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2. Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

Author

Yoneyama, S, Yao, J, Guo, X, Fernandez-Rhodes, L, Lim, U, Boston, J, Buzková, P, Carlson, CS, Cheng, I, Cochran, B, Cooper, R, Ehret, G, Fornage, M, Gong, J, Gross, M, Gu, CC, Haessler, J, Haiman, CA, Henderson, B, Hindorff, LA, Houston, D, Irvin, MR, Jackson, R, Kuller, L, Leppert, M, Lewis, CE, Li, R, Le Marchand, L, Matise, TC, Nguyen, K-Dh, Chakravarti, A, Pankow, JS, Pankratz, N, Pooler, L, Ritchie, MD, Bien, SA, Wassel, CL, Chen, Y-DI, Taylor, KD, Allison, M, Rotter, JI, Schreiner, PJ, Schumacher, F, Wilkens, L, Boerwinkle, E, Kooperberg, C, Peters, U, Buyske, S, Graff, M, and North, KE

Subjects
Humans, Genetic Predisposition to Disease, Waist-Hip Ratio, Genotype, Polymorphism, Single Nucleotide, Adult, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiposity, Body Fat Distribution, Genetic Variation, Genome-Wide Association Study, Obesity, Abdominal, Polymorphism, Single Nucleotide, Obesity, Abdominal, Endocrinology & Metabolism, Medical and Health Sciences, Education
Abstract

Background/objectivesCentral adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.Subjects/methodsTo identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.ResultsOf the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.ConclusionsOf 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Published
2017

3. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Author

Lei, J, Rudolph, A, Moysich, KB, Behrens, S, Goode, EL, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Wang, Q, Benitez, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Fasching, PA, Haeberle, L, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marmé, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Nielsen, SF, Nordestgaard, BG, González-Neira, A, Menéndez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Fagerholm, R, Dörk, T, Bogdanova, NV, Mannermaa, A, Hartikainen, JM, Australian Ovarian Study Group, kConFab Investigators, Van Dijck, L, Smeets, A, Flesch-Janys, D, Eilber, U, Radice, P, Peterlongo, P, Couch, FJ, Hallberg, E, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Goldberg, MS, Kristensen, V, Borresen-Dale, AL, Zheng, W, Beeghly-Fadiel, A, Winqvist, R, Grip, M, Andrulis, IL, Glendon, G, García-Closas, M, Figueroa, J, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hall, P, Li, J, Cox, A, Cross, SS, Pharoah, PDP, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Ademuyiwa, F, Ambrosone, CB, Swerdlow, A, Jones, M, and Chang-Claude, J

Subjects
Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity
Abstract

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

Published
2016

6. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Author

Witte, John, Al, AA, Kote-Jarai, Z, Berndt, SI, Conti, DV, Schumacher, F, Han, Y, Benlloch, S, Hazelett, DJ, Wang, Z, and Saunders, E

Abstract

© 2014 Nature America, Inc. All rights reserved.Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this c

Published
2014

7. Functional bridging of protein disulfide bonds with maleimides

Author

Schumacher, F. F. and Baker, J. R.

Subjects
540
Abstract

The application of chemical methods to biological systems has led to great advances in all life sciences and the discovery of novel approaches for therapy and diagnosis. Pivotal amongst these methods is the ability to chemically modify proteins to enhance their biophysical properties or add new functionality. Despite the success, the chemical toolbox of efficient and widely applicable protocols is relatively limited. In the work presented in this thesis the idea of protein modification via the targeting of solvent accessible disulfide bonds is explored. These are fairly common in secreted proteins and their reduction affords two cysteine residues, which are highly reactive nucleophiles. However, to preserve their native function – stabilisation and maintenance of the protein structure – ideally bis-reactive compounds are used that react simultaneously with both thiols and keep the covalent connection of the disulfide bond intact. To this end a selection of maleimides substituted with good leaving groups in the 3 and 4 positions as well as their N-functionalised versions were synthesised and tested for their reactivity. The findings were transferred to the small peptide hormone somatostatin, which served as a model system to explore kinetics and feasibility of the proposed “functionalisation by bridging”. Changing the leaving groups from halides to thiols enabled the development of in situ protocols where the bridging reagent could be employed in tandem with the reducing agent, greatly decreasing the reaction time and unwanted side reactions such as dimerisation or unfolding. The developed methods were then utilised to bridge the cystines of insulin as well as a selection of full length antibodies and antibody fragments. PEGylated, biotinylated, fluorescent or spin labelled analogues of these proteins were also synthesised. The biological activity, stability and functionality of the conjugates were assessed in biochemical and biophysical assays. Overall the functionalisation of disulfide bonds with maleimides was found to be site-specific, fast, high yielding and the inserted bridge was stable under various conditions. The modification was well tolerated and all prepared analogues exhibited the desired functionality. The scope and potential of present and future applications of the method are discussed.

