Citations

The genome sequence of a lycophyte hints at ancient evolutionary transitions.

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease‐modifying therapies may be most efficacious.

Abstract Prostate cancer patients with regional lymph node involvement at radical prostatectomy often experience disease progression to other organs, with the bone as the predominant site. The transcription factor Runx2 plays an important role in bone formation and prostate cancer cell migration, invasion, and metastasis. Here we showed that the forkhead box O (FOXO1) protein, a key downstream effector of the tumor suppressor PTEN, inhibits the transcriptional activity of Runx2 in prostate cancer cells. This inhibition was enhanced by PTEN but diminished by active Akt. FOXO1 bound to Runx2 in vitro and in vivo and suppressed Runx2's activity independent of its transcriptional function. FOXO1 inhibited Runx2-promoted migration of prostate cancer cells, whereas silencing of endogenous FOXO1 enhanced prostate cancer cell migration in a Runx2-dependent manner. Forced expression of FOXO1 also inhibited Runx2-promoted prostate cancer cell invasion. Finally, we found that expression of PTEN and the level of FOXO1 in the nucleus is inversely correlated with expression of Runx2 in a cohort of prostate cancer specimens from patients with lymph node and bone metastasis. These data reveal FOXO1 as a critical negative regulator of Runx2 in prostate cancer cells. Inactivation of FOXO1 due to frequent loss of PTEN in prostate cancer cells may leave the oncogenic activities of Runx2 unchecked, thereby driving promiscuous expression of Runx2 target genes involved in cell migration and invasion and favoring prostate cancer progression. Cancer Res; 71(9); 3257–67. ©2011 AACR.

Pain is one of the most common and incapacitating symptoms experienced by patients with advanced cancer. Methadone is a potent opioid with strong affinity for the µ opioid receptor. In addition to being a potent µ opioid receptor ligand, methadone blocks the N-methyl-D-aspartic acid receptor and modulates neurotransmitters involved in descending pain modulation. These 3 properties enhance analgesic activity. Methadone's lack of active metabolites makes it an attractive option when opioid responsiveness declines and renal insufficiency complicates opioid therapy. A lipophilic opioid, methadone can be given by multiple routes. Clinical trial data show equivalence with morphine as an analgesic in moderate to severe cancer pain. Further investigations are needed to define the role of methadone in the management of breakthrough pain and neuropathic pain and to determine whether it is truly superior to morphine, the gold standard of cancer analgesia.

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

Abstract Cancers of the head and neck rank as the 6th most commonly observed cancers worldwide with an average 5-year survival rate of only 50% for advanced disease. Nearly 95% of head and neck cancers are squamous cell carcinomas (SSC) and these are frequently highly invasive metastatic tumors. The newly developing technologies of Next Generation Sequencing have allowed for the most comprehensive genetic analysis of these cancers to date. We have taken 3 tumor/normal pairs from patients with oral squamous cell carcinoma and performed full transcriptome and mate-pair DNA sequencing analysis using the AB SOLiD system. These runs generated 129-256 million 50bp long sequence reads per sample, with 21 to 56 million reads per sample uniquely aligning to human genome sequence. Analysis of these samples has revealed pathways with aberrant expression in tumor versus normal tissue. Our results show up-regulation of some metalloproteinase genes, HGMA2, which is a prognostic marker for oral carcinoma, and extracellular matrix, adhesion, and motility gene classes in tumors. Our functional analysis also indicates extensive down-regulation, in the tumors, of genes functioning in epidermal development. We were also able to measure allelic specific expression for the 50% most highly expressed genes and detect examples of allelic imbalance linked to pathways with dysregulated gene expression. Additionally, the depth of sequencing that was achieved (5-16X coverage of RefSeq Exons) also allowed us to detect mutations occurring in the transcripts. We have also detected evidence of RNA editing associated with point mutations, which we are validating in a larger group of samples. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2957.

