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Clonal acquisition of the Ly49A NK cell receptor is dependent on the trans-acting factor TCF-1.

Families of clonally expressed major histocompatibility complex (MHC) class I-specific receptors provide specificity to and regulate the function of natural killer (NK) cells. One of these receptors, mouse Ly49A, is expressed by 20% of NK cells and inhibits the killing of H-2D(d) but not D(b)-expressing target cells. Here, we show that the trans-acting factor TCF-1 binds to two sites in the Ly49A promoter and regulates its activity. Moreover, we find that TCF-1 determines the size of the Ly49A NK cell subset in vivo in a dosage-dependent manner. We propose that clonal Ly49A acquisition during

Cost-Effectiveness of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Blood Cancers: An Updated Systematic Review.

BackgroundChimeric antigen receptor (CAR) T-cell therapy is an area of rapid development, showing the promise of curing blood cancers. While substantial health gains may justify high costs, it is currently unclear the extent to which the overall cost effectiveness of these therapies is driven by i) context-specific factors, such willingness-to-pay thresholds and study perspective, or ii) important subgroups such as line of treatment and therapy product.ObjectiveThis paper aims to critically review published evidence on the cost effectiveness of CAR T-cell therapies and assess the key factors t

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… Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy. Expert Rev Pharmacoecon Outcomes Res. 2019;19(5):529–36. 24. Petrou P. Is it a chimera? A systematic review of the economic evaluations of CAR-T cell therapy—an update. …

Epigenetic drugs in cancer therapy: mechanisms, immune modulation, and therapeutic applications.

Epigenetic regulation is a fundamental mechanism controlling gene expression and cellular function, primarily mediated through reversible modifications such as DNA methylation, histone acetylation, and chromatin remodeling. Dysregulation of critical epigenetic enzymes, including histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and bromodomain and extraterminal domain (BET) proteins, has been closely associated with tumor initiation, progression, metastasis, immune evasion, and resistance to conventional therapies. Targeting these epigenetic regulators with small-molecule inhibitor

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… Innovative strategies, including metabolic modulators such as IDH1/2 inhibitors, locus-specific CRISPR-dCas9 systems, proteolysis-targeting chimeras (PROTACs), and metal-based agents, offer enhanced specificity, efficacy, and combinatorial potential. … PROTAC-based BET inhibitors Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic strategy to overcome the limitations of traditional BET inhibitors [ 170 , 171 ]. …

Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators re

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… On the other hand, the emerging proteolysis targeting chimera (PROTAC) technology, which was introduced by Crews and Deshaies in 2001 via disrupting the endogenous ubiquitin (Ub)-E2 ligase-E3 ligase complex [ 174 ], which is widely applicable for degrading abnormal protein targets including epigenetic … Proliferator-Activated Receptors and γ coactivator 1α Valproic Acid Lacosamide Bassoon Gene Tuberous Sclerosis Complex 2 Sodium Butyrate Trichostatin A Glutamate Receptor 2 Vorinostat A Type GABA receptor γ 2 Food and Drug Administration European Medicines Agency Blood-Brain Barrier Proteolysis Targeting Chimera …

From Selection to Use: Aptamers as Targeting Reagents in Hematology.

Aptamers are synthetic nucleic acid ligands that have been proposed as alternatives to antibodies for targeting molecules and cells. In hematology, most reviews have organized aptamer literature around diseases or technological platforms. This framing has obscured how unevenly different blood cell types have been covered. In this review, we present developed aptamers organized by blood cell lineages. Specifically, we examine aptamers for B cells, T cells, natural killer cells, and red blood cells. This organization revealed a strong concentration on a small set of canonical surface markers and

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… In a humanized mouse model with multilineage human hematopoiesis, this aptamer-siRNA chimera selectively entered infected T cells, suppressed viral replication by several orders of magnitude, and protected against CD4 + T cell depletion. …

:: разработка системы запретов на использование кинжалов на основе капсаицина для модуляции взаимодействия киназы A/PHB2 и митофагии в раковых клетках.

