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BACKGROUND: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. MATERIALS AND METHODS: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab). RESULTS: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups. CONCLUSION: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles.
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Objective: To explore the histopathological factors affecting the stiffness of papillary thyroid carcinoma (PTC). Methods: Ninety-six patients with PTC confirmed by surgery and pathology in Shanxi Bethune Hospital from January 2019 to December 2020 were selected, including 101 nodules. Two-dimensional ultrasound and shear-wave elastography (SWE) were performed before surgery and the average Young's modulus (Emean) of PTC nodules were measured. Histopathological examinations on the nodules were conducted after surgery to decide the lesion size, number of lesions, calcification type, presence or absence of capsular and extracapsular invasion, degree of fibrosis, microvessel density, and number of tumor cells. The correlations between the lesion size, degree of fibrosis, microvessel density, and number of tumor cells and the Emean were analyzed. The Emeans of nodules with different numbers of lesions, presence or absence of capsular and extracapsular invasion, and different pathological calcification types were compared. The multiple linear regression analysis was used to evaluate the histopathological factors influencing the Emean. Results: The ranges of the lesion sizes, degrees of fibrosis, microvascular density, numbers of tumor cells, and the Emeans of the 101 investigated PTC nodules were (1.29±0.95) cm, (30.64±18.37)%, (101.64±30.7) vessels per high power field, (373.52±149.87) cells per high power field, and (36.47±19.62) kPa, respectively. Correlation analysis showed that the lesion size of PTC and the degree of fibrosis were positively correlated with the Emean (r=0.660, Pï¼0.001; r=0.789, Pï¼0.001), while the microvessel density was negatively correlated with the Emean (r=-0.198, P=0.047). The Emean of the group with capsular and extracapsular invasion was higher than that of the group without (P=0.014). There were statistical differences in the Emeans among different types of pathological calcification (Pï¼0.001). The multiple linear regression analysis showed that the lesion size (ß=0.325, Pï¼0.001), degree of fibrosis (ß=0.563, Pï¼0.001), psammoma bodies (ß=0.177, P=0.001), stromal calcification (ß=0.164, P=0.003), and mixed calcification of both psammoma bodies and stroma (ß=0.163, P=0.003) were independent influencing factors for the Emean. The degree of fibrosis had the greatest impact on the Emean. Conclusions: The Emean of PTC lesions was correlated with the histopathological characteristics of PTC. The lesion size, degree of fibrosis, and calcification had significant impact on the Emean, among which the degree of fibrosis had the greatest impact.
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Calcinosis , Diagnóstico por Imagen de Elasticidad , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología , Módulo de Elasticidad , Ultrasonografía/métodos , Diagnóstico por Imagen de Elasticidad/métodos , Calcinosis/diagnóstico por imagen , FibrosisRESUMEN
Populus talassica Kom. is an ecologically important species endemic to central Asia. In China, its main distribution is restricted to the Ili region in the Xinjiang Autonomous Region. An understanding of genetic diversity and population structure is crucial for the development of a feasible conservation strategy. Twenty-six high-level simple sequence repeat (SSR) markers were screened and used to genotype 220 individuals from three native populations. A high level of genetic diversity and low population differentiation were revealed. We identified 163 alleles, with a mean of 6.269 alleles per locus. The observed and expected heterozygosities ranged from 0.472 to 0.485 (with a mean of 0.477), and from 0.548 to 0.591 (mean 0.569), respectively. Analysis of molecular variance revealed 93% variation within populations and 7% among populations. A model-based population structure analysis divided P. talassica into two groups (optimal K = 2). These genetic data provide crucial insight for conservation management.