Published
2013

9. The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: A nested case-control study in the California Teachers Study cohort

Author

Lee, E, Schumacher, F, Lewinger, JP, Neuhausen, SL, Anton-Culver, H, Horn-Ross, PL, Henderson, KD, Ziogas, A, Van Den Berg, D, Bernstein, L, and Ursin, G

Abstract

Introduction: The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy.Methods: We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).Results: The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT= 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT= 0.002; overall PACT= 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.Conclusions: We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT. © 2011 Lee et al.; licensee BioMed Central Ltd.

Published
2011

14. Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

Author

Péricat, D., primary, Leon-Icaza, S. A., additional, Sánchez-Rico, M., additional, Mühle, C., additional, Zoicas, I., additional, Schumacher, F., additional, Planès, R., additional, Mazars, R., additional, Gros, G., additional, Carpinteiro, A., additional, Becker, K. A., additional, Izopet, J., additional, Strub-Wourgaft, N., additional, Sjö, P., additional, Neyrolles, O., additional, Kleuser, B., additional, Limosin, F., additional, Gulbins, E., additional, Kornhuber, J., additional, Meunier, E., additional, Hoertel, N., additional, and Cougoule, C., additional

Published
2023
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20. Die Lunge im Fokus der Therapie

Author

Schumacher, F, Berger, M, Wollsching-Strobel, M, Kroppen, D, Schwarz, SB, Windisch, W, Strunk, J, Schumacher, F, Berger, M, Wollsching-Strobel, M, Kroppen, D, Schwarz, SB, Windisch, W, and Strunk, J

Published
2022

23. Medical students' mental burden and experiences of voluntary work in COVID-19 patient support and treatment services: a qualitative analysis

Author

Nikendei, C, Dinger-Ehrenthal, U, Schumacher, F, Bugaj, TJ, Cranz, A, Friedrich, HC, Herpertz, SC, and Terhoeven, V

Subjects
medizinische Ausbildung, COVID-19-Pandemie, ddc: 610, clinical assignment, COVID-19 pandemic, klinischer Einsatz, medical education, Unterstützungsangebote, psychological support
Abstract