Abstract Development of efficacious strategies for eradication of glioblastoma multiforme (GBM) remains a significant challenge. While treatment of GBM with radiation and temozolomide (TMZ) has improved clinical outcome, lack of long-term efficacy can be due to the ability of GBM to acquire resistance to therapy by modulation of signaling pathways that control DNA repair and cell survival. The HDM2 antagonist, Nutlin3, blocks interactions of HDM2 with key signaling molecules such as p53, p73α, and HIF1α, and modulates their downstream effector function. A panel of human GBM cell lines is currently being used to monitor the extent to which Nutlin3 can sensitize cells to TMZ. In vitro survival assays indicate that Nutlin3 potentiates TMZ-mediated cell death; analysis of cell survival data using Dose Effect CalcuSyn software indicates that the combination index value was < 1 and indicative of a synergistic effect between Nutlin3 and TMZ. Western analyses of p53 wild-type GBM indicated increased p53 stabilization and activation of down-stream targets in cells treated with the combination of Nutlin3/TMZ compared to vehicle, TMZ, or Nutlin3. In addition, time-course studies indicated that U87-MG cells treated with Nutlin3/TMZ in comparison to single agent resulted in increased γ-H2AX and DNA-strand breaks. Efficacy studies using ectopic U87-MG xenografts indicated that 2 cycles of 5-consecutive days of Nutlin3/TMZ led to a significant decrease in tumor growth compared to vehicle or single agent (p < 0.001) with no signs of off-target toxicity. Regulation of DNA repair was further analyzed using the primary GBM.10 line that when grown as an ectopic xenograft, expresses the direct-reversal repair protein, O6-methylguanine DNA methyltransferase (MGMT) and proteins involved in base-excision repair (BER). In vivo target-validation studies using GBM.10 xenografts confirmed that repair of TMZ-mediated DNA damage is modulated in the presence of Nutlin3. GBM.10 xenografts were treated with vehicle, TMZ, nutlin3, or TMZ/Nutlin3 and modulation of critical targets determined by Western analyses. Increases in total p53, p53 phosphorylated at residue serine16, p73α, and substantial decreases in MGMT and the BER protein, APE-1, were observed following treatment with Nutlin3/TMZ compared to vehicle or single-agent exposure. Busso et al (Oncogene 2009) recently reported that HDM2 can monoubiquitinate APE-1 leading to proteosomal-mediated degradation. In addition, recombinant activity assays in our laboratory indicate that HDM2 directly monoubiquitinates recombinant MGMT and may play a role in its degradation. These data suggest that DNA repair proteins required for repair of TMZ-mediated DNA damage can be downregulated by altering HDM2-mediated signaling. Combination therapy that targets the p53-HDM2 E3 ligase network and DNA repair represents a novel approach towards improving treatment of GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5373.

Abstract To clarify the role of previous lung diseases (PLDs) (chronic bronchitis, emphysema, pneumonia, tuberculosis, asbestosis and silicosis) in the development of lung cancer we conducted a pooled analysis in the International Lung Cancer Consortium (ILCCO). Data from 16 studies (9 population based case-control, 4 hospital based case-control, 2 mixed case-control and 1 cohort - 10 from North America, 5 from Europe and 1 from Asia) were pooled, including 24044 cases and 81256 controls. Study-specific effect estimates were derived using logistic regression models for case-control studies and Cox proportional hazards models for cohort studies adjusted for age, sex, education and pack-years of smoking. Effect estimates were then pooled using random effects models where summary effects for each of the PLDs were evaluated separately. Stratified analyses were conducted based on smoking status, histology and study design or control source. Heterogeneity was evaluated using the Cochrane Q statistic and Galbraith plots, and publication bias was evaluated using funnel plots as well as the Begg test. A previous history of emphysema conferred a relative risk (RR) of 2.17, 95% confidence interval (CI): 1.67-2.82 (from 15 studies, p-het<.001). A previous history of chronic bronchitis conferred a RR of 1.49, 95% CI: 1.33-1.60 (from 12 studies, p-het.=0.434). Tuberculosis was associated with a RR of 1.54, 95% CI: 1.19-1.99 (from 15 studies, p-het.=0.001). Both asbestosis (RR 2.51, 95% CI: 1.53-4.12 (from 7 studies, p-het=0.379)) and silicosis (RR 1.70, 95% CI: 1.15-2.54, (from 3 studies, p-het. p=0.476)) were also associated with lung cancer risk. When the outlying studies were removed, effect estimates changed minimally and heterogeneity was reduced. Findings were consistent in subgroup analyses by smoking status and histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer). Effect estimates among never smokers were for emphysema a RR of 2.21, 95% CI: 0.99-4.90 (from 8 studies), for chronic bronchitis 1.12, 95% CI: 0.78-1.62 (from 9 studies), for pneumonia 1.37, 95% CI: 1.10-1.70 (from 10 studies) and for tuberculosis 1.54, 95% CI: 0.99-2.39 (from 9 studies). In this analysis of data from multiple continents, PLDs were associated with an increased risk of lung cancer. The evidence among never smokers supports a direct relationship between previous lung diseases and lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4826.