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Variación Genética , Repeticiones de Microsatélite/genética , Filogenia , Populus/genética , Alelos , China , Genética de Población , GenotipoRESUMEN
Glial cell line-derived neurotrophic factor (GDNF) has strong neuroprotective and neurorestorative effects on dopaminergic (DA) neurons in the substantia nigra (SN); however, the underlying molecular mechanisms remain to be fully elucidated. In this study, we found that the expression level of transcription factor Six2 was increased in damaged DA neurons after GDNF rescue in vivo and in vitro. Knockdown of Six2 resulted in decreased cell viability and increased the apoptosis of damaged DA neurons after GDNF treatment in vitro. In contrast, Six2 overexpression increased cell viability and decreased cell apoptosis. Furthermore, genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) indicated that Six2 directly bound to the promoter CAGCTG sequence of smad ubiquitylation regulatory factor 1 (Smurf1). ChIP-quantitative polymerase chain reaction (qPCR) analysis showed that Smurf1 expression was significantly upregulated after GDNF rescue. Moreover, knockdown of Six2 decreased Smurf1 expression, whereas overexpression of Six2 increased Smurf1 expression in damaged DA neurons after GDNF rescue. Meanwhile, knockdown and overexpression of Smurf1 increased and decreased p53 expression, respectively. Taken together, our results from in vitro and in vivo analysis indicate that Six2 mediates the protective effects of GDNF on damaged DA neurons by regulating Smurf1 expression, which could be useful in identifying potential drug targets for injured DA neurons.
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Neuronas Dopaminérgicas/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Proteínas de Homeodominio/genética , Fármacos Neuroprotectores/farmacología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Regulación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Motivos de Nucleótidos , Oxidopamina/antagonistas & inhibidores , Oxidopamina/toxicidad , Porción Compacta de la Sustancia Negra/citología , Porción Compacta de la Sustancia Negra/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Técnicas Estereotáxicas , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Sophora moorcroftiana is a perennial leguminous low shrub endemic to the middle reaches of Yarlung Zangbo River in Tibet. It is an important species to fix sand dunes and to avoid the formation of shifting sands; therefore, its progressive over-exploitation may enhance land desertification. The levels and distribution of genetic variability of this species were evaluated from 10 natural populations at 24 loci encoding 13 enzymes, using allozyme analysis by starch gel electrophoresis. Data obtained revealed moderate levels of genetic variation within populations (Pp=27.5%, Ap=1.5, Hep=0.122) and a considerable divergence among populations (FST=0.199). Significant positive correlations (r2=0.49, p<0.05; r2=0.46, p<0.05) were found between elevation and both mean number of alleles per locus (A) and gene diversity (He) in the studied populations of S. moorcroftiana. Lower genetic diversity in lower elevation populations might be due to the negative effects of human pressures and habitat fragmentation, to adaptation to high altitudes as a consequence of a peripatric speciation process, or to directional gene flow along the river basin from the source populations located in the west at higher altitudes. The evaluation of the degree of threat has led to the inclusion of this species in the category of EN ("endangered"), and conservation strategies for this endemic species are discussed on the basis of these findings.
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Sophora/genética , Alelos , Altitud , Conservación de los Recursos Naturales , Frecuencia de los Genes , Variación Genética , Isoenzimas/genética , Sophora/enzimología , TibetRESUMEN
Through investigation on germinating rate and process of unreduced diploidy pollen and monoploid pollen in Populus tomentosa x P. alba and P. tomentosa, it was proved that there were different radiosensitivities to 60Co gamma-ray among different ploidy pollen, i.e. the radiosensitivity of monoploidy pollen was two times higher than diploidy pollen. To overcome the problems of late germination and poor compatibility of diploidy pollen during fertilization, a certain dose of radiation can be applied to stimulating the diploidy pollen germination, meanwhile to restrain of kill some monoploidy pollen based on their different radiosensibilities. Therefore the rate of germination and faster germinating process of diploidy pollen on stigmas can be increased relatively to certain extent. The efficiency of radiation was proved by breeding practice. In the hybidization of (P. alba x P. glandulosa) x (P. tomentosa x P. bolleana), 3.8% of triploid could be produced by 1,470 rad treatment; while no triploid is examined in the control. 12.9% of triploids were produced by the treatment of 1,680 rad from the above cross.