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Therapeutic biomarkers in acute myeloid leukemia: functional and genomic approaches.

Acute myeloid leukemia (AML) is clinically and genetically a heterogeneous disease characterized by clonal expansion of abnormal hematopoietic progenitors. Genomic approaches to precision medicine have been implemented to direct targeted therapy for subgroups of AML patients, for instance, IDH inhibitors for IDH1/2 mutated patients, and FLT3 inhibitors with FLT3 mutated patients. While next generation sequencing for genetic mutations has improved treatment outcomes, only a fraction of AML patients benefit due to the low prevalence of actionable targets. In recent years, the adoption of newer f

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… In case of organoid models, tumor microenvironment cells are excluded. These cells play a role in regulating drug responses ( 150 ) and therefore, this method does not truly represent the tumor and the interaction with their tumor microenvironment. … Applications of patient-derived tumor xenograft models and tumor organoids . J Hematol Oncol ( 2020 ) 13 : 1 – 16 . doi: 10.1186/S13045-019-0829-Z 31910904 PMC6947974 152 Choi Y Lee S Kim K Kim SH Chung YJ Lee C . …

Epigenetic Modulation and Bone Metastasis: Evolving Therapeutic Strategies.

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to

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… Importantly, patient-derived bone organoid models are now being employed to study bone-specific epigenetic signatures and drug responses in a physiologically relevant context [ 251 ]. … In parallel, the development of patient-derived bone organoids and microfluidic “osteon-on-a-chip” platforms that recapitulate osteoblast, osteoclast, and marrow stromal crosstalk under physiologic shear forces and mineral gradients will offer a powerful ex vivo system for screening epigenetic drug combinations …

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma.

Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeut

Targeting urological cancers with CAR-T cell therapy: current landscape and future directions.

BACKGROUND: Urological cancers, including renal, bladder, and prostate cancers, are among the most prevalent solid tumors. The success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies has spurred its exploration for treating urological cancers. MAIN BODY: In the past decade, preclinical studies have demonstrated promising antitumor activity of CAR-T cells against urological cancers. Meanwhile, multiple clinical trials are currently underway to evaluate their safety and efficacy. However, significant challenges impede the efficacy of CAR-T cell therapy in urological

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… In a study by Yu et al. [ 174 ], patient-derived bladder cancer organoids (BCOs) were established to evaluate CAR-T cell cytotoxicity, and 2G anti-mucin 1 (MUC1) CAR-T cells induced significant cancer cell killing and immune activation against MUC1 + BCOs. … Advanced experimental models, such as tumor spheroids, patient-derived organoids, and biomimetic tumor microenvironment systems, are increasingly utilized to address these limitations [ 174 , 323 ]. …

Абстрактный сборник ISEV2022.

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Bruton Tyrosine Kinase в лизах множественных склерозов и 3 модели.

ПАТОфизиология множественного склероза (MS) обусловлена лимфоцитами B, макрофагами и микроглией. Bruton tirosine cinase (BTK) — внутриклеточный фермент внутри этих клеток, который модифицирует их подстрекательские свойства. Таким образом, центральные ингибиторы нервной системы и пенектора BTK могут противодействовать регулированию иммунной дистракции, и это стремление высвечивается с помощью 11 фазы 3 Клинические испытания в MS, чтобы остановить этот фермент. Несмотря на большой интерес, пространственное и временнóе возвышение BTK в повреждениях MS и его моделей не является достаточно точным.М

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… proinflammatory features of microglia (numerous cytokines, chemokines, and metalloproteinases) and microglia toxicity to neurons (neurofilament release) are lowered by fenebrutinib. 12 Reduced TNF-α and neurofilament release in activated microglia by treatment with fenebrutinib is also observed in human brain organoids …

Artificial intelligence enabled interpretation of ECG images to predict hematopoietic cell transplantation toxicity.

AbstractArtificial intelligence (AI)-enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo

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… Modeling effects of immunosuppressive drugs on human hearts using induced pluripotent stem cell-derived cardiac organoids and single-cell RNA sequencing. Circulation. 2022;145(17):1367–1369. doi: 10.1161/CIRCULATIONAHA.121.054317. 25. Dogan A, Dogdu O, Ozdogru I, et al. …

Исследование новых биомаркеров для нейродегенеративных заболеваний с использованием протеомного анализа и лигандно-объеденных анализов.

