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Устроенная ЦАР клеточная терапия: текущее понимание и перспективы на будущее.

Инженерная клеточная терапия химерического антигенного рецептора (CAR) представляет собой значительный прорыв в иммунотерапии, первоначально в раке и в настоящее время распространяется на различные клинические области. Хотя изначально эти платформы разрабатывались для онкологии, они все чаще адаптируются к таким ненасытным условиям, как аутоиммунные расстройства, инфекционные заболевания, фиброз, проблемы старения и трансплантация органов. В настоящем обзоре содержится подробная информация об эволюции и диверсификации методов ЦАР, включая CAR-T, CAR-NK, CA-Macrophages и CAR-NKT, а также о новы

Mesenchymal Stromal Cells: Bridging the Gaps in Hematologic Disease Therapy.

Mesenchymal stromal cells (MSCs) have demonstrated therapeutic potential in hematologic diseases by modulating immune responses, supporting hematopoiesis, and remodeling the bone marrow microenvironment. Clinically, MSCs have been explored for graft-versus-host disease and hematopoietic stem cell transplantation support, while their applications in hematologic malignancies, including acute myeloid leukemia, multiple myeloma, and myelodysplastic syndromes, remain under investigation. However, therapeutic heterogeneity, safety concerns, and standardization challenges limit their clinical transla

Systemic Ozone Therapy Improves Oral Hard and Soft Tissue Healing in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Study in Senescent Female Rats.

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging condition often associated with bisphosphonate use, leading to impaired bone healing and difficult clinical management. Given the lack of predictable therapeutic options, this study investigated the effects of systemic ozone therapy on MRONJ healing. This study aimed to analyze the effects of systemic ozone therapy on oral hard and soft tissue healing in senescent rats with medication-related osteonecrosis of the jaw (MRONJ) induced by antiresorptive therapy. Methods: Twenty-eight senescent Wistar rats,

Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide.

Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in GBM cell lines and GBM stem-like cells. For most GBM-derived cells, IC50 concentrations for Eltanexor were below 100 nM. In correlation with reduced cell viability, apoptosis rates were significantly increased. GBM stem-like cells presented a combinatorial effect of Eltanex

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… Likewise, TMZ-generated DNA damage in GBM cells primarily induces cellular senescence [ 31 , 32 , 33 ]. Most GBM cells do even evade apoptosis upon the presence of TMZ, entering a senescent state that protects them against anticancer therapy. …

Сверхклеточная везикла в качестве главных регуляторов иммунной модуляции в Мультимиломе.

Множественная миелома (ММ) — генетически и клинически разнородная плазменная порча клеток, характеризующаяся клональным расширением различных клеток В внутри костного мозга (БМ). Пациенты начинают с моноклональной гаммопатии неизвестного значения (MMUS) и переходят на промежуточную стадию под названием Smouldering multieloma (SMM), характеризующуюся несколькими генетическими изменениями, представляющими геномную основу злокачественного клона. Проходы на контрольно-пропускных пунктах иммунной системы играют ключевую роль в формировании иммуноподавляющей ниши BM, что способствует дисфункции Т-кл

Ageing, autoimmunity and arthritis: senescence of the B cell compartment - implications for humoral immunity.

Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline. Taken together, these studies suggest that age-associated loss of the ability to generate protective humoral immunity results in part from reduced B lymphopoiesis. As the output

Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures.

Chemotherapy and targeted therapy have opened new avenues in clinical oncology. However, there is a lack of response in a substantial percentage of cancer patients and diseases frequently relapse in those who even initially respond. Resistance is, at present, the major barrier to conquering cancer, the most lethal age-related pathology. Identification of mechanisms underlying resistance and development of effective strategies to circumvent treatment pitfalls thereby improving clinical outcomes remain overarching tasks for scientists and clinicians. Growing bodies of data indicate that stromal

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… Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9(5):667–684. doi: 10.1111/j.1474-9726.2010.00608.x. 38. Sheng X, Mittelman SD. The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia. … NF-kappaB in cellular senescence and cancer treatment. Mol Cells. 2014;37(3):189–195. doi: 10.14348/molcells.2014.2353. 117. Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Waller JL, Liles GB, Lee JR, Liu K. …

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

Inflammation and Cancer: Molecular Mechanisms and Therapeutic Targets.

