Asta Literature Retrieval: Pathophysiology and clinical mechanisms of erythromelalgia. Core disease mechanisms, molecular and cellular pathways,...

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

• Papers retrieved: 17
• Snippets retrieved: 20

Relevant Papers

[1] Primary Erythromelalgia: Historical Perspective and Current Update

• Authors: Allison C Eaton, H. Mayrovitz
• Year: 2025
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/e3de27ab06fee87bc63dc6e12c98323f5a902e5d
• DOI: 10.7759/cureus.78576
• PMID: 40062126
• PMCID: 11890538
• Summary: This literature review provides a comprehensive historical perspective and current update on primary erythromelalgia or PEM, categorizing and tracing the clinical knowledge of the condition and identifying key milestones of historical research.
• Evidence snippets:
• Snippet 1 (score: 0.415) > Erythromelalgia's historical understanding was shaped by two prevailing and interconnected theoriesperspectives concentrating on neuropathic or microcirculatory pathological origin. These concurrent viewpoints delved into the intricate interplay between neural and vascular mechanisms, characterizing the comprehension of the condition. However, pivotal genetic discoveries in the late 20th century would prove to unveil underlying genetic aspects. This redirection from dominant vascular and neuropathic theories to emerging genetic paradigms centered around ion channel dysfunction propelled advancements in research, signifying a transformative phase in exploring erythromelalgia's complex pathophysiology.
• Snippet 2 (score: 0.399) > The exploration of erythromelalgia's etiology significantly revolved around neuropathic theories. The neuropathic theory evolved in part based on the fact that many patients presented with a distal small fiber neuropathy featuring selective involvement of cutaneous sympathetic fibers, implicated as a key factor influencing the condition's manifestation [22]. This neuropathic perspective highlighted the crucial role of altered peripheral nerve function and signaling pathways in the onset of PEM. Specifically, research findings suggested that postganglionic sympathetic dysfunction and denervation hypersensitivity might play a role in PEM, while local neurogenic function and endothelial function seemed unaffected [23,24]. Notably, at that stage of research preceding genetic studies, the distinction between whether the neuropathy associated with erythromelalgia represented a primary or secondary disorder remained unclear [23]. This intricate relationship between neural abnormalities and their impact on vascular dynamics underscored the complexity of the neuropathic mechanisms contributing to PEM, necessitating further thorough investigations into these specific pathways.
• Snippet 3 (score: 0.395) > It is hoped that this will enable researchers, clinicians, and patients to gain insights into the advances made in diagnosing and managing PEM. Additionally, this review will explore the impact of genetic studies and molecular investigations on our current understanding of PEM. Identifying mutations in the SCN9A gene, encoding a sodium channel critical for pain perception, has emerged as a significant breakthrough, highlighting the underlying mechanisms of the disorder. identify and review the literature. Search terms included "erythromelalgia," "erythermalgia," "SCN9A," and "sodium channelopathy." Advanced search options (AND, OR) were used to combine search terms. Reference sections of relevant articles were reviewed to further establish the knowledge production trajectory. The inclusion criteria were as follows: publication in a scientific journal, texts published in English, studies focusing on either clinical or scientific aspects of erythromelalgia, and studies including a qualitative description of erythromelalgia pathology. As an analytic technique, thematic analysis was employed to identify critical moments in the history of knowledge production around erythromelalgia. Limitations include scarcity of erythromelalgia research and inconsistency in nomenclature utilized in some reviewed studies.
• Snippet 4 (score: 0.344) > Erythromelalgia is a condition characterized by intense burning pain, redness, and heat in the extremities that has garnered increasing attention in recent years. This literature review provides a comprehensive historical perspective and current update on primary erythromelalgia or PEM, categorizing and tracing the clinical knowledge of the condition and identifying key milestones of historical research. In a sequential fashion, the review explores the evolution of understanding of PEM, starting from its initial descriptions in the medical literature to the present day. Early case reports and pivotal studies that contributed to recognizing and characterizing the disorder are examined. Important discoveries, diagnostic criteria, and therapeutic approaches that have shaped the management of erythromelalgia over time are highlighted. Additionally, the impact of genetic studies and molecular investigations on current understanding of PEM is discussed. Identifying mutations in the SCN9A gene is emphasized as a significant breakthrough, shedding light on the role of sodium channels in the disorder's pathogenesis. Overall, this review consolidates the wealth of clinical knowledge and research milestones related to PEM. Integrating historical research milestones offers a comprehensive overview of the condition, from early descriptions to the current state of knowledge. This knowledge serves as a foundation for further research and can assist in improving diagnosis and management strategies for individuals with PEM.

