Clinical and translational discovery最新文献

The world is transitioning into an aging society, a phenomenon that escalates the risk of age-related diseases, posing a significant threat to human health. Addressing how to delay aging or achieve healthy aging has become an urgent and pivotal issue. Presently, diverse anti-aging drugs are under development and entering clinical validation stages. However, the absence of specific aging biomarkers has hindered the identification of corresponding targets for diagnosing and treating aging and age-related diseases. Aptamer, a novel molecular recognition tool, has found broad application in diagnosing and treating various diseases. Additionally, cell-based selection holds the potential to identify unidentified molecules that could serve as biomarkers for diseases. Recent years have seen a surge in attention towards aging and age-related diseases, with the application of aptamer in this domain rapidly advancing. Consequently, this review will provide a concise overview of the aging, with a focus on the utilisation of aptamer in aging and age-related diseases.

Exportin 1 (XPO1), formerly known as chromosomal region maintenance 1, belongs to the karyopherin family of proteins that are responsible for the import and export of macromolecules through the nuclear pore complex. XPO1 is the sole exporter of hundreds of cargoes including several RNA species and key proteins such as tumor suppressors and cell cycle proteins. Despite its essential and housekeeping function in normal cells, in their review, Lai et al note that upregulation of XPO1 is associated with a wide variety of cancers, including but not limited to colorectal cancer, osteosarcoma, lung cancer, gastric cancer, ovarian cancer, glioma, pancreatic cancer and oesophagal cancer.¹ In non-cancer cells, XPO1 shuttles RNA and proteins from the nucleus to the cytoplasm while also regulating mitosis during interphase. After performing its export function, XPO1 returns to the nucleus to repeat the process, making it a vital part of sustaining normal cellular physiological functions (Figure 1). However, increased expression of XPO1 leads to increased export and imbalance of nucleo-cytoplasmic transport.

Though the exact mechanisms regulating the overexpression of XPO1 in solid cancers are not yet completely understood, chromosome 2p amplification accounts for this in a subset of hematologic neoplasms. Another means of dysregulation of XPO1 that is found in hematologic malignancies is the missense mutation XPO1 E517K, which has been linked to facilitating the growth of malignant B cells in chronic lymphocytic leukaemia and Hodgkin lymphoma.² Clinical trials of XPO1 inhibitors in hematologic malignancies have shown response rates ranging from 26% to 45% in those with advanced multiple myeloma, and a 28% response rate in those with relapsed or refractory diffuse large B cell lymphoma.^3-5 Due to this success, selinexor, the first-in-class XPO1 inhibitor has been Food and Drug Administration-approved for these two indications.

This leads to the big question—can targeting XPO1 be successful in solid tumours? According to Lai et al, while promising, it comes with considerable challenges. The first XPO1 inhibitors were natural products that irreversibly bound XPO1 and caused severe toxic side effects, leading to the discontinuation of their development as anticancer therapies. In response, small molecule XPO1 inhibitors were designed to be slowly reversible and are more tolerable in patients. Preclinical data suggests that selinexor is active in tumours with previous drug resistance in vitro and in vivo and induces apoptosis in many cancerous cell lines including but not limited to prostate, bladder, and renal cell carcinoma. While reducing the tumour is the main goal for these preclinical studies, there are questions of dose dependency for cancers like sarcomas, which may not be feasible for humans in clinical trials.⁶ However, that is not to di

Conventional cancer therapies are often limited by inherent and acquired drug resistance, non-specific toxicity, and suboptimal drug delivery. Bacterial extracellular vesicles (BEVs), including outer membrane vesicles and membrane vesicles, present a novel therapeutic strategy for cancer treatment. BEVs were found in both Gram-negative and Gram-positive bacteria. This article provides a classified investigation of the therapeutic potential of BEVs in cancer treatment. We discuss the molecular mechanisms underlying their observed anti-tumor effects, including the induction of apoptosis in cancer cells, suppression of angiogenesis within the tumor microenvironment, and stimulation of both innate and adaptive anti-tumor immune responses. Moreover, BEVs being biocompatible opens avenue for targeted drug delivery systems, potentially improving the therapeutic index of conventional chemotherapeutics. Challenges to clinical translation, such as BEV heterogeneity and potential immunogenicity, are addressed. We also explore future directions for research and development, comprehensively highlighting how BEVs transform the landscape of precision oncology and cancer treatment, eventually improving patient outcomes.

Exosomes are signalling molecules related to cell-to-cell communication. Based on sources (plants, stem cells, and immune cells derived exosomes) it offers promising therapeutic activity against cancer. Plant-derived exosomes (PDEs) are natural extracellular vesicles (EVs) that are potent to provide organic precision nanomedicine to cancer therapeutics including targeted drug delivery. PDEs are gaining attention due to their safety and efficacy. There are plenty of different sources of PDEs in nature. This article explores various plants such as carrots, ginger, lemons, cabbages, blueberries, oranges, tomatoes, grapefruits, and tea leaves, which provide exosomes with distinct therapeutic properties, including anti-inflammatory, antioxidant, and anticancer activities. PDEs exhibit significant potential in drug delivery. Ongoing research and clinical trials predict that PDEs will become effective, and affordable solutions for cancer treatment.

