Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

Hedgehog signalling--an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer--may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis.     

通过权重共表达网络分析胰腺癌转移的特异基因网络

胰腺癌是一种高度恶性的消化道肿瘤,临床表现不具有特征性,在早期难诊断易转移,发展迅速;胰腺癌转移率高,且转移后难以治愈进而导致死亡率升高。因此相比胰腺癌未转移来说,研究确定预测胰腺癌转移、转移后的新治疗方法及治疗的潜在靶标尤为迫切并具有重要意义。而且近两年兴起的基于基因之间相关关系的共表达网络分析法,为多种复杂疾病的研究提供了新的线索和思路。我们应用TCGA数据库中的大量胰腺癌转录组数据,筛选胰腺癌转移差异表达基因,使用共表达网络分析法(WGCNA)筛选胰腺癌转移后,基因间出现一个52个差异表达基因构建的新共表达网络模块,且挖掘到其中ASIC4,GLDC,MMD2,CTNNA2,FOXC4-AS1,SNHG19和BCAN等11个枢纽基因。我们推测认为它们为胰腺癌转移提供了新的潜在诊断、治疗靶标。同时KEGG富集分析发现,该新基因网络模块内基因富集于炎症介质对色氨酸通道的调节,卵母细胞减数分裂,乙醛酸和二元羧酸盐代谢和甘氨酸、丝氨酸和苏氨酸代谢等4条代谢通路。     

Polypeptide ligation occurs during post-translational modification of concanavalin A

Lectins are proteins with multivalent carbohydrate-binding sites, which confer the ability to agglutinate. The seeds of legumes are particularly rich in lectins, for example, concanavalin A (Con A) comprises up to 15% of the protein in the cotyledons of jack bean (Canavalia ensiformis) seeds. The amino acid sequences of Con A and several other legume lectins have been partially or fully determined, and comparison of these sequences from different species reveals a circular homology (Fig. 1A); rearrangements within the genome have been suggested to explain this. We report here that the circular homology displayed by Con A is due to a post-translational transposition and ligation within the initial polypeptide. This type of modification has not been reported previously for eukaryotes, although it has been suggested to occur in bacteriophage lambda.     

浅析遗传算法与进化策略

介绍了遗传算法和进化策略的算法模型，着重讨论了遗传算法和进化策略的特点以及各自的局限性，并分析了遗传算法和进化策略的区别与联系，最后指出遗传算法和进化策略有待解决的问题和二者可以联合发展的趋势。     

RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.     

Involvement of chemokine receptors in breast cancer metastasis

Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.     

远程会诊系统的开发思路与技术要素探讨

在走访工程技术人员及临床专家的基础上,我们体会到开发一套符合本院及本地区实际的远程会诊系统具有明确的必要性,但目前市面使用的系统存在一定的局限性,部分表现为只支持视频及音频,不能传输影像学、检验学资料,更不能实时传输如心肺听诊等重要生命信息,故临床专家反馈的效果不够满意,此为影响当前远程会诊系统可用性及卖座率的关键因素。因此笔者对信息量丰富、能够实时反映生命信息的远程会诊系统开发的思路及部分技术要素进行一些探讨,以此抛砖引玉,为开发更为先进实用的系统提供一些参考性意见。     

Mechanism of ribosome frameshifting during translation of the genetic code

Some frameshift mutations are strongly suppressed by limitation for particular aminoacyl-tRNA species. Here, we show that ribosome frameshifting at a specific tryptophan codon during Trp-tRNA limitation accounts for suppression of a group of downstream frameshift alleles in the rIIB gene of bacteriophage T4. Genetic and physiological observations strongly suggest that ribosome frameshifting at this position depends on the binding of a noncognate (leucine) tRNA.     

A carbon isotope record of CO2 levels during the late Quaternary

Analyses of gases trapped in continental ice sheets have shown that the concentration of CO2 in the Earth's early atmosphere increased from 180 to 280 p.p.m. during the most recent glacial-interglacial transition. This change must have been driven by an increase in the concentration of CO2 dissolved in the mixed layer of the ocean. Biochemical and physiological factors associated with photosynthetic carbon fixation in this layer should lead to a relationship between concentrations of dissolved CO2 and the carbon isotopic composition of phytoplanktonic organic material, such that increased atmospheric CO2 should enhance the difference in 13C content between dissolved inorganic carbon and organic products of photosynthesis. Here we show that a signal related to atmospheric CO2 levels can be seen in the isotope record of a hemipelagic sediment core, which we can correlate with the CO2 record of the Vostok ice core. Calibration of the relationship between isotope fractionation and CO2 levels should permit the extrapolation of CO2 records to times earlier than those for which ice-core records are available.     

