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The aim of this Policy Review was to compare China's overall and synchronous participation in clinical trials for innovative anticancer drugs with that of the USA, the EU, Japan, and South Korea, and to assess changes in the participation rate trends in these five regions. Relevant data from the top 20 international pharmaceutical companies from 2011 to 2021 were systematically collected from the Trialtrove and Pharmaprojects databases. Among the 8260 trials for 954 new anticancer drugs identified, China was involved in 8·8% of the trials and with 20·4% of the drugs being trialled. These participation rates are significantly lower than those for South Korea (14·5% of trials and 36·3% of drugs), Japan (16·1% of trials and 38·7% of drugs), the EU (40·6% of trials and 67·7% of drugs), and the USA (65·7% of trials and 91·2% of drugs; p<0·0001 for all). Similar results were found for the synchronous participation rate, defined as the proportion of drugs or trials at the highest development stage internationally, for the 803 tested drugs, which ranged from 9·0% in China to 87·7% in the USA. China's participation rate in early phase trials (4·4%) and in synchronous trials (5·4%) was even lower, in stark contrast to that of the USA (66·1% for early phase trials and 89·1% for synchronous trials). The fastest growing annual rate of participation in trials was observed in China (15·7%), followed by South Korea (8·2%) and Japan (6·8%); no change was detected in the USA or the EU. This Policy Review shows that Chinese participation in the clinical development of innovative cancer drugs by international pharmaceutical companies has increased over the past decade, but an obvious gap persists in comparison with the USA, the EU, Japan, and South Korea, especially in its synchronous participation and early participation rates.
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Antineoplásicos , Humanos , Antineoplásicos/uso terapéutico , China , Japón , República de Corea/epidemiología , Industria FarmacéuticaRESUMEN
PURPOSE: Because of less attention to the sagittal component of maxillary fractures, these fractures are often misdiagnosed or the reduction is missed leading to maxillary transverse discrepancies. Therefore, the purpose of this study was to identify factors associated with good or adverse postoperative outcomes of maxillary sagittal fractures. MATERIALS AND METHODS: This study was a single-center retrospective cohort study. The sample was composed of cases of maxillary sagittal fractures treated at the Department of Oral and Maxillofacial Surgery, Craniomaxillofacial Trauma Unit of Xi'an Jiaotong University (Xi'an, China) from January 2008 through December 2013. The predictor variables were age, gender, occupation, cause of injury, injury severity, treatment timing, treatment method, and quality of fracture reduction. The outcome variable was the postoperative treatment effect index. Descriptive, bivariate, and multivariate statistics were computed. The P value was set to .05. RESULTS: The sample was composed of 40 cases. The male-to-female ratio was 4:1; the most vulnerable age group was 20 to 30 years (30%); laborers (72.5%) were more prone to injury; and the main cause of injury was motor vehicle accident (62.5%). No cases of isolated sagittal fracture were found and most (35%) occurred with other maxillary fractures, including Le Fort fractures. A statistically significant association between treatment timing and quality of fracture reduction and the postoperative treatment effect index (P < .05) was found. CONCLUSION: The results of this study suggest that better results are achieved when fractured bone is treated sooner. Anatomic repositioning of the fractured bone is the important predictor for good postoperative outcomes.
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Fijación de Fractura/métodos , Fracturas Maxilares/cirugía , Adulto , Factores de Edad , China , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Fracturas Maxilares/diagnóstico por imagen , Fracturas Maxilares/etiología , Persona de Mediana Edad , Ocupaciones , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Objective: To deliver a comprehensive picture of the landscape and changing trend of trials and approvals on targeted anticancer drugs in China from 2012 to 2021. Methods: Trials, investigated products, and listed drugs were acquired from national databases. The status quo, changing trend of absolute number, and proportion of targeted trials, products, and drugs, as well as the corresponding difference between domestic and foreign companies were analyzed. Results: A total of 2,632 trials on 1,167 targeted antitumor drugs were identified, accounting for 81.5% of all registered trials. The number and proportion of trials on targeted drugs increased steadily, with an average growth rate of 36.0% and 6.2%, respectively. A similar growth trend was observed in the number (33.7%) and proportion (13.8%) of targeted drugs. Targeted drugs and trials owned by domestic companies accounted for a higher proportion than that by foreign companies (80.5% vs. 19.5%; 83.2% vs. 16.8%, respectively), and the growing trend for both targeted drugs (13.8% vs. 5.7%) and trials (13.8% vs. 33.7%) owned by domestic companies was faster. The proportion of targeted drug trials (80.5% vs. 85.6%) and multicenter trials (6.0% vs. 69.9%) initiated by domestic companies was lower than that by foreign companies, with the gap gradually narrowing. Among the identified 18 targets of the 126 immune drugs under development, only one globally new target was found. Conclusions: Research and development of targeted antitumor drugs in China are booming and advancing rapidly, and domestic enterprises have become the pillar. Encouraging genomics activities and establishing incentives and public-private collaboration frameworks are crucial for innovation-oriented drug development in China.