[2] Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review

• Authors: Abdullah S. Algarni, Reem M Alharthi, Shaden O Alqurashi, Ruba M Alghanmi, Rimaz R. Aldawsari et al.
• Year: 2025
• Venue: Medicina
• URL: https://www.semanticscholar.org/paper/0ec3e76d190491e6c2d7d1b648eecd2047a353eb
• DOI: 10.3390/medicina61050920
• PMID: 40428878
• PMCID: 12113215
• Citations: 1
• Summary: Comparing interventions demonstrated consistent clinical benefit with varied tolerability, however, adverse events ranged from mild gastrointestinal symptoms to severe complications such as disability and depression, requiring careful monitoring.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Background and Objectives: Erythromelalgia (EM) is an uncommon condition marked by recurring redness, intense burning sensations, and elevated limb warmth. This syndrome can be significantly debilitating, and finding effective treatment options often proves to be quite difficult. The symptoms can severely impact the quality of life of those affected, resulting in considerable disability. This systematic review aims to compare available medical treatments for EM by evaluating their efficacy and safety. Materials and Methods: Following PRISMA guidelines, the search included the PubMed, Medline, and Web of Science databases, using the keywords (“Erythromelalgia” OR “Mitchell’s Disease”) AND (“Erythromelalgia Treatment” OR “Erythromelalgia Management”). Results: From the 103 papers extracted through the database search, six articles were considered suitable for the systematic review. The included studies investigated various interventions used for a total of 120 patients, including iloprost (n = 8), misoprostol (n = 21), topical amitriptyline-ketamine (n = 36), lidocaine (n = 27), chemical lumbar sympathectomy (CLS, n = 13), and various pharmacological agents (n = 11). The outcomes showed significant improvements in areas like pain reduction, cooling scores, and temperature regulation. Iloprost and misoprostol exhibited notable benefits in cooling scores, sympathetic dysfunction, and EM severity compared to placebos. About 75% of the patients reported pain relief with topical amitriptyline-ketamine, while lidocaine reduced nociceptive feelings in a dose-dependent manner. Conclusions: Comparing interventions demonstrated consistent clinical benefit with varied tolerability. However, adverse events ranged from mild gastrointestinal symptoms to severe complications such as disability and depression, requiring careful monitoring. Given EM’s diverse symptoms and comorbidities, treatment efficacy varies among individuals. A personalized approach incorporating genetic testing, multidisciplinary care, and long-term monitoring is essential to optimize outcomes. Continued research is vital to advance understanding of EM’s pathophysiology and improve patient care.

[3] Clinical Characterization of Pediatric Erythromelalgia: A Single-Center Case Series

• Authors: Jenn-Mou Sun, Don Daniel Ocay, Meghan Halpin, Kimberly Lobo, Dafni F. T. Frohman et al.
• Year: 2023
• Venue: Children
• URL: https://www.semanticscholar.org/paper/850f3ddbb5e329261b9d74c21797c736cc7dd27a
• DOI: 10.3390/children10081282
• PMID: 37628281
• PMCID: 10453121
• Citations: 2
• Summary: Based on the currently published literature, this cohort is the largest pediatric study of erythromelalgia to date and many findings are consistent with those of previously published case series.
• Evidence snippets:
• Snippet 1 (score: 0.380) > The clinical observation of the exacerbation of pain by heat and relief by cold in vivo fits well with the observation of the altered temperature dependence of ionic currents in reconstituted channels in vitro. > Secondary erythromelalgia may be associated with a range of diseases, including Fabry disease, vasculitis, sarcoidosis, Sjögren's syndrome, amyloidosis, and small-fiber neuropathy [12][13][14][15][16]. For these diseases, as well as for most other cases of non-inherited/symptomatic erythromelalgia, the detailed molecular mechanisms that give rise to burning pain, triggering with heat, and partial/temporary relief by cold are largely unknown. > There is limited information on the incidence or prevalence of erythromelalgia in different populations. A population-based study in Minnesota estimated the overall incidence to be 1.3 per 100,000 people per year [17]. Most case series report a female predominance, with a female to male ratio of about 2:1 [1,14,18]. > A clinical diagnosis derives largely from the history and physical examination, often aided by pictures of affected areas taken during pain episodes. There is limited information to guide clinicians for how best to use clinical and epidemiologic variables to prioritize laboratory testing for systemic diseases that could present as symptomatic erythromelalgia [2,5]. Laboratory testing may in some cases lead to the diagnosis of treatable underlying conditions [12,13]. > For a small subset of patients with inherited erythromelalgia, a genetic diagnosis may inform the selection of treatments [7,19,20]. For most other patients, pharmacologic treatment is largely based on custom and extrapolation, rather than on clinical trials or on underlying mechanisms. There is variability in the effectiveness of any single available therapy, ultimately leading to empirical trials of multiple medications in most patients [2]. Analgesics may be combined with non-pharmacological methods of preventing or minimizing symptoms, such as managing pain triggers [3].