ВАЖНЕЙШИЕ/ОБЯЗАТЕЛЬНЫЕ ЦЕЛИ: Нейродегенеративные заболевания являются одной из основных причин заболеваемости и смертности во всем мире, и их бремя в области общественного здравоохранения продолжает расти. Необходимо срочно разработать надежные и чувствительные биомаркеры для содействия своевременной диагностике, мониторингу прогрессии заболеваний и терапевтическому развитию нейродегенеративных расстройств. Протеомные скрининговые стратегии, в том числе антителные микроаррары, являются мощным инструментом для обнаружения биомаркеров, однако их результаты должны быть подтверждены с помощью коли

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… antibodies against a variety of targets, such as chemokines, cytokines, growth factors, immune cell markers, immune checkpoint molecules, inflammatory mediators, and vascular/angiogenic targets, and can be used for the analysis of samples derived from CSF, plasma, cells, tissues, supernatants, and organoids …

Nanoparticle Strategies for Bone Metastasis Immunotherapy: Targeting, Immune Reprogramming and Combination Therapy.

Bone metastases remain one of the most clinically devastating complications of advanced cancer, particularly in breast, prostate, and lung malignancies, where they drive pain, fractures, hypercalcemia, and progressive functional decline. Their management is further complicated by a highly immunosuppressive bone microenvironment characterized by osteoclast-driven bone destruction, myeloid cell dominance, impaired antigen presentation, and weak effector T-cell infiltration, all of which limit the activity of conventional immunotherapies. In this setting, nanoparticles are emerging not merely as

Advances and prospects in cell therapy for cancer: explorations from T cells to stem cells.

The increasing global burden of cancer necessitates innovative therapeutic strategies. Cell therapy represents a major breakthrough in oncology, evolving rapidly from the successful application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies to a multiplatform landscape characterized by the concurrent development of diverse strategies. Current research focuses on T cell receptor-engineered T (TCR-T) cells, tumor-infiltrating lymphocytes (TILs), gamma delta (γδ) T cells, CAR-natural killer (CAR-NK) cells, CAR-macrophages (CAR-Ms), and various strategies based on dendrit

How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal t

Integrated Engineering of CAR-T Cells for Solid Tumours.

Chimeric antigen receptor (CAR) T-cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T-cell dysfunction. This review examines the transition from single-axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next-generation CAR-T cells are designed for precise spatiotemporal activation through logic-gated and pharmacologically regulatable receptors, while being reinforced by metaboli

A comprehensive review on pain: Model, target, therapy, and prospect (Review).

Pain serves as both a protective physiological response essential for species survival and a global health issue affecting human well‑being and societal development. The present review systematically summarized and analyzed the research progresses on pain through a multidimensional analytical framework encompassing animal models, molecular targets, therapeutic approaches and future prospects. In animal modeling, neuropathic pain paradigms have evolved from traditional mechanical compression to composite models that combine dynamic displacement and chemical stimulation. Cancer‑induced pain mode

Nanotechnology in Prostate Cancer: PSMA-Targeted Nanoplatforms, TME-Responsive Therapy, Immunomodulation, and Clinical Translation Challenges.

The field of nanotechnology has demonstrated considerable potential in the diagnosis and treatment of prostate cancer, particularly through the use of prostate-specific membrane antigen (PSMA)-targeted platforms and tumor microenvironment (TME)-responsive systems. In the context of diagnosis, nanoparticle-based molecular imaging probes have been shown to enhance detection sensitivity and specificity. These probes include superparamagnetic iron oxide, which is utilized in magnetic resonance imaging, and near-infrared fluorescent nanomicelles. Additionally, nanostructured liquid biopsy systems h

Целенаправленная деградация белка разрушает ненаркомные цели, чтобы обратить вспять иммунное уклонение и терапию устойчивости к раку.

