Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Activated PI3K-delta Syndrome. Core disease mechanisms, molecular and cell...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Activated PI3K-delta syndrome

• Authors: Unknown authors
• Year: 2020
• Venue: Definitions
• URL: https://www.semanticscholar.org/paper/2d9cd678f1ad514aad537ed315a6394d425c888a
• DOI: 10.32388/q6iuae
• Citations: 4
• Influential citations: 1
• Summary: People with activated PI3K-delta syndrome develop recurrent infections, particularly in the lungs, sinuses, and ears, and may have chronic active viral infections, commonly Epstein-Barr virus or cytomegalovirus infections.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Activated PI3K-delta syndrome

[2] The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights

• Authors: Abutaleb Asiri, A. A. Al Qarni, Ahmed Bakillah
• Year: 2024
• Venue: Diagnostics
• URL: https://www.semanticscholar.org/paper/e4de6095f95951d23b6467a7a213148e94c4125a
• DOI: 10.3390/diagnostics14192132
• PMID: 39410536
• PMCID: 11475808
• Citations: 14
• Summary: An overview of shared molecular mechanisms between diabetes and cancer as well as established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.428) > T2DM and cancer are complex diseases that share common mechanisms including obesity, inflammatory stress, chronic hyperglycemia, and insulin resistance. These mechanisms are involved in the association with tumor development and progression by promoting cell growth, proliferation, migration, and invasion as well as inhibiting apoptosis in tumor cells. Understanding these mechanisms linking both diseases is crucial for developing effective methods for diagnosis, prevention, and treatment. Furthermore, certain pathways such as the PI3K/AKT/mTOR pathway, which are associated with glucose metabolism, frequently exhibit molecular alterations in various cancer subtypes. To overcome the impact of drug resistance and toxicities, a therapeutic combination targeting these specific pathways could provide a promising intervention strategy to reduce the burden impact in both diseases. However, the inhibition of PI3K/AKT/mTOR by small molecule inhibitors may lead to insulin resistance in cancer cells, posing a significant challenge that could worsen disease outcomes. Identifying predictive biomarkers for effective treatments involving PI3K/AKT/mTOR inhibitors is essential to anticipate potential complications. Moreover, antidiabetic drugs appear to reduce cancer risk. Understanding the precise mechanism by which these treatments prevent cancer may help identify novel strategies to treat cancer patients and prevent the disease's incidence. Further research into the cellular and molecular interactions driving the intricate relationship between T2DM and cancer is essential. This will enhance our understanding and improve the clinical outcomes of patients affected by both diseases.

[3] Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

• Authors: L. Berglund
• Year: 2023
• Venue: Journal of Clinical Immunology
• URL: https://www.semanticscholar.org/paper/2ea3bdb89da3e207aeaea857a20bbc6a3fb0dfac
• DOI: 10.1007/s10875-023-01626-0
• PMID: 38148368
• PMCID: 10751257
• Citations: 17
• Summary: Key aspects of PI3K pathway biology are summarized and potential options for nuanced modulation of the PI3K pathway in APDS from a clinical perspective are discussed, highlighting differences from PI3K inhibition in haematological malignancies.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

[4] Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

• Authors: Vyanka Redenbaugh, T. Coulter
• Year: 2021
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/7dc479c651fab24017fc959690b058a1262fda47
• DOI: 10.3389/fped.2021.702872
• PMID: 34422726
• PMCID: 8374435
• Citations: 26
• Influential citations: 2
• Summary: The common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.419) > Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

