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Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most s

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… Del(5q) MDS is characterized by haploinsufficiency micro RNAs miR-145 and miR-146a, which stimulate overexpression of downstream effects of TLR signaling, including TRAF-interacting protein-6, and interleukin-receptor-associated kinase (IRAK) proteins, which in turn up-regulate NF-κB [ 11 , 12 , 33 ] …

B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients?

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients' outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering import

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… Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. J. Exp. Med. 2011;208:1135–1149. doi: 10.1084/jem.20101947. 76. Ott C.J., Kopp N., Bird L., Paranal R.M., Qi J., Bowman T., Rodig S.J., Kung A.L., Bradner J.E., Weinstock D.M. …

Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.

Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model for understanding how genetic disruptions in endothelial junction biology, mechanotransduction, and kinase signaling drive vascular instability in the central nervous system. Pathogenic loss-of-function variants converge on signaling abnormalities that promote barrier dysfunction, iron deposition, inflammation, and progressive lesional growth. Clinically, FCCM may manifest with

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… Thus, despite their genetic heterogeneity, most CCM mutations produce functionally equivalent cellular effects, consistent with haploinsufficiency as the dominant mechanism in familial CCM (Akers et al. 2025 ). …

Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond.

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defi

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… Only a few inherited single-gene disorders have yet been identified to be associated with elevated BST levels, such as autosomal recessive Gaucher’s disease (GD) and GATA2 haploinsufficiency [ 143 , 144 ]. …

What Zebrafish and Nanotechnology Can Offer for Cancer Treatments in the Age of Personalized Medicine.

Cancer causes millions of deaths each year and thus urgently requires the development of new therapeutic strategies. Nanotechnology-based anticancer therapies are a promising approach, with several formulations already approved and in clinical use. The evaluation of these therapies requires efficient in vivo models to study their behavior and interaction with cancer cells, and to optimize their properties to ensure maximum efficacy and safety. In this way, zebrafish is an important candidate due to its high homology with the human genoma, its large offspring, and the ease in developing specifi

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… Haploinsufficiency of the genes encoding the tumor suppressor Pten predisposes zebrafish to hemangiosarcoma. DMM Dis. Model. Mech. 2012;5:241–247. doi: 10.1242/dmm.008326. 80. Haramis A.P.G., Hurlstone A., van der Velden Y., Begthel H., van den Born M., Offerhaus G.J.A., Clevers H.C. …

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches.

Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the

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… Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev. 2012;26:344–349. doi: 10.1101/gad.184341.111. 155. Okano M, Bell DW, Haber DA, Li E. …

Rare Hematologic Malignancies and Pre-Leukemic Entities in Children and Adolescents Young Adults.

There are a variety of rare hematologic malignancies and germline predispositions syndromes that occur in children and adolescent young adults (AYAs). These entities are important to recognize, as an accurate diagnosis is essential for risk assessment, prognostication, and treatment. This descriptive review summarizes rare hematologic malignancies, myelodysplastic neoplasms, and germline predispositions syndromes that occur in children and AYAs. We discuss the unique biology, characteristic genomic aberrations, rare presentations, diagnostic challenges, novel treatments, and outcomes associate

The Bone Microenvironment Soil in Prostate Cancer Metastasis: An miRNA Approach.

Bone metastatic prostate cancer (PCa) is associated with a high risk of mortality. Changes in the expression pattern of miRNAs seem to be related to early aspects of prostate cancer, as well as its establishment and proliferation, including the necessary steps for metastasis. Here we compiled, for the first time, the important roles of miRNAs in the development, diagnosis, and treatment of bone metastasis, focusing on recent in vivo and in vitro studies. PCa exosomes are proven to promote metastasis-related events, such as osteoblast and osteoclast differentiation and proliferation. Aberrant m

Свойства антиракера ВИЧ-ингибатора Нелфинавира.

