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Vulnerability of Vietnam to typhoons: A spatial assessment based on hazards, exposure and adaptive capacity

Nguyen KA, Liou YA, Terry JP

Sci Total Environ, 2019 Sep 10;682:31-46.
PMID: 31121354 DOI: 10.1016/j.scitotenv.2019.04.069

Typhoons have devastating impacts across many Asian countries. Vietnam is presently one of the most disaster-prone nations. Typhoons regularly disrupt human lives and livelihoods in various ways and cause significant damage. Making efficient policy decisions to minimize the vulnerability of affected communities is crucial. This requires a deep understanding of the factors that make a society vulnerable to extreme events and natural disasters. An appropriate approach is integrating the three dimensions of hazard, exposure and sensitivity, and community adaptive capacity. However, the vulnerability and adaptive capacity response to typhoons within Vietnam is poorly investigated. Here, we develop a conceptual framework that incorporates 21 indicators to identify vulnerability and adaptive capacity (VAC) using geospatial techniques at regional scales, applied over Vietnam. We find large spatial differences in VAC and are able to identify the top-priority regions that need to enhance their adaptation to typhoons. The Southern Coastal area, South East and Red River Delta demonstrate high and very high vulnerability because of their physical features and the intensity of typhoons that frequently cross these parts of Vietnam. The lower Mekong Delta and Northern Coastal areas are vulnerable to typhoon-driven flood threats, in particular where compounded by sea-level rise. Our framework successfully identified the spatial distribution and different levels of VAC within acceptable limits of uncertainty. It can therefore serve as a template to tackle national issues in disaster risk reduction in Vietnam and assist in the development of suitable mitigation strategies to achieve sustainable outcomes.
UEFA expert group statement on nutrition in elite football. Current evidence to inform practical recommendations and guide future research

Collins J, Maughan RJ, Gleeson M, Bilsborough J, Jeukendrup A, Morton JP, et al.

Br J Sports Med, 2021 Apr;55(8):416.
PMID: 33097528 DOI: 10.1136/bjsports-2019-101961

Football is a global game which is constantly evolving, showing substantial increases in physical and technical demands. Nutrition plays a valuable integrated role in optimising performance of elite players during training and match-play, and maintaining their overall health throughout the season. An evidence-based approach to nutrition emphasising, a 'food first' philosophy (ie, food over supplements), is fundamental to ensure effective player support. This requires relevant scientific evidence to be applied according to the constraints of what is practical and feasible in the football setting. The science underpinning sports nutrition is evolving fast, and practitioners must be alert to new developments. In response to these developments, the Union of European Football Associations (UEFA) has gathered experts in applied sports nutrition research as well as practitioners working with elite football clubs and national associations/federations to issue an expert statement on a range of topics relevant to elite football nutrition: (1) match day nutrition, (2) training day nutrition, (3) body composition, (4) stressful environments and travel, (5) cultural diversity and dietary considerations, (6) dietary supplements, (7) rehabilitation, (8) referees and (9) junior high-level players. The expert group provide a narrative synthesis of the scientific background relating to these topics based on their knowledge and experience of the scientific research literature, as well as practical experience of applying knowledge within an elite sports setting. Our intention is to provide readers with content to help drive their own practical recommendations. In addition, to provide guidance to applied researchers where to focus future efforts.
Two Groups of Phytoplasmas from Japan Distinguished on the Basis of Amplification and Restriction Analysis of 16S rDNA

Okuda S, Prince JP, Davis RE, Dally EL, Lee IM, Mogen B, et al.

