Результаты поиска

Over-expression of wild-type and mutant HFE in a human melanocytic cell line reveals an intracellular bridge between MHC class I pathway and transferrin iron uptake.

Hereditary hemochromatosis (HH) is a frequent recessive disorder of iron metabolism characterised by systemic iron overload. In Northern Europe, more than 90% of HH patients are homozygous for a mis-sense mutation (C282Y) in the HFE1 gene product. The HFE protein is the heavy chain of a MHC class I-related molecule and associates with beta2 microglobulin and the transferrin receptor. Its precise roles in iron metabolism and in the pathophysiology of HH are still unclear. In order to identify the cellular processing of HFE, an important step towards the understanding of the function of the prot

Воспаление и иммунная микроокружающая среда в миелопролазерных неоплазмах: патогенные механизмы и терапевтические возможности.

Филадельфия-отрицательная (Ph-отрицательная) миелопролиферативные новообразования (MPNs) включают полицифемию (PV), основную тромбоцитемию (ET) и первичный миэлофиброз (PMF), которые являются клональными гематопоэтическими расстройствами, вызванными соматическими генными мутациями в генах JAK2, CALR или MPL. Мутации активируют путь JAK-STAT и прерывают сигнализацию NF-IB, что приводит к хроническому подстрекательству, вызванному провоспалительными цитокинами и реактивными видами кислорода (ROS). Эта изменившаяся микроокружающая среда вызывает серьезные клинические особенности заболевания, таки

Совпадение в полном тексте источника
… In contrast, most patients with MPN carry distinct somatic mutations in one of three key driver genes: MPL (exon 10 of the thrombopoietin receptor gene), CALR (a frameshift mutation in exon 9 affecting calreticulin), or JAK2 (typically in exon 12 or 14) [ 22 , 23 ]. … Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis Oncoimmunology 2017 6 e1345402 10.1080/2162402x.2017.1345402 29123956 PMC5665081 48. Tu Y.C. Wang S.X. Li F. …

Abscopal Effects in Metastatic Cancer: Is a Predictive Approach Possible to Improve Individual Outcomes?

Patients with metastatic cancers often require radiotherapy (RT) as a palliative therapy for cancer pain. RT can, however, also induce systemic antitumor effects outside of the irradiated field (abscopal effects) in various cancer entities. The occurrence of the abscopal effect is associated with a specific immunological activation in response to RT-induced cell death, which is mainly seen under concomitant immune checkpoint blockade. Even if the number of reported apscopal effects has increased since the introduction of immune checkpoint inhibition, its occurrence is still considered rare and

Совпадение в полном тексте источника
… Calreticulin is essential for the recognition of tumor cells by DCs and subsequently by T cells, in fact, depletion of calreticulin in the tumor cells reduced the T cell killing [ 193 ]. … Sublethal irradiated tumor cells increase their calreticulin expression while radiation induces the translocation of calreticulin from the endoplasmic reticulum to the cell surface. …

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compar

Совпадение в полном тексте источника
… Mutant Calreticulin Requires Both Its Mutant C-Terminus and the Thrombopoietin Receptor for Oncogenic Transformation. Cancer Discov. 2016;6:368–381. doi: 10.1158/2159-8290.CD-15-1434. 15. … Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T-Cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms. Cancer Discov. 2019;9:1192–1207. doi: 10.1158/2159-8290.CD-18-1356. 132. …

JCMM Annual Review on Advances in Biotechnology for the Treatment of Haematological Malignancies: A Review of the Latest In-Patient Developments 2024-2025.

Advances in biotechnology are set to revolutionise the treatment of haematological malignancies. Current treatments have limited efficacy due to their high toxicity and poor long-term outcomes, particularly in acute myeloid leukaemia (AML). In 2024-2025, emerging targeted therapies promise improved results with reduced adverse effects. This review is the first of an annual series exploring the latest in-patient developments in several key areas, focusing on mechanisms. We present advances in the use and action of several therapies including epigenetic modulators, protein degraders, apoptotic i

Совпадение в полном тексте источника
… S., et al., “Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms,” New England Journal of Medicine 369, no. 25 (2013): 2379–2390, 10.1056/NEJMoa1311347. 95. Nangalia J. and Green A. … S., Chen E., et al., “Mutant Calreticulin Requires Both Its Mutant C‐Terminus and the Thrombopoietin Receptor for Oncogenic Transformation,” Cancer Discovery 6, no. 4 (2016): 368–381, 10.1158/2159-8290.CD-15-1434. 100. …

Magrolimab Therapy in Conjunction with Conventional Chemotherapeutics Slows Disease Progression in Pediatric Acute Myeloid Leukemia Patient-Derived Xenograft Models.

