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Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors.

BACKGROUND: Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM. METHODS: To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined.

Carbohydrate Targets for CAR T Cells in Solid Childhood Cancers.

Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside GD2 on the cell surface of neuroblastomas which derive from GD2-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentia

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… To be recognized by T cells, the antigens must be processed and presented by the major histocompatibility complex to engage native T cell receptors (Figure 1 ). Tumor neoantigens are created by somatic mutations in the tumor microenvironment ( 5 ). …

The Role of Platelet Dysfunctions in the Pathogenesis of the Hemostatic-Coagulant System Imbalances.

Platelet dysfunction plays a critical role in the pathogenesis of various disorders affecting the hemostatic-coagulant system. This review aims to explore the mechanisms by which platelet dysfunctions contribute to the disruption of hemostasis, leading to an increased risk of both thrombosis and bleeding. Platelets, traditionally known for their role in clot formation, can exhibit altered functionality under pathological conditions such as cardiovascular diseases, metabolic disorders, and autoimmune diseases, impacting their interaction with coagulation factors and vascular endothelium. The re

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… By releasing CD154, platelets enhance the adaptive immune response, and they can also help expand specific CD8+ T-cell clones by presenting antigens in the context of major histocompatibility complex I. …

Role of exosomes in pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies. Exosomes, which are released by multiple cell types, such as cancer cells, contain functional biomolecules (including proteins, nucleic acids and lipids) that can be horizontally delivered to recipient cells. Exosomes act as the most prominent mediator of intercellular communication and can regulate, instruct and re-educate their surrounding microenvironment and target specific organs. The present review performed an extensive search of multiple databases from 2005 to April 23 2017, for eligible literature relating to exosomes and their

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… Furthermore, pancreatic cancer-generated exosomes restrain regulatory factor X-associated protein expression by means of miR-212-3p, which could decrease the expression level of major histocompatibility complex (MHC) II and result in the immune tolerance of DCs. …

Muscle cramps and neuropathies in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease.

OBJECTIVE: Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. METHODS: In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical

Tuning epigenetics to enhance cancer virotherapy.

Cancer remains a major global health challenge, driving intensive research into novel therapeutic strategies. Oncolytic viruses (OVs) including herpesviruses, adenoviruses and echoviruses, have emerged as promising agents for cancer treatment, with several achieving regulatory approval. These viruses selectively lyse tumor cells and stimulate antitumor immunity. Nevertheless, their efficacy is constrained by limitations such as neutralization by serum factors and tumor cell resistance. Concurrently, epigenetic inhibitors modulate gene expression to suppress tumor proliferation and reshape immu

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… DNMTi-mediated induction of C-X-C chemokine receptor three ligands promotes T cell recruitment, while enhanced major histocompatibility complex class 1 (MHC-I) antigen presentation activates CD8 + T cell responses 36 . … (C) HDACis facilitate immune cell remodeling by reducing regulatory T cell (Treg)-mediated suppression, enhancing CD8 + T cell cytotoxicity via major histocompatibility complex class 1 (MHC-I) upregulation and PD-1/PD-L1 blockade, and boosting NK cell-mediated killing through granzyme and perforin release …

The paracrine effects of tumor-resident mesenchymal stem/stromal cells in the microenvironment of brain metastases.

BACKGROUND: Tumor-resident mesenchymal stem/stromal cells (MSCs) were identified in several cancers, and were implicated in regulating multiple aspects of tumor progression. However, the role of tumor-resident MSCs in the pathophysiology of brain metastases (BrMs) -the most prevalent type of malignant brain tumor- is currently unknown, and was investigated in this study. METHODS: Tumor-resident MSCs were isolated from fresh human lung-BrM tissues (n=3) and were phenotypically assessed in FFPE lung-BrM tissues (n=11). The paracrine effects of BrM-MSCs on neutrophil granulocytes and endothelial

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… MSCs generally have a low immunogenicity, due to the negligible expression of major histocompatibility complex (MHC) molecules ( 6 ). …

Возможная роль метаформы и фибробластного роста Factor-21 В Multical Sclerosis Neuropathology: Birds of a Feather Flock Common.