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Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule-guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors.
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Neoplasias , Humanos , China/epidemiología , Neoplasias/tratamiento farmacológico , Ensayos Clínicos Fase II como AsuntoRESUMEN
Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants' family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.
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The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of ß-catenin and GSK3ß, which are the two key regulators in the Wnt/ß-catenin signaling pathway. In addition, the Wnt/ß-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/ß-catenin pathway.
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Inductores de la Angiogénesis/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Células Endoteliales/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/farmacología , Presión Intracraneal , Neovascularización Fisiológica/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/fisiopatología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Edema Encefálico/patología , Edema Encefálico/fisiopatología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Proteínas Recombinantes/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Uniones Estrechas/patologíaRESUMEN
Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3ß pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.
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Ischemic strokes account for about 80% of all strokes and are associated with a high risk of mortality. Angiogenesis of brain microvascular endothelial cells may contribute to functional restoration following ischemia. Fibroblast growth factor 1 (FGF1), a member of FGF superfamily, involved in embryonic development, angiogenesis, wound healing, and neuron survival. However, the mitogenic activity of FGF1 is known to contribute to several human pathologies, thereby questioning the safety of its clinical applications. Here, we explored the effects and mechanism of action of non-mitogenic FGF1 (nmFGF1) on angiogenesis in mice after ischemia stroke and an oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) injury model. We found that intranasal administration nmFGF1 significantly promoted angiogenesis in mice after stroke, and significantly increased the formation of matrigel tube and promoted scratch migration in a dose-dependent manner in OGD-induced HBMECs in vitro. However, the co-administration of an FGF receptor 1 (FGFR1)-specific inhibitor PD173074 significantly reversed the effects of nmFGF1 in vitro, suggesting that nmFGF1 functions via FGFR1 activation. Moreover, nmFGF1 activated sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) in mice after stroke in vivo. S1P1 protein antagonist VPC23019 and agonist FTY720 were used to confirm that nmFGF1 promotes angiogenesis in vitro partially through the S1P1 pathway. OGD induced downregulation of S1P1 expression. The S1P1 antagonist VPC23019 blocked the stimulatory effects of nmFGF1, whereas the S1P1 agonist FTY720 exerted effects comparable with those of nmFGF1. Furthermore, PD173074 reversed the effect of nmFGF1 on upregulating S1P1 signaling. In conclusion, nmFGF1 enhanced angiogenesis in mice following stroke and OGD-induced HBMECs through S1P1 pathway regulation mediated via FGFR1 activation. This new discovery suggests the potential therapeutic role of nmFGF1 for the treatment of ischemic strokes.
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The use of propranolol for the treatment of infantile hemangioma (IH) has been widely investigated in recent years. However, the underlying therapeutic mechanism of propranolol for the treatment of IH remains poorly understood. The aim of the present study was to investigate the expression of proteins regulated by cellular tumor antigen p53 (p53) in associated apoptosis pathways in IH endothelial cells (HemECs) treated with propranolol. Furthermore, the present study aimed to investigate the exact apoptotic pathway underlying the therapeutic effect of propranolol against IH. In the present study, HemECs were subcultured and investigated using an inverted phase contrast microscope, immunocytochemical staining and a scanning electron microscope (SEM). Experimental groups and blank control groups were prepared. All groups were subjected to drug treatment. A high p53 expression model of HemECs was successfully established via transfection, and a low p53 expression model of HemECs was established using pifithrinα. The apoptosis rate of each group was determined using Annexin Vfluorescein isothiocyanate/propidium iodide double staining and flow cytometry. The expression levels of downstream proteins regulated by p53 [tumour necrosis factor receptor superfamily member 6 (FAS), p53induced death domaincontaining protein (PIDD), death receptor 5 (DR5), BH3interacting domain death agonist (BID), apoptosis regulator BAX (BAX), p53 unregulated modulator of apoptosis (PUMA), phosphatidylinositolglycan biosynthesis class S protein (PIGS), and insulinlike growth factorbinding protein 3 (IGFBP3)] were revealed in the experimental and control groups via western blotting. Microscopic observation revealed the growth of an adherent monolayer of cells, which were closely packed and exhibited contact inhibition. Immunocytochemical staining demonstrated increased expression of clotting factor VIII. SEM analysis revealed presence of WeibelPalade bodies. The results of the analyses verified that the cultured cells were HemECs. The staining of the samples resulted in a significantly increased rate of apoptosis in experimental groups compared with the blank control group. This result suggested that there is an association between p53 expression and the rate of apoptosis of propranololtreated HemECs. The results of the western blot analysis demonstrated an upregulation of BAX expression and a downregulation of IGFBP3 expression in the HemECs treated with propranolol. There were no significant differences in the expression levels of FAS, DR5, PIDD, BID, PUMA and PIGS between experimental and control groups. This result suggests that p53 has an important role in HemEC apoptosis. The results of the present study additionally suggest that the propranololinduced HemEC apoptosis pathway is a mitochondrial apoptosis pathway and is regulated by p53BAX signaling.
