A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.     

3D DNA origami designed with caDNAno

For about three decades, DNA-based nanotechnology has been undergoing development as an assembly method for nanostructured materials. The DNA origami method pioneered by Rothemund paved the way for the formation of 3D structures using DNA self assembly. The origami approach uses a long scaffold strand as the input for the self assembly of a few hundred staple strands into desired shapes. Herein, we present a 3D origami roller (75 nm in length) designed using caDNAno software. This has the potential to be used as a template to assemble nanoparticles into different pre-defined shapes. The roller was characterized with agarose gel electrophoresis, atomic force microscopy (AFM) and transmission electron microscopy (TEM).     

南药巴戟天化学成分

为研究巴戟天药材的化学成分.通过硅胶柱色谱和ODS柱色谱等方法对其分离纯化,根据理化性质和光谱数据进行了结构鉴定.从巴戟天药材的乙醇提取物中分离得到了7个化合物,分别为1, 2-二氧乙烯蒽醌(1)、1, 3-二羟基-2-丁酰基蒽醌(2)、1, 2-二羟基蒽醌(3)、β-谷甾醇(4)、3β, 20 (R),丁基-5-烯基-胆甾醇(5)、3β, 5-烯基螺旋甾(6)、水晶兰苷(7),其中化合物1、2、5、6属于首次从该植物中分离得到.     

The origins and the future of microfluidics

The manipulation of fluids in channels with dimensions of tens of micrometres--microfluidics--has emerged as a distinct new field. Microfluidics has the potential to influence subject areas from chemical synthesis and biological analysis to optics and information technology. But the field is still at an early stage of development. Even as the basic science and technological demonstrations develop, other problems must be addressed: choosing and focusing on initial applications, and developing strategies to complete the cycle of development, including commercialization. The solutions to these problems will require imagination and ingenuity.     

烯-二炔”模型化合物前体：6-硫杂-13-氧杂双环［9．3．0］-3，8-十四二炔的合成

以顺 1,2 ,3,6 四氢邻苯二甲酸酐为原料 ,经还原 ,羟基保护 ,双键臭氧化开环 ,Wittig反应 ,双炔化 ,酯化 ,二醇化 ,二磺酸酯化 ,硫化 ,醇缩合共十步 ,合成了“烯 二炔”前体物 :6 硫杂 13 氧杂双环 [9.3.0 ] 3,8 十四二炔 .该合成法收率较高 ,反应条件温和 ,新化合物 ( 8) ,( 10 ) ,( 11)经元素分析 ,核磁 ,红外 ,质谱确证结构 .     

Substrate color matching in the grasshopper, Circotettix rabula (Orthoptera: Acrididae)

Mechanisms important in maintaining substrate color matching in the grasshopper, Circotettix rabula, were studied near Aspen, Colorado, during the summers of 1968 – 70. Studies concentrated on populations on gray shale and red sandstone substrates. In both areas, collections revealed appreciable numbers of mismatched phenotypes among all age groups. The possibility of developmental homochromy was examined by observation of nymphs held in rearing boxes on matching and contrasting soil colors. The behavioral selection of matching substrate colors was tested by preference experiments. While not negating the possibility of these mechanisms, results suggested that they were of minor importance. Predation experiments, using Sceloporus lizards, demonstrated significant levels of selective predation on mismatched nymphs on both red and gray substrates. Experiments with bird and mammal predators, using adult grasshoppers, gave similar results. Release - recapture experiments with marked adults in areas of red and gray substrates showed markedly higher disappearance rates for mismatched animals. These results are interpreted to indicate that selective predation on mismatched animals is a major factor in maintaining substrate color matching in this species.     

Second occurrence of the long-nosed snake, Rhinocheilus lecontei lecontei, in Idaho

A second record of the long-nosed snake in Idaho was taken at the entrance to Bruneau Dunes State Park, Owghee County     

Cedar Hollow, an early Holocene faunal site From Whidbey Island, Washington

Coastal erosion at central Whidbey Island reveals a cross-section view of dune sands that contain the only known record of animals that inhabited the Pacific Northwest coast during the early Holocene. Mammal fossils include bones and teeth of deer, wolf, brown bear, and several species of rodents. A deer vertebra from basal beds yielded a 14 C age of 8840 ± 50 yr BP. The faunal diversity suggests that the region was repopulated relatively quickly following the final retreat of the Cordilleran sheet. This paleofauna was quite different from that of the late Pleistocene, when the region was inhabited by mammoth, musk oxen, giant sloth, and other large mammals. Avian remains include hawks, geese, and seabirds, 3 groups that occupied quite different ecological niches. Early Holocene bird fossils from Whidbey Island are dissimilar to late Pleistocene avifaunas from inland sites in California and Oregon, evidence that the coastal environment offered habitat conditions quite unlike those of interior wetlands.     

Notes on reproduction of the side-blotched lizard Uta stansburiana stansburiana in southwest Idaho

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} In 1968 and 1973 in southwestern Idaho, 275 Uta stansburiana were collected. Uta occupies low hills with rocky outcrops and flat sparse vegetation consisting of the following shrubs: Artemisia tridentata, Grayia spinosa, Atriplex confertifolia, Chrysothamnus nauseosus, and Atriplex canescens. Emergence from hibernation occurs from mid-March to early April and the first yolked follicles appear in early April, with oviducal eggs present in late April. Testicular cycle begins with the emergence of males, and spermatozoa are produced from April through July. Uta reaches sexual maturity in one year at a SVL of 40.0 mm in males and 43 mm in females. Overall clutch size is 3.75 eggs (1–2 clutches per year). Fat body size at emergence is not known, but what is present shows a decline in males and females until July, when a substantial increase occurs. Sex ratios are about 1:1 in all months and seasons except June 1968, according to chi-square analysis.