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Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies.

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited gen

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… Preclinical studies demonstrated that treatment with ascorbate (vitamin C), which is a cofactor for TET2, can restore TET2 activity in the setting of TET2 haploinsufficiency, resulting in increased DNA demethylation, normalization of HSPC function, and impaired leukemogenesis. 94 , 95 This compelling …

The Role of Platelet Dysfunctions in the Pathogenesis of the Hemostatic-Coagulant System Imbalances.

Platelet dysfunction plays a critical role in the pathogenesis of various disorders affecting the hemostatic-coagulant system. This review aims to explore the mechanisms by which platelet dysfunctions contribute to the disruption of hemostasis, leading to an increased risk of both thrombosis and bleeding. Platelets, traditionally known for their role in clot formation, can exhibit altered functionality under pathological conditions such as cardiovascular diseases, metabolic disorders, and autoimmune diseases, impacting their interaction with coagulation factors and vascular endothelium. The re

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… Similar regulatory mechanisms may underlie other dominant genetic disorders where haploinsufficiency or interference with the wild-type gene does not fully explain the condition. …

Role of Toll-Like Receptors in Myeloid Neoplasms: Focuses on the Molecular Mechanisms and Clinical Impact on Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myeloid Leukemia.

Toll-like receptors (TLRs) are essential components of the innate immune system, functioning as pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In hematological malignancies, particularly myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML), TLRs influence inflammation, disease progression, and therapeutic response. This review highlights the prognostic relevance of TLR expression, the role of the MyD88 signaling pathway in clonal evolution, and the dual

Hypophosphatasia.

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5'-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births

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… The severe HPP forms are mostly caused by homozygosity or compound heterozygosity for severe variants; moderate HPP forms are produced by dominant negative effect of missense variants; while mild adult HPP, that are usually characterized by unspecific signs, are probably related to haploinsufficiency …

Gene editing and CRISPR in the clinic: current and future perspectives.

Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases whic

Advances in CRISPR-Cas technology and its applications: revolutionising precision medicine.

CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated proteins) has undergone marked advancements since its discovery as an adaptive immune system in bacteria and archaea, emerged as a potent gene-editing tool after the successful engineering of its synthetic guide RNA (sgRNA) toward the targeting of specific DNA sequences with high accuracy. Besides its DNA editing ability, further-developed Cas variants can also edit the epigenome, rendering the CRISPR-Cas system a versatile tool for genome and epigenome manipulation and a pioneering force in precision medic

Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappoint

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… Lyn is a haploinsufficiency gene in autoimmunity ( 16 ), and it is implicated in human disease ( 10 ). …

Acute kidney injury: pathogenesis and therapeutic interventions.

Acute kidney injury (AKI) is a prevalent clinical condition that is associated with unacceptably high morbidity and mortality, as well as the development of chronic kidney disease (CKD). The pathogenesis of AKI is highly complex and heterogeneous, primarily attributed to metabolic disturbances arising from the disease itself and the administration of medications related to treatment. In recent years, AKI in cancer patients is highly concerned. The emergence of AKI caused injuries and dysfunction of remote organs but also enhanced the health-care costs. It's essential for early recognition of A

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… Additionally, a documented case of AKI linked to CTLA-4 haploinsufficiency, identified as acute granulomatous tubulointerstitial nephritis, led to the disruption of FOXP3 + regulatory T cells, heightened activity of effector T cells, and lymphocytic infiltration in various organs [ 188 ]. …

Cardiomyopathy: pathogenesis and therapeutic interventions.

Cardiomyopathy is a group of disease characterized by structural and functional damage to the myocardium. The etiologies of cardiomyopathies are diverse, spanning from genetic mutations impacting fundamental myocardial functions to systemic disorders that result in widespread cardiac damage. Many specific gene mutations cause primary cardiomyopathy. Environmental factors and metabolic disorders may also lead to the occurrence of cardiomyopathy. This review provides an in-depth analysis of the current understanding of the pathogenesis of various cardiomyopathies, highlighting the molecular and

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… On account of most MYBPC3 mutations leading to cMyBP‐C haploinsufficiency, the potential strategy to treat MYBPC3 ‐caused HCM is the introduction of wild‐type MYBPC3 cDNA into abnormal cardiomyocytes. 154 Recently, Prondzynski et al. 155 introduced the full‐length MYBPC3 cDNA into abnormal cardiomyocytes …

Antibody-Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen

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… Moreover, other studies suggested that it may show greater potency than BelaMaf [ 59 ], and preferential activity against high-risk deletion 17p models, in part due to co-deletion producing haploinsufficiency of RNA polymerase IIA [ 60 ]. …

Proceedings of the 27th European Paediatric Rheumatology Congress (PReS 2021) : Virtual. 19-21 September 2021

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Иммунотерапевтический ландшафт амиотропического бокового склероза: библиометрический анализ тенденций в области исследований, приоритетов в области перевода и сетей сотрудничества (см.2006-2025).