Множественный склероз (MS) — прогрессивное демиелинизирующее заболевание CNS, характеризующееся воспалением, образованием CNS-клеров и повреждением нейронной миелинской оболочки (graphical abstract). Фактор роста фибробласта 21 (FGF21) занимается различными метаболическими расстройствами и нейродегенеративными заболеваниями. FFF21 и его корецептор β-Kloth имеют существенно важное значение для процесса ремиелиции MS. Метформин, инсулин-сенсибилизирующее лекарство, которое является первой линией лечения для типа 2 Мэлитус диабета (T2DM) может оказывать потенциальное нейрозащитное воздействие, ре

Multiple myeloma, IL6, and risk of schizophrenia: A Mendelian randomization, transcriptome, and Bayesian colocalization study.

Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II di

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… Rs9273086 maps to the protein‐coding region of HLA‐DRB1 (major histocompatibility complex, class II, DR beta 1) in chromosome 6 based on the SZGR platform, a comprehensive SZ gene resource [ 57 ]. FIGURE 5 Bayesian colocalization between multiple myeloma (MM) and schizophrenia (SZ). …

Molecularly targeted therapy and immunotherapy in leukemias.

The advent of next-generation high-throughput sequencing and precision medicine has allowed the identification of recurrent genetic events of vital interest for leukemic cells and for the management of patients with leukemia, since it has a direct impact on prognosis and therapeutic stratification. The precise cytogenetic characterization of these diseases has rapidly enabled the development of innovative therapeutic strategies to improve outcomes and limit toxicities. New targeted therapies, including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug

Демографическая точность в онкологических оврагах, клинических и генетических детерминантах системной терапии.

Токсичность при лечении сдерживает применение эффективных методов лечения рака, однако ее клинические и генетические детерминанты по-прежнему недостаточно четко определены. Мы разработали подход, основанный на большой языковой модели, для производства MSK-Tox, панракорного ресурса, фиксирующего частотность, временнóсть и сорт токсичности для антираковой терапии в большей степени, чем 50,000 Пациенты. Анализ six Репрезентативные неблагоприятные явления - пневмонит, адренальная недостаточность, токсичность для печени, колит, гипертироидизм и гипотироидозные отдельные токсические ландшафты, опред

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… Figure 5: HLA fine-mapping identifies HLA-DRB1*15 as a genetic determinant of ICI-associated adrenal insufficiency. a, Regional association plot for adrenal insufficiency across the major histocompatibility complex on chromosome 6 (29.5-33.5 Mb). …

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review.

Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potent

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… In contrast to conventional T-cells, CAR-T cells possess the distinctive capability to recognize antigens independently of Major Histocompatibility Complex (MHC) molecules ( 35 ) which leads to potent T-cell activation and produces a strong, immediate, and long-term antitumor response ( 36 ). … Notably, the scFv can recognize and bind to an antigen in a major histocompatibility complex (MHC)-independent manner, leading to the activation of CAR-T cells and the induction of potent antitumor activity ( 41 ). …

Landscape of T-cell engagers in solid tumors.

T-cell engagers (TCEs) are a diverse class of bispecific and multispecific molecules that co-bind CD3 on T cells and tumor-associated antigens to form an immune synapse and induce targeted T-cell-mediated cytotoxicity. While TCEs have demonstrated remarkable efficacy in hematologic malignancies, translation into solid tumors has been more challenging. Recent advances seen with tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer have validated the approach and driven a rapidly expanding pipeline targeting other tumor associated antigens such as STEAP1, MUC16, and P

Гипоксия в множестве склерозов.

Низкая доступность кислорода (гипоксии) является заметной, но плохо понимаемой особенностью множественного склероза (МС). Неизвестно, вызывает ли гипоксия патологию и симптомы MS или она является следствием других патологических явлений, таких, как воспаление и сосудистая дисфункция. Здесь мы резюмируем имеющуюся литературу о взаимосвязи между гипоксией и как патологическими, так и симптомными характеристиками MS. Острая экологическая гипоксия (т.е. высота) может вызвать или облегчить события, связанные с MS, возможно, путем усиления гипоксии тканей в центральной нервной системе. Соответственн

Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision.