[5] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

• Authors: M. G. de Matos, Mafalda Pinto, A. Gonçalves, Sule Canberk, M. J. Bugalho et al.
• Year: 2025
• Venue: PeerJ
• URL: https://www.semanticscholar.org/paper/655de68f1a7e8137dcba8a2046f14dee4f07594d
• DOI: 10.7717/peerj.18801
• PMID: 39850836
• PMCID: 11756370
• Citations: 4
• Summary: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality.
• Evidence snippets:
• Snippet 1 (score: 0.416) > Knowledge of molecular mechanisms implicated in thyroid carcinogenesis has been attained in recent years. Thyroid neoplasm result from alterations in gene expression patterns, which occur due to a gradual accumulation of genetic and epigenetic events. These changes are associated with specific tumor phenotypes and are implicated in disease etiology. Molecular alterations induce the activation of different signaling pathways, such as the mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K/AKT/mTOR), which are involved in and promote carcinogenesis (Hsiao & Nikiforov, 2014). In a few years, the knowledge of molecular mechanisms implicated in thyroid carcinogenesis changed from understanding signaling pathways and identification of a few genes mutations to the knowledge of the main genes implicated in thyroid carcinogenesis, reviewed by De Leo et al. (2024). Genetic changes in thyroid neoplasms were divided in early/driver molecular alterations and late/progression events. Late/ progression events may be associated with early/driver molecular alterations and represent the evolution from well-differentiated to high-grade and undifferentiated carcinoma, being (Pozdeyev et al., 2018). Most frequent gene mutations present in follicular-cell derived thyroid tumors are BRAF, RAS, and TERTp mutations, associate with clinically relevant clinicopathologic features, as shown in Table 3.

[6] Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

• Authors: T. Coulter, Anita Chandra, C. Bacon, J. Babar, J. Curtis et al.
• Year: 2017
• Venue: The Journal of Allergy and Clinical Immunology
• URL: https://www.semanticscholar.org/paper/a890b4b187a0ade1f6ba97b4787f8700c0f6d4a1
• DOI: 10.1016/j.jaci.2016.06.021
• PMID: 27555459
• PMCID: 5292996
• Citations: 403
• Influential citations: 30
• Summary: The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease and clinical trials of selective PI3K&dgr; inhibitors offer new prospects for APDS treatment.
• Evidence snippets:
• Snippet 1 (score: 0.410) > Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

[7] Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment

• Authors: Liang Liu, Yin Luo, Guofu Zhang, Chunhui Jin, Zhenhe Zhou et al.
• Year: 2017
• Venue: Oncotarget
• URL: https://www.semanticscholar.org/paper/d84ac1f938cd73189ef4e9ba5c4718bfa34825f0
• DOI: 10.18632/oncotarget.21230
• PMID: 29156812
• PMCID: 5689702
• Citations: 5
• Summary: A correlation was observed between increased deficit syndrome severity and elevated expression levels of DRD2 in PBLs of chronic schizophrenia patients receiving long-term clozapine treatment.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Schizophrenia is a complex, severe, chronic psychiatric disorder with a heterogeneous clinical phenotype [1]. The prevalence of schizophrenia is approximately 1.1% of the population over the age of 18, and 25 million people worldwide are currently affected by this disorder [2]. However, at present, schizophrenia is primarily diagnosed using criterion-based approaches, such as the criteria from the International Classification of Diseases, Tenth Edition (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) [3]. Biomarkers for the diagnosis, prognosis or therapeutic efficacy of schizophrenia are currently being examined extensively. > Many efforts have been made to investigate the etiology of this disease, including studies focused on genetics, early environmental factors, psychology and neurobiology [4][5][6][7]. Gene-environmental interactions have been found to play a crucial role in the development of schizophrenia [8,9]. Considering these various factors, the development of genomics and molecular biology improved the understanding of the molecular pathophysiology of schizophrenia, especially the related neuronal signaling pathways and the influences of antipsychotic drugs on them [10][11][12][13]. The phosphoinositide-3 kinase -protein kinase B (PI3K-Akt) pathway is an important downstream intracellular pathway of DRD2, which is associated with the function and development of central nervous system and the pathophysiology of schizophrenia [10][11][12][13][14][15]. PI3K-Akt pathway is also the intracellular downstream pathway of glutamate, serotonin, dysbindin, disrupted in schizophrenia-1 (DISC-1), and neuregulin 1 (NRG1), which are all the targets for mood stabilizers and antipsychotic drugs [10,15,16]. Almost all aspects of the cell developments, such as growth, proliferation, metabolism and apoptosis, were modulated by PI3K-Akt pathway.

