Clinical and translational discovery最新文献

Adenocarcinomas of the stomach and gastroesophageal junction remain one of the most common malignant tumours in humans worldwide, often with a poor prognosis. Particularly in countries without upper gastrointestinal tract screening endoscopy, tumours that have been asymptomatic for a long time are only diagnosed at an advanced stage. This limits the therapeutic options. Often only palliative therapy concepts are available. Great progress has been made in the last two decades. The genetic basis of adenocarcinomas of the stomach and gastroesophageal junction has been deciphered and new targeted drugs have been developed. Cell and tissue-based predictive diagnostics are becoming increasingly important in therapy planning. Here, surgical pathology forms an important link between basic research, clinical trials, and translation into clinical application. This review article summarizes the experiences made in translational tumour research, which point to the problems of spatial and temporal intratumoral heterogeneity of adenocarcinomas of the stomach and gastroesophageal, the development and continuous re-assessment of therapeutically relevant cut-off values, resistance mechanisms, tumour microenvironment, sexual dimorphism and the pitfalls molecular tumour boards may face.

Exosomes, small extracellular vesicles secreted by cells, have emerged as pivotal players in cell-to-cell communication. Plant-derived exosomes, in particular, are gaining attention for their potential therapeutic applications in nano-medicine. These vesicles are naturally occurring nanoparticles that carry bioactive molecules such as proteins, lipids, and nucleic acids. Due to their biocompatibility, low toxicity, and ability to traverse biological barriers, plant-derived exosomes present a promising alternative to synthetic nanoparticles for drug delivery, especially in cancer and microbial infection therapy. Exosomes are secreted by almost every cell and are profusely present in all living organisms, making them excellent candidates for a large spectrum of research and applications. This paper describes the highly organized and regulated biosynthesis of exosomes and the prospects of their application in cancer therapy and treatment of microbial infections.

Patients with breast tumours that metastasise to the brain have limited treatment options and a very poor prognosis. More effective therapeutic strategies are desperately needed for this patient population. Recent evidence demonstrates that brain metastases arising from breast tumours display altered energy production that results in enhanced autophagy. Preclinical studies have shown that genetically or pharmacologically disrupting the autophagy pathway significantly decreases the brain metastatic burden, resulting in improved animal survival and increased sensitivity to lapatinib. These findings pave the way for the development of novel strategies targeting autophagy for breast cancer patients with brain metastatic disease.

Colorectal cancer (CRC) is a prevalent malignancy with a high mortality rate, necessitating innovative treatment strategies. PROTACs (PROteolysis Targeting Chimeras) represent a promising therapeutic approach by targeting and degrading oncogenic proteins via the ubiquitin-proteasome pathway. This study explores the potential of using exosomes as delivery vehicles for PROTACs to enhance treatment efficacy. Exosomes, due to their biocompatibility and inherent targeting capabilities, offer a precise method for delivering PROTACs to CRC cells, potentially overcoming challenges associated with traditional therapies such as drug resistance and off-target effects. By harnessing the advantages of both exosome-based delivery and PROTAC technology, this approach aims to improve targeted protein degradation and therapeutic outcomes in CRC treatment. Further research is required to optimize exosome engineering, ensure efficient PROTAC loading, and validate the safety and efficacy of this novel therapeutic strategy through preclinical and clinical trials.

Plant-derived exosomes (PDEs) are extracellular vesicles (EVs) occurring naturally,which have propitious applications in the development of cost-effective and fruitful cancer therapy with minimum aftereffects and ramifications. Recent advancements in research based on PDEs demonstrate their extraordinary advantages in cancer therapy. The components of PDEs exhibit accomplished cancer prevention activity and having insignificant or negligible toxicity. The conventional methods to deliver drugs to the target have various problems, several of which can be solved by using PDEs for drug delivery. The main constituents of PDEs are proteins, lipids, DNA and RNA. PDEs are believed to revolutionize cancer therapy due to their magnificent attributes, but only a few clinical trials on PDEs are in progress. The mechanisms and regulations by which PDEs execute anticancer properties are yet not completely understood. Hence, research are conducted worldwide to understand the mechanisms of action of cancer antagonist PDEs more comprehensively and perspicuously. Modified PDEs have prospect in evolution of precision medicine which can bring a new dimension in the treatment of cancer.

This study by Okuno et al. successfully identified eight exo-miRNAs through exosome-based discovery and established an exo-miRNA-based liquid biopsy assay for predicting therapeutic response in metastatic gastric cancer (mGC). Exosomes, a subpopulation of extracellular vesicles originating from endosomes, play a crucial role in this context. Liquid biopsy, analyzing blood for circulating tumor cells, extracellular vesicles, or cell-free nucleic acid, has revolutionized cancer diagnosis and monitoring. It significantly contributes to early detection, staging, and relapse detection in various cancers. Numerous studies have highlighted the clinical significance of miRNA and lncRNA within extracellular vesicles. The authors developed a response-prediction model for chemo-responsiveness in mGC patients. This study's model predicts responses robustly, demonstrating its potential efficacy in clinical practice. It offers a non-invasive and accessible method for therapeutic response prediction, crucial for precision medicine in mGC. Successful translation of these findings into clinical applications promises substantial benefits for patient care.

