HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

OBJECTIVES: To investigate the synergistic mechanism of the traditional Chinese medicine Rosa laevigata Michx. (RLM) for treatment of pulmonary arterial hypertension (PAH). METHODS: Network pharmacological analysis was carried out to screen the active ingredients of RLM and PAH disease targets and construct the "component-target-disease" interaction network, followed by gene enrichment analysis and molecular docking studies. In the cell experiments, primary cultures of rat pulmonary arterial smooth muscle cells were exposed to hypoxia for 24 h and treated with solvent or 100, 200 and 300 mg/mL RLM, and the changes in cell proliferation were detected using Western blotting for PCNA and immunofluorescence staining. In the animal experiment, male SD rats were randomized into 5 control group, monocrotaline (MCT) solvent group, and MCT with RLM (100, 200 and 300 mg/mL) treatment groups. HE staining and immunofluorescence staining were used to observe histopathological changes in the pulmonary blood vessels of the rats. RESULTS: Seven core active ingredients (including β-sitosterol and kaempferol) in RLM and 39 key disease targets were identified, and molecular docking showed that SRC was a high-affinity target. KEGG enrichment analysis showed that the differential genes were significantly enriched in calcium signaling and PI3K-AKT pathways. In rat pulmonary arterial smooth muscle cells, hypoxic exposure significantly up-regulated cellular expression of PCNA and phosphorylation levels of Src and AKT1, which were obviously lowered by RLM treatment. In RLM-treated rat models, the mean pulmonary artery pressure and right ventricular hypertrophy index (Fulton index) were significantly reduced, the tricuspid annular plane systolic excursion (TAPSE) was improved, and pulmonary vascular wall thickening and fibrosis were obviously ameliorated. CONCLUSIONS RLM inhibits pulmonary arterial smooth muscle cell proliferation in rat models of hypertension possibly by regulating the Src-AKT1 axis, suggesting the potential of RLM as a new natural drug for treatment of pulmonary hypertension.
Animals ; Cell Proliferation/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Rats, Sprague-Dawley ; Pulmonary Artery/cytology* ; Male ; Rats ; Myocytes, Smooth Muscle/cytology* ; Hypertension, Pulmonary/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Signal Transduction/drug effects* ; Muscle, Smooth, Vascular/cytology* ; src-Family Kinases/metabolism* ; Cells, Cultured

This case report described an 80-year-old male patient with Parkinson disease(PD)complicated with myasthenia gravis(MG).Six years ago,the patient was diagnosed with PD based on the motor symptoms including bradykinesia and static tremor and treated with levodopa-benserazide and piribedil sustained-release tablets.He was admitted to the hospital due to left eyelid ptosis one month ago.The result of Neostigmine test was positive and anti-acetylcholine receptor(AChR)antibodies of serum was positive,which met the diagnostic criteria for myasthenia gravis(MG).The symptom of MG improved significantly after treatment with glucocorticoid and pyridostigmine but the PD symptoms worsened.The symptoms of PD were improved after withdrawal of pyridostigmine and use of the levodopa-benserazide and his condition maintained stable at 3 years of follow-up.The PD complicated with MG was fairly rare.We also reviewed the literature on the possible comorbidity mechanism and treatment strategies to improve the comprehensive understanding and ability of diagnosis and treatment of clinicians.

Female ; Humans ; Pregnancy ; Septate Uterus ; Uterus/surgery* ; Hysteroscopy/methods* ; Estrogens ; Tissue Adhesions/surgery* ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic

While neuroblastoma accounts for 15% of childhood tumor-related deaths, treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs. Currently, maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical, especially high-risk patients. However, differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy, unclear mechanism, and few drug options. Through compound library screening, we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691. The protein kinase B (AKT) pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation, yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear. Here, we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines. Further evidence including neurites outgrowth, cell cycle arrest, and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691. Meanwhile, with the introduction of other AKT inhibitors, it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation. Furthermore, silencing AKT was found to have the effect of inducing neuroblastoma differentiation. Finally, confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo, suggesting that Hu7691 is a potential molecule against neuroblastoma. Through this study, we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.

OBJECTIVE To improve the quality standard for Jubei mixture . METHODS The chemical reaction of trinitrophenol and hydrocyanic acid was used to identify Armeniacae Amarum solution . Platycodon grandiflorus ，Fritillaria thunbergii，Scutellaria baicalensis ，the leaves of Eriobotrya japonica and Glycyrrhiza uralensis in Jubei mixture were identified by thin-layer chromatography （TLC）. High-performance liquid chromatography was used to simultaneously determine the contents of four active components ，such as amygdalin ，baicalin，wogonoside and monoammonium glycyrrhizinate in Jubei mixture . RESULTS Trinitrophenol test paper showed brick red . TLC spots of five medicinal materials were clear ，without interference from negative control . The linear ranges of amygdalin ，baicalin，wogonoside and monoammonium glycyrrhizinate were 0.066 8-1.335 5 μg（R2＝0.9994），0.189 8-3.796 9 μg（R2＝0.999 9），0.062 6-1.251 3 μg（R2＝0.999 9），0.041 8-0.835 5 μg（R2＝0.999 8）， respectively. RSDs of precision ，repeatability and stability tests were all lower than 2%. The average recoveries were 98.2%， 99.5%，98.3%，99.6%，and RSDs were 0.7%，1.6%，1.5%，1.1%（n＝6）. The contents of 15 batches of samples were different ， and the content of sample from company A was generally lower than those from companies B and C . CONCLUSIONS The standard established can reflect the inherent quality of Jubei mixture well .

