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Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.

T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcr

The Emerging Role of CD8+ T Cells in Shaping Treatment Outcomes of Patients with MDS and AML.

CD8+ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8+ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8+ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8+ T cells in MDS and AML, often driven by the immunosuppressive bone

Molecular factors associated with lung cancer in people living with HIV.

Lung cancer is the most common Non-AIDS-Defining Cancer (NADC) and a leading cause of cancer-related death in People Living With HIV (PLWH). Despite antiretroviral therapy, PLWH are at higher risk of developing cancer compared to the general population. This increased susceptibility reflects a combination of immunosuppression, chronic inflammation, smoking, and direct oncogenic effects of HIV proteins. Tat, gp120, and Nef modulate cell cycle control, apoptosis, epithelial-mesenchymal transition, angiogenesis, and immune evasion. Persistent HIV reservoirs in lung tissue (mainly effector memory

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… Participates in autophagy Down 53 P16 INK4a Inhibits the cell cycle and induces cellular senescence by blocking CDK4/6, preventing RB phosphorylation. Induces cell cycle arrests avoiding G1/S transition. Down 79 P53 Tumor suppressor. … Comparative evaluation of cellular senescence in naturally aged and stress-induced murine macrophages for identifying optimum senescent macrophage study systems Mol Biol Rep 52 2025 123 39812869 10.1007/s11033-025-10232-9 68 Buhl R. …

The Role of Extracellular Vesicles (EVs) in the Epigenetic Regulation of Bone Metabolism and Osteoporosis.

Extracellular vesicles (EVs) are complex phospholipidic structures actively released by cells. EVs are recognized as powerful means of intercellular communication since they contain many signaling molecules (including lipids, proteins, and nucleic acids). In parallel, changes in epigenetic processes can lead to changes in gene function and finally lead to disease onset and progression. Recent breakthroughs have revealed the complex roles of non-coding RNAs (microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)) in epigenetic regulation. Moreover, a substantial body of evidence demonstrates tha

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… Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 2017;23:1072–1079. doi: 10.1038/nm.4385. 134. Khosla S., Farr J.N., Kirkland J.L. Inhibiting Cellular Senescence: A New Therapeutic Paradigm for AgeRelated Osteoporosis. J. Clin. Endocrinol. …

Метаболомическое исследование синдромов миэлодипластика, множественной миеломы и гомозиговой β-Талассемии.

Хроническая анемия, как правило, диагностируется у пожилых людей и служит важным показателем как реактивных, так и клональных заболеваний. Многие основные заболевания, такие, как миэллодипластические синдромы и множественная миелома, более распространены среди пожилых людей, в то время как новые терапевтические подходы превратили педиатрические расстройства слабого прогноза, такие, как бета-талассемия, в хроническое заболевание пожилых людей. Таким образом, растущая распространенность хронической анемии в пожилом возрасте в значительной степени объясняется более частыми диагностическими и тера

Large-Scale Plasma Proteomics and Genetic Integration Uncover Novel Biological Pathways in Male Pattern Baldness.

Male pattern baldness (MPB) is a highly prevalent condition with a complex, poorly understood molecular basis that limits therapeutic innovation. This study aimed to bridge the gap between statistical genetic associations and biological function by identifying and prioritizing causal proteins and pathways involved in MPB. Using data from 24,069 men in the UK Biobank, we performed a proteome-wide association study of 2911 plasma proteins with self-reported MPB severity via multivariable ordinal logistic regression, adjusting for age, Body Mass Index (BMI), ethnicity, lifestyle, socioeconomic fa

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… Based on these established findings, we hypothesize that, in genetically susceptible individuals, persistent androgen signaling and resulting chronic inflammation could induce cellular senescence in the follicular niche [ 22 ], leading to an inflammatory microenvironment whose SASP factors upregulate … CD38 implicates a testable hypothesis linking chronic inflammation, cellular senescence, and NAD + depletion to follicular miniaturization. These insights advance understanding of MPB pathophysiology and highlight promising non-hormonal therapeutic targets for future interventions. …

Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression.

Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structur

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… A Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma: Mesenchymal Stromal Cells and Multiple Myeloma. Stem Cells. 2017;35:739–753. doi: 10.1002/stem.2499. 48. …

Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Throug

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… Extracellular vesicles as new players in cellular senescence Int. J. Mol. Sci. 2016 17 1408 10.3390/ijms17091408 PMC5037688 27571072 132. Borrelli C. Ricci B. Vulpis E. Fionda C. Ricciardi M.R. Petrucci M.T. Masuelli L. Peri A. Cippitelli M. Zingoni A. …

Circular RNAs in cancer.

Circular RNA (circRNA), a subtype of noncoding RNA, has emerged as a significant focus in RNA research due to its distinctive covalently closed loop structure. CircRNAs play pivotal roles in diverse physiological and pathological processes, functioning through mechanisms such as miRNAs or proteins sponging, regulation of splicing and gene expression, and serving as translation templates, particularly in the context of various cancers. The hallmarks of cancer comprise functional capabilities acquired during carcinogenesis and tumor progression, providing a conceptual framework that elucidates t

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… Most importantly, senescence‐associated secretory phenotype (SASP) is activated during cellular senescence. … senescence, and transcriptional dysregulation in cancer. …

Convergence of mRNA technology and chimeric antigen receptor therapy: targeted technology optimizing targeted therapy.

