The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

Genomic analysis of sexual dimorphism of gene expression in the mouse adrenal gland.

A relevant gender difference exists in adrenal physiology and propensity to disease. In mice, a remarkable sexual dimorphism is present in several components of the hypothalamic-pituitary-adrenal axis, with females displaying higher adrenal weight, plasma ACTH, corticosterone, and aldosterone levels than males. The molecular bases of this sexual dimorphism are little known. We have compared global gene expression profiles in males vs. female mouse adrenal glands and also studied the effect that testosterone treatment and castration have on adrenal gene expression in female vs. male mice, respectively. Our study evidenced a set of 71 genes that are coordinately modulated according to sex and hormonal treatments and represent the core sexually dimorphic expression program in the mouse adrenal gland. Moreover, we show that some genes involved in steroid metabolism have a remarkable sexual dimorphic expression and identify new potential markers for the adrenal X-zone, a transitory cellular layer in the inner adrenal cortex, which spontaneously regresses at puberty in males and during the first pregnancy in females and has an uncertain physiological role. Finally, sexually dimorphic expression of the transcriptional regulators Nr5a1 and Nr0b1 may explain at least in part the differences in adrenal steroidogenesis between sexes.

Screening for BRCA1 large genomic rearrangements in female Egyptian hereditary breast cancer patients.

Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCAl gene. Large genomic rearrangements (LGRs) in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases (18.2%) of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at or=45 years and having BRCAl-positive LGRs. However, focusing on cases with first- and second-degree relatives affected, we observed a significant difference between the percentage of patients with BRCA1-positive versus BRCAl-negative LGRs. Our results provide the first evidence that LGRs in BRCA1 exist in the Egyptian population. Screening for these alterations may be desirable when breast cancer patients are diagnosed at an early age, especially if these cases have first- and second-degree of relatives with breast cancer.

Screening for BRCA1 large genomic rearrangements in female Egyptian hereditary breast cancer patients

Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCA1 gene. Large genomic rearrangements [LGRs] in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases [18.2%] of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at < or >/= 45 years and having BRCA1-positive LGRs. However, focusing on cases with first- and second-degree relatives affected, we observed a significant difference between the percentage of patients with BRCA1-positive versus BRCA1-negative LGRs. Our results provide the first evidence that LGRs in BRCA1 exist in the Egyptian population. Screening for these alterations may be desirable when breast cancer patients are diagnosed at an early age, especially if these cases have first- and second-degree of relatives with breast cancer

Iodometric microgram determination of chromium(III) and (VI) by use of chemical amplification reactions.

A simple, rapid and sensitive method is described for the iodometric determination of microgram amounts of chromium(III), based on the oxidation of chromium(III) with periodate at pH 3.2, removal of the unreacted periodate by masking with molybdate and subsequent iodometric determination of the liberated iodate. Chromium(VI) can be determined by this method after prior reduction to chromium(III) with sodium sulphite. The method can also be used for the analysis of organochromium compounds.

Iodometric microgram determination of Mn(II) in aqueous media by an indirect chemical amplification reaction.

A rapid, simple and highly sensitive iodometric amplification method is described for the determination of microgram amounts of Mn(II). The method is based on oxidation of Mn(II) with an excess of periodate in acetate buffer (pH 2.8-3.0), masking of the unreacted periodate with molybdate, and after addition of iodide, titration of the liberated iodine is with thiosulphate. The proposed method offers 20-fold amplification for Mn(II) and was found suitable for the determination of Mn(II) in the presence of permanganate ions. Mn(II) in tap water and an industrial waste water has been successfully determined by the proposed method.

Detection and semiquantitative determination of nickel with dimethylglyoxime-loaded foam.

Rapid, sensitive and selective detection and semiquantitative determination of nickel in aqueous solution can be obtained by using dimethylglyoxime loaded on polyurethane foam, either by batch or column extractions, the detection limits being 0.05 and 0.01 ppm respectively.

Solvent extraction of Ga(III) and In(III) from aqueous halide media by adogen-364.

Adogen-364 has been used for the extraction ofgallium(III) and indium(III) from halogen acid solutions, and the dependence of the extraction on chloride, bromide and iodide ion concentration studied. The separation of Ga(III), In(III) and Al(III) is reported and some conclusions have been drawn about the stoichiometry of the extracted species.