Studies Needed to Address Public Health Challenges of the 2009 H1N1 Influenza Pandemic: Insights from Modeling

In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health decision making.The authors acknowledge support from the Bill & Melinda Gates Foundation (MDVK, CF, NMF); Royal Society (CF); Medical Research Council (MDVK, CF, PJW, NMF); EU FP7 programme (NMF); UK Health Protection Agency (PJW); US National Institutes of Health Models of Infectious Disease Agent Study program through cooperative agreement 1U54GM088588 (ML); NIH Director's Pioneer Award, DP1-OD000490-01 (DS); EU FP7 grant EMPERIE 223498 (DS); the Wellcome Trust (DS); 3R01TW008246-01S1 from Fogerty International Center and RAPIDD program from Fogerty International Center with the Science & Technology Directorate, Department of Homeland Security (SR); and the Institut de Veille Sanitaire Sanitaire funded by the French Ministry of Health (J-CD). The funders played no role in the decision to submit the article or in its preparation

IN VITRO AND IN VIVO DISPOSITION OF 2,2-DIMETHYL-N-(2,4,6- TRIMETHOXYPHENYL)DODECANAMIDE (CI-976) Identification of a Novel Five-Carbon Cleavage Metabolite in Rats

ABSTRACT: The metabolism of CI-976, a potent inhibitor of liver and intestinal acyl coenzyme A:cholesterol acyltransferase, was investigated in isolated rat hepatocytes and Wistar rats after oral administration. The major metabolite observed both in vitro and in vivo was identified as the 6-carbon, chain-shortened 5,5-dimethyl-6-oxo-[(2,4,6-trimethoxyphenyl)amino]hexanoic acid (M-4). M-4 was determined to be formed from the -carboxylic acid 11,11-dimethyl-12-oxo ACAT 2 , (E.C. 2.3.1.1.26) is a key enzyme involved in cholesterol absorption from the gastrointestinal tract and cholesterol deposition in the body (1). The therapeutic potential of ACAT inhibitors as lipid lowering and antiatherosclerotic agents has been postulated for the treatment of hypercholesterolemia (2). The fatty acid anilide, CI-976 ( In vivo pharmacokinetic studies in male rats found CI-976 to have moderate absorption and bioavailability (29%), with an intravenous elimination half-life of 8 hr (6). After intravenous or oral administration to male rats, CI-976 was extensively metabolized to a single major urinary metabolite identified as M-4 ( To understand further the metabolism of CI-976, studies to determine the disposition and metabolism in rats were performed. The metabolism of CI-976 was examined both in hepatocyte suspensions and after oral administration to both male and female rats. In these studies, the metabolic pathways leading to the formation of M-4 were explored using metabolic intermediates as substrates, and by examining the effects of various inhibitors and inducers on the metabolism of CI-976 in hepatocyte incubations. Metabolites found in postreaction hepatocyte incubations and rat urine were characterized by HPLC, LC/MS, and GC/MS. Similar types of experiments were conducted with a new metabolite observed both in vitro and in vivo, which arises from an unusual mechanism (i.e. removal of 5-carbon units from the CI-976 fatty acid side chain). Materials and Methods CI-976 and [ 14 C]CI-976 (20.72 Ci/mg ring-labeled, 99.5% chemical and radiochemical purity); methyl-5,5-dimethyl-6-oxo-6-[(2,4,6-trimethoxyphe

Simultaneous siRNA Targeting of Src and Downstream Signaling Molecules Inhibit Tumor Formation and Metastasis of a Human Model Breast Cancer Cell Line

Src and signaling molecules downstream of Src, including signal transducer and activator of transcription 3 (Stat3) and cMyc, have been implicated in the development, maintenance and/or progression of several types of human cancers, including breast cancer. Here we report the ability of siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc to inhibit the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S, a widely used model for breast cancer research.Src and its downstream signaling partners were specifically targeted and knocked-down using siRNA. Changes in the growth properties of the cultured cancer cells/tumors were documented using assays that included anchorage-dependent and -independent (in soft agar) cell growth, apoptosis, and both primary and metastatic tumor growth in the mouse tumor model. siRNA-mediated Src knock-down alone, and simultaneous knock-down of Src and Stat3 and/or cMyc inhibited the neoplastic phenotype of a highly metastatic human model breast cancer cell line, MDA-MB-435S. This knock-down resulted in reduced growth in monolayer and soft agar cultures, and a reduced ability to form primary tumors in NOD/SCID mice. In addition, direct intra-tumoral injection of siRNAs targeting these signaling molecules resulted in a substantial inhibition of tumor metastases as well as of primary tumor growth. Simultaneous knock-down of Src and Stat3, and/or Myc exhibited the greatest effects resulting in substantial inhibition of primary tumor growth and metastasis.These findings demonstrate the effectiveness of simultaneous targeting of Src and the downstream signaling partners Stat3 and/or cMyc to inhibit the growth and oncogenic properties of a human cancer cell line. This knowledge may be very useful in the development of future therapeutic approaches involving targeting of specific genes products involved in tumor growth and metastasis

