Successful drug development despite adverse preclinical findings part 2: examples

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.     

Meiotic chromosome pairing in intergeneric hybrids of colchicaceous ornamentals revealed by genomic in situ hybridization (GISH)

Diploid and triploid intergeneric hybrids obtained by crosses among Gloriosa superba ‘Lutea’ (2n = 2x = 22), G. ‘Marron Gold’ (2n = 4x = 44), Littonia modesta (2n = 2x = 22), and Sandersonia aurantiaca (2n = 2x = 24) were analyzed for their meiotic chromosome pairing in pollen mother cells by genomic in situ hybridization (GISH) with digoxigenin-labeled total DNA of one parent as probe. Chromosomes from each parent could be clearly distinguished in pollen mother cells of all the five intergeneric hybrids by GISH. For three diploid hybrids, L. modesta × G. superba ‘Lutea’ (2n = 2x = 22), L. modesta × S. aurantiaca (2n = 2x = 23) and S. aurantiaca × G. superba ‘Lutea’ (2n = 2x = 23), 0.04?0.27 autosyndetic bivalents (intragenomic pairing of non-homologous chromosomes) and 0.13?0.36 allosyndetic bivalents (intergenomic chromosome pairing) were observed per pollen mother cell, indicating that there are some homologous chromosomal regions within each genome and among the genomes of Gloriosa, Littonia and Sandersonia. Differences in the average number of allosyndetic bivalents per pollen mother cell among different genome combinations may reflect the evolutionary distances among the three genera, and Gloriosa and Littonia may be closely related to each other, while Sandersonia may have relatively distant relationships with Gloriosa and Littonia. For two triploid hybrids, L. modesta × G. ‘Marron Gold’ (2n = 3x = 33) and S. aurantiaca × G. ‘Marron Gold’ (2n = 3x = 34), no allosyndetic bivalents were observed. Based on the results obtained in the present study, possible utilization of the diploid and triploid intergeneric hybrids for further breeding of colchicaceous ornamentals is discussed.     

棉花早熟性研究进展及其应用

早熟棉适于麦(油)后直播,实现粮棉一年两熟,对棉花产业稳定发展具有重要意义。本文对早熟性的遗传特性、早熟相关QTL定位、早熟相关基因挖掘的进展进行了阐述;总结了早熟棉的发展与育种现状以及早熟棉种质资源的创新利用;介绍了早熟棉在我国黄河流域、长江流域、西北内陆棉区的生产示范应用情况;提出了我国早熟棉育种的研究展望,为我国早熟棉育种提供参考。     

北疆棉花合理密植技术及其机制

以影响棉花产量的主要因子种植密度为主要处理,分析测定棉花各生育期的根系干物质积累、茎秆和叶片的干物质变化、叶面积指数和叶片光合速率变化以及棉花生育进程和产量构成,研究棉花合理密植技术及其机理。结果表明,中等肥力棉田膜下滴灌栽培时的最佳收获密度为1.20万/667 m2,播种密度1.40万/667 m2,实现匀株密植,说明北疆中等肥力棉田中密度栽培时具有较高产量水平。     

The polarity protein Par-3 directly interacts with p75NTR to regulate myelination

Cell polarity is critical in various cellular processes ranging from cell migration to asymmetric cell division and axon and dendrite specification. Similarly, myelination by Schwann cells is polarized, but the mechanisms involved remain unclear. Here, we show that the polarity protein Par-3 localizes asymmetrically in Schwann cells at the axon-glial junction and that disruption of Par-3 localization, by overexpression and knockdown, inhibits myelination. Additionally, we show that Par-3 directly associates and recruits the p75 neurotrophin receptor to the axon-glial junction, forming a complex necessary for myelination. Together, these results point to a critical role in the establishment of cell polarity for myelination.     

砾漠区微地形下梭梭群落特征1）

以克拉玛依盐渍化砾漠梭梭群落为研究对象,通过对不同形态地形进行植被调查,研究微地形对梭梭植被群落特征的影响。结果表明：研究区域发现植物14种,隶属7科11属,不同地形之间物种组成存在差异;地形改变对梭梭群落草本层和灌木层植被密度、盖度影响显著;地形扰动有利于梭梭群落优势种生物量的提高,地形以深沟效果最优;不同形态地形导致梭梭群落多样性存在差异,深沟物种多样性和丰富度最高,土垄一次之,CK最小。根据梭梭群落盖度、灌木密度、优势种生物量和物种多样性可知,深沟是进行砾漠植被生态恢复的有利工程措施,并为盐渍化砾漠植被恢复提供新途径。     

用HI试验检测鸡血清和卵黄中鸡毒霉形体抗体的研究

用超声波裂解的鸡毒霉形体（ＭＧ）Ｓ６菌液作抗原建立了检测鸡血清和卵黄中ＭＧ抗体的血凝抑制（ＨＩ）试验，ＨＩ试验的敏感性比血清平板凝集（ＳＰＡ）试验提高了２～３２倍。ＨＩ试验可检出卵黄中ＳＰＡ试验不足以检出的ＭＧ抗体。以ＳＰＦ鸡血清、卵黄抗体、鸡滑液囊霉形体（ＭＳ）阳性血清作对照，证明无假阳性反应及交叉反应     

“土法”提取杉木屑精油化学成份GC／MS分析及探讨

“土法”提取精油因其设备简单、拆装方便、容易运输、易操作、成本低等特点,在偏远农村广泛使用,本试验对“土法”水蒸汽蒸馏方法提取精油进行化学成份的GC／MS分析．共分出71个色谱峰．采用GC峰面积归一化法进行定量,其中鉴定出47个化合物,占该精油总量的91．8％。其主要成分为α-柏木烯（22．4％）、柏木醇（20．07％）、α-松油醇（4．29％）、α-蒎烯（2．26％）等．本试验为更好的利用“土法”提取杉木屑精油提供参考,为改进“土法”提取设备提供可靠依据。     

Anthracnose of snapdragon caused by <Emphasis Type="Italic">Colletotrichum destructivum</Emphasis>

Severe spotting and blight of leaves caused by Colletotrichum destructivum were found on snapdragon (Antirrhinum majus L.), a scrophulariaceous ornamental, in open fields in Shizuoka Prefecture, Japan, from June through September 2004. The fungus is added to the group of the pathogens causing anthracnose of snapdragon.     

Effect of Nitrogen Sources on Aluminum Toxicity in Wheat Varieties Differing in Tolerance to Aluminum

Extract

As previously reported (Taylor and Foy 1985; Keltjens and Ulden 1987; Grauer and Horst 1990; Galvez and Clark 1991), plant species and varieties widely differ in Al tolerance. Although many hypotheses about the physiological mechanism(s) involved in Al tolerance have been formulated, the mechanism(s) has not been elucidated. However, it is obvious that when exposed to Al at high concentrations, Al-tolerant plants seem to be able to avoid the toxicity by refraining from excess uptake of Al or by chelating of Al in the rhizosphere or in the roots. In such ways, Al can not affect the growth of tolerant plants (Foy et al. 1978).