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PROTAC Technology as a New Tool for Modern Pharmacotherapy.

The publication focuses on the innovative applications of PROTAC (proteolysis-targeting chimera) technology in modern pharmacotherapy, with particular emphasis on cancer treatment. PROTACs represent an advanced therapeutic strategy that enables selective protein degradation, opening new possibilities in drug design. This technology shows potential in the treatment of cancers, viral infections (such as HIV and COVID-19), and chronic diseases including atherosclerosis, Alzheimer's disease, atopic dermatitis, and Huntington's disease. Promising results from clinical studies on the compound ARV-47

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… CLIPTAC | | Utilise click chemistry to assemble bifunctional molecules within cells, enhancing targeted protein degradation. 6.1. Antibody–PROTAC The antibody–PROTAC approach is an innovative technology that combines the PROTAC protein degradation mechanism with precise antibody delivery. … “Click chemistry,” introduced by Sharpless’ lab, has been used to describe a series of chemical reactions with mild reaction conditions, high product efficiency, and high selectivity. …

PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice.

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long-lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small-molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identifie

Study of Cinobufagin as a Promising Anticancer Agent in Uveal Melanoma Through Intrinsic Apoptosis Pathway.

Uveal melanoma (UM) is the most common primary intraocular carcinoma in adults. Cinobufagin, secreted by the Asiatic toad Bufo gargarizans, is a traditional Chinese medicine, widely used in tumor treatment. Here, we explored the potential antitumor function of cinobufagin and investigated its biochemical mechanisms in UM cells. The antitumor potential of cinobufagin was determined via cell viability, cell cycle, and apoptosis assays. Colony formation assays confirmed that cinobufagin exerted potent antitumor activity in a dose-dependent manner. We found that cinobufagin could induce cell apopt

Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels.

To study the individual functions of hyaluronan interacting proteins in prostate cancer (PCa) motility through connective tissues, we developed a novel three-dimensional (3D) hyaluronic acid (HA) hydrogel assay that provides a flexible, quantifiable, and physiologically relevant alternative to current methods. Invasion in this system reflects the prevalence of HA in connective tissues and its role in the promotion of cancer cell motility and tissue invasion, making the system ideal to study invasion through bone marrow or other HA-rich connective tissues. The bio-compatible cross-linking proce

Antibody-drug conjugates in urinary tumors: clinical application, challenge, and perspectives.

Urinary tumors primarily consist of kidney, urothelial, and prostate malignancies, which pose significant treatment challenges, particularly in advanced stages. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach, combining monoclonal antibody specificity with cytotoxic chemotherapeutic payloads. This review highlights recent advancements, opportunities, and challenges in ADC application for urinary tumors. We discuss the FDA-approved ADCs and other novel ADCs under investigation, emphasizing their potential to improve patient outcomes. Furthermore, we explore stra

Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA.

Background:  It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in

Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma.

BackgroundThe attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739).MethodsE

Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

BackgroundDaratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM).MethodsA multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed diseas

Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis.

Mucositis is a complex, dose-limiting toxicity of chemotherapy or radiotherapy that leads to painful mouth ulcers, difficulty eating or swallowing, gastrointestinal distress, and reduced quality of life for patients with cancer. Mucositis is most common for those undergoing high-dose chemotherapy and hematopoietic stem cell transplantation and for those being treated for malignancies of the head and neck. Treatment and management of mucositis remain challenging. It is expected that multiple genes are involved in the formation, severity, and persistence of mucositis. We used Ingenuity Pathway A

Vision of Life's Code: Molecular Probe Nanoarchitectonics for Deep RNA/DNA Illumination.

Visualization of RNA and DNA provides a window of opportunity for the early detection of multiple diseases and approaches to manipulate them before any pathological processes occur. However, current imaging systems often fail to meet these demands due to the need for multiple RNA and DNA chemical probes, which increases experimental complexity, reduces awareness of false positives, and limits imaging accuracy in complex biosystems. In this work, we identify the key challenges associated with using multiple probes for RNA and DNA imaging and analyze the mechanisms and performance of existing im

Microorganisms Associated with the Marine Sponge Scopalina hapalia: A Reservoir of Bioactive Molecules to Slow Down the Aging Process.

Aging research aims at developing therapies that delay normal aging processes and some related pathologies. Recently, many compounds and extracts from natural products have been shown to slow aging and/or extend lifespan. Marine sponges and their associated microorganisms have been found to produce a wide variety of bioactive secondary metabolites; however, those from the Southwest of the Indian Ocean are much less studied, especially regarding anti-aging activities. In this study, the microbial diversity of the marine sponge Scopalina hapalia was investigated by metagenomic analysis. Twenty-s

Resveratrol and Other Natural Oligomeric Stilbenoid Compounds and Their Therapeutic Applications.