[4] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[5] Cyclosporine-induced Erythromelalgia

• Authors: Lorin A. Bibb, Randi P Winter, S. Leicht
• Year: 2018
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/996e1300ec50435fff0aa42c3f9fa502f1cc47fb
• DOI: 10.7759/cureus.3506
• PMID: 30648046
• PMCID: 6318136
• Citations: 10
• Influential citations: 1
• Summary: As drug-induced erythromelalgia represents a reversible cause of disease, physicians should obtain a detailed medication history during the diagnostic workup, specifically inquiring about the use of cyclosporine.
• Evidence snippets:
• Snippet 1 (score: 0.358) > Although the true pathophysiology of erythromelalgia is complicated and disputed, it is suspected that abnormalities in nerve fibers and blood flow underlie the symptoms [6]. The small nerve fibers affected are involved in sensing pain (Aδ afferent fibers) and the sympathetic nervous system (C efferent fibers) [5][6]. In a retrospective study of 52 patients with erythromelalgia examined from 2010 to 2015, Mantyh et al. found that most of these patients had epidermal nerve fiber densities within normal limits on biopsy but presented with functional abnormalities of the small nerve fibers within the epidermis. The functional abnormalities included abnormal sweat test results in 60% of the studied population, abnormal pain thresholds in 42%, and abnormal blood pressure or heart rate in 38%. Such findings can be used to distinguish erythromelalgia from similarly presenting disorders with painful distal neuropathy, including diabetes, HIV, or Fabry disease, in which patients are found to have decreased epidermal nerve fiber density [5]. In erythromelalgia, abnormalities of the small nerve fibers cause an aching, burning, and stabbing pain thought to be the result of increased perfusion through arteriovenous shunts which bypass tissue capillaries and cause ischemia [6,[9][10][11]. Increased flow though arteriovenous shunts ultimately decreases the oxygenated blood delivered to the capillaries of the distal extremities and causes tissue ischemia and pain [5,6,[9][10][11]. Another theory suggests that vasodilatory medications can cause the pain and inflammation experienced in secondary erythromelalgia [6,12]. Overall, it is likely an intricate interaction involving vascular dysfunction and resultant neuronal dysregulation which most likely underlies the true pathogenesis of the disease [6,11,13]. > The diagnosis of erythromelalgia involves a thorough physical exam targeted at identifying the most common disease presentations [14]. Patients may present with episodes of burning (96%), warmth (93%), pain (87%), erythema (83%), swelling (65%), and/or

[6] Intravenous immunoglobulin therapy in erythromelalgia management: a case report

• Authors: Renato Ádler Pomilio de Sousa, L. Vasconcelos, Marcus Villander Barros de Oliveira Sá
• Year: 2025
• Venue: Einstein
• URL: https://www.semanticscholar.org/paper/8ca8f5318cb4411c4a98c6f466b0f5d7322d5a9f
• DOI: 10.31744/einstein_journal/2025RC1236
• PMID: 40053049
• PMCID: 11869793
• Summary: In conclusion, intravenous immunoglobulins may offer a more effective approach to pain control than conventional pain relievers, representing a promising direction for understanding the pathogenesis of erythromelalgia.
• Evidence snippets:
• Snippet 1 (score: 0.354) > (3) Various classification schemes have been proposed, but most authors have separated erythromelalgia into two main categories: primary and secondary. The secondary form is a complication of a predisposing condition, notably myeloproliferative disease, and tends to resolve with treatment of the underlying disorder. (1) In contrast, the primary form engenders more debate. > Categorizing a patient with primary erythromelalgia (PE) alone indicates no identifiable causative factors. (6) There is a strong association between inherited cases and gain-of-function mutations in the SCN9A gene, which encodes the Nav1.7 voltage-gated sodium channel (VGSC). (7,8) This channel depolarizes small-fiber neurons, particularly unmyelinated nociceptive C-fibers. Conversely, patients who develop symptoms in adulthood usually lack a clear etiopathogenesis. > einstein (São Paulo). 2025;23:1-4

