treatment. At the same time the continuous rise of antimicrobial resistance requires the discovery of novel therapeutic strategies. A key medical challenge for infectious diseases is to understand the cellular response to infections and develop novel precision immune-based therapeutic strategies to combat infections. > The high burden of chronic inflammatory diseases is due to long-term debilitating consequences resulting from structural destruction of affected organs or tissue. Current therapies only treat the symptoms and do not cure or fully control the chronic inflammatory pathophysiology. While many different targeted therapies exist, they are expensive and are 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 61,62 and how this relates to the predicted course of disease and response of a patient to one of the numerous available therapies. > Many cardiovascular and metabolic diseases lack effective therapies due to a lack of knowledge of the underlying causes and the link between abnormal cardiac cell structure/function and pathophysiology. The identified medical priority is to understand cellular and molecular mechanisms involved to enable early diagnosis and to design new mechanism-based therapies for precise clinical treatment.

[8] A Case of Paroxysmal Cold Hemoglobinuria Possessing Moderate Paroxysmal Nocturnal Hemoglobinuria-Type Erythrocytes

• Authors: T. Sugimoto, Eri Masui, Shinya Ohata, H. Goto, Takako Tomita et al.
• Year: 2021
• Venue: The American Journal of Case Reports
• URL: https://www.semanticscholar.org/paper/64927f1369f0d4642bd8d21c18e179ea76d5e0da
• DOI: 10.12659/AJCR.933102
• PMID: 34819489
• PMCID: 8630556
• Citations: 1
• Summary: The persistent mild anemia of an 82-year-old female patient was caused by concomitant diseases of PCH and PNH, although determining which of the 2 hemolytic systems was primarily responsible for the anemia was difficult.
• Evidence snippets:
• Snippet 1 (score: 0.392) > Two types of diseases related to anemia are primarily associated with the cold type of autoimmune hemolysis: cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH). The causes of these 2 diseases are independent from each other. CAD occurs when cold agglutinin increases, which is due to the IgM class antibody. CAD is known as a complication of infections, such as mycoplasma, Epstein-Barr virus, legionella, or malignant lymphoma. However, CAD can also be idiopathic. PCH is caused by a biphasic autoantibody, the Donath-Landsteiner (DL) antibody, which is classified as an IgG. This autoantibody specifically binds to the P blood group antigen [1]. > Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disease that manifests as anemia, thrombosis, bone marrow failure, and renal dysfunction. PNH occurs due to a disability in the synthesis of the glycosyl phosphatidylinositol (GPI) anchor portion. PNH lacks all, or parts of, the CD55 or CD59 protein, resulting in the deregulation of the complement cascade and increased hypersensitivity for hemolytic attacks in erythrocytes [2]. A direct antiglobulin test (DAT) is usually negative. > The mechanisms of the above hemolytic diseases are distinct, and a differential diagnosis that leads to adequate treatment is important. The differential diagnosis of hemolytic diseases is based on clinical symptoms and the results of laboratory tests, including DAT or the indirect antiglobulin test (IAT), cold agglutinin titer, DL test, and specificity of erythrocyte antibody. The diagnostic surveillance for background diseases, such as lymphoma, myelodysplastic syndromes, collagen disease, and viral or bacterial infections, is also important. Here, we report a case of PCH possessing massive PNH-type clone cells.

[9] Clinical and molecular landscapes of steroid-refractory graft-versus-host disease following hematopoietic stem cell transplantation: a narrative review