The use of natural compounds as an alternative to synthetic molecules has become a significant subject of interest in recent decades. Stilbenoids are a group of phenolic compounds found in many plant species and they have recently gained the focus of a multitude of studies in medicine and chemistry, resveratrol being the most representative molecule. In this review, we focused on the research that illustrates the therapeutic potential of this class of natural molecules considering various diseases with higher incidence rates. PubChem database was searched for bioactivities of natural stilbenoi

Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that mult

Antibody-Drug Conjugates and Peptide-Drug Conjugates: Current Understandings and Future Perspectives.

Antibody-drug conjugates (ADCs) and peptide-drug conjugates (PDCs) are modular targeted therapeutics in which molecular recognition is coupled with controlled payload delivery. Owing to their high specificity and precision, they have been regarded as a transformative paradigm for cancer therapy. In this review, current understandings and future perspectives of ADCs and PDCs are synthesized across rational design principles, historical evolution, clinical translation, and emerging formats, aiming to improve practical comprehension and application in oncology. Key determinants of performance: ta

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BM

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… Active encapsulations include electroporation [ 77 ], sonication [ 78 ], freeze and thaw cycles [ 79 ], click chemistry [ 80 ], extrusion [ 81 ] and incubation with saponin [ 82 ] ( Table 3 ). Notably, these methods result in different encapsulation rates and stability of drugs in exosomes or EMs. … This process is repeated at least 3 times. | The drug-loading efficiency is higher than that in passive incubation. | The dilution ratio of lipid may be affected. | [ 79 ] Click chemistry | Drugs can be directly attached to the surface of the exosome through covalent bonds. | Fast and efficient; This …

Всемирный конгресс молекулярного воображения 2022.

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Microgel-Based 3D Bioprinting: A Convergent Strategy Integrating Material Design, Jamming Dynamics, and Biological Function.

Driven by rapid technological innovation and an increasing demand for personalized medicine, microgel-based bioprinting emerges as a versatile strategy for generating physiologically relevant tissue models and patient-specific constructs. By integrating microgel systems with 3D bioprinting, this approach enables the creation of complex, cell-laden architectures that closely recapitulate native tissue architecture and function. Pivotal to this potential are microgels that offer significant advantages over conventional hydrogel-based bioinks, including tunable rheological behavior, enhanced prin

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… These versatile stabilization strategies rely on a variety of physical and chemical interactions between neighboring microgel particles, and might include enzymatic reactions, photopolymerization, click chemistry, amine coupling, or non‐covalent interactions such as hydrogen bonding and electrostatic … chemistry | Stiffer microgels promote cell spreading, increased focal adhesions, and reduced swelling vs. bulk | Tissue engineering | 40‐layer cylindrical structure with strong layer adhesion; anatomically relevant ear and nose models printed with high fidelity Gelatin [ 8 , 98 , 128 , 129 ] | Spherical …

Hotspots and trends in multiple myeloma bone diseases: A bibliometric visualization analysis.

Objective: This study aims to explore the research hotspots and trends of multiple myeloma bone disease in the past 20 years by bibliometric visualization analysis. Methods: With the Web of Science Core Collection database as the data source, the relevant publications of multiple myeloma bone disease from 2002 to 2021 are retrieved. These data are analyzed using software CiteSpace 5.8.R3 and Scimago Graphica 1.0.24, together with the Online Analysis Platform of Literature Metrology. Results: A total of 6,168 published research papers, including 4668 articles and 1500 review papers, are include

Progress in high-throughput screening for drug and material discovery in orthopedic diseases: a literature review.

Orthopedic diseases are referred to as a series of conditions affecting the normal structure and function of the skeletal system. With a wide variety of types and a year-by-year increasing incidence, they have a severe impact on patients' quality of life. Traditional research has made relatively significant progress in understanding the pathogenesis and treating orthopedic diseases, however, it remains constrained by limitations such as low-throughput experimentation, and difficulty in mimicking the complex bone microenvironment. In recent years, high-throughput screening (HTS) technology has

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… Kavya Ganabady and her team successfully synthesized 90 polymers by leveraging thiol-ene click chemistry technology and employing ultraviolet (UV) rapid curing processes. … In terms of screening technology integration, the candidates can be divided into five categories: HTS combined with polymer microarray and high-sensitivity imaging detection (1-S2-FT01), which integrates thiol-ene click chemistry, UV rapid curing, fluorescence microscopy and ImageJ quantitative analysis …

Antibody-based drug delivery systems for cancer therapy: Mechanisms, challenges, and prospects.

In recent years, antibody-based cancer therapy has emerged as one of the efficient therapeutic strategies, such as immune checkpoint inhibitors (ICIs), angiogenesis inhibitors, antibody-drug conjugates (ADCs), multi-specific antibodies, and chimeric antigen receptor T (CAR-T) cells, among others. To date, various drug delivery platforms have been developed to improve the bioavailability, delivery convenience, and reduced toxicity towards increased therapeutic efficacy of antibodies. Herein, we emphasize the clinical manifestations of various antibody-based tumor therapies, highlighting their m

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… Xie and colleagues have co-coupled anti-CD47 and anti-signal regulatory protein alpha (SIRPa) antibodies to M1 macrophage exosomes via click chemistry ( Figure 7 C ) 66 . …