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

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 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: 0.353) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[8] Sporadic Erythromelalgia Associated with a Homozygous Carrier of Common Missense Polymorphism in SCN9A Gene Coding for NaV1.7 Voltage-gated Sodium Channel

• Authors: P. Janicki, V. Ruiz-Velasco, S. Adhikary
• Year: 2019
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/e8a6690294294ea7eb7da64579f8f86dceec8107
• DOI: 10.7759/cureus.4587
• PMID: 31309012
• PMCID: 6609274
• Citations: 4
• Summary: A 68-year-old female with a history of sporadic type and presumably secondary erythromelalgia with chronic intractable pain presented for foot surgery and was a homozygous carrier of the common missense mutation in the SCN9A gene coding for voltage-gated sodium channel.
• Evidence snippets:
• Snippet 1 (score: 0.351) > The two main forms of erythromelalgia are the primary and secondary types. Myeloproliferative diseases, together with thrombocythemia, are responsible for approximately 20% of cases of secondary erythromelalgia. The pathological signs in patients with secondary erythromelalgia include arteriolar intimal proliferation with thrombotic occlusions secondary to platelet aggregation [1][2]. Secondary erythromelalgia is most commonly associated with blood dyscrasias, connective tissue disorders, and drug reactions. Secondary erythromelalgia can result from a number of diseases such as myeloproliferative disorders (with a 3%-65% prevalence in patients with myeloproliferative disorders, especially polycythemia vera and essential thrombocytosis), hypercholesterolemia, autoimmune disorders, small fiber peripheral neuropathy, Fabry's disease, mercury poisoning, mushroom poisoning, sciatica, and some medications, including bromocriptine, verapamil, and ticlopidine [1][2]. > codes for the voltage-gated sodium channel NaV1.7 α subunit. These channels are preferentially expressed in the nociceptive dorsal root ganglion (DRG) [7][8][9]. Genomic studies in humans have provided compelling evidence emphasizing that high-impact rare mutations in hNaV1.7 with gain-of-function have marked effects on the channel function and clinical phenotype of familial primary erythromelalgia syndrome. The role of these mutations in pain pathways has been previously described [9]. The mutations associated with primary erythromelalgia are not always inherited as de novo mutations have been described. > Common missense SNPs in the exons of the SCN9A gene have more subtle and quantitative effects than the major mutations mentioned above but may also significantly influence an individual's pain perception. A common polymorphism (rs6746030) was previously found in the intracellular loop between domains II and III, with the minor allele occurring at a frequency of ~10%. The polymorphism results in a change of positively charged arginine (R

[9] Dysregulation of sphingolipid metabolism in pain

• Authors: Jianfeng Wang, Guangda Zheng, Linfeng Wang, Linghan Meng, Juanxia Ren et al.
• Year: 2024
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/2ba8fca03cb2da50d55c589404ff80427428c33d
• DOI: 10.3389/fphar.2024.1337150
• PMID: 38523645
• PMCID: 10957601
• Citations: 11
• Summary: Sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.
• Evidence snippets:
• Snippet 1 (score: 0.350) > Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.

[10] Multi-Omics Profiles of Chronic Low Back Pain and Fibromyalgia - Study Protocol

• Authors: Michele Curatolo, Abby P. Chiu, Catherine Chia, Ava Ward, Sandra K Johnston et al.
• Year: 2024
• Venue: Research Square
• URL: https://www.semanticscholar.org/paper/9370990318ae0504a3da39dd2eeb7ca6613d5a04
• DOI: 10.21203/rs.3.rs-4669838/v1
• PMID: 39149502
• PMCID: 11326421
• Citations: 1
• Summary: This study addresses the need for a better understanding of the molecular mechanisms underlying chronic low back pain and fibromyalgia by using a multi-omics approach to identify converging evidence for potential targets of future therapeutic developments, as well as promising candidate biomarkers for further investigation by biomarker validation studies.
• Evidence snippets:
• Snippet 1 (score: 0.349) > Metabolomics studies in chronic pain have been sparse, as we have shown in a previous review (12). Most studies in chronic low back pain had a partial focus, such as on single metabolites or pathways (83), tissue metabolites (84), or association with radiological ndings (85). Comprehensive studies on the metabolome are lacking, and the literature does not provide strong indications on which metabolic pathways are of relevance in chronic low back pain. The metabolic pro le of bromyalgia has been better studied. Some studies have focused on single metabolic pathways, such as purine (86). Other ones adopted a comprehensive metabolomics approach, but the results have not converged to clearly identi ed pathways involved in the pathophysiology of bromyalgia (87-90). Despite the importance of lipid metabolism for the understanding of cellular function and alterations in processes related to disease, such as in ammation, lipidomics studies in low back pain and bromyalgia are sparse and mostly limited to few target lipids (16). Most of the proteomics literature has focused on immune and in ammatory markers (91). A recent systematic review in bromyalgia identi ed dysregulated proteins associated with oxidative stress response, but the correlations with pain outcomes was weak (17). > Our study addresses the need for a better understanding of the molecular mechanisms underlying chronic low back pain and bromyalgia. Using a multi-omics approach, we hope to identify converging evidence for potential targets of future therapeutic developments, as well as promising candidate biomarkers for further investigation by biomarker validation studies. We believe that accurate patient phenotyping will be essential for the discovery process, as both conditions are characterized by high heterogeneity and complexity, likely rendering molecular mechanisms phenotype speci c.