Inflammation is a core pathological factor regulating tumor initiation, progression, and therapeutic resistance, and elucidating its molecular crosstalk with tumors is crucial for developing effective clinical therapies. Internal drivers of inflammation-tumor transformation include genomic disorder, epigenetic memory, mitochondrial stress, and metabolic reprogramming, which synergistically initiate carcinogenesis. External factors amplifying tumor progression cover immune dysfunction, stromal fibrosis, microbial dysbiosis, vascular neoplasia, and neurotoxicity, collectively accelerating tumor

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… Oxidative stress, a core pathological state of inflammation, leads to excessive accumulation of reactive oxygen species that directly damage mitochondrial DNA (mtDNA), disrupt functional homeostasis, and trigger cellular senescence. …

Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial.

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.

The role of heat shock protein 90 in idiopathic pulmonary fibrosis: state of the art.

Heat shock protein 90 (HSP 90) and its isoforms are a group of homodimeric proteins that regulate several cellular processes, such as the elimination of misfolded proteins, cell development and post-translational modifications of kinase proteins and receptors. Due to its involvement in extracellular matrix (ECM) remodelling, myofibroblast differentiation and apoptosis, HSP 90 has been investigated as a key player in the pathogenesis of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common and deadly interstitial lung disease, due to the progressive distortion of lung parenchyma

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… Cellular senescence, one of the hallmarks of aging, is characterised by the aggregation of senescent cells, such as epithelial cells and fibroblasts, which are nonproliferative and resistant to apoptosis [ 48 ]. … Extracellular HSP90α promotes cellular senescence by modulating TGF-β signaling in pulmonary fibrosis. FASEB J 2022; 36: e22475. doi: 10.1096/fj.202200406RR 61. Wrighton KH, Lin X, Feng XH. Critical regulation of TGFβ signaling by Hsp90. …

Editorial: Cancer therapy: The challenge of handling a double-edged sword.

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… Olszewska et al. (2021) suggested that cellular senescence/senescence escape may be one of the mechanisms of this phenomenon. Authors showed that hypoxia, which is a common feature in tumors, may enhance the escape of cancer cells from therapy-induced senescence. …

Skeletal organoids.

The skeletal system, composed of bones, muscles, joints, ligaments, and tendons, serves as the foundation for maintaining human posture, mobility, and overall biomechanical functionality. However, with ageing, chronic overuse, and acute injuries, conditions such as osteoarthritis, intervertebral disc degeneration, muscle atrophy, and ligament or tendon tears have become increasingly prevalent and pose serious clinical challenges. These disorders not only result in pain, functional loss, and a marked reduction in patients' quality of life but also impose substantial social and economic burdens.

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… For instance, constructing anti-ageing organoid scaffolds through 3D bioprinting technology can effectively mitigate cellular senescence and alleviate symptoms of osteoarthritis. 116 Alternatively, combining microfluidic technology with DNA hydrogels to construct cartilage organoids can enhance tissue …

The perioperative management of geriatric patients in transplantation surgery-clinical, immunological, and translational considerations.

Transplant surgery encompasses two primary branches: solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA). As the global population ages, elderly transplant patients become a more pressing clinical challenge. Elderly transplant recipients require specialized care that addresses their unique needs, including increased comorbidities and frailty. Despite the growing recognition of these challenges, there is a paucity of studies that synthesize the current knowledge on this patient cohort, from immunological changes over translational challenges to tailored clinic

Network Pharmacology Approaches Used to Identify Therapeutic Molecules for Chronic Venous Disease Based on Potential miRNA Biomarkers.

