Annals of translational medicine最新文献

Acute lymphocytic leukemia (ALL) is an aggressive hematological malignancy of highly proliferative lymphoblasts. ALL is the most common cancer in children, and is typically treated with combination chemotherapy. The 5-year survival of ALL improved significantly in recent decades with this treatment approach. However, certain age groups (below 2 and over 10 years of age) have much worse prognosis, and over 50% of patients with ALL experience long-term side effects proportional to the dosage of anticancer drugs. Therefore, different treatment strategies are required to improve survival in ALL and to reduce side effects of chemotherapy. Since epigenetic modifications are dominantly reversible, "epidrugs" (drugs targeting epigenetic markers) are considered for feasibility in the treatment of ALL as epigenetic modifications, and acetylation of histones was demonstrated to play a critical role in the pathogenesis of ALL. Histone deacetylases (HDACs) have been shown to be differentially expressed in several hematological malignancies, including ALL. HDAC inhibitors (HDACis) have been shown to express selective toxicity for ALL cells, but they showed limited efficacy and higher than expected toxicity in mouse models or clinical trials in ALL. The aim of this review is to examine the role of the microbiota and microbial metabolites in the mechanisms of HDAC functions, and explore the utilization of the microbiota and microbial metabolites in improving the efficacy of HDACi in ALL. HDAC regulators and natural HDACi are depleted in ALL due to microbiota change leading to a decrease in butyrate and propionate, and HDACi treatment is not effective in ALL due to their short half-life. We propose that HDACi released by the microbiota may be necessary in HDAC regulation and this process is impaired in ALL. Furthermore, the review will also consider the role of restoration of the microbiota or supplementation of natural HDACi in potentially restoring HDAC and HDACi functions.

Arthritis, defined as a chronic inflammation often accompanied by swelling of one or more joints, encompasses more than 100 conditions that affect the joints, tissues around them as well as other connective tissues. This condition causes severe discomfort compromising the quality of life drastically, and thereby inflicts severe financial and social impact on the people affected. The incidence rate of arthritis is increasing all around the globe including the United States every year. In general, osteoarthritis (OA) affects more people in comparison to rheumatoid arthritis (RA). In the USA itself, more than 14 million people are affected by OA in comparison to 1.4 million people suffering from RA. In both conditions, elevated levels of proinflammatory cytokines have been recorded, this incidence generally precedes the cartilage degradation observed in the patients. The use of mesenchymal stem cells (MSCs) has proven to be a safe and efficient therapeutic option for treating many inflammation-rooted pathological conditions. Evidence suggests that MSCs down-regulate the effects of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1B, IL-2, and IL-17, and help restore the functions of immune cells. In addition, these cells promote the polarization of M2 phenotype macrophages, thus contributing to the suppression of the inflammatory process and consequentially to cartilage regeneration. Preclinical and clinical trials have proven the safety and effectiveness of this therapy, supported by the fact that these do not provoke any host immune response, and their influence on the cytokine profiles. An attempt to survey the results of stem cell therapy for treating arthritis has been carried out in this review.

There is a growing demand for lung parenchymal-sparing localized therapies due to the rising incidence of multifocal lung cancers and the growing number of patients who cannot undergo surgery. Lung cancer screening has led to the discovery of more pre-malignant or early-stage lung cancers, and the focus has shifted from treatment to prevention. Transbronchial therapy is an important tool in the local treatment of lung cancers, with microwave ablation showing promise based on early and mid-term results. To improve the precision and efficiency of transbronchial ablation, adjuncts such as mobile C-arm platforms, software to correct for computed tomography (CT)-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy are useful. Other forms of energy such as steam vapor therapy, pulsed electric field, and photodynamic therapy are being intensively investigated. In addition, the future of transbronchial therapies may involve the intratumoral injection of novel agents such as immunomodulating agents, gene therapies, and chimeric antigen receptor T cells. Extensive pre-clinical and some clinical research has shown the synergistic abscopal effect of combination of these agents with ablation. This article aims to provide the latest updates on these technologies and explore their most likely future applications.

