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.

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

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.

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]

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

The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated trimethylation of histone H3 lysine 27 (H3K27me3) regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system. Here, we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line. The results showed that a lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and increased dendritic spine density. Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis. In particular, the gene encoding p21-activated kinase 3 (Pak3) was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density. Finally, the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development, and has long-lasting effects on cognitive function in adult mice.
Animals ; Mice ; Enhancer of Zeste Homolog 2 Protein/metabolism* ; Histone Methyltransferases/metabolism* ; Histones/genetics* ; Morphogenesis ; Neuronal Plasticity ; Neurons/metabolism*

Radical gastrectomy with D2 lymphadenectomy has been widely performed as the standard surgery for patients with gastric cancer in major medical centers in China and abroad. However, the exact extent of lymph node dissection is still controversial. In the latest version of the Japanese Gastric Cancer Treatment Guidelines, No. 14v lymph nodes (along the root of the superior mesenteric vein) are again defined as loco-regional lymph nodes, and it is clarified that distal gastric cancer presenting with infra-pyloric regional lymph node (No.6) metastasis is recommended for D2+ superior mesenteric vein (No. 14v) lymph node dissection. To explore the relevance and clinical significance of No.6 and No.14v lymphadenectomy in radical gastric cancer surgery, a review of the national and international literature revealed that No.6 lymph node metastasis was associated with No.14v lymph node metastasis, that No.6 lymph node status was a valid predictor of No.14v lymph node negative status and false negative rate, and that for gastric cancer patients with No. 14v lymph node negative and No.6 lymph node positive, the dissection of No.14v lymph node may also have some significance. The addition of No. 14v lymph node dissection in radical gastrectomy is safe, but it is more important to distinguish the patients who can benefit from it. Professor Liang Han of Tianjin Medical University Cancer Hospital is currently leading a multicenter, large-sample, prospective clinical trial (NCT02272894) in China, which is expected to provide higher level evidence for the clinical significance of lymph node dissection in No.14v.
Humans ; Stomach Neoplasms/pathology* ; Lymphatic Metastasis/pathology* ; Prospective Studies ; Retrospective Studies ; Lymph Nodes/pathology* ; Lymph Node Excision ; Gastrectomy ; Multicenter Studies as Topic