Таргетированная деградация белков (ТД) использует эндогенные протеолитические системы — систему убиквина и протеасомы и лизосомальные пути — для селективного удаления белков, вызывающих болезни, которые не реагируют на традиционное ингибирование. В онкологической иммунотерапии ТД разрушает критические иммунодепрессивные узлы в экзоцитоплазматическом, мембранном и цитоплазматическом компартментах, перепрограммируя микросреду опухоли от иммунологически «холодной» к «горячей» состоянию. Эта статья рассматривает молекулярные принципы инженерии бифункциональных деградаторов и обобщает клинические д

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… In cervical cancer models, NP1192 achieved nearly 70% NAT10 degradation, inhibited the HIF-1α/PD-L1 axis, reversed hypoxic glycolysis, and demonstrated anti-tumor activity in patient-derived organoids. … The Copanlisib-based PROTAC restored drug sensitivity in lapatinib-resistant HER2+ breast cancer xenografts and patient-derived organoids ( 102 ). …

The UK's Early Access to Medicines Scheme 10 years on: an evaluation using publicly available data.

ObjectivesTo investigate the drugs and indications that have passed through the UK's Early Access to Medicines Scheme (EAMS) to date, the type of evidence the regulator considers when accepting a drug into the EAMS, and potential risks to patients.DesignAnalysis of publicly available data: MHRA Public Assessment Reports; Electronic Medicines Compendium database; interactive Drug Analysis Profiles database; Eudravigilance database.SettingUnited Kingdom.ParticipantsThe 51 'scientific opinions' available on the MHRA website in June 2024.Main outcome measuresPublic Assessment Reports, pharmacovigi

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… this is not uncommon for expedited drugs, as we noted in the introduction. 13 – 15 The safety of expedited drugs might be improved with greater preclinical use of human biology-based technologies, the value of which is increasingly evident. 39 – 43 The use of advanced in vitro technologies such as organoids …

Utilizing Three-Dimensional Culture Methods to Improve High-Throughput Drug Screening in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine neoplasm, with a median survival of just four to six months post-diagnosis. Even with surgical and chemotherapeutic interventions, the five-year survival rate is less than 5%. Although combination dabrafenib/trametinib therapy was recently approved for treatment of the ~25% of ATCs harboring BRAFV600E mutations, there are no approved, effective treatments for BRAF-wildtype disease. Herein, we perform a screen of 1525 drugs and evaluate therapeutic candidates using monolayer cell lines and four corresponding spheroid models of

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… Patient-derived organoids model treatment response of metastatic gastrointestinal cancers Science 2018 359 920 926 10.1126/science.aao2774 29472484 PMC6112415 11. Lagies S. Schlimpert M. Neumann S. Waldin A. Kammerer B. Borner C. Peintner L. …

Advances in preclinical hematopoietic stem cell models and possible implications for improving therapeutic transplantation.

Hematopoietic stem cell transplantation (HSCT) is a treatment for many malignant, congenital, and acquired hematologic diseases. Some outstanding challenges in the HSCT field include the paucity of immunologically-matched donors, our inability to effectively expand hematopoeitic stem cells (HSCs) ex vivo, and the high infection risk during engraftment. Scientists are striving to develop protocols to generate, expand, and maintain HSCs ex vivo, however these are not yet ready for clinical application. Given these problems, advancing our understanding of HSC specification, regulation, and differ

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… capacities, including co‐culture with cytokines and growth factors. 11 In preclinical studies, humanized ossicles have been engineered to facilitate targeted investigation of HSC interactions with the niche in healthy and malignant hematopoietic settings. 12 Humanized ossicles are bone marrow‐like organoids …

CNS Toxicity of Immunotherapy.

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… These organoids can be derived from iPSCs and serve as advanced, patient-specific models to help create personalized treatment by allowing researchers to determine the efficacy and toxicity of a particular drug [ 65 ]. …

Bridging the gap: ferroptosis of immune cells in the tumor microenvironment.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal immunomodulatory mechanism within the tumor microenvironment (TME). Beyond its well-established role in tumor cell elimination, emerging evidence reveals that immune cell subsets exhibit distinct susceptibility to ferroptosis, with profound consequences for antitumor immunity. This review systematically delineates the dual and cell-type-specific roles of ferroptosis across innate and adaptive immune populations: while ferroptosis-mediated depletion of immunosuppress