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Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics.

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18-21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normal

Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT) protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA), vectorized in an HIV-1-derived lentiviral vector (LV), that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL) ba

Nanoparticle-based strategy in CAR-T cell immunotherapy: challenges, implications, and perspectives.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable progress in treating hematologic malignancies, yet its broader application faces challenges such as manufacturing complexity, solid tumor microenvironment barriers, and immune toxicity. Nanoparticles (NPs), leveraging their precise delivery, immunomodulation, and multifunctional integration capabilities, offer innovative strategies to optimize CAR-T cell therapy. This review provides a comprehensive elucidation of the fundamental framework of CAR-T cell therapy and the challenges in oncological applications. Subsequently, w

Spiegelmer Aptamers: Innovative Approach in Breast Cancer.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide, emphasizing the urgent need for improved diagnostic and therapeutic strategies. Aptamers which are synthetic oligonucleotides that specifically bind to target molecules, offer high affinity, low immunogenicity, and superior tumor penetration compared to antibodies. However, their clinical translation has been limited by instability in biological systems. Spiegelmers, a novel class of mirror-image aptamers composed of L-nucleotides, overcome this limitation through intrinsic nuclease resistance an

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… Finally, there is a scarcity of studies on spiegelmer behavior within biological environments, representing another area in need of further investigation. 131 A recent study demonstrated that single-stranded G-rich L-RNA sequences interact with numerous proteins containing RNA recognition motifs (RRMs …

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers.

Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical cancer. This aberra

The progress and perspective of nanomedicine in modulating the tumor immune microenvironment.

The widespread application of nanomedicine in oncology is reshaping cancer treatment paradigms. Using the precise targeting mechanisms and the rapid advancements in nanoscale materials, nanomedicine is driving progress in cancer therapy, particularly within the complex landscape of the tumor immune microenvironment (TIM). This review provides a comprehensive overview of recent studies elucidating the critical role of nanomedicine in modulating the TIM, augmenting the efficacy of immunotherapies, and overcoming therapeutic resistance. Emphasis is placed on the significance of targeted drug deli

XPO1: From basic research to clinical treatment (Review).

Exportin 1 (XPO1) is a key nuclear export receptor that mediates the nuclear export of tumor suppressor proteins and growth‑regulatory mRNAs from the nucleus to the cytoplasm. In several types of cancer, XPO1 is overexpressed or hyperactivated, leading to aberrant cytoplasmic sequestration of key tumor suppressors such as p53, p21, p73, FOXO and Rb. This mislocalization abrogates their nuclear transcriptional functions, disrupting cell cycle arrest, apoptosis and DNA repair, thereby promoting uncontrolled proliferation, survival and therapy resistance. Targeting XPO1 with selective inhibitors

Остеопонтин по хроническим воспламенительным болезням: механизмы, биомаркеры и терапевтические стратегии.

Хронические подстрекательские заболевания, такие, как ревматуидный артрит (RA), системный волчан Эрематосус (SLE), множественный склероз (MS), атеросклероз и воспалительный кишечник (IBD), вызывают серьезную озабоченность во всем мире. Эти расстройства характеризуются стойким воспалением, дисфункцией иммунной системы, повреждением тканей и фиброзом, что в конечном счете приводит к серьезной дисфункции органов и снижению качества жизни. Остеопонтин (OPS), многофункциональный внеклеточный белок, играет решающую роль в иммунном регулировании, воспалении и реконструкции тканей. Она поощряет набор

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces chal

Комплексный метаанализ транскриптомов астроцитов человека показывает, что в ответ на подстрекательские и иммунные стимулы потенциальные признаки повторяются.

Астроциты являются ключевыми регуляторами подстрекательской и иммунной реакции в центральной нервной системе, особенно в патологических условиях. Мы проводили систематический поиск баз данных НКОИ по ГЭП и ЭНА в целях выявления транскриптивных исследований стимулируемых астроцитов. Этот метаанализ объединяет 11 наборов данных RNA-Seq, охватывающих в общей сложности 153 пробы (91 стимулируемый и 62 средства контроля), подвергающиеся воздействию провоспалительных стимулов, таких, как цитокины (TNF-α, IL-6 и IL-1β), пальмовая кислота и патогены, такие, как SARS-COV-2 и Borrelia burborferi. Благод

T-cell Immunotherapies and the Role of Nonclinical Assessment: The Balance between Efficacy and Pathology.

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it

Exploring the impact of m6A modification on immune diseases: mechanisms and therapeutic implication.

N6-methyladenosine (m6A) is a chemical modification of RNA and has become a widely discussed topic among scientific researchers in recent years. It is distributed in various organisms, including eukaryotes and bacteria. It has been found that m6A is composed of writers, erasers and readers and is involved in biological functions such as splicing, transport and translation of RNA. The balance of the human immune microenvironment is important for human health abnormalities. Increasing studies have found that m6A affects the development of immune diseases such as inflammatory enteritis and system

Integrative analysis of bulk and single-cell gene expression profiles to identify bone marrow mesenchymal cell heterogeneity and prognostic significance in multiple myeloma.

