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Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.

Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway - has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequ

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… Also, neutrophil extracellular traps (NETs) - decondensed nuclear chromatin associated with proteins and released by neutrophils during an inflammatory response in order to prevent pathogen dissemination and exert immunomodulatory effects – were shown to activate effector functions of neutrophils through …

Иммуномодулирующие механизмы мезенхимальных ячеек: цитокинские сети и терапевтический потенциал через иммунные, воспаленные и регенеративные расстройства.

Мезенхимические стромальные клетки (МСЦ) представляют собой многопоточные клетки, характеризующиеся их регенеративной способностью и сильными иммунодуляторными свойствами. В последние годы терапия на базе МСЦ привлекла к себе значительное внимание в качестве потенциального средства лечения широкого круга иммунных и дегенеративных заболеваний. Терапевтические эффекты MSC главным образом получают через паракринную сигнализацию и секрецию цитокинов, которые регулируют иммунную реакцию и содействуют ремонту тканей. В настоящем обзоре основное внимание уделяется пяти ключевым цитокинам, участвующим

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Skeletal Site-specific Effects of Zoledronate on in vivo Bone Remodeling and in vitro BMSCs Osteogenic Activity.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been associated with long-term oral or intravenous administration of nitrogen-containing bisphosphonates (BPs). However, the pathogenesis of BRONJ remains unknown, and definitively effective treatment has not yet been established. Bisphosphonate-related osteonecrosis (BRON) tends to occur in maxillofacial bones. Why this occurs is still unclear. Here we show that zoledronate (Zol) treatment suppresses alveolar bone remodeling after tooth typical clinical and radiographic hallmarks of the human BRONJ, whereas enhances peripheral bone q

Secondary Neutropenias.

Neutrophils are a critical component of immunity, particularly against bacteria and other pathogens, but also in inflammation and tissue repair. As a consequence, individuals with neutropenia, defined by a reduction in absolute neutrophil counts, exhibit a strong propensity to severe infections that typically present with muted symptoms. Neutropenias encompass a heterogeneous set of disorders, comprising primary neutropenias, in which specific genes are mutated, and the more common secondary neutropenias, which have diverse non-genetic causes. These include hematological and other cancers, inv

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… traps (NETs) [ 9 ]. … NETosis and neutrophil extracellular traps in COVID-19: Immunothrombosis and beyond. Front. Immunol. 2022;13:838011. doi: 10.3389/fimmu.2022.838011. 64. Santos E.W., Oliveira D.C., Silva G.B., Tsujita M., Beltran J.O., Hastreiter A., Fock R.A., Borelli P. …

CAR-T cell therapy in nephrology.

In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising immunotherapeutic strategy beyond oncology, offering new treatment opportunities for immune-mediated kidney diseases. These conditions including systemic lupus erythematosus, ANCA-associated vasculitis, membranous nephropathy, and monoclonal gammopathy-related nephropathies are characterized by dysregulated B cell and plasma cell activity that often proves refractory to standard immunosuppression. CAR-T cells, engineered to target antigens such as CD19 or BCMA, enable potent and durable depletion of pa

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… In the kidney, activated neutrophils can drive acute tissue injury through the release of proteases, reactive oxygen species, and the formation of neutrophil extracellular traps (NETs), which are implicated in the pathogenesis of AAV and lupus nephritis [ 16 , 17 ]. … Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2 . Ann Rheum Dis . 2015 ; 74 ( 7 ): 1417 – 1424 . doi: 10.1136/annrheumdis-2013-204837 . 24570026 PMC4143484 17 Shiratori-Aso S , Nakazawa D. …

Targeted therapy in the treatment of malignant gliomas.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In additi

MicroRNAs and Osteolytic Bone Metastasis: The Roles of MicroRNAs in Tumor-Induced Osteoclast Differentiation.