• Authors: Thomas S. Gunning, Jack Cucchiara, Elahe Golalipour, Steven Ghanny
• Year: 2025
• Venue: Regenerative Medicine Reports
• URL: https://www.semanticscholar.org/paper/86b47929065c82ae1fcf3c0db63ea76b8c54a571
• DOI: 10.4103/regenmed.regenmed-d-24-00022
• Summary: Through comprehensive elucidation of the molecular mechanisms underlying steroid-refractory graft-versus-host disease, the development of mechanism-based, regenerative medicine-targeted therapeutic strategies, and the optimization of clinical trial design, it is anticipated that the prognosis and quality of life for patients with steroid-refractory graft-versus-host disease will be significantly improved.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Allogeneic hematopoietic stem cell transplantation is a highly effective stem cell-based therapy, but graft-versus-host disease remains a major post-transplant complication. While first-line graft-versus-host disease treatment involves high-dose corticosteroids, up to half of patients go on to develop steroid-refractory graft-versus-host disease, where graft-versus-host disease symptoms persist or worsen despite steroid treatment. This review provides an update on the clinical and molecular landscapes of steroid-refractory graft-versus-host disease, examining the challenges in diagnosis, management, and general understanding of steroid-refractory graft-versus-host disease pathophysiology. Progression to steroid-refractory graft-versus-host disease confers a poor prognosis and is associated with increased morbidity. There are multiple mechanisms that drive steroid-refractory graft-versus-host disease, which include the overactivation of T-cell and B-cell mechanisms, a heightened inflammatory state, and cell-intrinsic factors that mediate steroid responses. Current treatment options beyond corticosteroids include JAK pathway inhibition, mesenchymal stem cell therapy, extracorporeal photopheresis, and additional therapies currently under investigation in clinical trials. Potential avenues for future directions must aim to improve patient outcomes and post-transplant survivorship. Through comprehensive elucidation of the molecular mechanisms underlying steroid-refractory graft-versus-host disease, the development of mechanism-based, regenerative medicine-targeted therapeutic strategies, and the optimization of clinical trial design, it is anticipated that the prognosis and quality of life for patients with steroid-refractory graft-versus-host disease will be significantly improved. From a clinical standpoint, these advancements are expected to catalyze a transition from empirical to more personalized, mechanism-directed therapies, ultimately providing more durable and effective treatment options for patients with steroid-refractory graft-versus-host disease.

[10] 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: 5
• 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: 0.389) > : 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.

[11] Complement‐Dominant Relapse of Mixed Autoimmune Hemolytic Anemia After Rituximab Response

• Authors: Naru Tomigaki, Seiji Kakiuchi, Akimasa Sakamoto, Shutaro Fujioka, Isamu Harima et al.
• Year: 2026
• Venue: EJHaem
• URL: https://www.semanticscholar.org/paper/5cf2b59bb470a3f75614c6f0db10f76afb38784f
• DOI: 10.1002/jha2.70381
• PMID: 42634707
• PMCID: 13500038
• Summary: Mixed autoimmune hemolytic anemia (AIHA) may show temporal shifts in its predominant effector mechanism.
• Evidence snippets:
• Snippet 1 (score: 0.388) > The relapse phenotype was clinically similar to cold agglutinin disease, with winter worsening, markedly elevated cold agglutinin titers, erythrocyte agglutination, C3d-dominant DAT findings, low C4 before treatment, and hematologic improvement after C1s inhibition. However, the same patient initially presented with anti-IgG-positive hemolysis and was later reassessed as having mixed AIHA after cold-triggered relapse [ 5 ]. We therefore interpreted the later episode as a cold-and complementdominant relapse within the longitudinal course of mixed AIHA rather than as newly developed isolated cold agglutinin disease. > The rapid transfusion-free increase in hemoglobin, reduction in LDH, recovery of C4, and suppression of CH50 after sutimlimab were consistent with classical complement pathway inhibition [ 3,4 ]. Persistent cold agglutinin titers, direct agglutination, and DAT reactivity during the early response suggested that the treatment controlled the complement-dependent effector phase without eliminating upstream antibody activity. > The cellular source of the antibody activity remained unresolved. The pretreatment κ-restricted CD20-positive population was no longer detectable by flow cytometry at relapse, although marrow histology showed approximately 1% CD20-positive B cells. IgGκ and IgM-κ monoclonal proteins were identified later, but their antigen specificity, pathogenicity, cellular source, and clonal relationship were not established. Detection of the IgG-κ protein did not establish that the warm-reactive erythrocyte antibody was monoclonal. Neither marrow examination showed lymphoplasmacytic infiltration or lymphoid aggregates, and pre-rituximab CT showed no lymphadenopathy or splenomegaly. However, relapse-phase imaging, MYD88 L265P testing, next-generation sequencing, IGH clonality analysis, and clonal tracking were not performed; an underlying small B-cell lymphoproliferative eJHaem, 2026 disorder therefore could not be definitively excluded [ 6 ].