A/AURKA — киназа серена/трионина, часто перевоплощающаяся в рак. Недавние открытия указывают на подклеточные пулы АУРКА, в том числе в митохондрии. Там AURKA вызывает расчистку органеллой митофагией вместе с автоматическим посредником LC3 и его рецептором PHB2. Здесь мы показываем, что натуральный продукт капсаицин изменяет взаимодействие AURKA/PHB2. Мы синтезируем 16 Аналоговые аналоги капсаицина и передача энергии/флюоресценция Förster's Energy Transport/Fluorescence Life Time Imageing Microscope (FRET/FLIM) в клетках рака груди показывают, что соединения 12 и 13 :: расширение взаимодействия

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… Molecular modelling of capsaicin and capsaicin derivatives, structural models of the AURKA-PHB2-LC3 tripartite complex, and molecular docking simulations The molecular structures of compounds 5, 12, and 13 were built by Discovery Studio 4.5 (Dassault Systèmes BIOVIA) and minimized by Chimera 1.14 39 … UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25 , 1605–1612 (2004). 40. Kim, S. et al. PubChem 2023 update. Nucleic Acids Res. 51 , D1373–D1380 (2023). 41. Kwon, S., Jung, N., Yang, J., and Seok, C. …

Enhanced sialylation of bone marrow mesenchymal stromal cells contributes to immune remodeling through macrophage polarization in multiple myeloma patients.

INTRODUCTION: In multiple myeloma (MM), the immune system is disrupted, partly due to tumor-modified bone marrow mesenchymal stromal cells (BM-MSCs). These MSCs show altered glycosylation, including increased sialylation, which may promote immune evasion through Siglec interactions. METHODS: We quantified sialic acids and Siglec ligands on healthy donors-, MM-, T-MM-(treated multiple myeloma) and MGUS (monoclonal gammopathy of undetermined significance)-MSCs, and examined how different culture conditions (myeloma coculture, conditioned medium, hypoxia, inflammation, 3D culture) affect MSC gly

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… Siglec ligands (Siglec-7L and Siglec-9L) were labeled on MSCs using recombinant Siglec-7 and Siglec-9-Fc chimeras combined with an anti-Fc-PE antibody (Jackson ImmunoResearch Labs, West Grove, PA, USA). … For Siglec ligand detection, BM-MSCs obtained from healthy donors, patients diagnosed with MM and treated patients with MM stained were with a recombinant Siglec-7 (D) and Siglec-9 (E) chimera protein linked with a PE antibody. MSCs were cultured in 1 mL DMEM (ctrl) and 1mL pro-inflammatory medium. …

Temporal variation in oral microbiome composition of patients undergoing autologous hematopoietic cell transplantation with keratinocyte growth factor.

IntroductionAutologous hematopoietic cell transplantation (AHCT) is a well-established treatment for lymphoma. Unintended effects of this therapy include oral mucositis (OM) and gastrointestinal toxicities, resulting in poor clinical outcomes. The gut microbiome has been previously linked to transplant toxicities among allogeneic recipients, but little is known about the effects of AHCT on the oral microbiome.MethodsSeven patients with non-Hodgkin or Hodgkin lymphoma undergoing AHCT with palifermin (keratinocyte growth factor) were included. Buccal swab samples were collected at baseline and 1

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… UCHIME improves sensitivity and speed of chimera detection. Bioinformatics. 2011;27(16):2194–200. doi: 10.1093/bioinformatics/btr381. 30. Cole JR, Wang Q, Cardenas E, Fish J, Chai B, Farris RJ, et al. The ribosomal database project: improved alignments and new tools for rRNA analysis. …

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… The resulting chimera exhibited a notably extended half‐life in the bloodstream, which enabled it to suppress tumor cell growth with greater efficiency. Shigdar et al. reported another notable example showcasing the great potential of aptamer chimeras [ 420 ]. … Upon exposure to intracellular ATP, the chimera readily discharged its doxorubicin cargo, as confirmed by functional testing. …

Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating?

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodru

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… MTC/TPP NPs | EA, PE, BF, GEF | NA | RAW 264.7 | syntaxin6 −/− and NPC1 −/− mice | Gene therapy | [ 267 ] Golgi apparatus-dependent cell death | Nanoparticles | Ag@ZnO | RR, CI | 70 | A375 normal dermal fibroblasts | NA | PDT | [ 247 ] Proteasome | Proteasome-targeting agents | Proteolysis-targeting chimeras … For instance, proteolysis-targeting chimeras (PROTACs) can effectively activate the UPS, facilitating the recognition and degradation of target proteins within tumors, thereby suppressing tumor cell function [ 254 , 255 ]. …

Price and Prejudice? The Value of Chimeric Antigen Receptor (CAR) T-Cell Therapy.