Background/Objectives: Magrolimab (Magro) is a humanized naked anti-CD47 monoclonal antibody that blocks the SIRPα CD47 interaction, allowing macrophages to target and destroy cancer cells. To evaluate its preclinical efficacy in vivo, Magro was tested as a single agent and in combination with conventional chemotherapy drugs, Cytarabine (Ara-C) or Azacitidine (Aza), in three pediatric AML (pAML) patient-derived xenograft (PDX) models-AML006 (KMT2A::MLLT1), AML010 (+10, WT1), and AML013 (KMT2A::MLLT4). Methods: After PDX model establishment, mice were assigned to treatment groups hulgG4 (VC, ve

Совпадение в полном тексте источника
… They showed that Magro in conjunction with ruxolitinib increased the expression of the pro-phagocytic protein, calreticulin, in CD34+ bone marrow (BM) cells from myelofibrosis (MF) patients. This effect was significant compared to calreticulin expression from either drug alone. … Effects of ruxolitinib and magrolimab on calreticulin in myelofibrosis CD34+ cells in vitro: Proof of concept for combination therapy. J. Clin. Oncol. 2023;41 doi: 10.1200/JCO.2023.41.16_suppl.7064. 12. …

The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: "Crafting" a Microenvironment That Matters.

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of

Совпадение в полном тексте источника
… “Driver” mutations in three genes ( Janus kinase ( JAK)2, calreticulin (CALR) and myeloproliferative leukemia virus oncogene ( MPL )) that activate the JAK2 signaling pathway have been detected in MPN. … Interestingly, only the red blood cell- and platelet-derived microparticles were increased in the JAK2V617F -mutated patients as compared with the Calreticulin-mutated and triple negative patients [ 111 ]. …

Implications of Angiogenesis Involvement in Arthritis.

Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others.

Совпадение в полном тексте источника
… Calreticulin increased NO production and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, and promoted their proliferation, migration and tube formation. … The effects of calreticulin on the proliferation, migration and morphological differentiation of HUVECs were significantly inhibited by l -NAME, a specific eNOS inhibitor. …

Research progress in inducing immunogenic cell death of tumor cells.

Immunogenic cell death (ICD) is a regulated cell death (RCD) pathway. In response to physical and chemical signals, tumor cells activate specific signaling pathways that stimulate stress responses in the endoplasmic reticulum (ER) and expose damage-associated molecular patterns (DAMPs), which promote antitumor immune responses. As a result, the tumor microenvironment is altered, and many tumor cells are killed. The ICD response in tumor cells requires inducers. These inducers can be from different sources and contribute to the development of the ICD either indirectly or directly. The combinati

Совпадение в полном тексте источника
… These include calreticulin (CRT), high mobility group box 1 protein (HMGB1), adenosine triphosphate (ATP), and heat shock proteins (HSP) ( 16 ). However, different ICD inducers do not activate the same stress response, and the DAMPs activated during the stress process differ significantly ( 16 ). … Therefore, understanding the structure of these DAMPs and the mechanisms by which they function is crucial for an in-depth study of ICD. 2.1 Calreticulin Calreticulin (CRT), the major calcium-binding protein in the endoplasmic reticulum, is highly conserved, present in all cells except erythrocytes …

СТАТ3 ингибирует инъекцию иммуногенной клеточной смерти в множестве миеломы.

В одном из недавних публикаций, опубликованных в журнале " Blood Science " ( < < Кровные науки > > ), Sha et al., сообщается, что STAT3 ингибирует несколько стволовых клеток, похожих на миелому, и одновременно выявляет признаки смерти иммуногенных клеток. Эти очень интригующие выводы связывают ствол, комплексную реакцию на стресс и иммунитет от антитуманков, однако для того, чтобы эта стратегия могла считаться иммуногенной, по-прежнему необходимо подтвердить в vivo.

Совпадение в полном тексте источника
… Napabucasin-treated cells exposed calreticulin (CALR), HSP70, and HSP90 and released ATP. They also promoted CD80/CD86 upregulation on monocyte-derived dendritic cells and enhanced dendritic-cell-dependent T-cell cytotoxicity. … Abbreviations: CALR, calreticulin; DC, dendritic cell; eIF2α, eukaryotic translation initiation factor 2 alpha; ICD, immunogenic cell death; ISR, integrated stress response; MM, multiple myeloma; PERK, protein kinase R-like endoplasmic reticulum kinase; PKR, protein kinase R; STAT3, signal transducer …

Improved oncolytic and immunostimulatory activity of the spontaneous jin-3 reovirus mutant in preclinical bladder cancer models.