[12] Editorial: Impact of system biology and molecular medicine on the management of complex immune mediated respiratory diseases, volume II

• Authors: B. Cárdaba, G. Pelaia
• Year: 2023
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/89edb8e4f39ba41177cc4caa98150836f54e16f0
• DOI: 10.3389/fmed.2023.1187941
• PMID: 37351067
• PMCID: 10282990
• Summary: The impact of system biology and molecular medicine on the management of complex immune mediated respiratory diseases, volume II and the need for further research into this area is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.379) > Complex Immune-Mediated Respiratory Diseases are highly complex and heterogeneous inflammatory disorders, sharing a common organ-disease target which is the lung, but including a broad clinical spectrum. The most frequent obstructive respiratory diseases include bronchial asthma and, chronic obstructive pulmonary disease (COPD). These disorders are characterized by airflow limitation, cough, dyspnea, chest tightness, shortness of breath, and mucus production that could be caused by numerous environmental agents, as well as, genetic, pharmacologic, physiologic, biological, or immunologic mechanisms, which give rise to distinct phenotypes, with underlying molecular mechanisms or endotypes that need to be understood. This great heterogeneity translate to a lack of good therapeutic options for an important percentage of patients that do not respond to standard treatments, who could receive relevant benefits by a precision or personalized strategy, which requires new diagnostic and therapeutic approaches. Our purpose in the second volume of this Research Topic was to collect the latest advances in the molecular and clinical characterization of these complex diseases, in order to better understand the underlying mechanisms and improve the overall management. > In this volume, five novelty works have been published: 4 original articles, 2 of them related to severe asthma, and the other 2 regarding COPD. The fifth is a mini review that summarizes the latest new advances about the T cell-mediated lung inflammation in COVID-19 infection. > In regard to bronchial asthma studies, the two published articles pursue a better understanding of underlying mechanisms of severe uncontrolled asthma, thus searching for cellular and molecular pathways involved in the pathobiology of asthmatic endotypes that do not respond to standard asthma treatments and remain uncontrolled, thereby being responsible for exacerbations and hospitalizations every year. > Asthma is a common, chronic respiratory disease, defined as "a heterogeneous disease, usually characterized by chronic airway inflammation" by the Global Initiative of Asthma (1). Despite its clinical heterogeneity, allergic mechanisms have been implicated in 50-80% of asthmatic patients and in ∼50% of severe asthma cases (2,3). Such considerations explain why there are several new biological treatments mainly directed against this subtype of inflammation (type 2 inflammation).

[13] Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome

• Authors: A. Warren
• Year: 2017
• Venue: Advances in Biological Regulation
• URL: https://www.semanticscholar.org/paper/25603c68626d81d80c1cea2463b1580dd21ca55b
• DOI: 10.1016/j.jbior.2017.09.002
• PMID: 28942353
• PMCID: 6710477
• Citations: 157
• Influential citations: 10
• Summary: Recent advances in cryo-electron microscopy, coupled with genetic, biochemical and prior structural data, have revealed that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle.
• Evidence snippets:
• Snippet 1 (score: 0.376) > For SDS patients and their families, it will be important to identify informative prognostic biomarkers to predict who is at highest risk of progressing to MDS/AML and who may benefit from early therapeutic intervention. International registries will help expand the range of clinical phenotypes in SDS and define the natural history of the condition. Exome sequencing will likely reveal further gene variants among the 5e10% of individuals clinically diagnosed as SDS who are negative for SBDS and DNAJC21 mutations, while prospective sequencing of serial samples from SDS patients will be important to identify the key genetic changes that promote clonal progression to MDS and leukaemia. The generation of viable SDS animal models will be important both for elucidating mechanisms of disease and for testing novel therapeutics, but significant progress may also come from cellular and induced pluripotent stem cell disease models (Pellagatti et al., 2016). The development of targeted therapeutics will ultimately depend on better understanding of the fundamental molecular mechanisms of cytoplasmic ribosome maturation that are corrupted in SDS. In particular, the recent advances in single-particle cryo-EM are set to rapidly transform our understanding of ribosome assembly and have the potential to provide structural frameworks for drug design. There are a number of outstanding unanswered questions. What is the precise mechanism of eIF6 release and the role of eIF6 phosphorylation? What is the molecular basis of the allosteric modulation of EFL1 function by SBDS and what is the timing and precise role of EFL1 GTP hydrolysis? What is the molecular mechanism of p53 activation in response to eIF6 retention, defective subunit joining and attenuated translation in SBDS-deficient cells? What are the molecular mechanisms that evoke tissue-specific phenotypes downstream of p53? Understanding the molecular pathophysiology of SDS and related human ribosomopathies is an exciting area of research that is likely to provide significant new insights into the fundamental conserved mechanisms of ribosome assembly, its quality control and cancer biology more generally.