Background and objective: Pancreatic ductal adenocarcinoma (PDAC) is 3^rd most lethal cancer in the USA leading to a median survival of six months and less than 5% 5-year overall survival (OS). As the only potentially curative treatment, surgical resection is not suitable for up to 90% of the patients with PDAC due to late diagnosis. Highly fibrotic PDAC with an immunosuppressive tumor microenvironment restricts cytotoxic T lymphocyte (CTL) infiltration and functions causing limited success with systemic therapies like dendritic cell (DC)-based immunotherapy. In this study, we investigated the potential benefits of irreversible electroporation (IRE) ablation therapy in combination with DC vaccine therapy against PDAC.

Methods: We performed a literature search to identify studies focused on DC vaccine therapy and IRE ablation to boost therapeutic response against PDAC indexed in PubMed, Web of Science, and Scopus until February 20^th, 2023.

Key content and findings: IRE ablation destructs tumor structure while preserving extracellular matrix and blood vessels facilitating local inflammation. The studies demonstrated IRE ablation reduces tumor fibrosis and promotes CTL tumor infiltration to PDAC tumors in addition to boosting immune response in rodent models. The administration of the DC vaccine following IRE ablation synergistically enhances therapeutic response and extends OS rates compared to the use of DC vaccination or IRE alone. Moreover, the implementation of data-driven approaches further allows dynamic and longitudinal monitoring of therapeutic response and OS following IRE plus DC vaccine immunoablation.

Conclusions: The combination of IRE ablation and DC vaccine immunotherapy is a potent strategy to enhance the therapeutic outcomes in patients with PDAC.

Background: Circulating tumor DNA (ctDNA) analysis has been applied in cancer diagnostics including lung cancer. Specifically for the early detection purpose, various modalities of ctDNA analysis have demonstrated their potentials. Such analyses have showed diverse performance across different studies.

Methods: We performed a systematic review of original studies published before 1 January 2023. Studies that evaluated ctDNA alone and in combination with other biomarkers for early detection of lung cancer were included.

Results: The systematic review analysis included 56 original studies that were aimed for early detection of lung cancer. There were 39 studies for lung cancer only and 17 for pan-cancer early detection. Cancer and control cases included were heterogenous across studies. Different molecular features of ctDNA have been evaluated, including 7 studies on cell-free DNA concentration, 17 on mutation, 29 on methylation, 5 on hydroxymethylation and 8 on fragmentation patterns. Among these 56 studies, 17 have utilised different combinations of the above-mentioned ctDNA features and/or circulation protein markers. For all the modalities, lower sensitivities were reported for the detection of early-stage cancer.

Conclusions: The systematic review suggested the clinical utility of ctDNA analysis for early detection of lung cancer, alone or in combination with other biomarkers. Future validation with standardised testing protocols would help integration into clinical care.

Background and objective: Although millions of patients receive neuromuscular blocking agents (NMBAs) each year as part of an anesthetic, residual neuromuscular blockade (NMB) remains a too-frequent occurrence and its adverse consequences continue to negatively impact patient outcomes. The goal of this manuscript is to provide clinicians with the information they need to decrease the incidence of residual NMB.

Methods: Published literature was reviewed and incorporated into the narrative as appropriate. Search terms for articles included nondepolarizing NMBAs, residual NMB, monitoring depth of NMB, qualitative monitoring, quantitative monitoring, reversal agents, sugammadex, and anticholinesterases.

Key content and findings: This review will define what is currently considered adequate recovery of neuromuscular function, discuss and compare the different modalities to determine the depth of NMB, discuss the currently available NMBAs-including their durations of action and dosing, describe the incidence and complications associated with residual NMB, and discuss reversal of nondepolarizing NMB with neostigmine or sugammadex. Nondepolarizing NMBAs are commonly used as part of a general anesthetic. Understanding the pharmacology of the neuromuscular blocking and reversal agent, in combination with quantitative monitoring of depth of NMB is essential to avoid residual paralysis.

Conclusions: Quantitative monitoring and dosing of either neostigmine or sugammadex based on the results of monitoring is essential to eliminate residual NMB associated with the use of nondepolarizing NMBAs.

[This corrects the article DOI: 10.21037/atm-23-762.].