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and

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… Third, CAR-T cells are engineered, major histocompatibility complex (MHC)-independent antigen-specific T cells. 29 As antigen-dependent therapeutics, CAR-T cells share some of the same antigen-related challenges as cancer vaccines and bispecific T cell engagers. …

The phenotypic and genetic association between endometriosis and immunological diseases.

STUDY QUESTION: Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk? SUMMARY ANSWER: Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis. WHAT IS KNOWN ALREADY: The epidemiologi

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… The major histocompatibility complex (MHC) region of Chr6:24000000–35000000 was excluded as it has a dense clustering of immune-relevant genes with complex (non-binary) polymorphisms unsuitable for use in GWAS analyses and very strong long-range linkage disequilibrium, which complicates the determination …

Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.

The therapeutic landscape of acute myeloid leukaemia (AML) has evolved beyond the classic '7 + 3'/DA regimen, through the approval and incorporation of targeted treatments in both front-line and relapsed/refractory settings. Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates. Arguably one of the most exciting advancements has been the clinical development of menin inhibitors for the treatment of patients harbouring speci

The Role of Macrophage in the Pathogenesis of Osteoporosis.

Osteoporosis is a systemic disease with progressive bone loss. The bone loss is associated with an imbalance between bone resorption via osteoclasts and bone formation via osteoblasts. Other cells including T cells, B cells, macrophages, and osteocytes are also involved in the pathogenesis of osteoporosis. Different cytokines from activated macrophages can regulate or stimulate the development of osteoclastogenesis-associated bone loss. The fusion of macrophages can form multinucleated osteoclasts and, thus, cause bone resorption via the expression of IL-4 and IL-13. Different cytokines, endoc

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… Major histocompatibility complex class II molecules and CD23 are also found. These receptors are important for the progression of phagocytosis. IL-4 and IFN-γ can regulate the different functions of macrophages. …

Выявление потенциальных целей терапевтических препаратов для сепсиса путем сочетания человеческого плазменного протеома и генома: исследование менделианской случайности.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: В настоящее время сепсис имеет чрезвычайно высокий уровень смертности и не предусматривает какого-либо конкретного лечения. Мендельская рендемизация (MR) может использовать генетические варианты в качестве инструментальных переменных (IVs) для определения причинно-следственных связей между биомаркерами белка и сепсисом. Мы провели протеомное исследование MR для выявления биологических маркеров и терапевтических целей, связанных с сепсисом. МЕТОДЫ: белковый количественный орех (pQTL) анализировался с использованием two Источники данных: 734 - белки из Zeng et al.; и 4,907

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… The IV cis-pQTL were selected based on the following criteria: (I) P value <5×10 −8 ; (II) the SNP was not located within the human major histocompatibility complex region; (III) the SNP was located within 1 MB upstream and downstream; and (IV) a removal of linkage disequilibrium (r 2 ) value <0.1. …

Precision Reprogramming in CAR-T Cell Therapy: Innovations, Challenges, and Future Directions of Advanced Gene Editing.

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in cancer immunotherapy, demonstrating impressive clinical outcomes, particularly for hematologic malignancies. However, its broader therapeutic application, especially against solid tumors, remains limited. Key challenges include T cell exhaustion, limited persistence, cytokine-mediated toxicities, and logistical hurdles associated with manufacturing autologous products. Emerging gene editing technologies, such as CRISPR/Cas systems, base editing, and prime editing, offer novel approaches to optimize CAR-T cells, aiming

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… CARs are engineered receptors designed to redirect T cells toward tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent fashion, facilitating tumor eradication. … histocompatibility complex matrix metalloproteinase Cas9 nickase on-target off-tumor receptor-interacting protein kinases single-cell CRISPR single-cell RNA sequencing signaling domain second primary malignancies synthetic Notch tumor-associated antigens T-cell acute lymphoblastic leukemia …