BackgroundMultiple myeloma is a hematologic malignancy characterized by complex interactions within the tumor microenvironment, where mesenchymal stem cells (MSCs) contribute significantly to disease progression, immune suppression, and drug resistance.MethodsThis study investigated the heterogeneity of MSCs in multiple myeloma using single-cell RNA sequencing (10X) and bulk transcriptomic data. Further analysis was performed by Seurat, SCENIC, CellChat. GSE4581 and GSE136337 were used as training set and validation set to construct a newly described prognostic model through COX and LASSO.Resu

RNA N 6-Methyladenosine in Cancer Metastasis: Roles, Mechanisms, and Applications.

Cancer metastasis is a symptom of adverse prognosis, a prime origin of therapy failure, and a lethal challenge for cancer patients. N 6-methyladenosine (m6A), the most prevailing modification in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) of higher eukaryotes, has attracted increasing attention. Growing studies have verified the pivotal roles of m6A methylation in controlling mRNAs and ncRNAs in diverse physiological processes. Remarkably, recent findings have showed that aberrant methylation of m6A-related RNAs could influence cancer metastasis. In this review, we illuminate how m6A m

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies.

Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs-oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive ef

Investigating the functions and molecular mechanisms of DTX3L in cancer progression.

In the field of tumor research, the process by which E3 ubiquitin ligases specifically ubiquitinate substrate proteins and promote their degradation has garnered significant attention. DTX3L, an emerging E3 ubiquitin ligase of the Deltex family, is closely associated with the development and progression of various malignant tumors. Through multiple mechanisms such as epigenetic modifications, signal pathway activation, and protein interaction networks, DTX3L precisely regulates key biological processes, including cell proliferation, cycle progression, migration, invasion, and apoptosis. This r

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… It contains an RRM domain (RNA recognition motif 1), five KH domains (K homology RNA-binding domain), a RING domain (RING finger domain) and a DTC domain (Deltex C-terminal domain) ( Figure 2 ) ( 8 – 10 ). Figure 2 Schematic diagram of DTX3L structure. (A) The schematic diagram of DTX3L domain. … The RNA recognition motif, a plastic RNA-binding platform to regulate post-transcriptional gene expression. FEBS J. (2005) 272:2118–31. doi: 10.1111/j.1742-4658.2005.04653.x, PMID: 12. Hentze MW, Sommerkamp P, Ravi V, Gebauer F. …

Genome-edited allogeneic CAR-T cells: the next generation of cancer immunotherapies.

Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized cancer immunotherapy, particularly in hematological malignancies. However, the clinical application of autologous CAR-T cells faces significant high cost and manufacturing challenges. Universal allogeneic CAR-T cells, derived from healthy donors, represent a promising solution to these obstacles. These "off-the-shelf" therapies aim to reduce the complexity and cost of CAR-T production. Despite exciting advancements in genome-editing technologies and promising clinical trial data, significant challenges remain, including graft-

NTRK Fusion in Non-Small Cell Lung Cancer: Diagnosis, Therapy, and TRK Inhibitor Resistance.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusion has been identified as an oncogenic driver of various solid tumors, and it is rare in non-smalll cell lung cancer (NSCLC) with a frequency of approximately less than 1%. Next-generation sequencing (NGS) is of priority for detecting NTRK fusions, especially RNA-based NGS. Currently, the tropomyosin receptor kinase (TRK) inhibitors have shown promising efficacy and well tolerance in patients with NTRK fusion-positive solid tumors, regardless of tumor histology. The first-generation TRK inhibitors (larotrectinib and entrectinib) are reco

Изучение общих генных сигнатур и механизмов между тремя аутоиммунными заболеваниями по массовому секвенированию РНК в сочетании с последовательности одноклеточного РНК.

ВАЖНЕЙШАЯ ИНФОРМАЦИЯ: Появляющиеся данные подчеркивают наличие механизмов коморбидности среди аутоиммунных заболеваний (АИД), при этом инновационные технологии, такие, как секвенирование РНК в одной клетке (scRNA-seq), значительно улучшают разведку в этой области. Цель этого исследования заключалась в изучении общих генов трех AID-Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE) и Rheumatoid Artritis (RA) с использованием баз данных биоинформатики, а также в выявлении потенциальных биомаркеров для ранней диагностики. Мы извлекли стеноскопические данные о пациентах MS, SLE и RA из об

Множественная миелома: сказка о дерегулированных факторах транскрипции.

Всеобъемлющее понимание молекулярных механизмов, лежащих в основе множественных миэломных (ММ) патогенеза, крайне важно для разработки терапевтических стратегий, позволяющих преодолеть гетерогенность заболеваний и рецидив лечения. В этом обзоре мы сосредоточимся на коэффициентах транскрипции (TF), ключевых регуляторах генного экспрессия, которые играют важнейшую роль в обычной гематопоизисе и биологии MM. Сначала мы обсудим физиологические функции ТФ в составе лимфоидной линии и конечной дифференциации В-клеток на плазменные клетки. Это позволяет получить представление о вкладе ключевых ЦГ, та