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.     

对模拟退火算法解不均匀性的改善

模拟退火算法(SA)是一种对复杂的组合问题很有效的最优化算法,例如LSI设计中的布局设计,但模拟退火算法需要很长的执行时间,所以许多的研究者都在研究更快的模拟退火技术.在观察到模拟退火算法得到的结果可能会产生不均匀性,并且在几个简单集成模块布局问题的实验中发现这种不均匀性超过了30%,由此提出了一个改善SA算法结果的方法,称之为TOSA算法.通过对标准布局问题的实验,证明了SA算法结果的不均匀性和TOSA算法的有效性.在应用TOSA算法对8个全局标准布局问题IBM01～IBM02和IBM07～IBM12进行的布局实验中,相较于原始的模拟退火算法,在解的质量上获得了平均4%～7%的改善.     

平面曝光型光造型装置的研究

微型光造型法的一个很大的缺点是构造物的制造时间长。为了解决这一问题，在报告微型光固化立体成型法现状的基础上，提出了一种新颖的平面曝光型光造型方案，设计并制作了实验装置，利用热敏色带制作微型平面掩膜，进行了平面固化成型实验，实验结果表明，利用平面曝光型光造型方案进行成型，单层硬化时间可缩短至１２０ｓ。     

Saccharide Recognition by Oligo( meta-ethynylpyridine)s in Protic Media

1Introduction Previously, we have reported tris(ethynylpyridine) macrocycles as synthetic receptors for ribofuranosides, deoxyribofuranosides, and glucopyranosides[1]. The hydrogen-bonding skeletons of the macrocycles consisted of "meta"-tethered ethynylpyridine trimers. If the ethynylpyridine unit is polymerized, the resulting oligo- and poly(meta-ethynylpyridine) s would adopt unfolded, somewhat zigzag conformations because each pyridine nitrogen is mainly located on opposite sides of the ethynediyl bonds to cancel the dipoles. When the polymer meets with a saccharide, its pseudolinear conformation may be guided to a well-ordered helical structure in order that the nitrogen atoms of the pyridine rings inwardly interact with peripheral saccharide-OH groups in a manner similar to those of the macrocycles (Fig. 1). Thus, the chirality of saccharides added can be transferred to the helical sense of the polymer, depending on the stereochemistry of the saccharides.     

The role of autophagy during the early neonatal starvation period

At birth the trans-placental nutrient supply is suddenly interrupted, and neonates face severe starvation until supply can be restored through milk nutrients. Here, we show that neonates adapt to this adverse circumstance by inducing autophagy. Autophagy is the primary means for the degradation of cytoplasmic constituents within lysosomes. The level of autophagy in mice remains low during embryogenesis; however, autophagy is immediately upregulated in various tissues after birth and is maintained at high levels for 3-12 h before returning to basal levels within 1-2 days. Mice deficient for Atg5, which is essential for autophagosome formation, appear almost normal at birth but die within 1 day of delivery. The survival time of starved Atg5-deficient neonates (approximately 12 h) is much shorter than that of wild-type mice (approximately 21 h) but can be prolonged by forced milk feeding. Atg5-deficient neonates exhibit reduced amino acid concentrations in plasma and tissues, and display signs of energy depletion. These results suggest that the production of amino acids by autophagic degradation of 'self' proteins, which allows for the maintenance of energy homeostasis, is important for survival during neonatal starvation.     

Catalytic Asymmetric Carbon-Carbon Forming Reactions Catalyzed Chiral Schiff Base-Metal Complexes

1 Results In 1991, we disclosed the novel asymmetric catalysts prepared from chiral Schiff base and titanium alkoxide in the reaction of asymmetric silylcyanation of aldehydes (eq.1)[1]. Since our first report, chiral Schiff base-metal complex was proven to be efficient in a variety of asymmetric reactions. We reported the first example of enantioselective addition of diketene to aldehydes promoted by chiral Schiff base-titanium alkoxide complexes (eq.2)[2]. The products of this reaction have been cove...     

Direct control of shoot meristem activity by a cytokinin-activating enzyme

The growth of plants depends on continuous function of the meristems. Shoot meristems are responsible for all the post-embryonic aerial organs, such as leaves, stems and flowers. It has been assumed that the phytohormone cytokinin has a positive role in shoot meristem function. A severe reduction in the size of meristems in a mutant that is defective in all of its cytokinin receptors has provided compelling evidence that cytokinin is required for meristem activity. Here, we report a novel regulation of meristem activity, which is executed by the meristem-specific activation of cytokinins. The LONELY GUY (LOG) gene of rice is required to maintain meristem activity and its loss of function causes premature termination of the shoot meristem. LOG encodes a novel cytokinin-activating enzyme that works in the final step of bioactive cytokinin synthesis. Revising the long-held idea of multistep reactions, LOG directly converts inactive cytokinin nucleotides to the free-base forms, which are biologically active, by its cytokinin-specific phosphoribohydrolase activity. LOG messenger RNA is specifically localized in shoot meristem tips, indicating the activation of cytokinins in a specific developmental domain. We propose the fine-tuning of concentrations and the spatial distribution of bioactive cytokinins by a cytokinin-activating enzyme as a mechanism that regulates meristem activity.