Традиционные методы лечения рака могут потерять свою эффективность после появления новых мутации или развития химиотерапии. Несвоевременная диагностика, высокая стоимость лечения и потребность в высокоэффективной инфраструктуре для лечения раковых заболеваний затрудняют доступ к надлежащему лечению в условиях с низким уровнем доходов и ограниченными ресурсами. Переориентация утвержденных лекарственных средств на лечение рака может привести к снижению стоимости и сокращению сроков разработки новых лекарственных средств и к ускорению появления новых и эффективных вариантов лечения для нуждающихс

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… To identify the molecular target, the authors conducted a genome-wide screening of nelfinavir using haploinsufficiency yeast strains, which revealed HSP82—the yeast orthologue of mammalian HSP90—to be a possible binding partner. …

The nutrigenomic-epigenetic axis in cancer: from dietary bioactives to precision oncology.

Cancer development and progression are increasingly understood to arise from dynamic interactions between genetic alterations and environmentally driven epigenetic regulation, with dietary exposures representing one of the most biologically influential and modifiable factors. Given the expanding evidence linking nutrition to epigenomic remodeling, a comprehensive synthesis of how specific dietary components influence cancer-relevant epigenetic mechanisms is needed to clarify their preventive and therapeutic relevance. This review brings together mechanistic, epidemiologic, and translational fi

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… For instance, conditional knockout of the DNMT1 gene has been shown to effectively halt the progression of leukemia, while its haploinsufficiency has been shown to significantly delay the progression of leukemogenic processes and adversely affect the self-renewal capacity of LSCs, all without a detrimental …

Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: e-Posters.

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… Wieacker 1 1 Institute for Human Genetics, Münster, Germany, 2 Department of Medical Genetics, Izmir, Turkey Haploinsufficiency of the SOX9 gene in humans causes the skeletal malformation syndrome campomelic dysplasia (CD), which is a semilethal disorder characterised by congenital bowing of the long … We speculate that haploinsufficiency of BCO1 may be related to congenital bilateral iris coloboma in our patient. B. Aleksiūnienė: None. B. Tumienė: None. R. Strupaitė–Šileikienė: None. A. Utkus: None. …

A guide to cancer immunotherapy: from T cell basic science to clinical practice.

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regar

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… Moreover, human patients with CTLA4 haploinsufficiency exhibit similar severe multiorgan lymphocytic infiltration and autoimmunity (CHAI disease) that can be treated with abatacept, an FDA-approved CTLA4Ig 23 , 24 . …

E3 ubiquitin ligases orchestrate chemo-resistance in gastrointestinal malignancies: from DNA damage response to therapeutic targeting.

Therapy resistance in gastrointestinal tumors remains a critical challenge in clinical oncology, severely compromising therapeutic efficacy and long-term patient survival. E3 ubiquitin ligases, as core enzymes involved in the protein ubiquitination process, have been demonstrated to play indispensable roles in regulating key biological processes in tumor cells, including DNA damage repair, cell cycle progression, apoptosis, cancer stem cell maintenance, and immune evasion. Additionally, E3 ligases are key regulators of resistance to multiple anticancer strategies, such as chemotherapy, radioth

Геномический диагноз детских расстройств: революция и эволюция.

Мощные, последние достижения в технологиях анализа генома оказали глубокое воздействие на практику медицинской генетики как в лаборатории, так и в клинике. Более широкое использование общегеномных тестов, таких, как анализ хромосомных микроарра и последовательность экзомов, привело к переходу к "генотипному" подходу. В настоящее время имеются многочисленные методы диагностики конкретного синдрома или фенотипа, и, хотя традиционные методы остаются эффективными инструментами в некоторых ситуациях, технологии с более высокой производительностью фактически стали лабораторным инструментом диагности

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… This requires consideration of the inheritance of the variant, the literature detailing the genes functions, the expression profile in human tissues, the mechanism by which mutations are known to cause specific phenotypes (haploinsufficiency, dominant negative), frequency of the particular variant in …

The Anti-Cancer Effect of Polyphenols against Breast Cancer and Cancer Stem Cells: Molecular Mechanisms.