[11] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

• Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
• Year: 2022
• Venue: Frontiers in Medical Technology
• URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
• DOI: 10.3389/fmedt.2022.810315
• PMID: 35281671
• PMCID: 8907708
• Citations: 6
• Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
• Evidence snippets:
• Snippet 1 (score: 0.344) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[12] 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: 0.344) > 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.

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

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

[14] Mimicking the Usual Suspects: Erythromelalgia in the Differential Diagnosis

• Authors: Din Hoxha, Nikolai E Bayro Jablonski, Arjun Chatterjee, J. Abdallah, Richard Cartabuke
• Year: 2025
• Venue: Journal of Brown Hospital Medicine
• URL: https://www.semanticscholar.org/paper/e797b4e9fac32ad1f1fab21716db17d1bc2de915
• DOI: 10.56305/001c.137218
• PMID: 40612082
• PMCID: 12224332
• Summary: A female with a history of erythromelalgia, presenting with worsening bilateral leg pain and purple discoloration of her feet following a surgical procedure, is reported on, establishing a diagnosis of atypical erythromelalgia flare.
• Evidence snippets:
• Snippet 1 (score: 0.341) > Epidemiologic studies have estimated an annual incidence of between 0.36 and 1.3 per 100,000 people. 1,2 First thought to be a single entity, erythromelalgia was subsequently subdivided into primary, secondary, and idiopathic forms, with the identification of SCN9A mutations defining primary cases of the condition. 1,3 econdary erythromelalgia has been found in association with myeloproliferative, vascular, connective tissue, musculoskeletal, and neurologic disorders, as well as in relation to the consumption of certain drugs. 1,4 Interestingly, the onset of erythromelalgia precedes the first identification of myeloproliferative disorders by 2.5 years on average. 4 he pathogenesis of erythromelalgia is thought to result from a complex interaction between the nervous and the vascular system, 5 brought about by the ineffective function of voltage-gated sodium channels in the case of primary forms, 3 and arteriolar structural changes in myeloproliferative disorder-associated presentations. 1,6 on-hereditary Erythromelalgia is considered a neurovascular disorder, with studies reporting on abnormalities in cutaneous microvascular function and thermoregulatory control, autonomic function tests showing a component of small fiber neuropathy, and pathologic reports revealing a thrombotic component further contributing to the microvascular disturbance, primarily when associated with myeloproliferative disorders. 1,6,7 rythromelalgia has been associated with entities such as systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, systemic sclerosis, and myeloproliferative disorders like polycythemia vera and essential thrombocytosis. 8 Some reported triggers include certain antineoplastic agents (i.e., osimertinib), calcium channel blockers (notably nifedipine and verapamil), and rarely topiramate or other neuromodulators. 1,9,10 e present a case of a female patient with a known history of Erythromelalgia and documented flares triggered by surgical interventions.

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

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.339) > 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.

[16] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 11
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.339) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.

[17] Pediatric erythromelalgia from multidisciplinary perspectives: a scoping review

• Authors: Don Daniel Ocay, Maria Graziano Maloney, Genevieve D'Souza, C. Brownstein, J. Clinch et al.
• Year: 2025
• Venue: Pediatric Research
• URL: https://www.semanticscholar.org/paper/f00b1f0b1495ef2f0757b85b678e02d397f43d10
• DOI: 10.1038/s41390-025-03817-4
• PMID: 39821136
• PMCID: 12507648
• Citations: 2
• Summary: Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised.
• Evidence snippets:
• Snippet 1 (score: 0.337) > Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the most common clinical abnormality being isolated heat and pain abnormality. These findings supported the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies should explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia.

Notes

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