Osteolytic bone metastasis frequently occurs in the later stages of breast, lung, and several other cancers. Osteoclasts, the only cells that resorb bone, are hijacked by tumor cells, which break down bone remodeling systems. As a result, osteolysis occurs and may cause patients to suffer bone fractures, pain, and hypercalcemia. It is important to understand the mechanism of bone metastasis to establish new cancer therapies. MicroRNAs are small, noncoding RNAs that are involved in various biological processes, including cellular differentiation, proliferation, apoptosis, and tumorigenesis. Mic

The Dynamic Endothelial Activation and Stress Index (EASIX) as a Predictor of Early Death and Long-Term Survival in Acute Promyelocytic Leukemia (APL): A Multicenter Study.

Background/Objectives: Early death (ED) remains the primary barrier to long-term survival in acute promyelocytic leukemia (APL). Since current risk stratification models rely solely on static baseline parameters, they fail to capture the high biological volatility during the induction phase. We aimed to evaluate the prognostic value of the dynamic evolution of the endothelial activation and stress index (EASIX). Materials and Methods: This multicenter, retrospective study analyzed 131 newly diagnosed adult APL patients treated with the AIDA protocol. EASIX scores were calculated at admission (

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… While ATRA is essential for differentiation, it triggers the release of inflammatory cytokines and induces neutrophil extracellular traps (NETosis), which can aggravate endothelial injury and increase the risk of differentiation syndrome in the initial phase [ 42 , 44 ]. … Extracellular Traps Increase Burden of Bleeding by Damaging Endothelial Cell in Acute Promyelocytic Leukaemia Front. Immunol. 2022 13 841445 10.3389/fimmu.2022.841445 35479063 PMC9035902 45. Yang M.H. Chang K.J. Li B. Chen W.S. …

Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells.

Tumor angiogenesis is widely recognized as one of the "hallmarks of cancer". Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic

Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we describe

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… trap natural killer nitric oxide nitric oxide synthase non‐small cell lung cancer oligodeoxynucleotide programmed cell death protein 1 derived dendritic cell programmed death‐ligand 1 prostaglandin E2 phosphoinositide 3‐kinase protease 3 protein targeting methyltransferase 5 prostate specific … Neutrophils protect the body by releasing antimicrobial peptides, enzymes, reactive oxygen species (ROS), and neutrophils extracellular traps (NETs) to eliminate pathogens [ 146 , 147 ]. …

The role of myeloid derived suppressor cells in musculoskeletal disorders.

The immune system is closely linked to bone homeostasis and plays a pivotal role in several pathological and inflammatory conditions. Through various pathways it modulates various bone cells and subsequently sustains the physiological bone metabolism. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid-derived cells that can exert an immunosuppressive function through a direct cell-to-cell contact, secretion of anti-inflammatory cytokines or specific exosomes. These cells mediate the innate immune response to chronic stress on the skeletal system. In chronic

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… CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity (2020) 52(5):856–71.e8. doi: 10.1016/j.immuni.2020.03.001 158. Alfaro C, Teijeira A, Oñate C, Pérez G, Sanmamed MF, Andueza MP, et al. … Tumor-produced interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin Cancer Res (2016) 22(15):3924–36. doi: 10.1158/1078-0432.Ccr-15-2463 159. Kwak T, Wang F, Deng H, Condamine T, Kumar V, Perego M, et al. …

Tumor Whole-Genome Sequencing for Prediction of Venous Thromboembolism in Patients With Metastasized Solid Cancer.

BACKGROUND: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. METHODS: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). RESULTS: During 12-month follow-up, 237 (7.7

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… Two previous studies showed that CDKN2A mutations are related to VTE in cancer patients, possibly due to a positive effect on the expression of the prothrombotic proteins podoplanin and tissue factor. 18 , 44 The ELANE gene is known to be associated with VTE via neutrophil extracellular traps, which … Neutrophil extracellular traps: villains and targets in arterial, venous, and cancer-associated thrombosis. Arterioscler Thromb Vasc Biol. 2019;39:1724–1738. doi: 10.1161/ATVBAHA.119.312463 32. Toni IM, Zapponi K, Hounkpe BW, Martinelli BM, Montalvão SADL, De Paula E V, Annichino- Bizzacchi JM. …

Osteoprotective Roles of Green Tea Catechins.