[14] 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: 96
• 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: 0.376) > 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.

[15] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

• Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
• Year: 2025
• Venue: Scientific Reports
• URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
• DOI: 10.1038/s41598-025-97642-8
• PMID: 40229542
• PMCID: 11997208
• Citations: 1
• Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
• Evidence snippets:
• Snippet 1 (score: 0.375) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[16] Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells

• Authors: D. Gurda, L. Handschuh, Weronika Kotkowiak, H. Jakubowski
• Year: 2015
• Venue: Amino Acids
• URL: https://www.semanticscholar.org/paper/0e9ac31119ab67e72fdaa6e9cc442fa7ed2f4642
• DOI: 10.1007/s00726-015-1956-7
• PMID: 25802182
• PMCID: 4458266
• Citations: 94
• Influential citations: 3
• Summary: It is found that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
• Evidence snippets:
• Snippet 1 (score: 0.374) > The key to understanding mechanisms by which HHcy disrupts normal cellular function and ultimately causes disease is to identify genes whose expression is affected by individual Hcy metabolites. It is likely that each metabolite causes specific alterations in gene expression that individually contribute to endothelial dysfunction induced by HHcy. Defining metabolite-specific alterations in gene expression in endothelial cells will help to identify molecular pathways involved in the pathology of HHcy and to uncover novel pharmacologic targets for preventing or treating cardiovascular and neurological disorders of HHcy. > An analysis of genes and biological pathways responding to specific Hcy metabolites has not been previously reported. To determine whether changes in gene expression are metabolite-specific and to identify biological pathways altered by HHcy, we studied how treatments with Hcy-thiolactone, N-Hcy-protein, and Hcy affect gene expression in human umbilical vein endothelial cells (HUVECs), a frequently used model of vascular cells.

[17] Toxicity and mechanistic analysis of di(2-ethylhexyl)phthalate in renal cell carcinoma progression: a systematic study with network toxicology and molecular docking strategies

• Authors: Biao Ran, Xinyi Wang, Bohan Liu, Junjiang Ye, Liangren Liu et al.
• Year: 2025
• Venue: Discover Oncology
• URL: https://www.semanticscholar.org/paper/66397aea42392baaaa9cf4e6e031b21c70d46c48
• DOI: 10.1007/s12672-025-03543-7
• PMID: 41071403
• PMCID: 12514089
• Citations: 2
• Summary: The results suggest that DEHP exposure may promote the development of RCC by regulating apoptosis and proliferation through pathways such as neuroactive ligand–receptor interactions, pathways related to cancer, and apoptosis.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Additional relevant functions include proteoglycan binding, collagen binding, fibronectin binding, and cysteine-type endopeptidase activity, indicating diverse regulatory roles of these genes. Overall, these GO analyses (BP, CC, and MF) demonstrated that these genes are integral to a variety of biological processes, cellular structures, and molecular functions, contributing to essential cellular defense mechanisms, structural stability, and enzymatic regulation. > According to the KEGG pathway enrichment analysis shown in Fig. 5, these genes are significantly enriched in pathways such as neuroactive ligand-receptor interaction, the calcium signaling pathway, the TNF signaling pathway, the cAMP signaling pathway, and apoptosis, underscoring their critical roles in cellular communication, Fig. 3 The PPI network of core targets inflammation, and disease mechanisms. Additional significant pathways included pathways associated with cancer, pathways associated with neurodegeneration, diabetic cardiomyopathy, and lipid and atherosclerosis, highlighting their involvement in diverse disease processes. Figure 5A (bubble plot) shows the top 20 enriched KEGG pathways ranked by FDR values, where bubble size represents the number of enriched genes, and color intensity indicates statistical significance. These pathways suggest that these genes play roles in cellular functions and disease progression, such as DEHP-induced renal cell carcinoma. Figure 5B (bar plot) categorizes these pathways by the number of genes involved, with neuroactive ligand-receptor interactions having the highest gene count, followed by pathways in cancer, apoptosis, and the TNF signaling pathway. The pathways are grouped into categories such as Environmental Information Processing, Cellular Processes, and Human Diseases, which have broad gene distributions across biological systems. Together, Fig. 5A, B emphasize the significant involvement of these genes in cellular signaling, inflammation, and various disease mechanisms, highlighting their relevance to disease development and cellular regulation.