[8] Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics

• Authors: Elias A Alraqibah
• Year: 2025
• Venue: Cureus
• URL: https://www.semanticscholar.org/paper/64ca180c8b4dba5605a150d357db50ba117d38b7
• DOI: 10.7759/cureus.90448
• PMID: 40978950
• PMCID: 12446750
• Summary: An in-depth exploration of the genetic and molecular mechanisms underlying Activated PI3 kinase delta syndrome is provided, highlighting the complex interplay between immunodeficiency and autoimmunity.
• Evidence snippets:
• Snippet 1 (score: 0.406) > Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics

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

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 15
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.404) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[10] Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome

• Authors: Takaki Asano, S. Okada, M. Tsumura, Tzu-wen Yeh, Kanako Mitsui-Sekinaka et al.
• Year: 2018
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/d7a2168f57e26dccb1c4815aa7a08a5f2ff6d03a
• DOI: 10.3389/fimmu.2018.00568
• PMID: 29675019
• PMCID: 5895775
• Citations: 24
• Summary: The results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome

[11] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

• Authors: A. W. Rachfal, S. Grant, S. Schwartz
• Year: 2021
• Venue: International Journal of General Medicine
• URL: https://www.semanticscholar.org/paper/4c088a6a8b613c15e817f7491d24022497b7f5c4
• DOI: 10.2147/IJGM.S305156
• PMID: 33776471
• PMCID: 7987256
• Citations: 6
• Summary: The “Diabetes Syndrome”, an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions.
• Evidence snippets:
• Snippet 1 (score: 0.401) > Although many pathways lead to hyperglycemia in diabetes -the so-called "Egregious Eleven" (Listed in Table 1) -β-cell dysfunction is the core defect. 1,2 Four basic pathophysiologic mechanisms damage the β-cell, namely, genes and epigenetic changes, inflammation, an abnormal environment [especially fuel excess], and insulin resistance (IR). 1,2 2][3] The interplay between these pathophysiologic mechanisms influences the specific risk of development and progression of complications in an individual patient. [6][7][8][9][10][11][12][13][14][15] In clinical practice we often encounter these common diseases, frequently within one individual patient and they are treated as independent conditions. However, we believe their epidemiologic associations is, in part, due to the same underlying pathophysiologies driving β-cell damage and diabetic complications. That is, the same pathophysiologic mechanisms that damage the β-cell and promote diabetesspecific complications also have key roles in the pathogenesis of these diseases. ][9][10][11][12][13][14][15] However, we propose these connections go beyond mere epidemiologic links due to overlapping pathophysiology. In fact, these conditions occur together in enough frequency and have common overlapping pathophysiologic drivers that we have created a conceptual framework called "The Diabetes Syndrome". The name is inspired by the Greek meaning of syndromē (sun-[together] + dramein [to run]) as the conditions, indeed, run together (Figure 1). This article will describe the shared pathophysiologic and etiologic factors across these prevalent and related diseases within the Diabetes Syndrome conceptual framework discussed within the context of the 4 basic pathophysiologic mechanisms -genes and epigenetic changes, abnormal environment, inflammation, and IR -with a focus on commonalities between these diseases and DM. In brief, genetics can mediate susceptibility to damage from abnormal external and internal environmental factors, including inflammation and IR. All these mechanisms can promote epigenetic changes.

[12] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

• Authors: Liang Zhang, Yujie Jiang, Taojun Jin, Mingxian Zheng, Yixuan Yap et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/e7ce2244e2bc25df76718a7b46e860a9c0478c01
• DOI: 10.3390/biomedicines13092132
• PMID: 41007695
• PMCID: 12467098
• Citations: 3
• Summary: Findings are crucial for a deeper understanding of lipid metabolism pathways in AP and for the early implementation of preventive clinical measures, such as the control of blood lipid levels.
• Evidence snippets:
• Snippet 1 (score: 0.401) > FFAs have activated inflammatory cytokines, including tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1, which exacerbate the inflammatory cascade in AP [12,13]. These findings suggest that lipid metabolism disorders are closely linked to the regulation of the local immune micro-environment of the pancreas. Abnormal expression of specific lipid metabolism-related genes may play a crucial role in AP progression. Notably, ACSL4, a gene involved in cell membrane lipid synthesis, has been shown to be central to AP pathology and may serve as a potential therapeutic target [14]. However, the molecular mechanisms by which lipid metabolism abnormalities regulate AP development remain unclear. A systematic analysis of the expression patterns of relevant genes and their regulatory mechanisms could enhance our understanding of AP pathogenesis and inform personalized treatment strategies. > Advancements in high-throughput sequencing and computational biology have made machine learning and bioinformatics essential tools for exploring disease diagnosis, treatment, and underlying pathological mechanisms. In this study, we conducted a systematic analysis of AP-related lipid metabolism core genes and their regulatory mechanisms by integrating gene expression data, gene enrichment analysis, machine learning, protein interaction networks, and metabolic pathway analysis [15][16][17][18]. We then experimentally validated the candidate genes using an AP mouse model to ensure the reliability and clinical translational value of the identified biomarkers. > This study aims to identify key lipid metabolism-related genes involved in the pathogenesis of acute pancreatitis and elucidate their core regulatory mechanisms through integrative bioinformatics, machine learning, and animal experiments.

