Separation of human basophils into two fractions with different density and histamine content

We designed experiments in this study to test the hypothesis suggested by recent purification data that blood basophils comprise two populations of different density, which circulate in numbers characteristic for each human subject. Basophils were separated into two density bands by single step centrifugation on a discontinuous Percoll gradient. Band 1 cells were at the interface between plasma and Percoll of density 1.070 gm/ml. Band 2 cells were at the Percoll 1.070 to 1.080 interface. When the number of band 1 basophils was expressed as a percentage of the total in bands 1 and 2, this relative amount generally remained in a narrow range for blood obtained from the same donor on 3 successive days but differed markedly in different individuals. In a series of leukapheresis experiments, we demonstrated that the percentage of band 1 basophils in postleukapheresis venous blood was strikingly similar to the preleukapheresis value. If basophils that repopulated the leukapheresis-depleted circulation came from the bone marrow, we can conclude that blood levels of basophils in bands 1 and 2 are under physiologic control and that the two types of basophils are released in amounts characteristic for each human subject. Additional evidence for two distinct blood basophil populations was provided by histamine measurements. The histamine content per basophil was consistently higher in cells from band 1 than from band 2, the mean difference between pairs of values for 30 subjects being 0.3 +/- 0.04 pg or about 27% of the band 1 basophil histamine content of 1.1 pg.     

靶向纳米级免疫偶联物诱导检查点抑制剂抗体治疗颅内胶质瘤的可行性实验研究

目的 探讨靶向纳米级免疫偶联物(Nanoscale immunoconjugates,NCI)诱导检查点抑制剂抗体治疗颅内胶质瘤的可行性。方法 无特定病原体级(Specific pathogen free,SPF)级、雌性大鼠168只,随机分为磷酸缓冲盐溶液(Phosphate buffer saline,PBS)组(24只),游离组(72只)及NIC组(72只); 所有大鼠均进行颅内胶质瘤细胞植入,构建颅内胶质瘤大鼠模型; PBS组不进行治疗; 游离组给予T淋巴细胞相关抗原4(Cytotoxic T lymphocyte associated antigen-4,a-CTLA-4)和程序性细胞死亡1(Anti programmed cell death protein-1,a-PD-1)及两者联合注射,每种各24只; NCI组给予纳米级免疫偶联物诱导检查点抑制剂抗体[分别为聚苹果酸/ T淋巴细胞相关抗原4(Polymalic malic acid/ Cytotoxic T lymphocyte associated antigen-4,P/a-CTLA-4)、聚苹果酸/程序性细胞死亡1(Polymalic malic acid/Anti programmed cell death protein-1,P/a-PD-1)及两盒联合注射]注射,每种各24只; 使用荧光素标记法观察不同组大鼠药物血脑屏障穿透效率,比较不同治疗方式大鼠治疗后CD3+T细胞(CD3+Pan T Cells,CD3+)、CD4+,CD8+、调节性T细胞(Regulatory T cells,Treg)、巨噬细胞(MΦ)、自然杀伤细胞(Natural killer cell,NK)细胞、自然杀伤T细胞(Natural killer T cell,NKT)细胞、干扰素γ(Interferon-γ,IFNγ)水平及大鼠CD4+,CD8+增殖活跃程度、生存期。结果 荧光实验显示,NIC组各治疗方式大鼠脑部荧光面积均显著高于游离组及PBS组; NCI各组CD3+、CD4+、CD8+、Treg、CD4+ki67、CD8+ki67、MΦ、M1MΦ、M2MΦ、NK细胞、NKT细胞、IFNγ每孔计数及总体生存期显著高于游离组及PBS组(P<0.05)。结论 NCI诱导检查点抑制剂抗体能促进药物透过血脑屏障,刺激大脑驻留的免疫系统,促使CD8+ T细胞增殖并触发多种免疫细胞因子的释放,增加M1型巨噬细胞的产生,从而协调针对GBM的免疫反应,提高颅内胶质瘤大鼠存活时间。     