Plant Dis, 1997 Mar;81(3):301-305.
PMID: 30861775 DOI: 10.1094/PDIS.1997.81.3.301

Phytoplasmas (mycoplasmalike organisms, MLOs) associated with mitsuba (Japanese hone-wort) witches'-broom (JHW), garland chrysanthemum witches'-broom (GCW), eggplant dwarf (ED), tomato yellows (TY), marguerite yellows (MY), gentian witches'-broom (GW), and tsu-wabuki witches'-broom (TW) in Japan were investigated by polymerase chain reaction (PCR) amplification of DNA and restriction enzyme analysis of PCR products. The phytoplasmas could be separated into two groups, one containing strains JHW, GCW, ED, TY, and MY, and the other containing strains GW and TW, corresponding to two groups previously recognized on the basis of transmission by Macrosteles striifrons and Scleroracus flavopictus, respectively. The strains transmitted by M. striifrons were classified in 16S rRNA gene group 16SrI, which contains aster yellows and related phytoplasma strains. Strains GW and TW were classified in group 16SrIII, which contains phytoplasmas associated with peach X-disease, clover yellow edge, and related phytoplasmas. Digestion of amplified 16S rDNA with HpaII indicated that strains GW and TW were affiliated with subgroup 16SrIII-B, which contains clover yellow edge phytoplasma. All seven strains were distinguished from other phytoplasmas, including those associated with clover proliferation, ash yellows, elm yellows, and beet leafhopper-transmitted virescence in North America, and Malaysian periwinkle yellows and sweet potato witches'-broom in Asia.
Fulltext The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project

Hudson LN, Newbold T, Contu S, Hill SL, Lysenko I, De Palma A, et al.

Ecol Evol, 2017 Jan;7(1):145-188.
PMID: 28070282 DOI: 10.1002/ece3.2579

The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
Systematic review and meta-analysis of closed suction drainage versus non-drainage in primary hip arthroplasty

Kelly EG, Cashman JP, Imran FH, Conroy R, O'Byrne J

Surg Technol Int, 2014 Mar;24:295-301.
PMID: 24574017

The routine use of drains in surgery has been dogmatically instituted in some disciplines. Orthopaedic surgery is one such sub-speciality. The use of postoperative closed suction drainage in total hip arthroplasty (THA) has become increasingly controversial with multiple randomised control trials performed to assess the benefit to outcome in THA. The hypothesis of this systematic review is that closed suction drainage does not infer a benefit and increase transfusion requirements of primary total hip arthroplasty patients. A systematic review and meta-analysis was conducted adhering to the PRISMA guidelines. A search of the available literature was performed on PubMed, Cochrane Central Registry of Controlled Trials, MEDLINE (OVID) and EMBASE using a combination of MeSH terms and Boolean operators. All data analysis was performed using the Cochrane Collaboration's Review Manager 5.1. Sixteen studies (n=2705) were included in the analysis. Post-operative closed suction drainage was found to increase total blood loss and blood transfusion requirements (p<0.05). Surgical site infection demonstrated no significant difference between the two groups (p=0.82). No significant difference in haematoma formation between groups (p=0.19) was elicited. The routine use of closed suction drainage systems post primary hip arthroplasty is not supported by this meta-analysis. However, the heterogeneity between studies does limit the accuracy of the meta-analysis.
Small pelagic fish supply abundant and affordable micronutrients to low- and middle-income countries

Robinson JPW, Mills DJ, Asiedu GA, Byrd K, Mancha Cisneros MDM, Cohen PJ, et al.

Nat Food, 2022 Dec;3(12):1075-1084.
PMID: 37118295 DOI: 10.1038/s43016-022-00643-3

Wild-caught fish provide an irreplaceable source of essential nutrients in food-insecure places. Fishers catch thousands of species, yet the diversity of aquatic foods is often categorized homogeneously as 'fish', obscuring an understanding of which species supply affordable, nutritious and abundant food. Here, we use catch, economic and nutrient data on 2,348 species to identify the most affordable and nutritious fish in 39 low- and middle-income countries. We find that a 100 g portion of fish cost between 10 and 30% of the cheapest daily diet, with small pelagic fish (herring, sardine, anchovy) being the cheapest nutritious fish in 72% of countries. In sub-Saharan Africa, where nutrient deficiencies are rising, <20% of small pelagic catch would meet recommended dietary fish intakes for all children (6 months to 4 years old) living near to water bodies. Nutrition-sensitive policies that ensure local supplies and promote consumption of wild-caught fish could help address nutrient deficiencies in vulnerable populations.
Fulltext Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Lecarpentier J, Silvestri V, Kuchenbaecker KB, Barrowdale D, Dennis J, McGuffog L, et al.