[13] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

• Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
• Year: 2016
• Venue: Molecular Psychiatry
• URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
• DOI: 10.1038/mp.2016.89
• PMID: 27240529
• PMCID: 4995546
• Citations: 77
• Influential citations: 2
• Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.400) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

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

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 3
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[15] Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

• Authors: C. B. Machado, Flávia Melo Cunha de Pinho Pessoa, E. L. da Silva, Laudreísa da Costa Pantoja, Rita Almeida Ribeiro et al.
• Year: 2021
• Venue: Pharmaceutics
• URL: https://www.semanticscholar.org/paper/ee6315b5b8c029d8612812666dfaa8cd566c577f
• DOI: 10.3390/pharmaceutics13101604
• PMID: 34683897
• PMCID: 8540545
• Citations: 4
• Summary: Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Other relevant PI3K inhibitors with FDA approval to treat hematological malignancies include the pan-PI3K inhibitor with preferential activity towards PI3K-α/-δ copanlisib, the PI3K-γ/-δ inhibitor duvelisib and the recently approved PI3K-δ/Casein kinase 1 epsilon (CSNK1E) inhibitor umbralisib [134][135][136]. > The high prevalence of clinical trials evaluating PI3K inhibition as therapeutics for B-cell malignancies speaks to the favorable outcomes, especially when combined with chemo-immunotherapy treatment regimens, achieved in these studies, with ORRs reaching results as high as 75% of the treated population. Treatment efficacy, however, is diverse among different malignant B-cell subtypes, and patients afflicted with R/R diffuse large B-cell lymphoma (DLBCL) had generally lower rates of response to PI3K inhibition. Even among DLBCL patients, molecular profiles distinguishing the cell of origin in activated B-cell-like (ABC) DLBCL and germinal center B-cell-like (GCB) DLBCL represent a further stratification when predicting patient outcome to PI3K inhibition treatment [85,88,90,94,96,97,102,106]. > Mechanisms involved in tumor-acquired PI3K-inhibitor resistance are not fully elucidated yet, with no common mutation characterized across patient cohorts with progressive disease after idelalisib treatment [137]. However, analyses in human and murine models signal towards upregulation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathways in neoplastic cells resistant to PI3K-δ inhibition, which are major cellular mechanisms responsible for the regulation of proliferation, differentiation and cell death [138][139][140].

[16] Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

• Authors: Ke Zhu, Qifan Li, Lingli Han, Jinqiao Sun
• Year: 2024
• Venue: Pediatric Discovery
• URL: https://www.semanticscholar.org/paper/9856bc849611542f204bcc3f97ab7b9ee6e2df39
• DOI: 10.1002/pdi3.2504
• PMID: 40625457
• PMCID: 12118235
• Citations: 2
• Summary: Targeted therapies, such as the mTOR inhibitor sirolimus and the elective Phosphoinositide 3‐kinase delta inhibitor leniolisib, have emerged as promising options, demonstrating both safety and effectiveness.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

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

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 24
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.394) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[18] Chemotherapy and Mechanisms of Resistance in Breast Cancer

• Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
• Year: 2012
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
• DOI: 10.5772/24629
• Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
• Evidence snippets:
• Snippet 1 (score: 0.393) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[19] 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: 0.391) > 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

[20] Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype

• Authors: P. Zhao, Juan Huang, Huicong Fu, Jia-li Xu, T. Li et al.
• Year: 2024
• Venue: Pediatric Rheumatology
• URL: https://www.semanticscholar.org/paper/06f3fe8bbc9cdd6bae66177a0b4cd2c218da308a
• DOI: 10.1186/s12969-024-00955-7
• PMID: 38287413
• PMCID: 10823743
• Citations: 11
• Summary: This study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype

Notes

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