Exosomes, small extracellular vesicles secreted by cells, have gained attention as potential therapeutic agents due to their natural ability to deliver biomolecules and traverse biological barriers. However, their limited targeting specificity and payload capacity necessitate modifications for improved therapeutic efficacy. Click chemistry, known for its high specificity, efficiency, and mild reaction conditions, offers an innovative solution for modifying exosomal surfaces. This technique enables precise attachment of targeting ligands, imaging agents, and therapeutic molecules, enhancing the targeting, delivery, and overall effectiveness of exosome-based therapies. By addressing cancer heterogeneity, click chemistry-modified exosomes can target diverse cancer cell populations within tumors, improving treatment specificity and reducing drug resistance. The development of copper-free click chemistry, such as strain-promoted azide-alkyne cycloaddition (SPAAC), minimizes toxicity, ensuring biocompatibility and safety. As research progresses, this approach holds great promise for personalized and effective cancer treatment, paving the way for next-generation therapeutics and diagnostics.

Exosomes can be defined as extracellular vesicles, of size ranging from 30 to 150 nm, secreted from almost all kinds of cells and can also be obtained from the body fluids. Exosomes have different components depending on the type of cell from which they originate. Exosomes are capable of transporting various molecules such as proteins, nucleic acids, chemical compounds and metabolites. Experiments show that exosomes can perform important functions in cell growth, migration, differentiation, neuronal signalling, immune cell modulation. Exosomes can also be used in cancer therapy, as they can be key players in intercellular communication and signalling. Experiments have also demonstrated that exosomes are chief players in viral persistence and dissemination. The reasons why application of exosomes in targeted therapy is gaining significance are their ability to initiate cellular responses, high tolerance levels in host cells and high efficiency in penetrating other cells. Exosomes can be used both as therapeutic agents and escorts of drugs. Even though numerous studies have been performed in search of better anticancer therapies, most of them have come to a halt due to the failure in achieving a therapy best in all parameters. However, both in vitro and in vivo application of exosomes in diagnosis and therapy of tumours are prospective and has a future.

The recent article “Intravital imaging of muscle damage and response to therapy in a model of Pompe disease” by Meena et.al published in Clinical and Translational Medicine brings forth crucial insights into the utility of intravital microscopy (IVM) of muscle especially tongue muscle as a possible imaging technique that can be used for monitoring Pompe disease (PD).

PD is an autosomal recessive disease characterized by intralysosomal glycogen accumulation due to the deficiency of acid alpha-glucosidase enzyme. Based on the age of onset and clinical presentation, PD can be broadly divided into two categories: infantile-onset PD (IOPD) and late-onset PD (LOPD). Symptom onset in IOPD is usually before 12 months of age, with progressive hypertrophic cardiomyopathy, hypotonia, axial myopathy, and respiratory failure. LOPD, on the other hand, has a variable age of onset with usual clinical presentation after 12 months, primarily skeletal muscle myopathy with limb-girdle, axial, and respiratory muscle weakness. Lingual weakness resulting in dysarthria and dysphagia have been described as characteristic but commonly overlooked signs of PD.^{1, 2}

Meena et al. have introduced high-resolution IVM as a novel approach to visualize muscle damage in PD and monitor treatment responses. Utilizing a reporter mouse model expressing green fluorescent protein (GFP) fused to autophagosomal marker LC3, (noted as GFP-LC3: KO), researchers demonstrated autophagic buildup in muscle fibres, a hallmark of the disease, using this method. IVM allowed for real-time imaging of muscle tissues, revealing the effectiveness of gene therapy in reversing pathology in both limb and tongue muscles. Further, they combined the GFP signal with NAD(P)H fluorescence signal excited by two-photon microscopy, to measure mitochondrial function and subcellular metabolic activity in live animals. This non-invasive imaging technique offers insights into disease progression and treatment efficacy, presenting a promising tool for assessing emerging therapies for PD.

IVM is a powerful method for visualizing individual cells within intact tissues in near physiological conditions. It is increasingly used in preclinical studies to evaluate dynamic cellular processes underlying disease pathology and response to therapy. Moreover, in combination with the surgical implantation of imaging windows, this technique is being used to facilitate repeated imaging over a prolonged period of time in the same animal.³ It has also been utilized to understand cellular dynamics and interactions in neurodegenerative conditions such as multiple sclerosis at the lesion site in vivo.⁴ Another application would be simultaneous imaging of different cellular and intracellular structures in the muscles, such as neuromuscular junctions and sarcomeres in skeletal muscles in myotubular myopathy disease models.⁵