Immunotherapy has emerged as a promising strategy for treatment of urothelial carcinoma of the bladder (UCB) but not all patients show clinically desirable responses upon treatment with immune-checkpoint inhibition. Oncolytic viruses may unleash the full potential of immunotherapy. Besides tumor-lysing properties, oncolytic viruses can induce durable and systemic anti-viral and anti-tumor immune responses. Here, we evaluated and compared oncolytic and immunostimulatory properties of wild-type reovirus (R124) and the junction-adhesion molecule-independent mutant reovirus (jin-3) in preclinical

Совпадение в полном тексте источника
… Cell surface expression of the DAMPs ecto-calreticulin and ecto-HSP90 was significantly increased upon exposure to reoviruses ( Figures 6 A and 6B). Strikingly, jin-3 caused a more pronounced increase in HMGB1 release, a well-established marker of immunogenic cell death 42 ( Figure 6 C). … This is further substantiated by the augmented release of immunogenic cell death markers HMGB1 and DAMPs (i.e., ectopic cell surface expression of calreticulin and HSP90 after exposure to jin-3 reovirus). …

Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosi

Совпадение в полном тексте источника
… The resulting mutant calreticulin protein has a positively charged peptide at the C terminal instead of the negatively charged in the non-mutated protein. … Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90. doi: 10.1056/NEJMoa1311347. 27. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. …

Implications of regulatory T cells in anti-cancer immunity: from pathogenesis to therapeutics.

Regulatory T cells (Tregs) play an essential role in maintaining immune tolerance and suppressing inflammation. However, Tregs present major hurdle in eliciting potent anti-cancer immune responses. Therefore, curbing the activity of Tregs represents a novel and efficient way towards successful immunotherapy of cancer. Moreover, there is an emerging interest in harnessing Treg-based strategies for augmenting anti-cancer immunity in different types of the disease. This review summarises the crucial mechanisms of Tregs' mediated suppression of anti-cancer immunity and strategies to suppress or to

Совпадение в полном тексте источника
… In particular, the study demonstrated that anthracyclins (such as mitoxantrone) treatment to tumor cells induce pre-apoptotic translocation of calreticulin to the cell surface and calreticulin blockade or knockdown resulted into suppression of phagocytosis of anthracyclin-treated tumor cells by Dcs in … Calreticulin exposure dictates the immunogenicity of cancer cell death Nat. Med. 13 2007 54 61 17187072 10.1038/nm1523 184 Gardai S.J. McPhillips K.A. Frasch S.C. …

Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have ch

Совпадение в полном тексте источника
… in myeloproliferative neoplasms N Engl J Med 2013 369 25 2379 2390 24325356 10.1056/NEJMoa1311347 54 Tefferi A Lasho T Finke C Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact Leukemia 2014 28 7 1568 1570 24569778 10.1038/leu.2014.83 … 55 Tefferi A Lasho TL Tischer A The prognostic advantage of calreticulin mutations in myelofibrosis might be confined to type 1 or type 1-like CALR variants Blood 2014 124 15 2465 2466 25301336 10.1182/blood-2014-07-588426 PMC4192754 56 Tefferi A Guglielmelli P Lasho TL CALR and ASXL1 mutations-based …

Протекционный субъект PSMD1 является ключевой терапевтической целью в множестве миеломы.

Мы пришли к выводу, что PSMD1 - ключевой субъект протеиновой регуляционной частицы 19S - был чрезмерно экспрессирован и коррелировал с плохим прогнозом в множестве миеломы (ММ). Генетическое истощение PSMD1 снизило жизнеспособность раковых клеток, вызвало поликутилизированное накопление белка и способствовало апоптозу. Протеомический анализ показал активацию иммунных путей, что свидетельствует о потенциале иммунной модуляции. Нацеливание PSMD1 на незначительную поражающую РНК (SIRNA), доставляемую через липидные наночастицы (LNPs), уменьшило рост опухоли в линиях клеток MM и первичных проб пац

Совпадение в полном тексте источника
… CALR, calreticulin; FC, fold change; FDR, false discovery rate. Intriguingly, PSMD1 knockout significantly upregulated immune-related pathways, particularly IFN-α and IFN-γ pathways ( Figure 3 B-C). … Moreover, cell surface calreticulin expression was upregulated in PSMD1-depleted cells, a hallmark of immunogenic cell death ( Figure 3 E; supplemental Figure 4 C), which would enhance the recognition and elimination of MM cells by immune cells. …

Megakaryocyte Contribution to Bone Marrow Fibrosis: many Arrows in the Quiver.

