Tovorafenib has been approved by the U.S.Food and Drug Administration(FDA)for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma(LGGs)harboring the serine threonine kinae v-RAF murine sarcoma viral oncogene homologue B1(BRAF)fusion or rearrangement,or BRAV600E mutation.Tovorafenib is an oral,greater brain-penetrant,selective,type Ⅱ RAF inhibitor which has potent activity against both oncogenic BRAF fusions and BRAFV600E mutations.Most tumors have been showed some degree of shrinkage.The mechanism of action,pharmacodynamics,pharmacokinetics,clinical study and safety were introduced.

Tovorafenib has been approved by the U.S.Food and Drug Administration(FDA)for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma(LGGs)harboring the serine threonine kinae v-RAF murine sarcoma viral oncogene homologue B1(BRAF)fusion or rearrangement,or BRAV600E mutation.Tovorafenib is an oral,greater brain-penetrant,selective,type Ⅱ RAF inhibitor which has potent activity against both oncogenic BRAF fusions and BRAFV600E mutations.Most tumors have been showed some degree of shrinkage.The mechanism of action,pharmacodynamics,pharmacokinetics,clinical study and safety were introduced.

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OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective:To explore the effects of activating α7 nicotinic acetylcholine receptor(α7nAChR)on cognitive function and polarization of hippocampal microglia in traumatic brain injury (TBI) rats.Methods:Totally 36 male SD rats with 6-8 weeks old were randomly divided into Sham group ( n=12), TBI group ( n=12), TBI+ α7nAChR agonist group ( n=6) and TBI+ α7nAChR antagonist group( n=6). The TBI model was established by the " free fall impact" method. From the 4th to 6th day after modeling, mice in the TBI+ α7nAChR agonist group were intraperitoneally injected with α7nAChR agonist PNU-282987 (3 mg/kg). Rats in TBI+ α7nAChR antagonist group were intraperitoneally injected with α7nAChR antagonist methyllycaconitine citrate (5 mg/kg) first, then 45 minutes later they were injected with α7nAChR agonist PNU-282987 (3 mg/kg). Rats in the TBI group and Sham group were intraperitoneally injected with an equal volume of 0.9% sodium chloride solution. Morris water maze test was used to evaluate the learning and memory function of rats. Immunofluorescence staining was used to observe the ionized calcium binding adapter molecule 1 (Iba-1)(a marker for microglia) and arginase 1 (Arg-1)(a marker for M2 microglia). Western blot was used to detect the protein level of Arg-1 in hippocampal tissue. Statistical analysis was performed using GraphPad Prism 9 software. Independent sample t test was used for comparison between two groups, one-way ANOVA was used for comparison among multiple groups, and Tukey test was used for multiple comparison. Results:The results of the water maze test showed that after 7 days of modeling, there was a statistical difference in the escape latency among the 4 groups of rats ( F=6.134, P<0.05). There was no statistical difference in the escape latency between the TBI group and the TBI+ α7nAChR antagonist group( P>0.05), but the both were higher than that of the Sham group (both P<0.05). The escape latency of the TBI+ α7nAChR agonist group((31.87±9.01)s) was shorter than that of the TBI group((56.75±2.62)s) and the TBI+ α7nAChR antagonist group((60.00±0.00)s) (both P<0.05). The results of immunofluorescence staining showed that there were statistical differences in the fluorescence intensity and cell numbers of Arg-1 + /Iba-1 + among the four groups ( F=17.37, 9.33, both P<0.05). The immune fluorescence intensity (0.27±0.03) and cell numbers (21.67±4.41) of Arg-1 + /Iba-1 + in the TBI+ α7nAChR agonist group were higher than those in the TBI group((0.14±0.03), (11.33±2.60)) and TBI+ α7nAChR antagonist group((0.10±0.03), (7.67±1.20)) (all P<0.05). The results of Western blot showed that there was a statistical difference in the level of Arg-1 protein in hippocampus among the 4 groups ( F=8.323, P=0.001). There was no significant difference in the level of Arg-1 protein between the TBI group and the TBI+ α7nAChR antagonist group( P>0.05), and the level of Arg-1 protein in the TBI+ α7nAChR agonist group(1.06±0.22) was higher than that in the TBI group(0.60±0.13) and TBI+ α7nAChR antagonist group(0.35±0.10) (both P<0.05). Conclusion:Activating α7nAChR can promote the polarization of M2 type microglia in rat hippocampal tissue and improve the learning and memory function of TBI rats.

