Patterns of RNA synthesis in early meiotic prophase oocytes from fetal mouse ovaries

In a study of the early meiotic prophase stages of mouse oogenesis from d12 of gestation to 10d post-partum the patterns of RNA synthesis during these stages of oogenesis using H³-uridine incorporation as visualized by light microscope autoradiography are reported. We find that chromosomal RNA synthesis occurs in all stages except early to mid-pachytene, the time of maximum chromosome condensation. Diplotene and dictyate nuclei are the most heavily labelled stages. Nucleolar labelling ceases before leptotene and reappears in late pachytene or early diplotene, even though nucleoli can be identified in all stages except early to mid-pachytene.     

beta-Amyloid peptide vaccination results in marked changes in serum and brain Abeta levels in APPswe/PS1DeltaE9 mice, as detected by SELDI-TOF-based ProteinChip technology.

Although the pathogenesis of Alzheimer's disease (AD) is not fully understood, growing evidence indicates that the deposition of beta-amyloid (Abeta) and the local reactions of various cell types to this protein play major roles in the development of the disease. Immunization with the Abeta 1-42 peptide has been reported to decrease Abeta deposits in the brains of mutant amyloid precursor protein (APP/V717F) transgenic (tg) mice (Schenk et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-177). We have replicated this finding in APPswe/PS1DeltaE9 tg mice, which also develop Abeta deposits in the brain. The immunized animals developed high titers of antibodies against Abeta 1-42 in serum, and Abeta deposits in the brains were significantly reduced. Using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry and ProteinChip((R)) technology, we detected trends toward increased soluble Abeta peptide in the brain and a decrease in assayable Abeta peptide in the serum of immunized compared with control animals. This last finding raises the possibility that anti-Abeta antibodies in the periphery sequester Abeta peptides or target them for degradation and in this way contribute to the enhanced Abeta clearance from the brain in immunized animals.     

X chromosome inactivation and micronuclei in normal and Turner individuals

Studies on aneuploidy have shown that the X is the most frequently lost chromosome in females, and that the number of X chromosome-positive micronuclei increases with age in women. Recently, we showed that the inactive X chromosome is incorporated preferentially in micronuclei. The objectives of the current study were, firstly, to determine the incidence of X chromosome incorporation into micronuclei in males and, secondly, to determine the incidence of X chromosome incorporation into micronuclei of females with Turner syndrome. Blood samples were obtained from 18 male newborns and 35 normal adult males ranging in age from 22 to 79 years and from seven women with non-mosaic Turner syndrome aged 11–39 years. Isolated lymphocytes were cultured in the presence of cytochalasin B and 2000 binucleated cells per subject were scored for micronuclei. Cells were then hybridized with the biotinylated X centromere-specific probe, pBamX7, and visualized with fluorescein-conjugated avidin. All micronucleated cells were relocated and evaluated for the presence or absence of the X chromosome. Of the 335 micronuclei observed, 6.6% (22/335) contained an X chromosome. Analysis of variance shows a statistically significant increase, for both males and Turner females, in the number of X chromosome-positive micronuclei with age (P < 0.001). These data also show that the X chromosome is included in micronuclei from males more often than would be expected by chance (P < 0.005; χ² analysis, 15 df). Here we show that there is a tenfold difference in the frequency of X chromosome-positive micronuclei in 46,XX females compared to 46,XY males and 45,X females, providing further support to our previous finding that the X chromosome in micronuclei is the inactive chromosome. Received: 29 April 1997 / Accepted: 9 May 1997     

Influence of Climate Change on Productivity of American White Pelicans,Pelecanus erythrorhynchos

In the past decade, severe weather and West Nile virus were major causes of chick mortality at American white pelican (Pelecanus erythrorhynchos) colonies in the northern plains of North America. At one of these colonies, Chase Lake National Wildlife Refuge in North Dakota, spring arrival by pelicans has advanced approximately 16 days over a period of 44 years (1965–2008). We examined phenology patterns of pelicans and timing of inclement weather through the 44-year period, and evaluated the consequence of earlier breeding relative to weather-related chick mortality. We found severe weather patterns to be random through time, rather than concurrently shifting with the advanced arrival of pelicans. In recent years, if nest initiations had followed the phenology patterns of 1965 (i.e., nesting initiated 16 days later), fewer chicks likely would have died from weather-related causes. That is, there would be fewer chicks exposed to severe weather during a vulnerable transition period that occurs between the stage when chicks are being brooded by adults and the stage when chicks from multiple nests become part of a thermally protective crèche.     

Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.     

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.     

Discovery of 13-oxa prostaglandin analogs as antiglaucoma agents: Synthesis and biological activity

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC₅₀) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF_2α (1 μg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 μg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.