Trends in Body Mass Index among Icelandic Adolescents and Young Adults from 1992 to 2007

Trends in body mass index (BMI) among 51,889 14- to 20-year-old Icelandic adolescents and young adults were examined using data from cross-sectional population surveys conducted from 1992 to 2007. Prevalence of overweight increased for both genders in all age groups, except for 14- and 20-year-old girls. Obesity prevalence increased among boys in all age groups, except for 16-year-olds, and among 15- and 20-year-old girls. The largest increase in obesity rates among both genders was found in the oldest age group. Moreover, not only has the prevalence of obesity increased, but also the extent of obesity has grown more severe among 15- and 17-year-olds boys and among girls in the oldest age group

Morbidity, Including Fatal Morbidity, throughout Life in Men Entering Adult Life as Obese

Background: The association between obesity in adults and excess morbidity and mortality is well established, but the health impact throughout adult life of being obese in early adulthood needs elucidation. We investigated somatic morbidity, including fatal morbidity, throughout adulthood in men starting adult life as obese. Methods: Among 362,200 Danish young men, examined for military service between 1943 and 1977, all obese (defined as BMI$31.0 kg/m 2), and, as controls, a random 1 % sample of the others was identified. In the age range of 18–25 years, there were 1,862 obese, which encompass the men above the 99.5 percentile, and 3,476 controls. Information on morbidity was obtained via national registers. Cox regression models were used to estimate the relative morbidity assessed as first incidence of disease, occurrence of disease in the year preceding death and prevalent disease at time of death. Results: From age 18 through 80 years the obese had an increased risk of becoming diseased by or die from a broad range of diseases. Generally, the incidence of first event, occurrence in the year prior to death, and prevalence at time of death showed the same pattern. As an example, the relative hazard of type 2 diabetes was constant throughout life at 4.9 (95% confidence intervals [CI]: 4.1–5.9), 5.2 (95 % CI: 3.6–7.5), and 6.8 (95 % CI: 4.6–10.1), respectively. Conclusions: Our findings strongly support the continued need to avoid beginning adult life as obese, as obese young me

Tobacco smoking, body mass index, hypertension, and kidney cancer risk in central and eastern Europe

In a case–control study of kidney cancer in four central European countries, with 1097 incident cases and 1476 controls, we found an increased risk for self-reported hypertension and for obesity. Additional unknown risk factors are likely to be responsible for the high rates of kidney cancer in this region

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Effects of Blood Collection Conditions on Ovarian Cancer Serum Markers

Evaluating diagnostic and early detection biomarkers requires comparing serum protein concentrations among biosamples ascertained from subjects with and without cancer. Efforts are generally made to standardize blood processing and storage conditions for cases and controls, but blood sample collection conditions cannot be completely controlled. For example, blood samples from cases are often obtained from persons aware of their diagnoses, and collected after fasting or in surgery, whereas blood samples from some controls may be obtained in different conditions, such as a clinic visit. By measuring the effects of differences in collection conditions on three different markers, we investigated the potential of these effects to bias validation studies.We analyzed serum concentrations of three previously studied putative ovarian cancer serum biomarkers-CA 125, Prolactin and MIF-in healthy women, women with ovarian cancer undergoing gynecologic surgery, women undergoing surgery for benign ovary pathology, and women undergoing surgery with pathologically normal ovaries. For women undergoing surgery, a blood sample was collected either in the clinic 1 to 39 days prior to surgery, or on the day of surgery after anesthesia was administered but prior to the surgical procedure, or both. We found that one marker, prolactin, was dramatically affected by collection conditions, while CA 125 and MIF were unaffected. Prolactin levels were not different between case and control groups after accounting for the conditions of sample collection, suggesting that sample ascertainment could explain some or all of the previously reported results about its potential as a biomarker for ovarian cancer.Biomarker validation studies should use standardized collection conditions, use multiple control groups, and/or collect samples from cases prior to influence of diagnosis whenever feasible to detect and correct for potential biases associated with sample collection