The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity, which has implications for understanding the cardioprotective effects of HDIs.

Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G_q complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Chinese medicine has been used for centuries to treat a range of health conditions.This history has produced a wealth of classical literature,case studies and clinical research data detailing its use and effectiveness.However,high-quality and conclusive evidence that meets modern requirements for clinical decision support is lacking.This evidence gap limits the integration of Chinese medicine with contemporary medicine,which in turn limits global access and acceptance of Chinese medicine as a form of safe and effective health care.Over the past 20 years,researchers and organisations around the world,including the World Health Organization(WHO)and United Nations,have worked to support the integration of traditional medicines,such as Chinese medicine,with conventional medicines to improve global health care.This paper provides an overview of Chinese medicine studies published in the top four general medical journals(BMJ,JAMA,Lancet and New England Journal of Medicine)from February 2005 to February 2024 in the past 20 years to highlight the progress in the development of this evidence base.It also highlights key actions taken to promote evidence-based clinical Chinese medicine,including product and practitioner regulation,formalising education standards,and international collaborations.Research conducted at the China-Australia International Research Centre for Chinese Medicine demonstrates the benefits of such a collaboration.Through development of its unique and inclusive'whole-evidence'approach,plus clinical studies and systematic reviews,the Centre has significantly contributed to the evidence base for clinical Chinese medicine.In addition,its high-impact papers and groundbreaking monographs have been cited in international conventional medicine guidelines.While progress has certainly been made during the past 20 years to build a stronger evidence base for clinical Chinese medicine,there is still a considerable gap that limits its integration with conventional medicine.Future funding and research are needed to continue this work and achieve to safe,effective and accessible traditional medicine as part of the WHO's Universal Health Coverage strategy.

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Humans ; Lymph Nodes/pathology* ; Lymph Node Excision ; Neoplasms/pathology* ; Dissection

Meropenem is one of the most widely used special-grade antimicrobial agents in the treatment of neonatal sepsis.However,its irrational use has led to an increasingly severe problem of bacterial multidrug resistance.The guideline was developed following standardized methods and procedures,and provides 12 recommendations specifically addressing 9 clinical issues.The recommendations cover various aspects of meropenem use in neonates,including timing of administration,recommended dosage,extended infusion,monitoring and assessment,antimicrobial adjustment strategies,treatment duration,and treatment strategies for carbapenem-resistant Enterobacteriaceae infections.The aim of the guideline is to provide evidence-based recommendations and guidance for the rational use of meropenem in neonates with sepsis.[Chinese Journal of Contemporary Pediatrics,2024,26(2):107-117]

OBJECTIVE: To construct a schistosomiasis transmission risk assessment system in Wuhan City and preliminary evaluate its application effect, so as to promote the rational allocation of schistosomiasis control resources and accelerate the progress towards schistosomiasis elimination. METHODS: The schistosomiasis risk assessment indicators were collected through referring schistosomiasis surveillance data of Wuhan City from 2014 to 2020, literature review and expert interviews. Indicators within each criterion and sub-criterion were screened using the Delphi method, and a hierarchical structure model was created based on analytic hierarchy process. Quantitative assignment of each indicator was conducted according to relative importance, and the weight and combination weight of each criterion were calculated in each analytic hierarchy framework to create a schistosomiasis transmission risk assessment system, which was used for the schistosomiasis transmission risk assessment in 12 national schistosomiasis surveillance sites in Wuhan City. RESULTS: A three-level schistosomiasis transmission risk assessment system was preliminarily constructed, which included a target layer, 5 criterion layers and 21 sub-criterion layers. Of all indicators in the criterion layer, transmission route had the highest weight (0.433), followed by source of Schistosoma japonicum infection (0.294); and among all indicators in the sub-criterion layer, S. japonicum infection in Oncomelania hupensis and sentinel mice had the highest combination weight (0.125), followed by prevalence of S. japonicum infection in humans (0.091) and bovines (0.053), snail control by chemical treatment (0.049), positive rate of inquiry examinations (0.048), allocation of schistosomiasis control professionals (0.045), and areas of submerged snail-infested settings (0.041). Of the 12 national schistosomiasis surveillance sites in Wuhan City, there were 5 sites with weights of > 0.8, 4 sites with weights of 0.6 to 0.8, and 3 sites with weights of < 0.6 in 2020. CONCLUSIONS A schistosomiasis transmission risk assessment system has been constructed based on analytic hierarchy process in Wuhan City, which may provide a evidence-based basis for health resource allocation and decision-making for schistosomiasis control.
Animals ; Humans ; Cattle ; Mice ; Analytic Hierarchy Process ; Schistosomiasis/prevention & control* ; Schistosomiasis japonica/epidemiology* ; Snails ; Risk Assessment