[18] A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype

• Authors: Yusuke Okamoto, Hiroshi Arima, Kenichi Ishiyama, K. Chonabayashi, J. Kanda et al.
• Year: 2026
• Venue: Oxford Medical Case Reports
• URL: https://www.semanticscholar.org/paper/cd6a87cbc1dd86b9df0eabfdedb8ccce3d7f6808
• DOI: 10.1093/omcr/omag061
• PMID: 42117133
• PMCID: 13157618
• Citations: 1
• Summary: A woman in her 50’s with progressive fatigue who presented with hemolytic anemia and an IgM-κ paraprotein is reported, supporting a diagnosis of CAD-LPD rather than monoclonal B-cell lymphocytosis.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia characterized by chronic hemolysis caused by cold-reactive, complement-fixing IgM autoantibodies that bind red blood cells at low temperatures and activate the classical complement pathway. In adults, CAD is now recognized as a clonal B-cell-driven disorder with IgM-κ paraprotein rather than a purely autoimmune condition. Most cases are associated with a distinct low-grade lymphoproliferative disorder, termed CAD-associated lymphoproliferative disorder (CAD-LPD), which is biologically and clinically separate from other mature B-cell neoplasms such as chronic lymphocytic leukemia (CLL) or lymphoplasmacytic lymphoma [1]. > Recent molecular studies have refined this concept. Somatic mutations in lysine methyltransferase 2D (KMT2D) and caspase recruitment domain-containing protein 11 (CARD11) encoded proteins were identified in 11 of 16 (69%) and 5 of 16 (31%) patients with CAD, respectively [2]. Pathological examination of bone marrow from 54 CAD patients showed a small population (less than 10%) of aggregates of small lymphoid cells expressing the cell surface markers CD20 + , IgMs + , CD27 + , CD5 −/+ , and CD23 − in 40 patients [3]. > Distinguishing CAD-LPD from other B-cell malignancies, such as CLL or monoclonal B-cell lymphocytosis (MBL) with a CLL phenotype can be challenging when marrow involvement is minimal and immunophenotypic overlap exists [4]. This distinction is nevertheless critical, as therapeutic strategies differ fundamentally. While Bcell-directed therapies are reserved for progressive or symptomatic CLL, complement inhibition has emerged as a highly effective and mechanism-based treatment for CAD. Sutimlimab, a humanized monoclonal antibody targeting complement C1s, has demonstrated rapid and sustained control of hemolysis and is now approved for CAD treatment in Japan [5].

[19] Prioritizing Molecular Biomarkers in Asthma and Respiratory Allergy Using Systems Biology

