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Ход работы сессии 29th Европейский конгресс педиатрии.

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… Early-onset autoimmunity associated with SOCS1 haploinsufficiency. Nat Commun 11 , 5341 (2020). Boussard, C. et al. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity. Blood blood.2022018486 (2023) doi:10.1182/blood.2022018486. …

Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics.

Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the

Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth.

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following forma

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… Haploinsufficiency of Parathyroid Hormone-Related Peptide (PTHrP) Results in Abnormal Postnatal Bone Development Dev. Biol. 1996 175 166 176 10.1006/dbio.1996.0104 8608863 122. Lanske B. Karaplis A.C. Lee K. Luz A. Vortkamp A. Pirro A. Karperien M. Defize L.H.K. Ho C. Mulligan R.C. …

Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential.

Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects t

Ход работы сессии 28th Европейский конгресс педиатрической ремуматологии (ПСР) 2022) Прага, Чешская Республика. 20-23 сентябрь 2022.

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… Pathway | Gene | Disease associated IC clearance | C1S | SLE-like disease, aHUS, primary angioedema C3 | SLE-like disease PEPD | SLE-like disease Immune cell signalling | BANK1 | AITD, CLL, SSc, RA, SLE PTPN22 | RA, T1D, CD, JIA, HT, SLE TNFSF4 | SSc, SLE NFκB signalling | TNFAIP3 | SS, RA, SSc, SLE, A20 haploinsufficiency …

17th Конгресс ЕВНОС: Милан, Италия, 4–6 Июнь, 2026 года

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… Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 4 Universitätsklinikum Heidelberg, Heidelberg, Germany Introduction : Bosch–Boonstra–Schaaf optic atrophy syndrome (BBSOAS) is a recently described autosomal dominant neurodevelopmental disorder caused by a pathogenetic mechanism of haploinsufficiency …

The multiple roles of interferon regulatory factor family in health and disease.

Interferon Regulatory Factors (IRFs), a family of transcription factors, profoundly influence the immune system, impacting both physiological and pathological processes. This review explores the diverse functions of nine mammalian IRF members, each featuring conserved domains essential for interactions with other transcription factors and cofactors. These interactions allow IRFs to modulate a broad spectrum of physiological processes, encompassing host defense, immune response, and cell development. Conversely, their pivotal role in immune regulation implicates them in the pathophysiology of v

Therapeutic Modulation of Autophagy in Leukaemia and Lymphoma.

Haematopoiesis is a tightly orchestrated process where a pool of hematopoietic stem and progenitor cells (HSPCs) with high self-renewal potential can give rise to both lymphoid and myeloid lineages. The HSPCs pool is reduced with ageing resulting in few HSPC clones maintaining haematopoiesis thereby reducing blood cell diversity, a phenomenon called clonal haematopoiesis. Clonal expansion of HSPCs carrying specific genetic mutations leads to increased risk for haematological malignancies. Therefore, it comes as no surprise that hematopoietic tumours develop in higher frequency in elderly peopl

Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibil

Myelin Displacement and Revention in the Central Nervous System: Молекулярные механизмы, болезни и перспективные терапевтические цели.

Майлин пластичность имеет основополагающее значение для формирования нейронных сетей и оптимизации нейронных функций, формирования схем, регулирующих эмоции, сознание, сенсацию и управление двигателем. Подкомбинированный олигодендроцитами, миелин подвергается пожизненной реконструкции, которая требует высокой метаболической активности; это делает миелин-олигодендроцитную единицу весьма восприимчивой к метаболическому стрессу, старению и патологическим оскорблениям. Хотя обезвоживание является основной характеристикой различных хронических неврологических расстройств, в настоящем обзоре особо п

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… In ASD, haploinsufficiency of the chromatin remodeler CHD8 represents one of the strongest genetic risk factors [ 239 , 240 , 241 ]. CHD8 deficiency directly impairs OPC differentiation and induces social and repetitive behavioral abnormalities in mice [ 242 ]. …

Genetic and Mechanistic Insights Inform Amyotrophic Lateral Sclerosis Treatment and Symptomatic Management: Current and Emerging Therapeutics and Clinical Trial Design Considerations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familia

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… In ALS, pathological intronic hexanucleotide GGGGCC expansions in the C9orf72 gene are thought to contribute to neurodegeneration by multiple mechanisms, including toxic cytoplasmic dipeptide repeat protein aggregates, toxic RNA gain-of-function, or loss of function due to haploinsufficiency [ 20 , 21 …

Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration.