OBJECTIVE: To investigate the spatial distribution characteristics of the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody, and to examine the correlation between the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province in 2020, so as to provide insights into advanced schistosomiais control in the province. METHODS: The epidemiological data of schistosomiasis in Hunan Province in 2020 were collected, including number of permanent residents in survey villages, number of advanced schistosomiasis patients, number of residents receiving serological tests and number of residents seropositive for anti-Schistosoma antibody, and the prevalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody were descriptively analyzed. Village-based spatial distribution characteristics of prevalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody were identified in Hunan Province in 2020, and the correlation between the revalence advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody was examined using Spearman correlation analysis. RESULTS: The prevalence of advanced schistosomiasis was 0 to 2.72% and the seroprevalence of anti-Schistosoma antibody was 0 to 20.25% in 1 153 schistosomiasis-endemic villages in Hunan Province in 2020. Spatial clusters were identified in both the prevalence of advanced schistosomiasis (global Moran's I = 0.416, P < 0.01) and the seroprevalence of anti-Schistosoma antibody (global Moran's I = 0.711, P < 0.01) in Hunan Province. Local spatial autocorrelation analysis identified 98 schistosomiasis-endemic villages with high-high clusters of the prevalence of advanced schistosomiasis, 134 endemic villages with high-high clusters of the seroprevalence of anti-Schistosoma antibody and 36 endemic villages with high-high clusters of both the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province. In addition, spearman correlation analysis showed a positive correlation between the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody (r_s = 0.235, P < 0.05). CONCLUSIONS There were spatial clusters of the prevalence of advanced schistosomiasis and seroprevalence of anti-Schistosoma antibody in Hunan Province in 2020, which were predominantly located in areas neighboring the Dongting Lake. These clusters should be given a high priority in the schistosomiasis control programs.
Animals ; Humans ; Prevalence ; Seroepidemiologic Studies ; Schistosomiasis/epidemiology* ; Schistosoma ; Spatial Analysis ; Antibodies, Helminth ; China/epidemiology*

This article reports two cases of children with B-cell acute lymphoblastic leukemia (B-ALL) complicated by invasive fungal disease (IFD) who received bridging treatment using blinatumomab. Case 1 was a 4-month-old female infant who experienced recurrent high fever and limb weakness during chemotherapy. Blood culture was negative, and next-generation sequencing (NGS) of peripheral blood, bronchoalveolar lavage fluid, and cerebrospinal fluid were all negative. Chest CT and cranial MRI revealed obvious infection foci. Case 2 was a 2-year-old male patient who experienced recurrent high fever with multiple inflammatory masses during chemotherapy. Candida tropicalis was detected in peripheral blood and abscess fluid using NGS, while blood culture and imaging examinations showed no obvious abnormalities. After antifungal and blinatumomab therapy, both cases showed significant improvement in symptoms, signs, and imaging, and B-ALL remained in continuous remission. The report indicates that bridging treatment with blinatumomab in children with B-ALL complicated by IFD can rebuild the immune system and control the underlying disease in the presence of immunosuppression and severe fungal infection.
Child, Preschool ; Female ; Humans ; Infant ; Male ; Antibodies, Bispecific/therapeutic use* ; Invasive Fungal Infections/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Remission Induction