In Primary Myelofibrosis (PMF), megakaryocyte dysplasia/hyperplasia determines the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis. The pathogenic mechanism and the cells responsible for progression to bone marrow fibrosis in PMF are not completely understood. This review article aims to provide an overview of the crucial role of megakaryocytes in myelofibrosis by discussing the role and the altered secretion of megakaryocyte-derived soluble factors, enzymes and extracellular matrices that are known to induce bone marrow fibrosis.

Совпадение в полном тексте источника
… The three currently recognized driver mutations in PMF are JAK2 (Janus kinase 2; located on chromosome 9p24), CALR (calreticulin; located on chromosome 19p13.2), and MPL (myeloproliferative leukemia virus oncogene; located on chromosome 1p34). … Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–2390. doi: 10.1056/NEJMoa1311347. 7. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. …

Dissecting Bone Marrow Fibrosis in Philadelphia-Negative Myeloproliferative Neoplasms: Multiple Roads Lead to Rome.

Philadelphia-negative myeloproliferative neoplasms (MPN), a spectrum of blood malignancies characterized by uncontrolled myeloid proliferation, persist as a key challenge in onco-hematology due to their intricate molecular background, heterogeneous clinical phenotypes, and variable prognoses. Although generally accepted as indolent disorders, a considerable fraction of MPN patients exhibit progressive, and sometimes accelerated, bone marrow fibrosis, reflecting a critical shift toward a more debilitating condition marked by an increased symptom burden. As marrow scarring advances, hematopoieti

Совпадение в полном тексте источника
… Driver Mutations Approximately 80%–90% of MPN patients harbor somatic gain‐of‐function mutations in one of three driver genes, Janus kinase‐2 ( JAK2 ), Calreticulin ( CALR ), and Thrombopoietin receptor ( MPL or TPOR ), which directly or indirectly induce constitutive activation of the Janus Kinase/ … AURKA, Aurora kinase A; CALR, calreticulin; ECM, extracellular matrix; JAK2, Janus kinase 2; MKs, megakaryocytes; MPL, thrombopoietin receptor; MPN, Philadelphia‐negative myeloproliferative neoplasms; PDGF, platelet‐derived growth factor; PF4, platelet factor 4; TGF‐β, transforming growth factor beta …

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms.

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation

Совпадение в полном тексте источника
… A greater portion, 30-35% of ET and MF patients, harbor mutations in calreticulin ( CALR ), a multifunctional protein typically resident in the endoplasmic reticulum, but occasionally exposed at the cell surface ( 29 , 30 , 34 ). … The single-pass transmembrane protein CALR (calreticulin) is a calcium-binding chaperone protein that normally recycles between plasma and intracellular membranes in the secretory pathway. …

The Role of NLRP3, a Star of Excellence in Myeloproliferative Neoplasms.

Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune diseases. NLRP3 belongs to the pattern recognition receptors (PRRs) family, expressed in numerous immune cells, and it plays its primary function in myeloid cells. NLRP3 has a crucial role in myeloproliferative neoplasms (MPNs), considered to be the diseases best studied in the inflammasome

Совпадение в полном тексте источника
… Calreticulin Mutant Myeloproliferative Neoplasms Induce MHC-I Skewing, Which Can Be Overcome by an Optimized Peptide Cancer Vaccine. Sci. Transl. Med. 2022;14:eaba4380. doi: 10.1126/scitranslmed.aba4380. 113. … Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms (MPNs) Blood. 2022;140:14–15. doi: 10.1182/blood-2022-159435. 114. Yu X., Lv J., Wu J., Chen Y., Chen F., Wang L. …

Роль микроглии в синаптогенезе, синаптической и синаптической пластичности в физиологических условиях и в нарушениях центральной нервной системы.

Микроглии являются постоянными иммунными клетками мозга, которые были широко изучены для их иммунного наблюдения и фагоцитоза. В последние годы постепенно признается важная роль микроглии в синапсовом образовании, ликвидации и пластичности. Синапсы являются основным режимом связи между нейронами. Они постоянно меняются в количестве и пластичности на протяжении всего жизненного цикла, который является основой обучения и памяти. Микроглии являются сильно мотилированными, ветковыми формами, которые осуществляют мониторинг микроокружающей среды центральной нервной системы (КНС) и поощряют синапсов

Совпадение в полном тексте источника
… Calreticulin Cell surface calreticulin is an alternative “eat me” signal that interacts with low-density lipoprotein receptor-associated protein 1 (LRP1) on microglia to initiate the phagocytic process [ 145 ]. … Blocking calreticulin on the surface of neurons or LRP1 of microglia inhibits lipopolysaccharide-induced phagocytosis of microglia to live synapses [ 147 ]. …