Although chimeric antigen receptor (CAR) T-cell therapy has shown a high response rate in lymphoma patients, its cost-effectiveness is controversial due to the high price and uncertainty of the clinical evidence. In addition to the high acquisition cost of CAR T-cell therapy, procedure and facility cost increase the financial burden considering the frequency of adverse events such as cytokine release syndrome. In clinical research, relatively short follow-up periods were used compared to traditional cancer agents. In addition, head-to-head comparative effectiveness data are unavailable, which

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… Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy. Expert Rev. Pharm. Outcomes Res. 2019;19:529–536. doi: 10.1080/14737167.2019.1651646. 34. Upadhaya S., Yu J.X., Shah M., Correa D., Partridge T., Campbell J. The clinical pipeline for cancer cell therapies. …

Структурная основа регламентации стенограмм с помощью нарождающегося элемента РНК, HK022 potRNA.

Переписка, в которой RNA полимеразы (RNAPs) производят RNA из ДНК, является первым шагом в генной экспрессии. Таким образом, она сильно регулируется либо трансэлементами, такими как белковые факторы, и/или резьбами, как конкретные последовательности на ДНК. В лямбдоидной фаге HK022 содержится резьбовое пятно, которое подавляет падение и прекращение во время транскрипции ранних фаговых генов. Протокол PotRNA осуществляет исключительно деятельность по борьбе с растлением/прекращением путем прямого взаимодействия с комплексом удлинения RNA E.coli (EC) с помощью неизвестного структурного механизма

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… In the model building, the models were first fitted onto the final cryo-EM map by using UCSF Chimera (version 1.11.12) 67 . Then, the RNAP domains were rigid-body refined in PHENIX (version 1.18.2) 68 , and the nucleic acid were mutated to have the correct sequence in Coot 69 . … UCSF chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084. 68. Adams PD, et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta. Crystallogr. D Biol. …

Bispecific antibodies in the treatment of epithelial ovarian, endometrial, and cervical cancer: an overview of current applications, challenges, and emerging opportunities.

Gynecological cancer remains one of the leading causes of mortality worldwide. Recent advances in genomic and molecular sequencing have significantly enhanced our understanding of the biological pathways that drive tumor progression and resistance to therapy. Targeted therapies, including monoclonal antibodies (mAbs), have revolutionized cancer treatment by selectively interfering with oncogenic proteins expressed on cancer cells. However, the long-term clinical benefit is often limited due to the emergence of drug resistance, frequently mediated by compensatory signaling pathways or immune es

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… This idea is inspired by the development of bispecific or multispecific small-molecule proteolysis-targeting chimeras (PROTACs). … killer no specific molecular profile objective response rate overall survival PARP inhibitors programmed cell death protein 1 programmed death-ligand 1 progression-free survival proficient mismatch repair partial response preferentially expressed antigen in melanoma proteolysis-targeting chimeras …

Окисляющий/нетрозирующий стресс, апоптоз и сигнализация " Redox " : основные игроки в нейродегенеративных заболеваниях.

Нейродегенеративные заболевания представляют собой серьезную проблему для здоровья, которая оказывает глубокое воздействие на качество и продолжительность жизни миллионов людей. Эти заболевания характеризуются патологическими изменениями в различных областях мозга, конкретными генетическими мутациями, связанными с болезнью, залежами аномальных белков и дегенерацией неврологических клеток. Поскольку нейродегенеративные расстройства различаются по своим эпидемиологическим характеристикам и степени уязвимости нейронов, лечение этих заболеваний обычно направлено на замедление развития заболеваний.

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… Qin et al. investigated the effects of synthesized methylthiazoles and NO‐chimeras on improving synaptic function and exerting neuroprotective effects in AD transgenic mice. … The study reported that NO‐chimeras improved in vivo learning and memory functions, provided neuroprotection and neurorestoration through their NO‐mimetic activity, and thus could be considered a prototype AD drug [ 124 ]. …

Автологическая трансплантация фекальной микробиоты в целях улучшения результатов пересадки ячеек стм: результаты технико-экономического обоснования в одном центре.

