CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer / 医学前沿

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis / 医学前沿

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.

Anthropometric indicators of obesity in the prediction of high body fat in adolescents / Indicadores antropométricos de obesidade na predição de gordura corporal elevada em adolescentes

OBJECTIVE: To determine the anthropometric indicators of obesity in the prediction of high body fat in adolescents from a Brazilian State. METHODS: The study included 1,197 adolescents (15-17 years old). The following anthropometric measurements were collected: body mass (weight and height), waist circumference and skinfolds (triceps and medial calf). The anthropometric indicators analyzed were: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and conicity index (C-Index). Body fat percentage, estimated by the Slaughter et al equation, was used as the reference method. Descriptive statistics, U Mann-Whitney test, and ROC curve were used for data analysis. RESULTS: Of the four anthropometric indicators studied, BMI, WHtR and WC had the largest areas under the ROC curve in relation to relative high body fat in both genders. The cutoffs for boys and girls, respectively, associated with high body fat were BMI 22.7 and 20.1kg/m², WHtR 0.43 and 0.41, WC 75.7 and 67.7cm and C-Index 1.12 and 1.06. CONCLUSIONS: Anthropometric indicators can be used in screening for identification of body fat in adolescents, because they are simple, have low cost and are non-invasive. .

OBJETIVO: Determinar os indicadores antropométricos de obesidade na predição da gordura corporal elevada em adolescentes de um estado brasileiro. MÉTODOS: O estudo incluiu 1.197 adolescentes (15-17 anos). As seguintes medidas antropométricas foram coletadas: massa corporal e estatura, perímetro da cintura e dobras cutâneas (tríceps e perna medial). Os indicadores antropométricos analisados foram: índice de massa corporal (IMC), perímetro da cintura (PC), razão cintura-estatura (RCE) e índice de conicidade (IC). A gordura corporal elevada, estimada pela equação de Slaughter et al., foi usada como método de referência. Estatística descritiva, teste U de Mann-Whitney e curva ROC foram usadas para a análise dos dados. RESULTADOS: Dos quatro indicadores antropométricos estudados, o IMC, a RCE e o PC tiveram as maiores áreas sob a curva ROC em relação à gordura corporal elevada relativa em ambos os sexos. Os pontos de corte para os rapazes e as moças, respectivamente, associados com gordura corporal elevada foram IMC 22,7 e 20,1 kg/m2, RCE 0,43 e 0,41, PC 75,7 e 67,7 cm e IC 1,12 e 1,06. CONCLUSÕES: Os indicadores antropométricos podem ser usados como ferramenta para identificação da gordura corporal em adolescentes, por serem um método simples, de baixo custo e não invasivo. .