Engineering cells to express chimeric antigen receptors (CARs) represents a novel approach in cancer immunotherapy, demonstrating remarkable efficacy in the treatment of hematologic malignancies while also encountering numerous challenges. Against the backdrop of the widespread application of COVID-19 mRNA vaccines, the integration of mRNA technology to produce CAR cells and enhance CAR therapies marks the cutting edge of cancer treatment innovation, offering potential solutions to the challenges faced by traditional CAR therapies. This convergence offers distinct advantages. It enables the ge

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… mRNA-based CAR therapy for cellular senescence Cellular senescence, characterized by irreversible proliferation arrest triggered by various stressors, is a hallmark of chronic inflammatory diseases. … CAR-T cells, with their precisely targeting capabilities, have shown promise in addressing cellular senescence. …

Boanmycin overcomes bortezomib resistance by inducing DNA damage and endoplasmic reticulum functional impairment in multiple myeloma.

BackgroundMultiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of plasma cells and is currently incurable. Despite advancements in therapeutic strategies, resistance to proteasome inhibitors, particularly bortezomib (BTZ), poses a substantial challenge to disease management. This study aimed to explore the efficacy of boanmycin, a novel antitumor antibiotic, in overcoming resistance to BTZ in MM.MethodsBTZ-resistant cells were generated over a period of at least 6 months by gradually increasing the concentration of BTZ. The viability of MM cell lines

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss

Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives.

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles

Impact of Galectin-3 Circulating Levels on Frailty in Elderly Patients with Systolic Heart Failure.

Background: Heart Failure (HF), a leading cause of morbidity and mortality, represents a relevant trigger for the development of frailty in the elderly. Inflammation has been reported to play an important role in HF and frailty pathophysiology. Galectin-3 (Gal-3), whose levels increase with aging, exerts a relevant activity in the processes of cardiac inflammation and fibrosis. The aim of the present study was to investigate the potential of Galectin-3 to serve as a biomarker of frailty in HF patients. Methods: 128 consecutive patients aged 65 and older with the diagnosis of systolic HF underw

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… Different studies performed in vitro or experimental models report that cellular senescence is dependent on Gal-3 signaling pathways [ 51 , 52 ]. … Biomarkers in the path from cellular senescence to frailty Exp. Gerontol. 2019 129 110750 10.1016/j.exger.2019.110750 31678465 PMC12153401 15. Soysal P. Stubbs B. Lucato P. Luchini C. Solmi M. Peluso R. Sergi G. Isik A.T. Manzato E. Maggi S. …

Translational Strategies to Target Metastatic Bone Disease.

Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escala

From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.

BACKGROUND/OBJECTIVE: A fundamental translational impasse in musculoskeletal disorders-from osteoarthritis to bone metastases-is the "undruggability" of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases. METHODS: In this

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… Nucleus pulposus and annulus fibrosus cells persist under harsh conditions of acidic pH, high osmolarity, and accumulated metabolic waste, leading to matrix breakdown, cellular senescence, and cell death. …

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments.

Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associate

Targeting homologous recombination and telomerase in Barrett's adenocarcinoma: impact on telomere maintenance, genomic instability and tumor growth.

Homologous recombination (HR), a mechanism to accurately repair DNA in normal cells, is deregulated in cancer. Elevated/deregulated HR is implicated in genomic instability and telomere maintenance, which are critical lifelines of cancer cells. We have previously shown that HR activity is elevated and significantly contributes to genomic instability in Barrett's esophageal adenocarcinoma (BAC). The purpose of this study was to evaluate therapeutic potential of HR inhibition, alone and in combination with telomerase inhibition, in BAC. We demonstrate that telomerase inhibition in BAC cells incre

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… Senescence One day before this assay, the treated cells were plated on Lab-Tek slides in the presence of mismatch or match (GRN163L) oligonucleotide and the attached cells were stained for β-galactosidase expression, a marker for cellular senescence 61 H. …

Навигация терапевтического ландшафта миеломы: иммунотерапия, микроокружающая среда и сопротивление.

Иммунотерапии, включая клетки химерика антигенного рецептора (CAR) T, биконкретные Т-клеточные агенты (BITEs) и антитело-наркотики (ADC), изменили ландшафт лечения множественной миеломы (MM). Несмотря на высокие показатели первоначальных ответов, достижение долговременной ремиссии по-прежнему сопряжено с трудностями из-за частых рецидивов, вызванных комплексными механизмами терапевтического сопротивления. В этом обзоре мы всесторонне исследуем врожденную устойчивость к опухоли, такую, как врожденный и приобретенный антигенный выход, обусловленный геномными изменениями, структурными вариациями

Overview of Ayurveda and Ashwagandha: Bioactive Phytochemicals and Potential Applications to Gliomas.

Ayurveda is the traditional medical system of India and has been in use for more than 5000 years. The focus of Ayurveda is to maintain harmony and balance of the three Doshas (Vata, Pitta, Kapha), or life forces, that govern the physiology and health of each individual. Ashwagandha is considered one of the most useful plants in the Ayurvedic system for various illnesses, including cancer. Ethnopharmacological and phytochemical analyses have been elucidating the bioactive compounds in ashwagandha that mediate the anti-cancer effects. The most bioactive compounds appear to be the withanolides, i