Lapatinib is a clinically important component of the treatment for HER2‐positive metastatic breast cancer and has an acceptable safety profile. Lapatinib‐associated Hy's Law cases have been ...characterized using human leukocyte antigen (HLA) DQA1*02:01/DRB1*07:01 and Gilbert's syndrome UGT1A1*28/*28 genotypes. The HLA‐positive cases had higher alanine aminotransferase (ALT) elevation, whereas the HLA‐negative cases had a higher incidence of Gilbert's syndrome. The findings of our study, which extend this HLA association to lapatinib‐associated serious liver injury, emphasize the importance of Gilbert's syndrome in the interpretation of Hy's Law and may lead to methods for enhancing patient safety.
Clinical Pharmacology & Therapeutics (2012); 91 4, 647–652. doi:10.1038/clpt.2011.277
Stars are giant thermonuclear plasma furnaces that slowly fuse the lighter elements in the universe into heavier elements, releasing energy, and generating the pressure required to prevent collapse. ...To understand stars, we must rely on nuclear reaction rate data obtained, up to now, under conditions very different from those of stellar cores. Here we show thermonuclear measurements of the 2 H(d, n)3 He and 3 H(t,2n)4 He S-factors at a range of densities (1.2-16 g cm-3 ) and temperatures (2.1-5.4 keV) that allow us to test the conditions of the hydrogen-burning phase of main-sequence stars. The relevant conditions are created using inertial-confinement fusion implosions at the National Ignition Facility. Our data agree within uncertainty with previous accelerator-based measurements and establish this approach for future experiments to measure other reactions and to test plasma-nuclear effects present in stellar interiors, such as plasma electron screening, directly in the environments where they occur.
Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with ...lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.
Specimen collection: An essential tool Rocha, L. A.; Aleixo, A.; Allen, G. ...
Science (American Association for the Advancement of Science),
05/2014, Letnik:
344, Številka:
6186
Journal Article
Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to ...1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.
HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and ...taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10
, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.
Asian turtles face an extinction crisis, and so it is imperative that systematists accurately determine species diversity in order to guide conservation strategies effectively. We surveyed ...mitochondrial and nuclear DNA (mtDNA and nuDNA) variation of the heavily exploited Mauremys mutica complex, a clade of Asian turtles that contains the endangered M. mutica from Japan, Taiwan, China and Vietnam, and the critically endangered Mauremys annamensis from central Vietnam. We discovered extensive mtDNA and nuDNA variation among samples that did not correspond to the currently recognized taxonomy. Both nuDNA and mtDNA data suggest that M. mutica is paraphyletic with respect to M. annamensis. Surprisingly, M. annamensis exhibits a previously unknown mtDNA structure in the form of two clades that are paraphyletic to M. mutica. These data reveal that the currently recognized taxonomy of the mutica complex does not reflect the genetic diversity of our samples. Unfortunately, many conservation-oriented captive-breeding efforts for turtles are also based on trade samples such as the ones studied here. These efforts include plans to breed trade-rescued individuals and release their progeny into the wild. Because our genetic survey reveals that the taxonomic identity of these samples does not reflect genetic diversity, we raise serious questions about the efficacy of these programs. In order to address conservation issues and provide more accurate estimates of evolutionary lineages within Mauremys, we recommend continued surveys for wild populations of the mutica complex to provide new genetic material and additional distributional data, attempts to extract DNA from historic museum specimens and a shift in conservation focus to in situ preservation of wild populations and associated habitat.
Rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta) represent two salmonid genera separated for 15--20 million years. cDNA sequences were determined for the classical MHC class I heavy ...chain gene UBA and the MHC class II beta-chain gene DAB from 15 rainbow and 10 brown trout. Both genes are highly polymorphic in both species and diploid in expression. The MHC class I alleles comprise several highly divergent lineages that are represented in both species and predate genera separation. The class II alleles are less divergent, highly species specific, and probably arose after genera separation. The striking difference in salmonid MHC class I and class II evolution contrasts with the situation in primates, where lineages of class II alleles have been sustained over longer periods of time relative to class I lineages. The difference may arise because salmonid MHC class I and II genes are not linked, whereas in mammals they are closely linked. A prevalent mechanism for evolving new MHC class I alleles in salmonids is recombination in intron II that shuffles alpha 1 and alpha 2 domains into different combinations.
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