Osteoporosis is the second most common disease only secondary to cardiovascular disease, with the risk of fracture increasing with age. Osteoporosis is caused by an imbalance between osteoblastogenesis and osteoclastogenesis processes. Osteoclastogenesis may be enhanced, osteoblastogenesis may be reduced, or both may be evident. Inflammation and high reactive oxygen enhance osteoclastogenesis while reducing osteoblastogenesis by inducing osteoblast apoptosis and suppressing osteoblastic proliferation and differentiation. Catechins, the main polyphenols found in green tea with potent anti-oxida

Precision medicine: The use of tailored therapy in primary immunodeficiencies.

Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patie

Clusterin and pentraxin 3 are markers of severity during febrile neutropenia in adults with haematological malignancies receiving intensive chemotherapy.

The identification of predictive biomarkers of severity can improve patient management because febrile neutropenia can be associated with significant morbidity and mortality. We prospectively studied pentraxin 3 (PTX3), a soluble innate immunity receptor, and clusterin (CLU), a chaperone protein that binds extracellular histones during sepsis, in patients experiencing febrile neutropenia after intensive treatment for haematological malignancies. One hundred and forty-three adult patients were included, with 158 episodes of neutropenia analysed. Febrile neutropenia was observed in 119 patients

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… The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007;204(4):793–804. 10.1084/jem.20061301 9. Chen H, Li T, Yan S, Liu M, Liu K, Zhang H, et al. …

The role of interleukin-17 in inflammation-related cancers.

Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity

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… . | ( 80 ) PDAC | IL-17A | Anti-IL17A treatment in the xenograft/orthotopic PDAC mice with KPC | Pro-tumor | Recruiting neutrophils, triggering neutrophil extracellular traps (NETs), and eliminating CD8 T cells from the tumor. | ( 158 ) Anti-IL17A treatment in the Pdx1-Cre (KPC) mice; Clinical pancreatic … It has been reported that IL17 plays a carcinogenic role in PDAC by recruiting neutrophils, triggering neutrophil extracellular traps (NETs), and eliminating CD8 T cells from the tumor ( 158 ). …

Application of cell-derived exosomes in the hematological malignancies therapy.

Exosomes are small membrane vesicles of endocytic origin that are produced by both tumor and normal cells and can be found in physiological fluids like plasma and cell culture supernatants. They include cytokines, growth factors, proteins, lipids, RNAs, and metabolites and are important intercellular communication controllers in several disorders. According to a vast amount of research, exosomes could support or inhibit tumor start and diffusion in a variety of solid and hematological malignancies by paracrine signaling. Exosomes are crucial therapeutic agents for a variety of illnesses, such

Активаторы Nrf2 для лечения редких заболеваний, связанных с перегрузкой железа: от скамейки до кровати.

Железная перегрузка и связанные с ней окислительные повреждения наблюдаются во многих редких болезнях в результате мутации генов, связанных с гомеостазом железа. Будучи основным регулятором реакции на клеточную антиоксидантную реакцию, Nrf2 может также снизить системный и клеточный уровень железа путем регулирования генов и путей, связанных с железом, что делает Nrf2 очень хорошими инициаторами для лечения нарушений, связанных с перегрузкой железа. К числу успешных примеров относится клиническое использование омавельоксолона для атаксии Фридрейха и диметилфумарата для повторного излучающего мн

Epidemiology, Pathophysiology, and Management of Cancer-Associated Ischemic Stroke.

Cancer and stroke are leading causes of global disability and mortality. With improvements in cancer-associated mortality and advancements in treatment of active malignancy, it is more common to encounter patients with ischemic stroke and active malignancy. Evidence suggests that cancer-associated ischemic stroke is a unique subtype of stroke; however, there is limited guidance when considering diagnostic workup, secondary prevention, rehabilitation, and future directions within this population. In this narrative review, we aim to describe the epidemiology, pathophysiological mechanisms, manag

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… Neutrophil extracellular traps (NETs), which are released from dying neutrophils, have been shown to be associated with an increased risk of VTE [ 38 ]. NETs can act as a substrate for fibrin deposition and platelet activation, and increasing levels of NETosis have been associated with CAIS [ 39 ]. … Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J. Thromb. Haemost. 2018;16:508–518. doi: 10.1111/jth.13951. 39. …