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"Francis, Stephen"
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Epidemiology of Brain and Other CNS Tumors
Purpose of ReviewBrain and other central nervous system (CNS) tumors, while rare, cause significant morbidity and mortality across all ages. This article summarizes the current state of the knowledge on the epidemiology of brain and other CNS tumors.Recent FindingsFor childhood and adolescent brain and other CNS tumors, high birth weight, non-chromosomal structural birth defects and higher socioeconomic position were shown to be risk factors. For adults, increased leukocyte telomere length, proportion of European ancestry, higher socioeconomic position, and HLA haplotypes increase risk of malignant brain tumors, while immune factors decrease risk.SummaryAlthough no risk factor accounting for a large proportion of brain and other CNS tumors has been discovered, the use of high throughput “omics” approaches and improved detection/measurement of environmental exposures will help us refine our current understanding of these factors and discover novel risk factors for this disease.
Journal Article
The landscape of host genetic factors involved in immune response to common viral infections
Background
Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.
Methods
We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.
Results
Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (
P
< 5.0 × 10
−8
), including
FUT2
(19q13.33) for human polyomavirus BK (BKV),
STING1
(5q31.2) for MCV, and
CXCR5
(11q23.3) and
TBKBP1
(17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including
ECSCR
:
P
= 5.0 × 10
−15
(MCV),
NTN5
:
P
= 1.1 × 10
−9
(BKV), and
P2RY13
:
P
= 1.1 × 10
−8
EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.
Conclusions
Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
Journal Article
GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21
Childhood acute lymphoblastic leukemia (ALL) (age 0–14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children’s Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near
IKZF3/ZPBP2/GSDMB/ORMDL3
, a locus encompassing a transcription factor important for lymphocyte development (
IKZF3
), and at an 8q24 region known for structural contacts with the
MYC
oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.
Childhood acute lymphoblastic leukemia is common in Latino Americans. Here, the authors conduct a genome-wide association study in a Californian cohort containing children of Latino heritage, and identify loci on 17q12 and 8q24 which may affect hematopoietic and growth-regulation pathways.
Journal Article
Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival
Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25,
p
= 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38,
p
= 0.007) and IDH
mut
1p/19q intact (IDH
mut-intact
OR = 1.53,
p
= 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDH
mut-intact
OR = 0.70,
p
= 0.004) and neutrophils (IDH
mut
OR = 0.69,
p
= 0.019; IDH
mut-intact
OR = 0.60,
p
= 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDH
mut
1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24–2.20), neutrophils (HR = 1.49, 1.13–1.97), and eosinophils (HR = 1.59, 1.18–2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications.
Glioma is an aggressive brain tumor subtype with few known risk factors. Here, the authors utilise Mendelian Randomisation to investigate correlation of immune cell counts with subtype-specific risk and mortality in glioma patients.
Journal Article
Effects of Caffeine Supplementation on Performance in Ball Games
Although a large body of evidence exists documenting the ergogenic properties of caffeine, most studies have focused on endurance performance. However, findings from endurance sports cannot be generalized to performance in ball games where, apart from having a high level of endurance, successful athletic performances require a combination of physiological, technical and cognitive capabilities. The purpose of this review was to critically evaluate studies that have examined the effect of a single dose of caffeine in isolation on one or more of the following performance measures: total distance, sprint performance, agility, vertical jump performance and accuracy in ball games. Searches of three major databases resulted in 19 studies (invasion games: 13; net-barrier games: 6) that evaluated the acute effects of caffeine on human participants, provided the caffeine dose administered, and included a ball games specific task or simulated match. Improvements in sprint performance were observed in 8 of 10 studies (80%), and vertical jump in 7 of 8 studies (88%). Equivocal results were reported for distance covered, agility and accuracy. Minor side effects were reported in 4 of 19 studies reviewed. Pre-exercise caffeine ingestion between 3.0 and 6.0 mg/kg of body mass appears to be a safe ergogenic aid for athletes in ball games. However, the efficacy of caffeine varies depending on various factors, including, but not limited to, the nature of the game, physical status and caffeine habituation. More research is warranted to clarify the effects of caffeine on performance measures unique to ball games, such as agility and accuracy. It is essential that athletes, coaches and practitioners evaluate the risk-benefit ratio of caffeine ingestion strategies on an individual case-by-case basis.
