The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers

Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.     

Ant assemblages in intact big sagebrush and converted cheatgrass-dominated habitats in Tooele County, Utah

Biological invasions are one of the greatest threats to native species in natural ecological systems. One of the most successful invasive species is Bromus tectorum L. (cheatgrass), which is having marked impacts on native plant communities and ecosystem processes. However, we know little about the effects of this invasion on native animal species in the Intermountain West. Because ants have been used to detect ecological change associated with anthropogenic land use, they seem well suited for a preliminary evaluation of the consequences of cheatgrass-driven habitat conversion. In our study, we used pitfall traps to assess ant community assemblages in intact sagebrush and nearby cheatgrass-dominated vegetation. Ant abundance was about 10-fold greater in cheatgrass-dominated plots than in sagebrush plots. We also noted differences in diversity and evenness between habitat types at both the species and the functional-group levels of organization. At the species level, Shannon’s diversity index was greater in sagebrush plots than in cheatgrass-dominated plots. However, at the functional-group level, Simpson’s and Shannon’s diversity indices and the Brillouin evenness index were greater in cheatgrass-dominated plots than in sagebrush plots. Further, common species / functional groups tended to be more abundant while less common species / functional groups tended to be less abundant in cheatgrass-dominated plots compared to intact sagebrush plots. Patterns appear to be at least partially related to resource availabilities. This initial survey of ant communities from intact-native and altered vegetation types may be indicative of similar trends of biodiversity shifts throughout the Intermountain West where cheatgrass has successfully replaced native species. We also discuss the implications of ant communities on land management activities, specifically in the context of aridland restoration.     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

用脸谱图对太子河本溪市区段河流沉积物中重金属污染进行评价的研究

本文将沉积学原理及国际上新发展的两种重金属污染评价方法与多变量的图表示法——脸谱图相结合,对太子河本溪市区段河道沉积物中重金属的污染状况及潜在生态危害进行了综合性的评价研究。从脸谱图上可以直观地看出各采样点重金属的污染情况和潜在生态危害程度。从研究结果可以看出,太子河本溪市区段河道沉积物中重金属的污染是很严重的。     

A functional role for vasoactive intestinal polypeptide in anterior cingulate cortex

Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the cerebral cortex, where it is the putative neurotransmitter of a major intracortical neuronal system. Homogenates of cortical tissue contain high-affinity, specific binding sites for VIP as well as an adenylate cyclase system which is sensitive to this peptide. As with many of the other peptidergic systems which have been identified in the central nervous system (CNS), it has proved extremely difficult to elucidate the nature and extent of the functional role of VIP in specific brain areas. Here, using the quantitative autoradiographic 14C-deoxyglucose technique in rats to provide insight into functional processes, we describe the increases in glucose utilization which occur locally in anterior cingulate cortex following the unilateral injection of VIP (20 pmol) into this key brain area and, additionally, the focal alterations in glucose use in CNS regions having known neuronal connections with the injected region (for example, ipsilateral mediodorsal thalamus, ventral tegmental area, nucleus accumbens, caudate nucleus and contralateral cingulate cortex). These data provide evidence that VIP may modify the processing of afferent and efferent information within the anterior cingulate cortex in the conscious rat.     

寻找四元域上n维线性空间中n/2维自对偶子空间的方法

本文讨论F4上n维线性空间的k维子空间W，这些子空间都有特定的自同构群(实际上是典型群GLn(F4)的一个子群)，根据群中元素形式的不同可将子空间W分为两类，并对寻找n维空间中形如这两类的n／2维自对偶子空间提供了一种采用降低维数寻找的方法。     

A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC

It is now possible to paint a detailed picture of how cytoplasmic proteins are handled by the immune system. They are apparently degraded in the cytoplasm into peptides. These are then transported into the endoplasmic reticulum where they encounter class I major histocompatibility complex (MHC) molecules. Once loaded with peptide, the HLA molecules move through the Golgi apparatus to the cell membrane. Until recently, it had not been established how peptides without signal sequences cross the ER membrane. However, a number of papers have now described a pair of membrane transporter genes of the ABC (ATP-binding cassette) super-family which are attractive candidates for this function. Both transporter genes, which may encode two halves of a heterodimer, are situated in the class II region of the MHC. There is evidence that other putative components of the processing machinery, the LMPs (low molecular mass polypeptides), are also encoded in the MHC. Similarities between the properties of the LMPs and a large intracellular protease complex, called proteasome, have led to the suggestion that LMPs are involved in processing antigens. We have now identified a human gene with sequence homology to proteasome components. Remarkably, this gene maps between the two putative peptide transporter genes.     

Energy source of flagellar type III secretion

Bacterial flagella contain a specialized secretion apparatus that functions to deliver the protein subunits that form the filament and other structures to outside the membrane. This apparatus is related to the injectisome used by many gram-negative pathogens and symbionts to transfer effector proteins into host cells; in both systems this export mechanism is termed 'type III' secretion. The flagellar secretion apparatus comprises a membrane-embedded complex of about five proteins, and soluble factors, which include export-dedicated chaperones and an ATPase, FliI, that was thought to provide the energy for export. Here we show that flagellar secretion in Salmonella enterica requires the proton motive force (PMF) and does not require ATP hydrolysis by FliI. The export of several flagellar export substrates was prevented by treatment with the protonophore CCCP, with no accompanying decrease in cellular ATP levels. Weak swarming motility and rare flagella were observed in a mutant deleted for FliI and for the non-flagellar type-III secretion ATPases InvJ and SsaN. These findings show that the flagellar secretion apparatus functions as a proton-driven protein exporter and that ATP hydrolysis is not essential for type III secretion.