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Apoptosis/efectos de los fármacos , Hemangioma/tratamiento farmacológico , Hemangioma/metabolismo , Propranolol/efectos adversos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Apoptosis/genética , Células Endoteliales , Femenino , Hemangioma/genética , Hemangioma/patología , Humanos , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Propranolol/farmacología , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Cuerpos de Weibel-Palade/genética , Cuerpos de Weibel-Palade/metabolismo , Cuerpos de Weibel-Palade/patología , Proteína X Asociada a bcl-2/genéticaRESUMEN
Polybrominated diphenyl ethers (PBDEs) are known as ubiquitous pollutants in ecological systems and thus pose a great threat to the health of humans and other organisms due to their bioamplification and bioaccumulation along the food chain. The present study was designed to investigate the biosorption capacity of biochar for the removal of 4-monobromodiphengl ether and its synergistic effect when used as a carrier to immobilize the 4-monobromodiphengl ether-degrading strain Sphingomonas sp. DZ3. The raw biochar material was prepared by pyrolyzing maize straw at 350 °C under oxygen-limited conditions. The maximum biosorption capacity of biochar for 4-bromodiphengl ether was determined to be 50.23 mg/L under an initial concentration of 800 mg/L at pH 7.0 and 40 °C. The data obtained from the biosorption studies were fitted successfully with the pseudo-first-order kinetic and Freundlich isotherm models. The Weber-Morris model analysis indicated that intraparticle diffusion was the limiting step in the biosorption of 4-bromodiphengl ether onto the biosorbent. The values of thermodynamic parameters â³G0 were calculated as -24.61 kJ/mol (20 °C), -24.35 kJ/mol (30 °C), and -23.98 kJ/mol (40 °C), â³S(0) was -8.45 kJ/mol/K, and â³H(0) was 21.36 kJ/mol. The artificial neural network analysis indicated that the initial concentration appeared to be the most influential parameter on the biosorption processes. The removal rate of 4-bromodiphengl ether achieved using the biochar-microorganism system was increased by 63 and 83% compared with the rates obtained with biochar and the strain individually, respectively. The morphology of the biochar and immobilized strain was determined using a scanning electron microscope, and information of the surface functional groups of biochar was obtained through an infrared spectra study.
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Carbón Orgánico/química , Contaminantes Ambientales/aislamiento & purificación , Éteres Difenilos Halogenados/aislamiento & purificación , Sphingomonas/crecimiento & desarrollo , Adsorción , Biodegradación Ambiental , Concentración de Iones de Hidrógeno , Cinética , Propiedades de Superficie , TermodinámicaRESUMEN
Biochar shows great promise for use in adsorbing pollutants. However, a process for enhancing its adsorption capacity and re-collection efficiency is yet to be further developed. Hence, in this study, we developed a type of biochar coated with magnetic Fe3O4 nanoparticles (i.e., magnetic biochar (MBC)) and assessed its use for crystal violet (CV) adsorption as well as its recycling potential. The coating of Fe3O4 nanoparticles, which was not only on the surface, but also in the interior of biochar, performed two functions. Firstly, it produced a saturation magnetization of 61.48 emu/g, which enabled the biochar being efficiently re-collected using a magnet. Secondly, it significantly enhanced the adsorption capacity of the biochar (from 80.36 to 99.19 mg/g). The adsorption capacity of the MBC was determined to be the largest by so far (349.40 mg/g) for an initial CV concentration of 400 mg/L, pH of 6.0, and temperature of 40 °C, and the adsorption capacity of re-collected MBC was 73.31 mg/g. The adsorption of CV by the MBC was found to be a spontaneous and endothermic physical process in which the intraparticle diffusion was the limiting step. These findings inspire us to use other similar materials to tackle the menace of pollutions.