Journal Article
VerSoX B07-B: a high-throughput XPS and ambient pressure NEXAFS beamline at Diamond Light Source
The beamline optics and endstations at branch B of the Versatile Soft X-ray (VerSoX) beamline B07 at Diamond Light Source are described. B07-B provides medium-flux X-rays in the range 45–2200 eV from a bending magnet source, giving access to local electronic structure for atoms of all elements from Li to Y. It has an endstation for high-throughput X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure (NEXAFS) measurements under ultrahigh-vacuum (UHV) conditions. B07-B has a second endstation dedicated to NEXAFS at pressures from UHV to ambient pressure (1 atm). The combination of these endstations permits studies of a wide range of interfaces and materials. The beamline and endstation designs are discussed in detail, as well as their performance and the commissioning process.
Journal Article
Socioeconomic status and childhood central nervous system tumors in California
Purpose
Childhood central nervous system (CNS) tumors are the leading cause of cancer mortality in children. Previous studies have suggested that some childhood cancers, including primary CNS tumors, may be associated with higher socioeconomic status (SES).
Methods
We linked data from the California Cancer Registry to California birth records for children (age 0–19 years) diagnosed with primary CNS tumors during 1988–2011 and analyzed multiple measures of parental SES around the birth of their children and subsequent risk for childhood CNS tumors. Our SES measures included birth record-derived parental education and insurance utilization. For a subset of subjects born between 1997 and 2007, we geocoded addresses and examined census-derived median household income and educational level.
Results
We analyzed data for 3,022 children with primary CNS tumors and 10,791 matched controls. We found consistent evidence across multiple measures that lower estimates of SES are associated with a reduced risk of CNS tumors. In tumor subgroup analyses, this relationship was most consistent in astrocytomas and ependymomas, with varying findings for embryonal tumors.
Conclusion
Higher parental SES appears to be a risk factor for childhood CNS tumors in California. Further research is needed to determine specific exposures that may explain this increased risk.
Journal Article
High prevalence of sexual infection by human papillomavirus and Chlamydia trachomatis in sexually-active women from a large city in the Amazon region of Brazil
The Human Papillomavirus (HPV) and Chlamydia trachomatis are the most prevalent Sexually Transmitted Infections (STIs) worldwide, and are associated cervical cancer and pelvic inflammatory disease, respectively. However, 80% of women testing positive are asymptomatic. In the Amazon region, young women, in particular, are widely exposed to the infections and their consequences. Determine the prevalence of sexual infection by HPV and C. trachomatis in young, sexually-active women treated at a university health program in a large city of the Brazilian Amazon region. We amplified the L1 gene of HPV. We amplified ompA gene of C. trachomatis by nested PCR, and the study participants filled in a questionnaire on their social, epidemiological, and reproductive health characteristics. The data were analyzed using the Odds Ratio, to evaluate the degree of association of these variables with the observed infections. The prevalence of infection by HPV was 15.5% (47/303). This infection was recorded in 32.2% of the women of less than 25 years of age (OR:3.02 [CI95%] = 1.32-6.92; p = 0.014), 17.9% of the single women (OR: 2.41 [CI95%] = 1.22-4.75; p = 0.014), 23.8% of the women that reported having first sexual intercourse at less than 15 years of age (OR: 2.22 [CI95%] = 1.16-4.23; p = 0.021), 20% of those that reported having had more than one sexual partner during their lifetime (OR: 3.83 [CI95%] = 1.56-9.37; p = 0.003), and in 28.3% that use oral contraceptives (CI95% = 1.33-5.43; p = 0.008). The prevalence of sexual infection by C. trachomatis was 4.6% (14/303), and this bacterium was present in 16.1% of the young women of less than 25 years of age (OR: 2.86 [CI95%] = 1.33-5.43; p = 0.008). We found a high prevalence of HPV in young, unmarried women who started their sex lives early, who had several sexual partners in their lives and who used oral contraceptives. The prevalence of C. trachomatis was high only in young women. Our data are in accordance with other studies in Brazil and in the world and may serve to base the formulation of diagnostic and screening measures for these infections in women in the Amazon.
Journal Article