The high incidence of breast cancer in developed and developing countries, and its correlation to cancer-related deaths, has prompted concerned scientists to discover novel alternatives to deal with this challenge. In this review, we will provide a brief overview of polyphenol structures and classifications, as well as on the carcinogenic process. The biology of breast cancer cells will also be discussed. The molecular mechanisms involved in the anti-cancer activities of numerous polyphenols, against a wide range of breast cancer cells, in vitro and in vivo, will be explained in detail. The in

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… It exhibits haploinsufficiency, and its identification may have unveiled a crosslink between autophagy and human cancer. Its monoallelic deletion has been detected in breast, ovary, and prostate cancers [ 98 , 99 ]. …

Терапевтические и диагностические проблемы передневременного слабоумия.

В поисках терапевтических модификаторов фронтовременное слабоумие (ФТР) традиционно омрачалось другими заболеваниями, такими, как болезнь Альцгеймера (AD). Будучи клиническим и патологическим по своему характеру заболеванием, ПТО было вызвано рядом недавних открытий, таких, как новые генетические варианты семейных и спорадических форм заболеваний и выявление белка, связывающего ДНК с ДНК. 43 kDa (kDa)TDP-43) в качестве определяющего компонента включения более чем в половине случаев. В сочетании с постоянно расширяющимися знаниями о функции и дисфункции белка тау-а, который патологически агреги

Are RNA Therapies a Solid Foundation or a Frontier Yet to Be Conquered?

The identification of microRNAs (miRNAs) has resulted in significant advancements in research, particularly regarding their utilization as diagnostic and therapeutic targets. This has generated enthusiasm for exploring the potential of non-coding RNAs (ncRNAs) in treating cancer and other diseases, with miRNAs and long non-coding RNAs (lncRNAs) showing particular promise. Over the past twelve years, there has been significant research into RNA-based treatments. Antisense oligonucleotides and small interfering RNAs are the most commonly used. Certain products have received Federal and Drug Admi

The γ-secretase complex: from discovery to a therapeutic target.

γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor

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… essential substrates ( i.e. , loss of function) or through the stalled E–S complex per se ( i.e. gain of toxic function). 218,219 However, a dominant loss-of-function mechanism alone can be ruled out, as PS1 mutants in the human population that lead to nonsense-mediated decay of the mRNA (and therefore haploinsufficiency …

Указываемые данные об автономной и аллогенетической трансплантации гематопоэтики стем-целлов у взрослых: состояние искусства.

Пересадка стволовых клеток (ХХСТ) гематополиетическая трансплантация превратилась из процедуры спасания лейкемии в лечебную форму, охватывающую почти все виды гематологической злокачественности и несколько ненасыщенных расстройств. Современный ландшафт был видоизменен тремя совпадающими силами: усовершенствованием стратификации с учетом конкретных рисков заболеваний (European LeukemiaNet [ELN] 2022 для острой миелоидной лейкемии, Молекулярной международной системы прогнозирования (IPSS-M) для миэлодипластических синдромов, Международной системы мутационного скручивания [MIPSS70+ v.2.0] и Myelo

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… Adult primary immunodeficiencies (e.g., CTLA-4 haploinsufficiency, common variable immunodeficiency with enteropathy) are increasingly referred for allo-HSCT at specialist centers [ 233 ]. 10. Transplant-Related Mortality, GVHD, GVL, and Future Directions 10.1. …

PARP Inhibitors and Haematological Malignancies-Friend or Foe?

Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with BRCA gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though BRCA mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is

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… For example, Fanconi Anaemia (FA)-BRCA pathway haploinsufficiency is implicated in the molecular pathogenesis of T-ALL [ 37 ], and several polymorphisms in the HRR pathway may affect susceptibility to childhood ALL [ 38 ]. …