Aim: Medical training is undergoing a dramatic shift toward alternative training methods due to the SARS-CoV-2 pandemic. This study is the first to examine medical students' expectations, experiences, and mental burden related to volunteering in COVID-19 patient support and treatment services using semi-structured interviews.Methods: In May 2020, all 194 Heidelberg University Medical School students involved in volunteer COVID-19 support and treatment services were invited to participate in a cross-sectional, qualitative interview study. The semi-structured interviews were digitally recorded, transcribed, and then analyzed using Mayring's principles for content analysis.Results: We interviewed 12 medical students (8 female, mean age 23.2 years, mean medical training 3.7 years) working in Heidelberg COVID-19 crises management services, i.e., the Heidelberg Medical Hospital COVID-19 inpatient and outpatient units. The analysis revealed two key themes: "Expectations and structural barriers" and "Experiences and mental burden". The participants reported uncertainty and apprehension before starting their voluntary work. Although they initially found volunteering to be somewhat disorganized, their roles became clearer with time. In addition, they reported good team cohesion, which helped reduce initial concerns and uncertainties. The participants also felt that working in the field had helped them maintain their professional identification while standard medical classes and bedside learning were suspended due to the COVID-19 crises. Overall, they reported little volunteer work-related mental burden.Conclusions: The participants felt that volunteering during the COVID-19 crisis had benefited their professional development. A designated liaison person, psychosocial support, and introductory and accompanying courses could help alleviate initial concerns and interim difficulties in future crisis-related assignments. Ziel: Die medizinische Ausbildung erfährt aufgrund der COVID-19-Pandemie eine dramatische Störung, einhergehend mit einer Umstellung auf Online-Unterricht und alternativen Lehrangeboten. Dies ist die erste Studie, die mit Hilfe halbstrukturierter Interviews die Erwartungen, Erfahrungen und psychischen Belastungen von Studierenden bei der freiwilligen Mitarbeit in Betreuungs- und Behandlungsdiensten für COVID-19-Patienten untersucht.Methoden: Im Mai 2020 wurden alle 194 Medizinstudenten, die an der Medizinischen Fakultät der Universität Heidelberg an freiwilligen Unterstützungs- und Behandlungsdiensten, während der COVID-19-Krise beteiligt waren, zur Teilnahme an einer qualitativen Querschnitt-Interview-Studie eingeladen. Die halbstrukturierten Interviews wurden digital aufgezeichnet, wortwörtlich transkribiert und nach den Prinzipien der induktiven Inhaltsanalyse nach Mayring ausgewertet.Ergebnisse: Wir befragten 12 Medizinstudierende (8 weiblich, Durchschnittsalter 23,2 Jahre) mit einer mittleren Ausbildungszeit von 3,7 Jahren, die in verschiedenen COVID-19-Managementdiensten wie der stationären COVID-19-Fachabteilung oder den COVID-19-Ambulanzen der Medizinischen Klinik Heidelberg tätig waren. Die qualitative Analyse ergab zwei zentrale Themen: "Strukturelle Hindernisse und Erwartungen" und "Erfahrungen" einschließlich emotionaler Aspekte wie psychische Belastung. Was die strukturellen Hindernisse und Erwartungen betrifft, so erlebten die Studierenden vor Beginn ihrer ehrenamtlichen Tätigkeit Gefühle der Unsicherheit und Befürchtungen. Was die Erfahrungen betrifft, so berichteten die Studierenden von einem Gefühl des Wohlbefindens und der Sicherheit bei der Arbeit in ihren Teams, so dass die eigentliche Arbeit nicht als so einschüchternd oder beängstigend wie befürchtet empfunden wurde. Das klinische Praktikum trug auch dazu bei, die Identifikation der Studierenden mit dem Arztberuf aufrechtzuerhalten, zumal der reguläre Unterricht und das Lernen am Krankenbett während der COVID-19-Krise ausfielen. Insgesamt war die psychische Belastung gering.Schlussfolgerungen: Medizinstudenten sahen ihre klinischen Praktika während der COVID-19-Krise als vorteilhaft für ihre berufliche Entwicklung an. Um anfänglichen Befürchtungen und zwischenzeitlichen Schwierigkeiten entgegenzuwirken, sollten Einführungs- und Begleitkurse, eine zentrale Kontaktperson sowie psychosoziale Unterstützung eingerichtet werden.

Published
2021

25. Nationwide central diagnosis review for childhood solid tumors: From concept to realization of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) integrated project

Author

Spreafico, F, Quarello, P, Alaggio, R, Collini, P, Haupt, R, Mastronuzzi, A, Prete, A, Rabusin, M, Rizzari, C, Schumacher, F, Zecca, M, Pession, A, Fagioli, F, Spreafico F., Quarello P., Alaggio R., Collini P., Haupt R., Mastronuzzi A., Prete A., Rabusin M., Rizzari C., Schumacher F., Zecca M., Pession A., Fagioli F., Spreafico, F, Quarello, P, Alaggio, R, Collini, P, Haupt, R, Mastronuzzi, A, Prete, A, Rabusin, M, Rizzari, C, Schumacher, F, Zecca, M, Pession, A, Fagioli, F, Spreafico F., Quarello P., Alaggio R., Collini P., Haupt R., Mastronuzzi A., Prete A., Rabusin M., Rizzari C., Schumacher F., Zecca M., Pession A., and Fagioli F.