Milk exosomes, extracellular nanovesicles that are naturally present in milk, have gained significant attention in cancer research for their potential to revolutionize cancer treatment strategies. They possess a specific set of characteristics that make them promising nanoscale vehicles for targeted drug delivery systems. Their inherent biocompatibility, coupled with their ability to effectively encapsulate and transport therapeutic agents directly into tumor cells, suggests the possibility of developing novel cancer therapies, potentially minimizing side effects associated with conventional therapies. However, recent studies have shown that milk exosomes have a dual nature, which is not entirely positive. Although they show potential in delivering anticancer therapeutics, evidence suggests they may also, under certain conditions, contribute to cancer progression. This paradoxical nature necessitates a better understanding of how they interact and work in different stages of cancer. Further investigation is crucial to understand the factors influencing their behaviour and to develop strategies that can maximize their therapeutic prospects while mitigating potential risks associated with their use in cancer treatment.

Chronic airway obstructive pulmonary disease (COPD) is a preventable and curable disease characterised by persistent airflow limitation. It is characterised by chronic bronchitis and/or emphysema, and its aetiology is related to various factors such as smoking and infectious factors, and so forth. The pathogenesis is complex and prone to frequent exacerbations, and the prognosis of acute exacerbations of COPD is often poor. As a crucial component of the innate immune system, lung macrophages significantly influence the onset and progression of COPD. When macrophage mitochondria become dysfunctional, many macrophage functions (e.g., phagocytosis, cytokine secretion, chemotaxis, etc.) change. The aim of this paper is to describe the three major pathological features of COPD (oxidative stress imbalance, macrophage polarisation and mitochondrial membrane potential [MMP] production and mitochondrial autophagy), to describe in detail the mechanism of mitochondrial autophagy pathway and its association with oxidative stress and macrophage polarisation and to emphasise the role of macrophage mitochondrial reactive oxygen species (mROS) in COPD, with the aim of providing ideas and directions for subsequent studies.

CDK12 is among the most frequently mutated cyclin-dependent kinases (CDKs) in various cancers, including prostate, ovarian, breast, esophageal, bladder, and colon cancers.¹ Specifically, biallelic aberrations of CDK12 occur in 3%–7% of metastatic castration-resistant prostate cancer (mCRPC) cases and correlate with poor prognosis.¹ One of the most well-studied functions of CDK12 is its orchestration of transcription initiation and elongation through cyclin K-dependent Ser2 phosphorylation of RNA polymerase II,² and therefore CDK12 is important in regulating the expression of long genes or genes with high exon numbers, especially DNA damage response (DDR)-related genes such as BRCA1, ATR, FANCI, and FANCD21.³ As a result, CDK12-deficient cancers are commonly characterized by focal tandem duplications (FTDs) and various features of genome instability.^{4, 5} Because FTDs often generate a large amount of neoantigens, it has been suggested that CDK12-deficient tumours may be more sensitive to immunotherapy.⁵ However, studies of immune checkpoint blockade therapy have shown only limited effects in mCRPC patients harbouring CDK12 mutations.⁶ Likewise, despite the observed sensitization of CDK12-deficient ovarian cancer cells to PARP inhibitors (PARPi) due to impaired DDR functionality,⁷ clinical trials of PARPi have produced unsatisfactory results in prostate cancer patients with CDK12 mutations.⁶ Therefore, there is an urgent need to identify exploitable vulnerabilities in CDK12-deficient prostate cancer.

In a recent study, Zhang et al. investigated the impact of CDK12 deficiency on cell metabolism and tumour progression in prostate cancer.⁸ By analyzing public datasets, they confirmed an association between CDK12 deficiency and poor prognosis in mCRPC, while noting higher levels of CDK12 mutations in Chinese patients (15.4%–27.2%) than in the global populations (4.7%). To further delineate how CDK12 deficiency promotes mCRPC, they generated CDK12-knockout prostate cancer cell lines using CRISPR-Cas9 technology and conducted metabolomic and transcriptomic analyses. The resulting data showed that CDK12 deficiency reprogrammed energy metabolisms in prostate cancer cells; specifically, CDK12 knockout cells exhibited higher levels of metabolites related to glycolysis, glutaminolysis, and the tricarboxylic acid cycle, but lower levels of metabolites related to β-oxidation. Further, the associated RNA-seq data showed enrichment of mitochondrial electron transport chain (ETC) and oxidative phosphorylation-related pathways in CDK12-deficient prostate cancers, suggesting that CD