J Clin Oncol, 2017 Jul 10;35(20):2240-2250.
PMID: 28448241 DOI: 10.1200/JCO.2016.69.4935

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Fulltext Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, et al.

Hum Mutat, 2018 05;39(5):593-620.
PMID: 29446198 DOI: 10.1002/humu.23406

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Fulltext Mucopyocele in the oral region: an unusual case

Telang , Ajay, Lahari, T., Chacko , James P.

Archives of Orofacial Sciences, 2011;6(2):1-4.
MyJurnal

Mucopyoceles are rare lesions defined as infected mucoceles. They have been reported only in the paranasal sinuses and appendix. Our case is the first to be reported in the oral region. A 58- year-old male presented with complaint of a painless swelling of two years duration in the right buccal sulcus with associated pus discharge. Radiographic examination ruled out pulpal and periodontal foci of infection and histopathology confirmed an underlying mucopyocele in the right buccal mucosa.
Modified palatal flap--a simpler approach for removal of palatal tori

Chacko JP, Joseph C

J Oral Maxillofac Surg, 2010 Apr;68(4):943-4.
PMID: 20307780 DOI: 10.1016/j.joms.2009.04.009
Fulltext Mitochondrial DNA integrity and function are critical for endothelium-dependent vasodilation in rats with metabolic syndrome

Kiyooka T, Ohanyan V, Yin L, Pung YF, Chen YR, Chen CL, et al.

Basic Res Cardiol, 2022 Jan 17;117(1):3.
PMID: 35039940 DOI: 10.1007/s00395-021-00908-1

Endothelial dysfunction in diabetes is generally attributed to oxidative stress, but this view is challenged by observations showing antioxidants do not eliminate diabetic vasculopathy. As an alternative to oxidative stress-induced dysfunction, we interrogated if impaired mitochondrial function in endothelial cells is central to endothelial dysfunction in the metabolic syndrome. We observed reduced coronary arteriolar vasodilation to the endothelium-dependent dilator, acetylcholine (Ach), in Zucker Obese Fatty rats (ZOF, 34 ± 15% [mean ± standard deviation] 10-3 M) compared to Zucker Lean rats (ZLN, 98 ± 11%). This reduction in dilation occurred concomitantly with mitochondrial DNA (mtDNA) strand lesions and reduced mitochondrial complex activities in the endothelium of ZOF versus ZLN. To demonstrate endothelial dysfunction is linked to impaired mitochondrial function, administration of a cell-permeable, mitochondria-directed endonuclease (mt-tat-EndoIII), to repair oxidatively modified DNA in ZOF, restored mitochondrial function and vasodilation to Ach (94 ± 13%). Conversely, administration of a cell-permeable, mitochondria-directed exonuclease (mt-tat-ExoIII) produced mtDNA strand breaks in ZLN, reduced mitochondrial complex activities and vasodilation to Ach in ZLN (42 ± 16%). To demonstrate that mitochondrial function is central to endothelium-dependent vasodilation, we introduced (via electroporation) liver mitochondria (from ZLN) into the endothelium of a mesenteric vessel from ZOF and restored endothelium-dependent dilation to vasoactive intestinal peptide (VIP at 10-5 M, 4 ± 3% vasodilation before mitochondrial transfer and 48 ± 36% after transfer). Finally, to demonstrate mitochondrial function is key to endothelium-dependent dilation, we administered oligomycin (mitochondrial ATP synthase inhibitor) and observed a reduction in endothelium-dependent dilation. We conclude that mitochondrial function is critical for endothelium-dependent vasodilation.
Fulltext Management of wooden foreign bodies in craniofacial region

Loganathan K, Chacko JP, Saravanan BS, Vaithilingam B

J Oral Biol Craniofac Res, 2012 Sep-Dec;2(3):210-2.
PMID: 25737868 DOI: 10.1016/j.jobcr.2012.10.011

Even though variety of foreign bodies has been reported in a various locations in the craniofacial region, wooden foreign bodies are uncommon. Appropriate management of wooden foreign bodies is considered essential because of their infectious complications and difficulty in radiographic localization. Even though literature is replete with articles on management of foreign bodies in the craniofacial region, specific management of wooden foreign bodies are rarely reported. The purpose of this article is to report two cases of deeply placed wooden foreign body and a protocol for managing them in the maxillofacial region.
Fulltext Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Silvestri V, Barrowdale D, Mulligan AM, Neuhausen SL, Fox S, Karlan BY, et al.