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to i

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… Evidence indicates that miR-34a is a crucial regulator of age-related tissue modifications and a promoter of cellular senescence. Levels of miR-34a have shown an increase with age. …

Obesity, the Adipose Organ and Cancer in Humans: Association or Causation?

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to

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… Circulating Extracellular Vesicles and Particles Derived from Adipocytes: The Potential Role in Spreading MicroRNAs Associated with Cellular Senescence. Front. Aging. 2022;3:867100. doi: 10.3389/fragi.2022.867100. 102. Rubio-Tomás T., Rueda-Robles A., Plaza-Díaz J., Álvarez-Mercado A.I. … Nutrition and cellular senescence in obesity-related disorders. J. Nutr. Biochem. 2021;99:108861. doi: 10.1016/j.jnutbio.2021.108861. 103. Maliniak M.L., Miller-Kleinhenz J., Cronin-Fenton D.P., Lash T.L., Gogineni K., Janssen E.A.M., McCullough L.E. …

Exosomes for angiogenesis induction in ischemic disorders.

Ischaemic disorders are leading causes of morbidity and mortality worldwide. While the current therapeutic approaches have improved life expectancy and quality of life, they are unable to "cure" ischemic diseases and instate regeneration of damaged tissues. Exosomes are a class of extracellular vesicles with an average size of 100-150 nm, secreted by many cell types and considered a potent factor of cells for paracrine effects. Since exosomes contain multiple bioactive components such as growth factors, molecular intermediates of different intracellular pathways, microRNAs and nucleic acids, t

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… ACE‐2 blocks Nox2‐mediated ROS production and miR‐126 hampers ERRFI1 activity, both lead to decreased oxidative stress and cellular senescence Exosomes and modulating inflammatory response Following an ischemic insult, an inflammatory response is occurred in the damaged area due to the apoptosis, oxidative … senescence | | Human CD34 + cells | miR‐126‐3p‐mediated SPRED1 suppression | IM | 214 | | | Glioblastoma | miR‐221‐mediated FGF‐2 and Ang‐2 upregulation | Local delivery | 183 | | | AD‐MSC | miR‐21‐mediated CSF‐1R and PI3K/Akt activation | IM | 106 | | | AD‐MSC | miR‐31‐mediated FIH1/HIF‐ …

Как изменяется первая терапия у пациентов с несколькими миеломами без трансплантации.

Результаты лечения пациентов с множественной миеломой улучшились в последние десятилетия благодаря новым представлениям о биологии болезни и внедрению новых лекарств и терапевтических подходов. Более половины пациентов с множественной миеломой не имеют права на трансплантацию, и в течение многих лет их лечение было затруднено из-за неоднородности этой группы пациентов и отсутствия вариантов лечения. В последнее время внимание было сосредоточено на концепции хрупкости и ее количественной оценке, с тем чтобы привести график и дозировку лечения в соответствие с требованиями физической пригодности

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… Processes that accelerate aging at the cellular and subcellular level, such as chronic inflammation, cellular senescence, mitochondrial dysfunction, and impaired nutrient sensing, are thought to contribute to multiple system dysfunctions leading to clinical manifestations of frailty. … reflecting both cellular senescence and biological aging, reflecting both cellular senescence and biological aging, predictor of toxicity in patients treated with chemotherapy), markers of DNA damage (γH2AX, ATM, MDC1), telomere dysfunction (TIF) and senescence-associated β-galactosidase (SA-βGal) can …

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for

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

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… The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 1992;27:383–389. doi: 10.1016/0531-5565(92)90069-C. 22. Kim N.W., Piatyszek M.A., Prowse K.R., Harley C.B., West M.D., Ho P.L., Coviello G.M., Wright W.E., Weinrich S.L., Shay J.W. …