Chromosomal integration of an avian oncogenic herpesvirus reveals telomeric preferences and evidence for lymphoma clonality

Abstract Background Herpesviruses are a major health concern for numerous organisms, including humans, causing both acute and chronic infections recurrent over an individual's lifespan. Marek's disease virus (MDV) is a highly contagious herpesvirus which causes a neoplastic condition in chicken populations. Several vertebrate-infecting herpesviruses have been shown to exist in an integrated state during latent periods of infection. However the status of MDV during latency has been a topic of debate. Results Here we employed high-resolution multi-color fluorescence in situ hybridization (FISH) to show integration of MDV at the telomeres of chicken chromosomes. Cytogenomic mapping of the chromosomal integrations allowed us to examine the clonal relationships among lymphomas within individuals, whereas analysis of tumors from multiple individuals indicated the potential for chromosomal preferences. Conclusions Our data highlight that substantive genome-level interactions between the virus and host exist, and merit consideration for their potential impact and role in key aspects of herpesvirus pathobiology including infection, latency, cellular transformation, latency-breaks and viral evolution

Childhood meat eating and inflammatory markers: The Guangzhou Biobank Cohort Study

BackgroundWe hypothesized that socio-economic development could, via nutritionally driven levels of pubertal sex-steroids, promote a pro-inflammatory state among men but not women in developing countries. We tested this hypothesis, using recalled childhood meat eating as a proxy for childhood nutrition, in southern China. MethodsWe used multivariable linear regression in the Guangzhou Biobank Cohort Study phase 3 (2006-8) to examine the adjusted associations of recalled childhood meat eating, \u3c1/week (n = 5,023), about once per week (n = 3,592) and almost daily (n = 1,252), with white blood cell count and its differentials among older (≥50 years) men (n = 2,498) and women (n = 7,369). ResultsAdjusted for age, childhood socio-economic position, education and smoking, childhood meat eating had sex-specific associations with white blood cell count and lymphocyte count, but not granulocyte count. Men with childhood meat eating almost daily compared to \u3c1/week had higher white blood cell count (0.33 109/L, 95% confidence interval (CI) 0.10 to 0.56) and higher lymphocyte count (0.16 109/L, 95% CI 0.07 to 0.25). Adjustment for obesity slightly attenuated these associations. ConclusionIf confirmed, this hypothesis implies that economic development and the associated improvements in nutrition at puberty may be less beneficial among men than women; consistent with the widening sex differentials in life expectancy with economic development

In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile

William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia

Life-course origins of social inequalities in adult immune cell markers of inflammation in developing southern Chinese population: the Guangzhou Biobank Cohort Study

BackgroundSocioeconomic position (SEP) throughout life is associated with cardiovascular disease, though the mechanisms linking these two are unclear. It is also unclear whether there are critical periods in the life course when exposure to better socioeconomic conditions confers advantages or whether SEP exposures accumulate across the whole life course. Inflammation may be a mechanism linking socioeconomic position (SEP) with cardiovascular disease. In a large sample of older residents of Guangzhou, in southern China, we examined the association of life course SEP with inflammation. MethodsIn baseline data on 9,981 adults (≥ 50 years old) from the Guangzhou Biobank Cohort Study (2006-08), we used multivariable linear regression and model fit to assess the associations of life course SEP at four stages (childhood, early adult, late adult and current) with white blood, granulocyte and lymphocyte cell counts. ResultsA model including SEP at all four life stages best explained the association of life course SEP with white blood and granulocyte cell count for men and women, with early adult SEP (education) making the largest contribution. A critical period model best explained the association of life course SEP with lymphocyte count, with sex-specific associations. Early adult SEP was negatively associated with lymphocytes for women. ConclusionsLow SEP throughout life may negatively impact late adult immune-inflammatory status. However, some aspects of immune-inflammatory status may be sensitive to earlier exposures, with sex-specific associations. The findings were compatible with the hypothesis that in a developing population, upregulation of the gonadotropic axis with economic development may obscure the normally protective effects of social advantage for men

Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site

Paracellular ion transport in epithelia is mediated by pores formed by members of the claudin family. The degree of selectivity and the molecular mechanism of ion permeation through claudin pores are poorly understood. By expressing a high-conductance claudin isoform, claudin-2, in high-resistance Madin-Darby canine kidney cells under the control of an inducible promoter, we were able to quantitate claudin pore permeability. Claudin-2 pores were found to be narrow, fluid filled, and cation selective. Charge selectivity was mediated by the electrostatic interaction of partially dehydrated permeating cations with a negatively charged site within the pore that is formed by the side chain carboxyl group of aspartate-65. Thus, paracellular pores use intrapore electrostatic binding sites to achieve a high conductance with a high degree of charge selectivity

Uptake of gases in bundles of carbon nanotubes

Model calculations are presented which predict whether or not an arbitrary gas experiences significant absorption within carbon nanotubes and/or bundles of nanotubes. The potentials used in these calculations assume a conventional form, based on a sum of two-body interactions with individual carbon atoms; the latter employ energy and distance parameters which are derived from empirical combining rules. The results confirm intuitive expectation that small atoms and molecules are absorbed within both the interstitial channels and the tubes, while large atoms and molecules are absorbed almost exclusively within the tubes.Comment: 9 pages, 12 figures, submitted to PRB Newer version (8MAR2K). There was an error in the old one (23JAN2K). Please download thi

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors

Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001. Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort

Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: The long life family study

Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes—TERC, MYNN, and OBFC1—were significantly associated with leukocyte telomere length at p(empirical) < 0.05