Breast Cancer Res, 2016 Feb 09;18(1):15.
PMID: 26857456 DOI: 10.1186/s13058-016-0671-y

BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).
METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.
RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).
CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Fulltext Malaria is a cause of iron deficiency in African children

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, et al.

Nat Med, 2021 Apr;27(4):653-658.
PMID: 33619371 DOI: 10.1038/s41591-021-01238-4

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
Fulltext Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers

Page EC, Bancroft EK, Brook MN, Assel M, Hassan Al Battat M, Thomas S, et al.

Eur Urol, 2019 Dec;76(6):831-842.
PMID: 31537406 DOI: 10.1016/j.eururo.2019.08.019

BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.
OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.
DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.
RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).
CONCLUSIONS: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.
PATIENT SUMMARY: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
Fulltext Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage

Guarini G, Kiyooka T, Ohanyan V, Pung YF, Marzilli M, Chen YR, et al.

Basic Res Cardiol, 2016 May;111(3):29.
PMID: 27040114 DOI: 10.1007/s00395-016-0547-4

Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.
Fulltext Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al.

Nat Genet, 2017 Dec;49(12):1767-1778.
PMID: 29058716 DOI: 10.1038/ng.3785

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
Fulltext Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Couch FJ, Kuchenbaecker KB, Michailidou K, Mendoza-Fandino GA, Nord S, Lilyquist J, et al.

Nat Commun, 2016 Apr 27;7:11375.
PMID: 27117709 DOI: 10.1038/ncomms11375

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Fulltext Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, et al.

Nat Genet, 2017 May;49(5):680-691.
PMID: 28346442 DOI: 10.1038/ng.3826

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Guinea pig genital tract lipidome reveals in vivo and in vitro regulation of phosphatidylcholine 16:0/18:1 and contribution to Chlamydia trachomatis serovar D infectivity

Wali S, Gupta R, Yu JJ, Mfuh A, Gao X, Guentzel MN, et al.

Metabolomics, 2016 Apr;12(4).
PMID: 27642272

INTRODUCTION: Chlamydia trachomatis (Ct), is the leading cause of sexually transmitted infections worldwide. Host transcriptomic- or proteomic profiling studies have identified key molecules involved in establishment of Ct infection or the generation of anti Ct-immunity. However, the contribution of the host metabolome is not known.
OBJECTIVES: The objective of this study was to determine the contribution of host metabolites in genital Ct infection.
METHODS: We used high-performance liquid chromatography-mass spectrometry, and mapped lipid profiles in genital swabs obtained from female guinea pigs at days 3, 9, 15, 30 and 65 post Ct serovar D intravaginal infection.
RESULTS: Across all time points assessed, 13 distinct lipid species including choline, ethanolamine and glycerol were detected. Amongst these metabolites, phosphatidylcholine (PC) was the predominant phospholipid detected from animals actively shedding bacteria i.e., at 3, 9, and 15 days post infection. However, at days 30 and 65 when the animals had cleared the infection, PC was observed to be decreased compared to previous time points. Mass spectrometry analyses of PC produced in guinea pigs (in vivo) and 104C1 guinea pig cell line (in vitro) revealed distinct PC species following Ct D infection. Amongst these, PC 16:0/18:1 was significantly upregulated following Ct D infection (p < 0.05, >twofold change) in vivo and in vitro infection models investigated in this report. Exogenous addition of PC 16:0/18:1 resulted in significant increase in Ct D in Hela 229 cells.
CONCLUSION: This study demonstrates a role for host metabolite, PC 16:0/18:1 in regulating genital Ct infection in vivo and in vitro.

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