BACKGROUND: To determine the prevalence and prognostic impact of hepatopulmonary syndrome (HPS) in patients with unresectable hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). METHODS: Fifty-four patients with unresectable HCC undergoing TACE between December 2014 and December 2015 were prospectively screened for HPS and were followed up for a maximum of 2 years or until the end of this prospective study. RESULTS: Nineteen of the 54 (35.2%) patients were considered to have HPS, including one (5.3%) with severe HPS, nine (47.4%) with moderate HPS, and nine (47.4%) with mild HPS. The median overall survival (OS) was 10.1 (95% confidence interval [CI], 3.9-16.3) months for patients with HPS and 15.1 (95% CI, 7.3-22.9) months for patients without HPS, which is not a significant difference ( P  = 0.100). The median progression-free survival was also not significantly different between patients with and without HPS (5.2 [95% CI, 0-12.8] vs. 8.4 [95% CI, 3.6-13.1] months; P  = 0.537). In the multivariable Cox regression analyses, carbon monoxide diffusing capacity (hazard ratio [HR] = 1.033 [95% CI, 1.003-1.064]; P  = 0.028) and Child-Pugh class (HR = 1.815 [95% CI, 1.011-3.260]; P  = 0.046) were identified to be the independent prognostic factors of OS. CONCLUSION Mild or moderate HPS is common in patients with unresectable HCC undergoing TACE, but it does not seem to have a significant prognostic impact.
Humans ; Carcinoma, Hepatocellular/pathology* ; Chemoembolization, Therapeutic ; Prospective Studies ; Liver Neoplasms/pathology* ; Prognosis ; Hepatopulmonary Syndrome/therapy* ; Prevalence ; Treatment Outcome ; Retrospective Studies

Tumor recurrence and metastasis after liver transplantation (LT) remains one of the most important factors that affect the outcome of LT for hepatocellular carcinoma (HCC). The diagnosis and treatment strategies in the era of precision medicine, including utilizing multi-omics, high-throughput gene sequencing analysis, big data and artificial intelligence to select the biomarkers which can accurately predict the prognosis after LT, evaluating the immune status comprehensively, inducing immune tolerance, providing effective prevention for patients at a high risk of recurrence with sensitive antitumor drugs and attaching importance to individualized treatment for recurrence and metastasis, may further improve the outcome of LT. Combined with experience and review of relevant research articles, the authors elaborate perioperative diagnosis and treatment strategies of LT for HCC, aiming to promote the application of precision medicine in the field of LT.

Objective    To evaluate the clinical value of three-dimensional (3D) printing model in accurate and minimally invasive treatment of double outlet right ventricle (DORV). Methods    From August 2018 to August 2019, 35 patients (22 males and 13 females) with DORV aged from 5 months to 17 years were included in the study. Their mean weight was 21.35±8.48 kg. Ten patients who received operations guided by 3D printing model were allocated to a 3D printing model group, and the other 25 patients who received operations without guidance by 3D printing model were allocated to a non-3D printing model group. Preoperative transthoracic echocardiography and CT angiography were performed to observe the location and diameter of ventricular septal defect (VSD), and to confirm the relationship between VSD and double arteries. Results    The McGoon index of patients in the 3D printing model group was 1.91±0.70. There was no statistical difference in the size of VSD (13.20±4.57 mm vs. 13.40±5.04 mm, t=−0.612, P=0.555), diameter of the ascending aorta (17.10±2.92 mm vs. 16.90±3.51 mm, t=0.514, P=0.619) or diameter of pulmonary trunk (12.50± 5.23 mm vs. 12.90±4.63 mm, t=−1.246, P=0.244) between CT and 3D printing model measurements. The Pearson correlation coefficients were 0.982, 0.943 and 0.975, respectively. The operation time, endotracheal intubation time, ICU stay time and hospital stay time in the 3D printing model group were all shorter than those in the non-3D printing model group (P<0.05). Conclusion    The relationship between VSD and aorta and pulmonary artery can be observed from a 3D perspective by 3D printing technology, which can guide the preoperative surgical plans, assist physicians to make reasonable and effective decisions, shorten intraoperative exploration time and operation time, and decrease the surgery-related risks.