Laboratory models of the thermal evolution of the mantle during rollback subduction

The subduction of oceanic lithosphere plays a key role in plate tectonics, the thermal evolution of the mantle and recycling processes between Earth's interior and surface. Information on mantle flow, thermal conditions and chemical transport in subduction zones come from the geochemistry of arc volcanoes, seismic images and geodynamic models. The majority of this work considers subduction as a two-dimensional process, assuming limited variability in the direction parallel to the trench. In contrast, observationally based models increasingly appeal to three-dimensional flow associated with trench migration and the sinking of oceanic plates with a translational component of motion (rollback). Here we report results from laboratory experiments that reveal fundamental differences in three-dimensional mantle circulation and temperature structure in response to subduction with and without a rollback component. Without rollback motion, flow in the mantle wedge is sluggish, there is no mass flux around the plate and plate edges heat up faster than plate centres. In contrast, during rollback subduction flow is driven around and beneath the sinking plate, velocities increase within the mantle wedge and are focused towards the centre of the plate, and the surface of the plate heats more along the centreline.     

Rapid collisional evolution of comets during the formation of the Oort cloud

The Oort cloud of comets was formed by the ejection of icy planetesimals from the region of giant planets--Jupiter, Saturn, Uranus and Neptune--during their formation. Dynamical simulations have previously shown that comets reach the Oort cloud only after being perturbed into eccentric orbits that result in close encounters with the giant planets, which then eject them to distant orbits about 10(4) to 10(5) AU from the Sun (1 AU is the average Earth-Sun distance). All of the Oort cloud models constructed until now simulate its formation using only gravitational effects; these include the influence of the Sun, the planets and external perturbers such as passing stars and Galactic tides. Here we show that physical collisions between comets and small debris play a fundamental and hitherto unexplored role throughout most of the ejection process. For standard models of the protosolar nebula (starting with a minimum-mass nebula) we find that collisional evolution of comets is so severe that their erosional lifetimes are much shorter than the timescale for dynamical ejection. It therefore appears that collisions will prevent most comets escaping from most locations in the region of the giant planets until the disk mass there declines sufficiently that the dynamical ejection timescale is shorter than the collisional lifetime. One consequence is that the total mass of comets in the Oort cloud may be less than currently believed.     

Regulation of cancer cell migration and bone metastasis by RANKL

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.     

鲁西隆起中-新生代伸展构造演化的模拟试验

通过野外地质调查对鲁西隆起伸展构造特征进行研究,并根据相似理论建立相关试验模型,对鲁西隆起晚中生代以来的伸展构造的发育演化进行构造物理模拟.结果表明:鲁西隆起晚中生代以来的伸展裂陷作用主要经历了晚侏罗-早白垩世、新生代两个阶段,新生代又分为古近纪古新世-始新世初期(65～53 Ma)、早始新世-晚始新世(53～39 Ma)和始新世末期-渐新世(39～23.5 Ma)3个时期,各个时期与研究区伸展构造的主要发育时期相符;物理模拟试验证实泰山在新生代有两次快速抬升,分别为始新世(45 Ma)和渐新世(23 Ma);伸展构造的形成归因于晚中生代和古近纪近南北向大规模的伸展作用,其深部背景主要为晚侏罗世以来太平洋板块俯冲方向及速度的改变、郯庐断裂带的走滑活动、新生代印欧板块的碰撞以及幔源岩浆活动.     

个性化教育——远程教育的基本模式

从学生的学习动机个性化,学习群体多样性,学习形式个性化,学习过程个性化,论述了远程教育的基本模式——个性化教育的特点,并对教学管理的个性化提出了设想.     

中晚期食管癌治疗疗效观察

目的：不适合手术治疗的中晚期食管癌,联合化疗全身用药加局部照射可提高其疗效。方法：对120例不能手术切除的中晚期食管癌患者随机分为化疗加放疗组和单纯放疗组,各为60例。两组照射方法相同DT50－70GY／5－7周。化疗使用FD方案,化疗在放疗前后各行一次。结果：1、2、3年生存率,化疗加放疗组为70．0％,53．3％,31．7％。单纯放疗组为46．7％,36.7％,20．0％。两组1、2、3年生存率对比有显著差异（P＜0．05）;结论：中位生存期,化疗加放疗组明显高于单放组。