Амиотрофный боковой склероз (ALS) по-прежнему является серьезной терапевтической проблемой, при этом иммунная диагностика все чаще признается в качестве одного из важнейших факторов развития заболеваний. Несмотря на обширные механистические исследования, никакой иммунотерапевтический подход не привел к последовательному изменению болезней, в связи с чем возникают вопросы о том, отражает ли этот переводный пробел биологическую сложность или структурную несогласованность в исследовательской экосистеме. Чтобы охарактеризовать интеллектуальную эволюцию исследований иммунотерапевтии ALS, определить

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… self-sustaining and largely irreversible; available evidence suggests that C9orf72-related pathology begins years before symptom onset, rendering post-symptomatic ASO treatment potentially insufficient. 58 Second, reduction of toxic repeat RNA species or DPR proteins may be inadequate if concurrent haploinsufficiency …

Genetic factors and management strategies in aortic health: a literature review of inherited aortopathy.

Inherited aortopathies, including Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, are genetic disorders characterized by structural abnormalities of the aorta that predispose individuals to life-threatening complications like aneurysms and dissections. These conditions result from mutations in genes essential for maintaining aortic wall integrity, such as FBN1, TGFBR1, and COL3A1, affecting extracellular matrix components and the transforming growth factor-beta (TGF-β) pathway. Marfan syndrome has a prevalence of approximately 1 in 5000, while Loeys-Dietz syndrome and vascul

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… The underlying pathogenesis of aortic abnormalities in Turner syndrome is multifactorial and may involve haploinsufficiency of genes on the X chromosome, altered hemodynamics, and abnormal connective tissue metabolism. …

The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) represents the most common and aggressive malignant form of brain tumour in adults and is characterized by an extremely poor prognosis with dismal survival rates. Currently, expanding concepts concerning the pathophysiology of GBM are inextricably linked with neuroinflammatory phenomena. On account of this fact, the identification of novel pathomechanisms targeting neuroinflammation seems to be crucial in terms of yielding successful individual therapeutic strategies. In recent years, the pleiotropic growth factor progranulin (PGRN) has attracted significant atten

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… Two studies published in 2006 suggest that haploinsufficiency and null mutations in the PGRN gene are responsible for the development of several familiar forms of frontotemporal lobar degeneration (FTLD) and sparked landmark studies focused on evaluating the precise role and function of PGRN in brain …

Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications.

Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis

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… Among the many processes which can lead to the hyperactivation of the NF-κB cascade and TNF function are decreased activity of the NF-κB negative regulators (e.g., A20 haploinsufficiency), increased activation by factors such as caspase recruitment domain–containing protein (CARD), and activating mutations …

Juvenile-onset Systemic Lupus Erythematosus: Recent Advances in Pathogenesis and Treatment.

PURPOSE OF REVIEW: This review summarizes recent advances in understanding the pathogenesis and therapeutic landscape of juvenile-onset systemic lupus erythematosus (jSLE), with a focus on how emerging genetic and immunologic insights inform patient stratification, targeted treatments, and Treat-to-Target (T2T) approaches in pediatric care. RECENT FINDINGS: Studies of (ultra-)rare gene variants (e.g., affecting TLR7, UNC93B1, PLD4, PTPN2, BACH2) aided in understanding key pathogenic pathways, and allowed linking these to associated clinical phenotypes. Multi-ancestral genomic studies and cumu

Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.

The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining- visceral pleura and outer lining- parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making dia

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… Environmental impact on carcinogenesis under BRCA1 haploinsufficiency. Genes Environ (2023) 45:1–7. doi: 10.1186/s41021-023-00258-5 37. Jain SL. The WetNet: what the oral polio vaccine hypothesis exposes about globalized interspecies fluid bonds. …

Molecular Mechanism of Autophagy and Its Regulation by Cannabinoids in Cancer.

Autophagy is a "self-degradation" process whereby malfunctioned cytoplasmic constituents and protein aggregates are engulfed by a vesicle called the autophagosome, and subsequently degraded by the lysosome. Autophagy plays a crucial role in sustaining protein homeostasis and can be an alternative source of energy under detrimental circumstances. Studies have demonstrated a paradoxical function for autophagy in cancer, displaying both tumour suppressive and tumour promotive roles. In early phases of tumour development autophagy promotes cancer cell death. In later phases, autophagy enables canc

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage-Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities.

Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) case

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… PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: A GRAALL study Leukemia 2009 23 1989 1998 10.1038/leu.2009.135 19587702 59. Martin-Lorenzo A. Auer F. Chan L.N. …

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy.

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening co

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… NF-κB/TNF disorders include haploinsufficiency of A20 (with TNFAIP3 gene disorder), OTULIN-related autoinflammatory syndrome (with OTULIN gene disorder), Blau syndrome (with NOD2 gene disorder), TNF receptor-associated periodic syndrome (with TNFRSF1A gene disorder), and deficiency of adenosine deaminase …