Frontiers of Medicine最新文献

Current guidelines encourage large studies in a diverse population to establish normal reference ranges for three-dimensional (3D) echocardiography for different ethnic groups. This study was designed to establish the normal values of 3D-left ventricular (LV) and left atrial (LA) volume and function in a nationwide, population-based cohort of healthy Han Chinese adults. A total of 1117 healthy volunteers aged 18-89 years were enrolled from 28 collaborating laboratories in China. Two sets of 3D echocardiographic instruments were used, and full-volume echocardiographic images were recorded and transmitted to a core laboratory for image analysis with a vendor-independent off-line workstation. Finally, 866 volunteers (mean age of 48.4 years, 402 men) were qualified for final analysis. Most parameters exhibited substantial differences between different sex and age groups, even after indexation by body surface area. The normal ranges of 3D-LV and 3D-LA volume and function differed from those recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines, presented by the World Alliance Societies of Echocardiography (WASE) study, and from the 2D values in the EMINCA study. The normal reference values of 3D echocardiography-derived LV and LA volume and function were established for the first time in healthy Han Chinese adults. Normal ranges of 3D-LV and 3D-LA echocardiographic measurements stratified with sex, age, and race should be recommended for clinical applications.

Epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling, and RNA modifications complicate gene regulation and heredity and profoundly impact various physiological and pathological processes. In recent years, accumulating evidence indicates that epigenetics is vulnerable to environmental changes and regulates the growth, development, and diseases of individuals by affecting chromatin activity and regulating gene expression. Environmental exposure or induced epigenetic changes can regulate the state of development and lead to developmental disorders, aging, cardiovascular disease, Alzheimer's disease, cancers, and so on. However, epigenetic modifications are reversible. The use of specific epigenetic inhibitors targeting epigenetic changes in response to environmental exposure is useful in disease therapy. Here, we provide an overview of the role of epigenetics in various diseases. Furthermore, we summarize the mechanism of epigenetic alterations induced by different environmental exposures, the influence of different environmental exposures, and the crosstalk between environmental variation epigenetics, and genes that are implicated in the body's health. However, the interaction of multiple factors and epigenetics in regulating the initiation and progression of various diseases complicates clinical treatments. We discuss some commonly used epigenetic drugs targeting epigenetic modifications and methods to prevent or relieve various diseases regulated by environmental exposure and epigenetics through diet.

Antibody-drug conjugates (ADCs) are biologically targeted drugs composed of antibodies and cytotoxic drugs connected by linkers. These innovative compounds enable precise drug delivery to tumor cells, minimizing harm to normal tissues and offering excellent prospects for cancer treatment. However, monoclonal antibody-based ADCs still present challenges, especially in terms of balancing efficacy and safety. Bispecific antibodies are alternatives to monoclonal antibodies and exhibit superior internalization and selectivity, producing ADCs with increased safety and therapeutic efficacy. In this review, we present available evidence and future prospects regarding the use of bispecific ADCs for cancer treatment, including a comprehensive overview of bispecific ADCs that are currently in clinical trials. We offer insights into the future development of bispecific ADCs to provide novel strategies for cancer treatment.

Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.

RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N⁶-methyladenosine (m⁶A), N¹-methyladenosine (m¹A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), N⁶,2'-O-dimethyladenosine (m⁶A_m), N⁴-acetylcytidine (ac⁴C), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially m⁶A) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.

Human cells contain two types of adenosine deaminases (ADA) each with unique properties: ADA1, which is present in all cells where it modulates intracellular functions and extracellular signaling, and ADA2, which is secreted by immune cells. The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1. ADA2 has distinct characteristics, such as low adenosine affinity, heparin-binding ability, and putative lysosomal entry. Here, we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9 (TLR9) agonists, specifically CpG oligodeoxynucleotides (CpG ODNs). We show that interferon-alpha (IFN-α) is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells (pDCs). Additionally, the pretreatment of pDCs with RNA further stimulates IFN-α secretion by pDCs after activation with CpG ODNs. Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs. In conclusion, decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-α secretion from pDCs, improving immune responses against intracellular infections and cancer.

To investigate the epidemiological characteristics of anemia of varying severity among women of reproductive age, we conducted a nationwide, cross-sectional study between January 1, 2019 and December 31, 2019, including 4 184 547 nonpregnant women aged 18-49 years from all 31 provinces in the mainland of China. Anemia was defined as having hemoglobin concentration < 120.0 g/L and categorized as mild, moderate, and severe. Multivariate logistic models with cluster effect were used to explore the association of anemia and metabolic risk factors. The standardized prevalence of anemia and moderate and worse anemia among women of reproductive age in China was 15.8% (95% CI 15.1%-16.6%) and 6.6% (6.3%-7.0%), respectively. The prevalence of anemia and the proportion of moderate and worse anemia significantly increased with age. We also observed great geographic variations in the prevalence of anemia, with a high likelihood in south, central, and northwest China. Moderate and/or severe anemia was positively associated with overweight and obesity, diabetes, and impaired kidney function. In conclusion, anemia remains a significant challenge for women of reproductive age in China. Geographic variations and metabolic risk factors should be considered in the comprehensive and targeting strategy for anemia reduction.

Regulatory T cells (Tregs) suppress immune responses and inflammation. Here, we described the distinct nonimmunological role of Tregs in fracture healing. The recruitment from the circulation pool, peripheral induction, and local expansion rapidly enriched Tregs in the injured bone. The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs. Punctual depletion of Tregs compromised the fracture healing process, which leads to increased bone nonunion. In addition, bone callus Tregs showed unique T-cell receptor repertoires. Amphiregulin was the most overexpressed protein in bone callus Tregs, and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways. The results of loss- and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction. Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells. Our findings indicate the distinct and nonredundant role of Tregs in fracture healing, which will provide a new therapeutic target and strategy in the clinical treatment of fractures.

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N⁶-methyladenosine (m⁶A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m⁶A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-β (TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.