Randomized phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer

PurposeThis randomized, open-label phase II study compared the efficacy of sunitinib monotherapy with that of single-agent standard-of-care (SOC) chemotherapy in patients with previously treated advanced triple-negative breast cancer (TNBC).MethodsPatients with advanced TNBC, relapsed after anthracycline- and taxane-based chemotherapy, were randomized to receive either sunitinib (37.5 mg/day) or the investigator's choice of SOC therapy. Progression-free survival was the primary endpoint.ResultsMedian progression-free survival was 2.0 months with sunitinib and 2.7 months with SOC chemotherapy (one-sided P = 0.888). Median overall survival was not prolonged with sunitinib (9.4 months) compared with SOC chemotherapy (10.5 months; one-sided P = 0.839). The objective response rate was 3% with sunitinib and 7% with SOC chemotherapy (one-sided P = 0.962).ConclusionsSunitinib monotherapy did not improve efficacy compared with SOC chemotherapy in patients with previously treated advanced TNBC, for which identification of effective treatments and therapeutic targets remains an urgent need.Trial registrationNCT00246571.     

Antagonism--no synergism--in pairwise tests of carcinogens in rats

In the mid-1970s, the National Cancer Institute issued a contract for the testing of a dozen chemicals, most of them known to be carcinogenic in animals, in pairwise combinations. Those tests, which involved 918 pairwise tests and over 14,500 laboratory rats, produced no good evidence for any synergistic interactions in which exposure to two chemicals resulted in a number of tumors greater than the number produced by exposure to either chemical alone. A number of tests resulted in antagonism, in which the number of tumors in animals exposed to a pair of carcinogens was less than the number seen after exposure to either carcinogen by itself. More generally, the results indicate that synergism is an unlikely consequence when animals are exposed to pairs of chemicals, even when both chemicals are carcinogens.     

Prédiction de la réponse aux anticancéreux par analyse du transcriptome. Les nouvelles voies de la pharmacogénomie

Résumé:   La prédiction de la réponse au traitement est un problème crucial en oncologie. Au cours de la décennie 1975-1985, des efforts importants ont tenté de mettre au point des essais cellulaires capables de prédire, sur une base individuelle, la réponse in vitro de cellules tumorales aux agents chimiothérapeutiques, mais de telles techniques ne sont pas applicables en routine. Des techniques de biologie moléculaire permettent maintenant didentifier des gènes impliqués dans la sensibilité et la résistance aux agents anticancéreux. La réalisation de profils dexpression génique a permis détablir des corrélations entre de tels profils et la sensibilité de cellules tumorales ou de tumeurs humaines aux médicaments anticancéreux. Ce type dapproche a été initié sur des systèmes in vitro par le National Cancer Institute aux USA et se poursuit dans plusieurs laboratoires privés et publics. Au niveau clinique, les profils dexpression génique sont pour le moment réalisés pour la définition diagnostique des tumeurs et létablissement dun pronostic, mais devraient permettre un jour de prédire la chimiosensibilité pour que les cliniciens puissent prescrire les traitements individuels sur des bases rationnelles.     

Glycidol exposure evaluation of humans who have ingested diacylglycerol oil containing glycidol fatty acid esters using hemoglobin adducts

Glycidol fatty acid esters (GEs) have been found as impurities in refined edible oils including diacylglycerol (DAG) oil, and concerns of possible exposure to glycidol (G), a known animal carcinogen, during digestion have been raised. We previously measured N-(2,3-dihydroxy-propyl)valine (diHOPrVal), a G hemoglobin adduct, for DAG oil exposed and non-exposed groups and showed there was no significant difference between them. In the present study, we conducted an additional analysis to verify the outcome of the previous report. The first experiment was designed as a matched case-control study to adjust variables with an increased sample size. The average levels of diHOPrVal were 6.9 pmol/g-globin (95%CI: 4.9–9.0) for 14 DAG oil exposed subjects and 7.3 pmol/g-globin (95%CI: 6.1–8.5) for 42 non-exposed volunteers, and no significant difference in levels was found between the two groups. In a second experiment, we compared the adduct levels of 12 DAG oil exposed subjects before and after discontinuing use of DAG oil, and found there was no significant change in diHOPrVal levels (from 7.1 ± 1.1 to 7.5 ± 1.4 pmol/g-globin). These results suggest that there was no increased exposure to G for humans who ingested DAG oil daily, although the evaluated population was limited.