The dynamic changes in chromatin conformation alter the organization and structure of the genome and further regulate gene transcription. Basically, the chromatin structure is controlled by reversible, enzyme-catalyzed covalent modifications to chromatin components and by noncovalent ATP-dependent modifications via chromatin remodeling complexes, including switch/sucrose nonfermentable (SWI/SNF), inositol-requiring 80 (INO80), imitation switch (ISWI) and chromodomain-helicase DNA-binding protein (CHD) complexes. Recent studies have shown that chromatin remodeling is essential in different stag

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling.

Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes sha

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… Heterozygous Pax2 mutants, mice and humans, have a phenotype due to a loss of gene dosage consistent with haploinsufficiency. A reduction of Pax2 gene dosage slowed the progression of PKD in two different mouse models of PKD ( Pkd1 mutant and cpk) ( Ostom et al., 2000 ; Stayner et al., 2006 ). …

Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.

The tumor suppressor p53, often referred to as the “guardian of the genome,” is mutated in more than half of human cancers. These mutations have a significant impact on cancer biology and response to therapy. p53 mutations involve a range of changes that interfere with DNA binding, eliminate tumor suppressor functions, and, in many cases, confer dominant-negative or gain-of-function characteristics that actively promote oncogenesis. These mutations are closely linked to poor clinical outcomes and resistance to standard treatments. This review examines the impact of p53 mutations on cancer ther

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… These often result in complete loss of p53 activity and contribute to haploinsufficiency or null phenotypes. Here are two examples of nonsense mutations in the TP53 gene: (a) TP53 p.R213X (c.637 C > T). …

PI3K/AKT сигнализирующий путь: молекулярный перекресток в опухоли и терапевтические инновации.

PI3K/AKT сигнализирующий путь служит центральным регулирующим узлом, регулирующим основные клеточные процессы, включая рост, распространение, метаболизм, выживание и миграцию. В контексте развития опухоли и рака аберральная активация этого пути приводит к злокачественным преобразованиям, усиливает инвазивный и метастатический потенциал и оказывает сопротивление терапевтическому вмешательству, что в конечном счете приводит к прогрессированию опухоли и более низким клиническим результатам. В этом исследовании всесторонне изучается ИП3К/АКТ, сигнализирующий о его причастности к различным человече

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… Consequently, constitutive hyperactivation of this pathway promotes malignant behaviors such as uncontrolled cell growth, resistance to apoptosis, altered metabolism, and metastatic potential in cancers such as glioblastoma, prostate cancer, BC, endometrial carcinoma, and melanoma. 87 , 88 Additionally, PTEN haploinsufficiency …

Tumor microenvironment signaling and therapeutics in cancer progression.

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss t

The role of autophagy in cancer: from molecular mechanism to therapeutic window.

Autophagy is a cellular degradation process that plays a crucial role in maintaining metabolic homeostasis under conditions of stress or nutrient deprivation. This process involves sequestering, breaking down, and recycling intracellular components such as proteins, organelles, and cytoplasmic materials. Autophagy also serves as a mechanism for eliminating pathogens and engulfing apoptotic cells. In the absence of stress, baseline autophagy activity is essential for degrading damaged cellular components and recycling nutrients to maintain cellular vitality. The relationship between autophagy a

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease.

The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin-proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and c

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… accompanied by impaired autophagic flux [ 42 , 43 ], toxic accumulation of protein aggregates (proteotoxicity) [ 44 ], and that key factors in the necroptotic pathway play a role in the death of cardiomyocytes, as inhibition of receptor interacting serine/threonine kinase 1(Ripk1) by necrotstatin-1 or haploinsufficiency …

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal t