BACKGROUND & AIMS: :Several attempts to classify gastric cancer (GCA) have been made over the past decades. Most successful, and widely used, is the classification by Laurén, which distinguishes, by microscopical morphology alone, two main cancer pathogeneses, diffuse (DGCA) and intestinal (IGCA) subtypes, which appear clearly as dissimilar clinical and epidemiological entities. Here we review the main differences in epidemiology, histopathology, and molecular pathology of the two main subtypes of gastric carcinomas based on Laurén classification. In clinical practice, however, clinical staging, particularly in predicting the survival, still remains superior to all classifications of gastric cancer independent of cancer type. The existence of local precursor lesions or conditions of IGCA tumours, i.e. Helicobacter pylori gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), adenoma, dysplasia, and intramucosal neoplasia, is firmly established. The links of DGCA with intestinal-type epithelium, AG or IM are poor, or do not exist. So far, H. pylori gastritis is the only universal precursor condition for DGCA. It implies that AG and achlorhydria are of minor significance and infrequent in the development of DGCA but are important steps in that of IGCA. Despite an increasing body of data, the overall view on molecular pathology of GCA remains fragmentary. No consistent differences in the molecular pathology of GCA subtypes to meet the Laurén classification have been established. With the exception of TP53, no gene mutation occurring regularly in both histological types of GCA has been reported. Chromosomal aberrations and loss of heterozygosity seem to be non-specific and do not follow any consistent route in the progression of GCA. Microsatellite instability is more commonly found in IGCA than in DGCA. The present epigenetic data suggest that most of the decrease (or loss) of gene expression may be explained by promoter hypermethylation which is more often found in IGCA. In DGCA specific genes such as CDH1 are more often hypermethylated. Compared with GCA, in premalignant condition lesions gene mutations and chromosomal aberrations are infrequent. Epigenetic dysregulation might also represent a major mechanism for altered gene expression in premalignant stages in gastric carcinogenesis.

背景与目标： : 在过去的几十年中，已经进行了几次对胃癌 (GCA) 进行分类的尝试。最成功且广泛使用的是lauren的分类，该分类仅通过显微镜形态学区分了两种主要的癌症病因，弥漫性 (DGCA) 和肠道 (IGCA) 亚型，它们显然是不同的临床和流行病学实体。在这里，我们根据lauren分类回顾了两种主要亚型胃癌流行病学，组织病理学和分子病理学方面的主要差异。然而，在临床实践中，临床分期 (尤其是在预测生存率方面) 仍然优于所有胃癌分类，而与癌症类型无关。IGCA肿瘤的局部前体病变或疾病的存在，即幽门螺杆菌胃炎，萎缩性胃炎 (AG)，肠上皮化生 (IM)，腺瘤，异型增生和粘膜内瘤变。DGCA与肠型上皮，AG或IM的联系较差或不存在。到目前为止，幽门螺杆菌胃炎是DGCA唯一的普遍前体疾病。这意味着AG和achlorhydria在DGCA的发展中意义不大，并不常见，但在IGCA的发展中却是重要的步骤。尽管有越来越多的数据，但对GCA分子病理学的总体看法仍然是零碎的。尚未建立符合Laurén分类的GCA亚型分子病理学的一致差异。除TP53外，没有报道在两种组织学类型的GCA中都定期发生基因突变。染色体畸变和杂合性丧失似乎是非特异性的，并且在GCA的发展过程中没有遵循任何一致的途径。微卫星不稳定性在IGCA中比在DGCA中更常见。目前的表观遗传数据表明，基因表达的大部分减少 (或丧失) 可以通过启动子高甲基化来解释，启动子高甲基化在IGCA中更常见。在DGCA中，特定基因 (例如CDH1) 通常被高甲基化。与GCA相比，在恶变前病变中，基因突变和染色体畸变很少。表观遗传失调也可能代表胃癌发生前恶性阶段基因表达改变的主要机制。

BACKGROUND & AIMS: :In a patient with temporomandibular disorder who does not respond to conservative treatment, treatment with intra-articular injection of high molecular weight sodium hyaluronate can be suggested. In our study, 27 patients with nonreduced disc displacement were diagnosed clinically and confirmed by magnetic resonance imaging. The age range was from 21 to 63 years old, with a mean of 39.3 years. Two cycles of injection of high molecular weight sodium hyaluronate was performed on alternative weeks. Pain intensity was measured by the visual analog scale. Maximal mouth opening, clicking joint noise, and lateral movement were measured before and after injection for more than 6 months. Reduction of pain intensity and improvement in the maximum mouth opening parameter was statistically significant. In conclusion, this intra-articular injection using high molecular weight sodium hyaluronate looks very positive for patients affected by nonreduced disc displacement and is encouraged to be used as a primary treatment of temporomandibular joint dysfunction.

背景与目标： : 对于对保守治疗无反应的颞下颌疾病患者，建议使用关节内注射高分子量透明质酸钠进行治疗。在我们的研究中，临床诊断出27例椎间盘移位未减少的患者，并通过磁共振成像证实。年龄范围为21至63岁，平均39.3岁。在其他星期进行了两个周期的高分子量透明质酸钠注射。疼痛强度通过视觉模拟量表测量。注射前后6个月以上，测量最大张口，点击关节噪声和侧向运动。疼痛强度的降低和最大张口参数的改善具有统计学意义。总之，这种使用高分子量透明质酸钠的关节内注射对于受椎间盘移位不全影响的患者看起来非常积极，并被鼓励用作颞下颌关节功能障碍的主要治疗方法。

BACKGROUND & AIMS: We previously showed via electron microscopic immunocytochemistry that a 73 kDa polypeptide was an authentic peroxisomal membrane protein (PMP73) integrated exclusively into the boundary membrane of glyoxysomes in cucumber seedlings. In this paper we test the hypothesis that this PMP73 is a member of the heat-shock 70 protein (Hsp70) family by comparing amino acid sequences of cyanogen bromide (CNBr)-cleaved polypeptide fragments, immunoreactivities on protein blots, and microscopic immunofluorescence within suspension-cultured BY-2 tobacco cells. A sequence of eight amino acids (DAVGPEIQ) in PMP73 showed a high degree of similarity (up to 88%) with sequences in the same carboxy-terminal region of four plant Hsp70 proteins. IgGs affinity purified to PMP73 recognized on blots a membrane-bound Hsp72 (in pea cotyledon microsomes) and a cucumber PMP61, the latter shown by CNBr cleavage to be a distinct, but immunorelated polypeptide to PMP73. Conversely, IgGs specific for tomato Hsc70 (C-terminal half) recognized cucumber PMP73, and IgGs specific for cucumber DnaJ homologue (entire protein) recognized cucumber PMP61. In BY-2 cells, cucumber PMP73-specific IgGs localized only to peroxisomes. Antibodies raised against portions of tomato Hsc70 also localized to the BY-2 peroxisomes (as well as to cytosolic proteins). Collectively, the data show that authentic cucumber PMPs73 and 61 are immunorelated to each another, and that both exhibit selective immunoreactivity to IgGs from two classes of molecular chaperones, namely Hsp70 proteins and plant DnaJ homologues. They appear to be unique membrane-bound chaperones that likely function as part of the peroxisomal protein translocation machinery.

背景与目标： 我们先前通过电子显微镜免疫细胞化学显示，一个73 kDa的多肽是真正的过氧化物酶体膜蛋白 (PMP73)，仅整合到黄瓜幼苗中乙醛酸体的边界膜中。在本文中，我们通过比较溴化氰 (CNBr) 切割的多肽片段的氨基酸序列，蛋白质印迹上的免疫反应性以及悬浮培养的by-2烟草细胞中的微观免疫荧光，检验了该PMP73是热休克70蛋白 (Hsp70) 家族成员的假设。PMP73中的八个氨基酸序列 (DAVGPEIQ) 与四种植物Hsp70蛋白的相同羧基末端区域中的序列显示出高度相似性 (高达88%)。纯化的与PMP73的IgGs亲和力在印迹上识别出与膜结合的Hsp72 (在豌豆子叶微粒体中) 和黄瓜PMP61，后者通过CNBr裂解显示为PMP73的独特但与免疫相关的多肽。相反，对番茄Hsc70 (C末端一半) 特异的igg识别黄瓜PMP73，对黄瓜DnaJ同源物 (整个蛋白质) 特异的igg识别黄瓜pmp61。在BY-2细胞中，黄瓜PMP73-specific igg仅定位于过氧化物酶体。针对番茄Hsc70部分产生的抗体也定位于BY-2过氧化物酶体 (以及胞质蛋白)。总的来说，数据表明，真实的黄瓜PMPs73和61彼此免疫相关，并且都对来自两类分子伴侣的igg表现出选择性免疫反应性，即Hsp70蛋白和植物DnaJ同源物。它们似乎是独特的膜结合伴侣，可能是过氧化物酶体蛋白易位机制的一部分。

BACKGROUND & AIMS: :cAMP signaling pathways play crucial roles in photoreceptor cells and other retinal cell types. Previous studies demonstrated a circadian rhythm of cAMP level in chick photoreceptor cell cultures that drives the rhythm of activity of the melatonin synthesizing enzyme arylalkylamine N-acetyltransferase and the rhythm of affinity of the cyclic nucleotide-gated channel for cGMP. Here, we report that the photoreceptor circadian clock generates a rhythm in Ca(2+)/calmodulin-stimulated adenylyl cyclase activity, which accounts for the temporal changes in the cAMP levels in the photoreceptors. The circadian rhythm of cAMP in photoreceptor cell cultures is abolished by treatment with the l-type Ca(2+) channel antagonist nitrendipine, while the Ca(2+) channel agonist, Bay K 8644, increased cAMP levels with continued circadian rhythmicity in constant darkness. These results indicate that the circadian rhythm of cAMP is dependent, in part, on Ca(2+) influx. Photoreceptor cell cultures exhibit a circadian rhythm in Ca(2+)/calmodulin-stimulated adenylyl cyclase enzyme activity with high levels at night and low levels during the day, correlating with the temporal changes of cAMP in these cells. Transcripts encoding two of the Ca(2+)/calmodulin-stimulated adenylyl cyclases, type 1 and type 8 (Adcy1 and Adcy8), displayed significant daily rhythms of mRNA expression under a light-dark cycle, but only the Adcy1 transcript rhythm persisted in constant darkness. Similar rhythms of Adcy1 mRNA level and Ca(2+)/calmodulin-stimulated adenylyl cyclase activity were observed in retinas of 2-week-old chickens. These results indicate that a circadian clock controls the expression of Adcy1 mRNA and Ca(2+)/calmodulin-stimulated adenylyl cyclase activity; and calcium influx into these cells gates the circadian rhythm of cAMP, a key component in the regulation of photoreceptor function.

背景与目标： : cAMP信号通路在感光细胞和其他视网膜细胞类型中起着至关重要的作用。先前的研究表明，雏鸡感光细胞培养物中cAMP水平的昼夜节律驱动褪黑激素合成酶芳基烷基胺N-乙酰基转移酶的活性节律和环状核苷酸门控通道对cGMP的亲和力节律。在这里，我们报告了感光体昼夜节律时钟在Ca(2)/钙调蛋白刺激的腺苷酸环化酶活性中产生节律，这说明了感光体中cAMP水平的时间变化。通过用l型Ca(2) 通道拮抗剂尼群地平处理，消除了感光细胞培养物中cAMP的昼夜节律，而Ca(2) 通道激动剂Bay K 8644在持续的黑暗中增加了cAMP水平，并持续了昼夜节律。这些结果表明，cAMP的昼夜节律部分取决于Ca(2) 的流入。感光细胞培养物在Ca(2)/钙调蛋白刺激的腺苷酸环化酶活性中表现出昼夜节律，夜间水平高，白天水平低，与这些细胞中cAMP的时间变化相关。编码两个Ca(2)/钙调蛋白刺激的腺苷酸环化酶 (1型和8型) (Adcy1和Adcy8) 的转录本在明暗循环下显示出明显的每日mRNA表达节律，但只有Adcy1转录本节律持续持续黑暗。在2周龄鸡的视网膜中观察到Adcy1 mRNA水平和Ca(2)/钙调蛋白刺激的腺苷酸环化酶活性的相似节律。这些结果表明，生物钟控制Adcy1 mRNA的表达和Ca(2)/钙调蛋白刺激的腺苷酸环化酶活性; 钙流入这些细胞中，激活了cAMP的昼夜节律，cAMP是调节感光细胞功能的关键组成部分。

BACKGROUND & AIMS: :Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.

背景与目标： : 几种分子靶向疗法已在治疗头颈部鳞状细胞癌 (HNSCC) 的临床试验中进行了测试。其中，针对表皮生长因子受体 (EGFR) 的疗法已被最广泛地研究，并且一些药物已证明可测量的临床有效性。然而，旨在定义可能对EGFR靶向治疗有反应的HNSCC患者亚组的分子研究尚未确定与临床反应相关的分子特征。在这里，作者总结了相关的临床发现，并重点报道了针对HNSCC的EGFR靶向治疗的分子相关研究。作者特别关注评估与临床反应相关的分子标志物，并包括来自其他癌症部位的EGFR靶向临床研究的数据，他们预计这些数据将对头颈癌症研究和治疗社区感兴趣。

BACKGROUND & AIMS: Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.

背景与目标： 对一名15岁女孩左心房切除的多形性肉瘤进行了细胞遗传学和分子遗传学研究。组织学分析与多形性恶性纤维组织细胞瘤 (MFH) 一致。尽管MFH是成年后期最常见的软组织肉瘤。在儿童时期极为罕见，其在儿科人群中的存在仍然存在争议。细胞遗传学分析显示了先前与成人MFH相关的几种改变，包括染色体带11p11和19p13的异常。此外，肿瘤显示出均匀染色区域 (HSR) 和双分钟染色体 (dmin)，提示基因扩增。因此，我们筛选了扩增定位于染色体带12q13-14的基因的案例，包括假定的原癌基因MDM2，CDK4，SAS，CHOP和CLI，它们在成年MFH中经常被扩增和过表达。Southern和Northern印迹分析证实了MDM2，CDK4，SAS和CHOP的共扩增。据我们所知，这种12q13-14扩增子的共扩增研究以前尚未在小儿MFH中检测到。我们的结果提供了细胞遗传学和分子遗传学证据，表明儿科和成年MFH是与组织遗传学相关的实体。

BACKGROUND & AIMS: :Cupriavidus necator JMP134(pJP4) harbors a catabolic plasmid, pJP4, which confers the ability to grow on chloroaromatic compounds. Repeated growth on 3-chlorobenzoate (3-CB) results in selection of a recombinant strain, which degrades 3-CB better but no longer grows on 2,4-dichlorophenoxyacetate (2,4-D). We have previously proposed that this phenotype is due to a double homologous recombination event between inverted repeats of the multicopies of this plasmid within the cell. One recombinant form of this plasmid (pJP4-F3) explains this phenotype, since it harbors two copies of the chlorocatechol degradation tfd gene clusters, which are essential to grow on 3-CB, but has lost the tfdA gene, encoding the first step in degradation of 2,4-D. The other recombinant plasmid (pJP4-FM) should harbor two copies of the tfdA gene but no copies of the tfd gene clusters. A molecular analysis using a multiplex PCR approach to distinguish the wild-type plasmid pJP4 from its two recombinant forms, was carried out. Expected PCR products confirming this recombination model were found and sequenced. Few recombinant plasmid forms in cultures grown in several carbon sources were detected. Kinetic studies indicated that cells containing the recombinant plasmid pJP4-FM were not selectable by sole carbon source growth pressure, whereas those cells harboring recombinant plasmid pJP4-F3 were selected upon growth on 3-CB. After 12 days of repeated growth on 3-CB, the complete plasmid population in C. necator JMP134 apparently corresponds to this form. However, wild-type plasmid forms could be recovered after growing this culture on 2,4-D, indicating that different plasmid forms can be found in C. necator JMP134 at the population level.

背景与目标： : Cupriavidus necatator JMP134(pJP4) 具有分解代谢质粒pJP4，该质粒赋予了在氯芳族化合物上生长的能力。在3-氯苯甲酸酯 (3-CB) 上重复生长导致选择重组菌株，该菌株可以更好地降解3-CB，但不再在2,4-二氯苯氧乙酸 (2,4-d) 上生长。我们先前已经提出，这种表型是由于该质粒在细胞内的多胞菌的反向重复之间发生了双重同源重组事件。这种质粒的一种重组形式 (pJP4-F3) 解释了这种表型，因为它包含两个拷贝的氯邻苯二酚降解tfd基因簇，这两个拷贝对于在3-CB上生长是必不可少的，但是已经失去了tfdA基因，编码2,4-d降解的第一步。另一个重组质粒 (pJP4-FM) 应该包含两个拷贝的tfdA基因，但没有拷贝的tfd基因簇。进行了分子分析，使用多重PCR方法将野生型质粒pJP4与其两种重组形式区分开。发现并测序了证实该重组模型的预期PCR产物。在几种碳源中生长的培养物中，几乎没有检测到重组质粒形式。动力学研究表明，含有重组质粒pJP4-FM的细胞不能通过唯一的碳源生长压力来选择，而那些具有重组质粒pJP4-F3的细胞在3-CB上生长时被选择。在3-CB上重复生长12天后，C. necator JMP134中的完整质粒群体显然对应于这种形式。但是，在2,4-d上生长该培养物后，可以恢复野生型质粒形式，这表明在种群水平上在C. necator JMP134中可以发现不同的质粒形式。

BACKGROUND & AIMS: Molecular dynamics simulations have been carried out with four polypeptides, Ala13, Val(13), Ser13, and Ala4Gly5Ala4, in vacuo and with explicit hydration. The unfolding of the polypeptides, which are initially fully alpha-helix in conformation, has been monitored during trajectories of 0.3 ns at 350 K. A rank of Ala < Val < Ser < Gly is found in the order of increasing rate of unwinding. The unfolding of Ala13 and Val(13) is completed in hundreds of picoseconds, while that of Ser13 is about one order of magnitude faster. The helix content of the peptide containing glycine residues falls to zero within a few picoseconds. Ramachandran plots indicate quite distinct equilibrium distributions and time evolution of dihedral angles in water and in vacuum for each residue type. The unfolding of polyalanine and polyvaline helices is accelerated due to solvation. In contrast, polyserine is more stable in water compared to vacuum, because its side chains can form intramolecular hydrogen bonds with the backbone more readily in vacuum, which disrupts the helix. Distribution functions of the spatial and angular position of water molecules in the proximity of the polypeptide backbone polar groups reveal the stabilization of the coiled structures by hydration. The transition from helix to coil is characterized by the appearance of a new peak in the probability distribution at a specific location characteristic of hydrogen bond formation between water and backbone polar groups. No significant insertion of water molecules is observed at the precise onset of unwinding, while (i, i+3) hydrogen bond formation is frequently detected at the initiation of alpha-helix unwinding.

背景与目标： 已在真空中并在显式水合作用下使用四种多肽Ala13，Val(13)，Ser13和Ala4Gly5Ala4进行了分子动力学模拟。在350 K处0.3 ns的轨迹期间，已经监测了最初在构象上完全为 α-螺旋的多肽的展开。Ala

BACKGROUND & AIMS: :The yeast S. cerevisiae is a central model organism in eukaryotic cell studies and a major component in many food and biotechnological industrial processes. However, the wide knowledge regarding genetics and molecular biology of S. cerevisiae is based on an extremely narrow range of strains. Studies of natural populations of S. cerevisiae, not associated with human activities or industrial fermentation environments, are very few. We isolated a panel of S. cerevisiae strains from a natural microsite, "Evolution Canyon" at Mount Carmel, Israel, and studied their genomic biodiversity. Analysis of 19 microsatellite loci revealed high allelic diversity and variation in ploidy level across the panel, from diploids to tetraploids, confirmed by flow cytometry. No significant differences were found in the level of microsatellite variation between strains derived from the major localities or microniches, whereas strains of different ploidy showed low similarity in allele content. Maximum genetic diversity was observed among diploids and minimum among triploids. Phylogenetic analysis revealed clonal, rather than sexual, structure of the triploid and tetraploid subpopulations. Viability tests in tetrad analysis also suggest that clonal reproduction may predominate in the polyploid subpopulations.

背景与目标： : 酵母酿酒酵母是真核细胞研究中的中心模式生物，也是许多食品和生物技术工业过程中的主要组成部分。然而，关于酿酒酵母的遗传学和分子生物学的广泛知识是基于极其狭窄的菌株范围。与人类活动或工业发酵环境无关的酿酒酵母自然种群研究很少。我们从以色列卡梅尔山的自然微位点 “进化峡谷” 中分离了一组酿酒酵母菌株，并研究了它们的基因组生物多样性。对19个微卫星基因座的分析显示，从二倍体到四倍体，整个面板的等位基因多样性和倍性水平变化很高，通过流式细胞术证实。在来自主要地区或微型物种的菌株之间的微卫星变异水平上没有发现显着差异，而不同倍性的菌株在等位基因含量上显示出较低的相似性。在二倍体中观察到最大的遗传多样性，在三倍体中观察到最小。系统发育分析显示，三倍体和四倍体亚群的克隆而非性结构。tetrad分析中的生存力测试还表明，克隆繁殖可能在多倍体亚群中占主导地位。

BACKGROUND & AIMS: :Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).

背景与目标： : 细胞周期蛋白依赖性激酶5 (CDK5) 是属于细胞周期蛋白依赖性激酶 (CDK) 家族的丝氨酸/苏氨酸激酶。CDK5参与多种神经元疾病 (包括阿尔茨海默病或帕金森氏病，中风，创伤性脑损伤)，疼痛信号传导和细胞迁移。在本信中，我们描述了新的2,6，9-三取代嘌呤的合成和生物学评估，这些嘌呤在结构上与roscovitine有关，roscovitine是目前在临床试验中有希望的CDK抑制剂 (CDK1/Cyclin B，IC(50)= 350 nM; CDK5/p25，IC(50)= 200 nM)。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的; 几种化合物 (3j，3k，3l，3e，4k，6b，6c) 显示出针对CDK5的有效激酶抑制能力 (IC(50) 值范围为17至50 nm)，并显示出显着的细胞死亡诱导活性 (IC(50) 值范围为2至9μm的SH-SY5Y)。抑制剂与CDK5催化位点的ATP结合结构域的对接突出了涉及CDK5 Lys-89的氢键的区分作用。此外，针对几种抑制剂测量的用于络合的计算的最终能量平衡与IC(50) 值的排名一致。最后，我们观察到几种化合物表现出对DYRK1A (双重特异性，酪氨酸磷酸化调节激酶1A) 的亚微摩尔活性，DYRK1A是一种与唐氏综合症和阿尔茨海默氏病有关的激酶 (3g，3h，4m; IC(50) 值范围从300到400 nM)。

BACKGROUND & AIMS: :Specification of limb field and initiation of limb development involve multiple steps, each of which is tightly regulated both spatially and temporally. Recent developmental analyses on various vertebrates have provided insights into the molecular mechanisms that specify limb field and have revealed several genetic interactions of signals involved in limb initiation processes. Furthermore, new approaches to the study of the developmental mechanisms of the lateral plate mesoderm of amphioxus and lamprey embryos have given us clues to understand the evolutionary scenarios that led to the acquisition of paired appendages during evolution. This review highlights such recent findings and discusses the mechanisms of limb field specification and limb bud initiation during development and evolution.

背景与目标： : 肢体场的规范和肢体发育的开始涉及多个步骤，每个步骤在空间和时间上都受到严格的调节。最近对各种脊椎动物的发育分析提供了对指定肢体场的分子机制的见解，并揭示了肢体起始过程中信号的几种遗传相互作用。此外，研究文昌鱼和七lamp鳗胚胎的侧板中胚层发育机制的新方法为我们提供了线索，以了解导致进化过程中获得成对附属物的进化方案。这篇综述重点介绍了这些最新发现，并讨论了发育和进化过程中肢体场规范和肢体芽萌发的机制。

BACKGROUND & AIMS: BACKGROUND:Advances in comprehension of molecular biology of glioblastoma (GBM) have led to the development of targeted therapies. The aim of the present study was to evaluate the efficacy and safety of a targeted therapeutic approach in which administration of bevacizumab and erlotinib was tailored on the molecular profile of recurrent GBM. METHODS:We prospectively enrolled ten adult patients suffering from recurrent GBM who had undergone surgical resection and standard chemo-radiotherapy. Tumor tissue was assessed for the expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for PTEN and VEGF expression by immunohistochemistry. Normal PTEN status was required for inclusion. Patients with VEGF overexpressing tumors (10/10) were treated with bevacizumab (10 mg/kg iv every 2 weeks in 6-week cycles); patients whose tumor expressed EGFRvIII (4/10) added erlotinib (150 mg/day orally; 300 mg/day if on enzyme-inducing antiepileptic drugs). Therapy was continued until disease progression or unacceptable toxicity. Primary endpoints of the study were response rate (RR), 6-month progression-free survival (PFS-6), and safety profile. RESULTS:The RR and PFS-6 were 100 % (4/4) and 50 % (3/6) in patients treated with bevacizumab+erlotinib (n = 4) and bevacizumab (n = 6), respectively. In the whole cohort (n = 10), RR and PFS-6 were both 70 % (7/10); median PFS and overall survival (OS) were 8.0 (3.0-31.0) and 9.5 (5.0-31.0) months, respectively. No grade 3/4 adverse events were observed; three patients treated with bevacizumab+erlotinib displayed grade 1/2 rash not requiring dose reduction; one patient treated with bevacizumab developed intratumoral hemorrhage requiring treatment discontinuation. CONCLUSION:To our knowledge, this is the first study on recurrent GBM in which administration of bevacizumab and erlotinib was tailored on the molecular profile of the patient's tumor. Although we treated a limited number of patients, we obtained significantly higher RR and PFS-6 than those reported in a previous trial lacking molecular tumor analysis.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:Pancreatic endocrine tumors (PETs) share numerous features with gastrointestinal neuroendocrine (carcinoid) tumors. Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs (44 cases). METHODS:Activating mutations in EGFR, KIT, and PDGFRA and nonresponse mutations in KRAS were evaluated. Copy number of EGFR and HER-2/neu was quantified by fluorescence in situ hybridization. Expression of EGFR, PDGFRA, VEGFR1, TGFBR1, Hsp90, SSTR2A, SSTR5, IGF1R, mTOR, and MGMT was measured immunohistochemically. RESULTS:Elevated EGFR copy number was found in 38% of cases but no KRAS nonresponse mutations. VEGFR1, TGFBR1, PDGFRA, SSTR5, SSTR2A, and IGF1R exhibited the highest levels of expression in the largest percentages of PETs.Anticancer drugs BMS-754807 (selective for IGF1R/IR), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, targeting Hsp90), and axitinib (directed toward VEGFR1-3/PDGFRA-B/KIT) induced growth inhibition of human QGP-1 PET cells with IC50 values (nM) of 273, 723, and 743, respectively. At growth-inhibiting concentrations, BMS-754807 inhibited IGF1R phosphorylation; 17-AAG induced loss of EGFR, IGF1R, and VEGFR2; and axitinib increased p21(CDKN1A) expression without inhibiting VEGFR2 phosphorylation. CONCLUSIONS:Results encourage further research into multidrug strategies incorporating inhibitors targeting IGF1R or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest.

背景与目标：

BACKGROUND & AIMS: :The solution of the forward problem in fluorescence molecular imaging strongly influences the successful convergence of the fluorophore reconstruction. The most common approach to meeting this problem has been to apply the diffusion approximation. However, this model is a first-order angular approximation of the radiative transfer equation, and thus is subject to some well-known limitations. This manuscript proposes a methodology that confronts these limitations by applying the radiative transfer equation in spatial regions in which the diffusion approximation gives decreased accuracy. The explicit integro differential equations that formulate this model were solved by applying the Galerkin finite element approximation. The required spatial discretization of the investigated domain was implemented through the Delaunay triangulation, while the azimuthal discretization scheme was used for the angular space. This model has been evaluated on two simulation geometries and the results were compared with results from an independent Monte Carlo method and the radiative transfer equation by calculating the absolute values of the relative errors between these models. The results show that the proposed forward solver can approximate the radiative transfer equation and the Monte Carlo method with better than 95% accuracy, while the accuracy of the diffusion approximation is approximately 10% lower.

背景与目标： : 荧光分子成像中正向问题的解决方案强烈影响荧光团重建的成功收敛。解决此问题的最常见方法是应用扩散近似。但是，该模型是辐射传递方程的一阶角近似，因此受到一些众所周知的限制。该手稿提出了一种方法，该方法通过在空间区域中应用辐射传递方程来应对这些限制，在空间区域中，扩散近似值降低了精度。通过应用Galerkin有限元近似求解了建立该模型的显式积分微分方程。通过Delaunay三角剖分实现了所研究域所需的空间离散化，而角度空间则使用了方位角离散化方案。该模型已在两个模拟几何上进行了评估，并通过计算这些模型之间相对误差的绝对值，将结果与独立的蒙特卡洛方法和辐射传递方程的结果进行了比较。结果表明，提出的前向求解器能够较好地逼近辐射传递方程和蒙特卡罗方法，精度优于95%，而扩散逼近的精度约为10%。

BACKGROUND & AIMS: :The human butyrylcholinesterase (BChE) activity is less than 1% in the serum of silent variant individuals of Vysya community in India. They are homozygous for a point mutation at codon 307 (CTT → CCT) resulting in the substitution of leucine 307 by proline. The reason for the disappearance of the protein in the serum has not been explicated till date. Based on this background, we performed molecular dynamics simulation to probe the structural stability of Indian variant (L307P) in comparison with wild and other BChE variants (D70G, E497V, V142M) having differential esterase activity. The simulation of all the mutants except D70G showed a much larger Cα root mean square deviation from the wild BChE crystal structure, showing the overall conformational disturbance. Further analysis revealed that secondary structure of the mutant proteins was not stable. The orientation of the catalytic triad is also distorted in all the mutants. The distance between δ nitrogen of His438 to ε oxygen of Glu325 and ε nitrogen of His438 to γ oxygen of Ser198 were highly altered in L307P mutant than the wild and other three variants throughout the simulation. Such disparity of distances between the catalytic residues may be due to the change in the protein conformation attributing to their differential catalytic activity. Our studies thus prove that the Indian BChE L307P mutant with negligible activity is possibly due to its structural instability when compared to other BChE variants.

背景与目标： : 在印度Vysya社区的沉默变异个体的血清中，人丁酰胆碱酯酶 (BChE) 活性低于1%。它们在密码子307 (CTT → CCT) 处的点突变是纯合的，导致亮氨酸307被脯氨酸取代。到目前为止，尚未阐明血清中蛋白质消失的原因。基于此背景，我们进行了分子动力学模拟，以探索印度变体 (L307P) 与野生和其他具有不同酯酶活性的BChE变体 (D70G，E497V，V142M) 的结构稳定性。除D70G外，所有突变体的模拟均显示出与野生BChE晶体结构相比更大的c α 均方根偏差，显示出总体构象干扰。进一步的分析表明，突变蛋白的二级结构不稳定。在所有突变体中，催化三联体的方向也会扭曲。在整个模拟过程中，在L307P突变体中，His438的 δ 氮与Glu325的 ε 氧之间的距离和His438的 ε 氮与Ser198的 γ 氧之间的距离变化很大。催化残基之间距离的这种差异可能是由于蛋白质构象的变化归因于其不同的催化活性。因此，我们的研究证明，与其他BChE变体相比，活性可忽略的印度BChE L307P突变体可能是由于其结构不稳定所致。