Published
2019

33. Gender differences in axial hair strength may explain gender related incidence variation in Pilonidal Sinus patients

Author

Dettmer, M, Schumacher, F, Matevossian, E, Wilhelm, D, Luedi, MM, and Doll, D

Subjects
integumentary system, otorhinolaryngologic diseases, sense organs
Abstract

Background: Pilonidal sinus disease is a disease of mostly young people with male preponderance and caused by ingrowth of cut head hair. We wondered if the gender difference in Pilonidal Sinus Disease (PSD) incidence of this disease was due to hair characteristics. To aim was to investigate the gender specific hair strength characteristics, linked to standardized PSD incidence. Methods: We analysed the axial strength of human head hair of a northern German healthy population. Standardised gender different PSD disease incidences were computed with raw data provided from the German Institut of Statistics and Health data. Results: Hair from females (n=150) and males (n=150) was analysed. Male axial hair force (1.59g +/- 0.9g) is significantly different from female axial hair force (1.25g +/- 0.76g; p=0.002). Male hair strength exceeds female hair strength by the factor of 1.2. During 2000 and 2017, male standardized PSD incidence exceeds female standardized PSD incidence by a factor of mean 3.1 in Germany. During that observational period, PSD incidence rose by 40% in Germany. Conclusion: A higher pilonidal incidence in males is paralleled with stronger axial hair force in males, as compared to females. Hair strength aka. axial hair force may thus be the major factor in gender specific differences between males and females. May be worthwhile testing if softening the hair could avoid PSD as a preventive method. Key words: hair, axial hair force, pilonidal sinus, incidence, prevention, gender specific differences ISSN: 2207-7537

Published
2021
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34. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Author

Hodgson S., De Vivo I., Dennis J., Dork T., Dowdy S.C., Dunning A.M., Durst M., Easton D.F., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankinson S.E., Hein A., Hillemanns P., Hoivik E.A., Holliday E.G., Hunter D.J., Kraft P., Krakstad C., Lambrechts D., Le Marchand L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Milne R.L., Mints M., Nassir R., Otton G., Palles C., Pooler L., Proietto T., Rebbeck T.R., Renner S.P., Risch H.A., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Tham E., Tomlinson I., Trovik J., Turman C., Tyrer J.P., Van Den Berg D., Wang Z., Wentzensen N., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Webb P.M., Thompson D.J., Spurdle A.B., Glubb D.M., O'Mara T.A., Chen C., Jones A., Kho P.-F., Amant F., Annibali D., Ashton K., Attia J., Auer P.L., Beckmann M.W., Black A., Brinton L., Buchanan D.D., Chanock S.J., Chen M.M., Cheng T.H.T., Cook L.S., Crous-Bous M., Czene K., Hodgson S., De Vivo I., Dennis J., Dork T., Dowdy S.C., Dunning A.M., Durst M., Easton D.F., Ekici A.B., Fasching P.A., Fridley B.L., Friedenreich C.M., Garcia-Closas M., Gaudet M.M., Giles G.G., Goode E.L., Gorman M., Haiman C.A., Hall P., Hankinson S.E., Hein A., Hillemanns P., Hoivik E.A., Holliday E.G., Hunter D.J., Kraft P., Krakstad C., Lambrechts D., Le Marchand L., Liang X., Lindblom A., Lissowska J., Long J., Lu L., Magliocco A.M., Martin L., McEvoy M., Milne R.L., Mints M., Nassir R., Otton G., Palles C., Pooler L., Proietto T., Rebbeck T.R., Renner S.P., Risch H.A., Rubner M., Runnebaum I., Sacerdote C., Sarto G.E., Schumacher F., Scott R.J., Setiawan V.W., Shah M., Sheng X., Shu X.-O., Southey M.C., Tham E., Tomlinson I., Trovik J., Turman C., Tyrer J.P., Van Den Berg D., Wang Z., Wentzensen N., Xia L., Xiang Y.-B., Yang H.P., Yu H., Zheng W., Webb P.M., Thompson D.J., Spurdle A.B., Glubb D.M., O'Mara T.A., Chen C., Jones A., Kho P.-F., Amant F., Annibali D., Ashton K., Attia J., Auer P.L., Beckmann M.W., Black A., Brinton L., Buchanan D.D., Chanock S.J., Chen M.M., Cheng T.H.T., Cook L.S., Crous-Bous M., and Czene K.

Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 x 10-8) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.Copyright © 2020 Union for International Cancer Control

Published
2021

35. Protein engineering of a stable and potent anti-inflammatory IL-37-Fc fusion with enhanced therapeutic potential.

Author

Bujotzek A., Tiefenthaler G., Lariviere L., D'Andrea L., Marquez E.A., Rudloff I., Cho S.X., Deen N.S., Richter W., Regenass-Lechner F., Poehler A., Whisstock J.C., Sydow-Andersen J., Reiser X., Schuster S., Neubauer J., Hoepfl S., Richter K., Nold M.F., Nold-Petry C.A., Schumacher F., Ellisdon A.M., Bujotzek A., Tiefenthaler G., Lariviere L., D'Andrea L., Marquez E.A., Rudloff I., Cho S.X., Deen N.S., Richter W., Regenass-Lechner F., Poehler A., Whisstock J.C., Sydow-Andersen J., Reiser X., Schuster S., Neubauer J., Hoepfl S., Richter K., Nold M.F., Nold-Petry C.A., Schumacher F., and Ellisdon A.M.

Abstract

Harnessing the immunomodulatory activity of cytokines is a focus of therapies targeting inflammatory disease. The interleukin (IL)-1 superfamily contains pro-inflammatory and anti-inflammatory members that help orchestrate the immune response in adaptive and innate immunity. Of these molecules, IL-37 has robust anti-inflammatory activity across a range of disease models through inhibition of pro-inflammatory signaling cascades downstream of tumor necrosis factor, IL-1, and toll-like receptor pathways. We find that IL-37 is unstable with a poor pharmacokinetic and manufacturing profile. Here, we present the engineering of IL-37 from an unstable cytokine into an anti-inflammatory molecule with an excellent therapeutic likeness. We overcame these shortcomings through site-directed mutagenesis, the addition of a non-native disulfide bond, and the engineering of IL-37 as an Fc-fusion protein. Our results provide a platform for preclinical testing of IL-37 Fc-fusion proteins. The engineering approaches undertaken herein will apply to the conversion of similar potent yet short-acting cytokines into therapeutics.Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.

Published
2021

36. Combined Associations of a Polygenic Risk Score and Classical Risk Factors with Breast Cancer Risk.

Author

Kapoor P.M., Mavaddat N., Choudhury P.P., Wilcox A.N., Lindstrom S., Behrens S., Michailidou K., Dennis J., Bolla M.K., Wang Q., Jung A., Abu-Ful Z., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Auer P.L., Freeman L.E.B., Becher H., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bernstein L., Bojesen S.E., Brauch H., Brenner H., Bruning T., Cai Q., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chanock S.J., Chatterjee N., Chenevix-Trench G., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dai J.Y., Earp H.S., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Gaudet M.M., Giles G.G., Gonzalez-Neira A., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hatse S., Heyworth J., Holleczek B., Hoover R.N., Hopper J.L., Howell A., Hunter D.J., John E.M., Jones M.E., Kaaks R., Keeman R., Kitahara C.M., Ko Y.-D., Koutros S., Kurian A.W., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Linet M., Lissowska J., Llaneza A., Macinnis R.J., Martinez M.E., Maurer T., Mclean C., Neuhausen S.L., Newman W.G., Norman A., O'brien K.M., Olshan A.F., Olson J.E., Olsson H., Orr N., Perou C.M., Pita G., Polley E.C., Prentice R.L., Rennert G., Rennert H.S., Ruddy K.J., Sandler D.P., Saunders C., Schoemaker M.J., Schottker B., Schumacher F., Scott C., Scott R.J., Shu X.-O., Smeets A., Southey M.C., Spinelli J.J., Stone J., Swerdlow A.J., Tamimi R.M., Taylor J.A., Troester M.A., Vachon C.M., Van Veen E.M., Wang X., Weinberg C.R., Weltens C., Willett W., Winham S.J., Wolk A., Yang X.R., Zheng W., Ziogas A., Dunning A.M., Pharoah P.D.P., Schmidt M.K., Kraft P., Easton D.F., Milne R.L., Garcia-Closas M., Chang-Claude J., Kapoor P.M., Mavaddat N., Choudhury P.P., Wilcox A.N., Lindstrom S., Behrens S., Michailidou K., Dennis J., Bolla M.K., Wang Q., Jung A., Abu-Ful Z., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Auer P.L., Freeman L.E.B., Becher H., Beckmann M.W., Beeghly-Fadiel A., Benitez J., Bernstein L., Bojesen S.E., Brauch H., Brenner H., Bruning T., Cai Q., Campa D., Canzian F., Carracedo A., Carter B.D., Castelao J.E., Chanock S.J., Chatterjee N., Chenevix-Trench G., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dai J.Y., Earp H.S., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Gaudet M.M., Giles G.G., Gonzalez-Neira A., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hatse S., Heyworth J., Holleczek B., Hoover R.N., Hopper J.L., Howell A., Hunter D.J., John E.M., Jones M.E., Kaaks R., Keeman R., Kitahara C.M., Ko Y.-D., Koutros S., Kurian A.W., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Linet M., Lissowska J., Llaneza A., Macinnis R.J., Martinez M.E., Maurer T., Mclean C., Neuhausen S.L., Newman W.G., Norman A., O'brien K.M., Olshan A.F., Olson J.E., Olsson H., Orr N., Perou C.M., Pita G., Polley E.C., Prentice R.L., Rennert G., Rennert H.S., Ruddy K.J., Sandler D.P., Saunders C., Schoemaker M.J., Schottker B., Schumacher F., Scott C., Scott R.J., Shu X.-O., Smeets A., Southey M.C., Spinelli J.J., Stone J., Swerdlow A.J., Tamimi R.M., Taylor J.A., Troester M.A., Vachon C.M., Van Veen E.M., Wang X., Weinberg C.R., Weltens C., Willett W., Winham S.J., Wolk A., Yang X.R., Zheng W., Ziogas A., Dunning A.M., Pharoah P.D.P., Schmidt M.K., Kraft P., Easton D.F., Milne R.L., Garcia-Closas M., and Chang-Claude J.

Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. Copyright © 2020 The Author(s).

Published
2021

38. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author

Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, Chang-Claude, J, Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, and Chang-Claude, J

Abstract

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Published
2021

42. Central acting Hsp10 regulates mitochondrial function, insulin sensitivity and impacts liver metabolism

Author

Wardelmann, K, additional, Rath, M, additional, Castro, JP, additional, Blümel, S, additional, Schell, M, additional, Hauffe, R, additional, Chudoba, C, additional, Schumacher, F, additional, Jähnert, M, additional, Warnke, K, additional, Flore, T, additional, Ritter, K, additional, Wernitz, A, additional, Hosoi, T, additional, and Ozawa, K, additional

Published
2021
Full Text
View/download PDF

43. Acid sphingomyelinase deactivation post-ischemia/ reperfusion promotes cerebral angiogenesis and brain remodeling via small extracellular vesicles

Author

Mohamud Yusuf, A, primary, Hagemann, N, additional, Zhang, X, additional, Zafar, M, additional, Hussner, T, additional, Bromkamp, C, additional, Martiny, C, additional, Tertel, T, additional, Börger, V, additional, Schumacher, F, additional, Solari, FA, additional, Hasenberg, M, additional, Kleinschnitz, C, additional, Doeppner, TR, additional, Kleuser, B, additional, Sickmann, A, additional, Gunzer, M, additional, Giebel, B, additional, Kolesnick, R, additional, Gulbins, E, additional, and Hermann, DM, additional

Published
2021
Full Text
View/download PDF

44. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author

Kho, P-F, Amant, F, Annibali, D, Ashton, K, Attia, J, Auer, PL, Beckmann, MW, Black, A, Brinton, L, Buchanan, DD, Chen, C, Chen, MM, Cheng, THT, Cook, LS, Crous-Bous, M, Czene, K, De Vivo, I, Dennis, J, Dörk, T, Dowdy, SC, Dunning, AM, Dürst, M, Easton, DF, Ekici, AB, Fasching, PA, Fridley, BL, Friedenreich, CM, García-Closas, M, Gaudet, MM, Giles, GG, Goode, EL, Gorman, M, Haiman, CA, Hall, P, Hankison, SE, Hein, A, Hillemanns, P, Hodgson, S, Hoivik, EA, Holliday, EG, Hunter, DJ, Jones, A, Kraft, P, Krakstad, C, Lambrechts, D, Le Marchand, L, Liang, X, Lindblom, A, Lissowska, J, Long, J, Lu, L, Magliocco, AM, Martin, L, McEvoy, M, Milne, RL, Mints, M, Nassir, R, Otton, G, Palles, C, Pooler, L, Proietto, T, Rebbeck, TR, Renner, SP, Risch, HA, Rübner, M, Runnebaum, I, Sacerdote, C, Sarto, GE, Schumacher, F, Scott, RJ, Setiawan, VW, Shah, M, Sheng, X, Shu, X-O, Southey, MC, Tham, E, Tomlinson, I, Trovik, J, Turman, C, Tyrer, JP, Van Den Berg, D, Wang, Z, Wentzensen, N, Xia, L, Xiang, Y-B, Yang, HP, Yu, H, Zheng, W, Webb, PM, Thompson, DJ, Spurdle, AB, Glubb, DM, and O'Mara, TA