Microplastics(MPs)and nanoplastics(NPs)have become hazardous materials due to the massive amount of plastic waste and disposable masks,but their specific health effects remain uncertain.In this study,fluorescence-labeled polystyrene NPs(PS-NPs)were injected into the circulatory systems of mice to determine the distribution and potential toxic effects of NPs in vivo.Interestingly,whole-body imaging found that PS-NPs accumulated in the testes of mice.Therefore,the toxic effects of PS-NPs on the reproduction systems and the spermatocytes cell line of male mice,and their mechanisms,were investigated.After oral exposure to PS-NPs,their spermatogenesis was affected and the spermatogenic cells were damaged.The spermatocyte cell line GC-2 was exposed to PS-NPs and analyzed using RNA sequencing(RNA-seq)to determine the toxic mechanisms;a ferroptosis pathway was found after PS-NP exposure.The phenomena and indicators of ferroptosis were then determined and verified by ferroptosis inhibitor ferrostatin-1(Fer-1),and it was also found that nuclear factor erythroid 2-related factor 2(Nrf2)played an important role in spermatogenic cell ferroptosis induced by PS-NPs.Finally,it was confirmed in vivo that this mechanism of Nrf2 played a protective role in PS-NPs-induced male reproductive toxicity.This study demonstrated that PS-NPs induce male reproductive dysfunction in mice by causing spermatogenic cell ferroptosis dependent on Nrf2.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease caused by abnormal expression of glycosylphosphatidylinositol (GPI) on the cell membrane due to mutations in the phosphatidylinositol glycan class A(PIGA) gene. It is commonly characterized by intravascular hemolysis, repeated thrombosis, and bone marrow failure, as well as multiple systemic involvement symptoms such as renal dysfunction, pulmonary hypertension, swallowing difficulties, chest pain, abdominal pain, and erectile dysfunction. Due to the rarity of PNH and its strong heterogeneity in clinical manifestations, multidisciplinary collaboration is often required for diagnosis and treatment. Peking Union Medical College Hospital, relying on the rare disease diagnosis and treatment platform, has invited multidisciplinary clinical experts to form a unified opinion on the diagnosis and treatment of PNH, and formulated the Expert Consensus of Multidisciplinary Diagnosis and Treatment for Paroxysmal Nocturnal Hemoglobinuria (2024), with the hope of promoting the standardization of PNH diagnosis and treatment.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective: To evaluate the long-term efficacy and safety of the implantable ventricular assist system EVAHEART I in clinical use. Methods: Fifteen consecutive patients with end-stage heart failure who received left ventricular assist device therapy in Fuwai Hospital from January 2018 to December 2021 were enrolled in this study, their clinical data were retrospectively analyzed. Cardiac function, liver and kidney function, New York Heart Association (NYHA) classification, 6-minute walk distance and quality of life were evaluated before implantation and at 1, 6, 12, 24 and 36 months after device implantation. Drive cable infection, hemolysis, cerebrovascular events, mechanical failure, abnormally high-power consumption and abnormal pump flow were recorded during follow up. Results: All 15 patients were male, mean average age was (43.0±7.5) years, including 11 cases of dilated cardiomyopathy, 2 cases of ischemic cardiomyopathy, and 2 cases of valvular heart disease. All patients were hemodynamically stable on more than one intravenous vasoactive drugs, and 3 patients were supported by preoperative intra aortic balloon pump (IABP). Compared with before device implantation, left ventricular end-diastolic dimension (LVEDD) was significantly decreased ((80.93±6.69) mm vs. (63.73±6.31) mm, P<0.05), brain natriuretic peptide (BNP), total bilirubin and creatinine were also significantly decreased ((3 544.85±1 723.77) ng/L vs. (770.80±406.39) ng/L; (21.28±10.51) μmol/L vs. (17.39±7.68) μmol/L; (95.82±34.88) μmol/L vs. (77.32±43.81) μmol/L; P<0.05) at 1 week after device implantation. All patients in this group were in NYHA class Ⅳ before implantation, and 9 patients could recover to NYHA class Ⅲ, 3 to class Ⅱ, and 3 to class Ⅰ at 1 month after operation. All patients recovered to class Ⅰ-Ⅱ at 6 months after operation. The 6-minute walk distance, total quality of life and visual analogue scale were significantly increased and improved at 1 month after implantation compared with those before operation (P<0.05). All patients were implanted with EVAHEART I at speeds between 1 700-1 950 rpm, flow rates between 3.2-4.5 L/min, power consumption of 3-9 W. The 1-year, 2-year, and 3-year survival rates were 100%, 87%, and 80%, respectively. Three patients died of multiple organ failure at 412, 610, and 872 d after surgery, respectively. During long-term device carrying, 3 patients developed drive cable infection on 170, 220, and 475 d after surgery, respectively, and were cured by dressing change. One patient underwent heart transplantation at 155 d after surgery due to bacteremia. Three patients developed transient ischemic attack and 1 patient developed hemorrhagic stroke events, all cured without sequelae. Conclusion: EVAHEART I implantable left heart assist system can effectively treat critically ill patients with end-stage heart failure, can be carried for long-term life and significantly improve the survival rate, with clear clinical efficacy.
Humans ; Male ; Adult ; Middle Aged ; Female ; Heart Failure/complications* ; Follow-Up Studies ; Retrospective Studies ; Heart-Assist Devices ; Quality of Life