• Authors: Lucía Cremades-Jimeno, M. D. de Pedro, M. López-Ramos, J. Sastre, P. Mínguez et al.
• Year: 2021
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/d8ca6e130adec2dfa39545eb1763827d9450e4f5
• DOI: 10.3389/fimmu.2021.640791
• PMID: 33936056
• PMCID: 8081895
• Citations: 15
• Influential citations: 1
• Summary: This study has enabled it to prioritize biomarkers depending on the functionality associated with each disease and with specific molecular motifs, which could improve the definition and usefulness of new molecular biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.372) > Firstly, the molecular characterization of the three pathophysiological processes of interest (respiratory allergy, allergic asthma, and nonallergic asthma) was performed using the Therapeutic Performance Mapping System (TPMS) technology (Anaxomics Biotech, Barcelona, Catalonia, Spain) (31). Briefly, systems biology generates models that are able to reproduce the behavior of a disease in a patient, thus identifying the key genes, proteins, or metabolites in the development of the disease. A dictionary has been created to translate clinical and medical terms into molecular biology data, effectively linking the molecular and the clinical words. This dictionary, called the Biological Effectors Database (BED), relates biological processes (adverse events of drugs, drug indications, diseases, etc.) with the proteins most closely associated with them. Thus, the dictionary acts as a translator of clinical phenotypes into terms comprehensible for protein networks, and conversely allows for the translation of molecular measures toward clinical outcomes. The BED is structured hierarchically, where the biggest level is the entire disease, which is divided into different pathophysiological molecular motifs, which in turn contain the proteins involved in the development of the disease. The motifs are classified into two levels depending on their respective implication, i.e. causal motifs, which are directly related to the onset or pathophysiology of the condition, and symptomatic (manifestative) motifs, which are a consequence of the disease. > In the present study, respiratory allergy, allergic asthma, and non-allergic asthma have been characterized at the molecular level. Therefore, the analysis of high throughput data by means of TPMS allows for identification of those proteins closely associated with the disease of interest and can provide a mechanistic rationale for their involvement. The effector proteins of the manifestative and causal molecular motifs of these three diseases have been identified through bibliographic review and curate data. Figure 1 summarizes the workflow used for this study.

[20] Molecular Genetics of Bartter Syndrome: Bridging Genotype–Phenotype Correlations and Precision Therapeutics

• Authors: Lina Zhu, Yang Li, Yiyao Bao
• Year: 2026
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/a5e1ddccfa7d333834c4d32be123c71bfd573f83
• DOI: 10.3390/cimb48040422
• PMID: 42042082
• PMCID: 13114623
• Summary: A comprehensive framework to provide a comprehensive framework to facilitate precise diagnosis and individualized treatment strategies, ultimately advancing precision medicine in the management of Bartter syndrome is provided.
• Evidence snippets:
• Snippet 1 (score: 0.370) > Molecular genetic research on Bartter syndrome has made remarkable strides, elucidating the principal BS genes SLC12A1, KCNJ1, CLCNKB, BSND, and MAGED2 and their corresponding protein defects, thereby refining the molecular framework of disease classification while separating CaSR-associated Bartter-like disease from the core canonical BS spectrum. This progress has significantly deepened our understanding of the underlying pathophysiology and provided an essential framework for correlating genotypes with clinical phenotypes. However, the intricate relationship between genetic mutations and clinical manifestations remains complex and multifaceted, reflecting the profound heterogeneity of the syndrome. Addressing these diagnostic challenges and refining disease classification beyond traditional clinical criteria requires an integrative approach that seamlessly balances high-throughput sequencing technologies with rigorous functional studies. > The mechanisms by which these genetic mutations lead to protein dysfunction are diverse, encompassing critical defects in protein expression, impaired membrane localization, and direct functional impairments. Notably, aberrant protein folding, endoplasmic reticulum-associated degradation (ERAD), and splicing abnormalities have emerged as critical pathogenic pathways. These mechanistic insights not only enhance our fundamental understanding of the disease but also highlight highly promising therapeutic targets. While current treatments remain predominantly symptomatic, focusing primarily on managing electrolyte imbalances and associated complications, they inherently fail to address the underlying molecular defects driving the disease. > The precise identification of specific molecular defects opens innovative avenues for the development of targeted interventions aimed at correcting or compensating for specific protein abnormalities. For instance, molecular chaperones that assist in protein folding, agents that modulate aberrant splicing, and future gene-based strategies represent important experimental directions for mechanism-based therapy. Consequently, the future of Bartter syndrome management may increasingly move toward precision medicine tailored to the molecular pathology of individual patients. However, the transition from concept to clinical implementation will require substantial additional functional, translational, and trial-level evidence. Such mechanism-based strategies promise not only to alleviate clinical symptoms but to fundamentally modify disease progression, thereby drastically improving long-term prognosis and quality of life for patients.

Notes

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

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