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

Published
2020

45. Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Author

Ngo D., McLean C.A., Stock M., Klassert T.E., Slevogt H., Mangan N.E., Cheng W., Fischer D., Gfroerer S., Sandhu M.K., Bui C.B., Bujotzek A., Lariviere L., Schumacher F., Tiefenthaler G., Beker F., Collins C., Kamlin C.O.F., Konig K., Malhotra A., Theda C., Veldman A., Ellisdon A.M., Whisstock J.C., Berger P.J., Nold M.F., Nold-Petry C.A., Tan K., Cho S.X., Rudloff I., Lao J.C., Pang M.A., Goldberg R., Ngo D., McLean C.A., Stock M., Klassert T.E., Slevogt H., Mangan N.E., Cheng W., Fischer D., Gfroerer S., Sandhu M.K., Bui C.B., Bujotzek A., Lariviere L., Schumacher F., Tiefenthaler G., Beker F., Collins C., Kamlin C.O.F., Konig K., Malhotra A., Theda C., Veldman A., Ellisdon A.M., Whisstock J.C., Berger P.J., Nold M.F., Nold-Petry C.A., Tan K., Cho S.X., Rudloff I., Lao J.C., Pang M.A., and Goldberg R.

Abstract

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORgammat+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORgammat+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.Copyright © 2020, The Author(s).

Published
2020

46. The Farm Nursery, grow your own trees from seed

Author

F.W. Schumacher Co, Schumacher, F. W., Henry G. Gilbert Nursery and Seed Trade Catalog Collection, U.S. Department of Agriculture, National Agricultural Library, F.W. Schumacher Co, Schumacher, F. W., and Henry G. Gilbert Nursery and Seed Trade Catalog Collection

Subjects
Boston, Catalogs, Forest plants, Massachusetts, Seed industry and trade, Seeds, Trees
Published
1944

47. List of surplus plants : spring 1942

Author

F.W. Schumacher Co, Schumacher, F. W., Henry G. Gilbert Nursery and Seed Trade Catalog Collection, U.S. Department of Agriculture, National Agricultural Library, F.W. Schumacher Co, Schumacher, F. W., and Henry G. Gilbert Nursery and Seed Trade Catalog Collection

Subjects
Boston, Massachusetts, Prices, Seed industry and trade, Seeds, Shrubs, Trees
Published
1942

48. Seeds for the nurseryman and forester, 1941-1942

Author

F.W. Schumacher Co, Schumacher, F. W., Henry G. Gilbert Nursery and Seed Trade Catalog Collection, U.S. Department of Agriculture, National Agricultural Library, F.W. Schumacher Co, Schumacher, F. W., and Henry G. Gilbert Nursery and Seed Trade Catalog Collection

Subjects
Boston, Massachusetts, Prices, Seed industry and trade, Seeds, Shrubs, Trees
Published
1941

49. Seeds for the nurseryman and forester, 1940-1941

Author

F.W. Schumacher Co, Schumacher, F. W., Henry G. Gilbert Nursery and Seed Trade Catalog Collection, U.S. Department of Agriculture, National Agricultural Library, F.W. Schumacher Co, Schumacher, F. W., and Henry G. Gilbert Nursery and Seed Trade Catalog Collection

Subjects
Boston, Massachusetts, Prices, Seed industry and trade, Seeds, Shrubs, Trees
Published
1940

50. Seeds for the nurseryman and forester, 1939-1940

Author

F.W. Schumacher Co, Schumacher, F. W., Henry G. Gilbert Nursery and Seed Trade Catalog Collection, U.S. Department of Agriculture, National Agricultural Library, F.W. Schumacher Co, Schumacher, F. W., and Henry G. Gilbert Nursery and Seed Trade Catalog Collection

Subjects
Boston, Massachusetts, Prices, Seed industry and trade, Seeds, Shrubs, Trees
Published
1939

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