Пересадка стволовых клеток (HSCT) является лечебным методом лечения рака крови, однако ее эффективность подрывается целым рядом острых и хронических осложнений. В свете растущего объема данных, свидетельствующих о том, что эти осложнения связаны с дизобиотическим кишечным микробиомом, мы намеревались оценить возможность трансплантации фекального микробиота (ФМТ) в ходе острой фазы после HSCT. Следует отметить, что в ходе этого испытания был сделан выбор в пользу ДРМ, подготовленной с использованием собственного стула (автологического стула ДРМ) для снижения риска передачи болезни от стула доно

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… Operational taxonomic unit (OTU) picking was performed with chimera filtering using the Silva 16S and 18S v132 99% database. The OTUs were aligned with MUSCLE and alpha diversity determined through Shannon’s diversity. 2.6. …

TSP-1 interaction with RANK and OPG: implications for bone remodeling and osteolytic bone metastasis.

Excessive bone disruption, driven by upregulation of bone-degrading osteoclasts, occurs in several pathologies, including breast cancer osteolytic bone metastasis, a condition associated with poor prognosis and diminished quality of life for patients. The matricellular protein thrombospondin-1 (TSP-1) plays pleiotropic roles in physiological and pathological remodeling of several tissues, including bone, and in shaping the microenvironment of primary tumors and metastasis. This study aimed to explore the role of TSP-1 in bone remodeling associated with osteolytic bone metastasis. We have ident

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… Recombinant human RANK/TNFRSF11A Fc Chimera and OPG/TNFRSF11B were from R&D Systems (Milan, Italy). Murine recombinant murine RANK-L was from PeproTech (Thermo Fisher Rodano, Italy). … The recombinant human RANK/Fc Chimera or OPG was immobilized by standard amine-coupling chemistry on a research-grade CM5 sensor chip (Cytiva). …

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

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… EP300 Degraders To completely ablate the CBP/EP300 function, CBP/EP300 degraders have been designed as heterobifunctional molecules termed proteolysis-targeting chimeras (PROTAC). A chimera consists of a specific target protein ligand linked to the ligand of an E3 ligase such as cereblon (CRBN). …

Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms.

Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connecti

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… In this regard, the possibility to induce JAK2 degradation by means of HSP90 inhibitors [ 90 ], or by proteolysis-targeting chimera (PROTAC) technology [ 93 , 94 , 95 ], is an interesting perspective for the development of innovative treatments. … Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary(s) AML cells Leukemia 2017 31 1951 1961 10.1038/leu.2016.393 28042144 PMC5537055 126. Fortunel N.O. Hatzfeld A. Hatzfeld J.A. …

Ligand-based CAR-T cell: Different strategies to drive T cells in future new treatments.

Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific evidence of the limitations of these therapies mainly due to immunogenicity issues, toxicities associated with the infusion of the product, and relapses of the tumor. As a result, novel approaches are appearing aiming to solve and/or mitigate the harmful effects of CAR-T therapies. These include strategies based on the use of ligands as binding moieties or ligand-based CAR-T cells. Several proposals are currently under development

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… Thus, a chimera was developed introducing N-terminal linear region of TGF-α into the EGF C-terminal sequence, resulting in high affinity for ErbB-2/ErbB-3 maintaining ErbB-1 specificity ( 87 ). ErbB-4 heterodimer binding was also reported. … Structural analysis of an epidermal growth factor/transforming growth factor-α chimera with unique ErbB binding specificity. J Biol Chem (2003) 278(40):39114–23. doi: 10.1074/jbc.M305603200 87. Stortelers C, Van de Poll MLM, Lenferink AEG, Gadellaa MM, Van Zoelen C, Van Zoelen EJJ. …

Aptamer Therapeutics in Cancer: Current and Future.

Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small-approximately one-tenth that of monoclonal antibodies-their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesize

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… Soldevilla et al. reported that CD40Apt-SMG1-shRNA chimera improved survival of BALB/c mice that were intravenously inoculated with A20 lymphoma cells compared to CD40Apt-control-shRNA or untreated mice [ 145 ]. 3.1.9. … Aptamer-siRNA chimeras: Discovery, progress, and future prospects Biomedicines 2017 5 45 10.3390/biomedicines5030045 28792479 PMC5618303 19. Bruno J.G. …