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1. The impact of hydrostatic pressure, nonstoichiometry, and doping on trimeron lattice excitations in magnetite during axis switching

Author

Kołodziej, T., Piętosa, J., Puźniak, R., Wiśniewski, A., Król, G., Kąkol, Z., Biało, I., Tarnawski, Z., Ślęzak, M., Podgórska, K., Niewolski, J., Gala, M. A., Kozłowski, A., Honig, J. M., and Tabiś, W.

Subjects
Condensed Matter - Strongly Correlated Electrons, Condensed Matter - Materials Science
Abstract

Trimeron lattice excitations in single crystalline magnetite, in the form of the $c$ axis switching (i.e. the reorganization of the lattice caused by external magnetic field) at temperatures below the Verwey temperature $T_V$ are observed by magnetization experiments. These excitations exhibit strong sensitivity to doping (with Zn, Al, and Ti), nonstoichiometry and hydrostatic pressure ($p < 1.2$ GPa). The considered indicators of the axis switching (AS) are: the switching field $B_{sw}$, the energy density needed to switch the axis $E_{sw}$ and the activation energy $U$. Our results show that hydrostatic pressure $p$ weakens the low$-T$ magnetite structure (decreases $T_V$) and has roughly similar effects on AS in Zn-doped Fe$_3$O$_4$ and, in much less extent, in stoichiometric magnetite. We have, however, found that while doping/nonstoichiometry also lowers $T_V$, making it more prone to temperature chaos, it drastically increases the switching field, activation and switching energies suggesting that the trimeron order, subject to change while AS occurs, is more robust. Consequently, we conclude that the manipulation of trimerons in the process of axis switching and the mechanisms leading to the Verwey transition are distinct phenomena., Comment: Manuscript contains Supplemental Material

Published
2023
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4. Predicting Enrollment Melt Among Community College Applicants.

Author

Ledezma, Gala M.

Subjects
COLLEGE applicants, ACADEMIC achievement, MELTING, PROBABILITY theory, STUDENTS
Abstract

This study examines enrollment melt patterns in a community college campus, aiming to quantify the predictive factors associated with students' likelihood of melting. Using a combination of survey and administrative data from applicants to a California Community College campus in Southern California, the author estimates changes in enrollment probability associated with various student-level factors, such as applications to multiple institutions and confidence in academic performance. This research aims to enhance comprehension of enrollment melt dynamics, providing insights that can guide strategies to tackle enrollment challenges in community colleges. [ABSTRACT FROM AUTHOR]

Published
2025

7. Heterogeneous Non Obtrusive Platform to Monitor, Assist and Provide Recommendations to Elders at Home: The MoveCare Platform

Author

Borghese, N. A., Bulgheroni, M., Miralles, F., Savanovic, A., Ferrante, S., Kounoudes, T., Cid Gala, M., Loutfi, A., Cangelosi, A., Gonzalez-Jimenez, J., Ianes, A., Angrisani, Leopoldo, Series Editor, Arteaga, Marco, Series Editor, Panigrahi, Bijaya Ketan, Series Editor, Chakraborty, Samarjit, Series Editor, Chen, Jiming, Series Editor, Chen, Shanben, Series Editor, Chen, Tan Kay, Series Editor, Dillmann, Ruediger, Series Editor, Duan, Haibin, Series Editor, Ferrari, Gianluigi, Series Editor, Ferre, Manuel, Series Editor, Hirche, Sandra, Series Editor, Jabbari, Faryar, Series Editor, Jia, Limin, Series Editor, Kacprzyk, Janusz, Series Editor, Khamis, Alaa, Series Editor, Kroeger, Torsten, Series Editor, Liang, Qilian, Series Editor, Ming, Tan Cher, Series Editor, Minker, Wolfgang, Series Editor, Misra, Pradeep, Series Editor, Möller, Sebastian, Series Editor, Mukhopadhyay, Subhas, Series Editor, Ning, Cun-Zheng, Series Editor, Nishida, Toyoaki, Series Editor, Pascucci, Federica, Series Editor, Qin, Yong, Series Editor, Seng, Gan Woon, Series Editor, Veiga, Germano, Series Editor, Wu, Haitao, Series Editor, Zhang, Junjie James, Series Editor, Casiddu, Niccolò, editor, Porfirione, Claudia, editor, Monteriù, Andrea, editor, and Cavallo, Filippo, editor

Published
2019
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8. Ustekinumab is effective for perianal fistulising Crohn's disease: a real-world experience and systematic review with meta-analysis

Author

Berkeley N Limketkai, Mark Lazarev, George Salem, Gala M Godoy Brewer, Muhammad A Afzal, Zadid Haq, Maryam Tajamal, Joanna Melia, Florin M Selaru, and Alyssa M. Parian

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background Perianal Crohn’s disease (pCD) is a debilitating complication affecting up to 30% of Crohn’s disease (CD) population, leading to increased morbidity, mortality and decreased quality of life. Despite the growing armamentarium of medications for luminal CD, their efficacy in pCD remains poorly studied.Aim To determine the efficacy of ustekinumab, a biologic approved for luminal CD, in pCD through a retrospective cohort study and systematic review.Methods A retrospective cohort study on patients with CD with active perianal fistulae treated with ustekinumab from September 2013 to August 2019 was performed to determine perianal fistula response and remission at 6 and 12 months after ustekinumab induction. A systematic review was performed to further establish rates of fistula response and remission with ustekinumab.Results At 6 months, 48.1% (13/27) patients achieved fistula response with none achieving fistula remission on provider exam, and 59.3% (16/27) achieved patient-reported symptomatic improvement with 3.7% (1/27) achieving symptomatic remission. At 1 year, on provider exam, 55.6% (5/9) had fistula response with none achieving fistula remission, and 100% (9/9) had symptomatic improvement with 22.2% (2/9) achieving symptomatic remission. There were no major safety signals during 1-year follow-up. The systematic review of 25 studies found 44% (92/209) of patients with active perianal fistulas had a clinical response within 6 months of follow-up, and 53.9% (85/152) of patients with 12 months of follow-up achieved clinical response.Conclusion Ustekinumab presents a safe and effective therapy for treatment of pCD. Prospective, randomised trials are needed to further elucidate long-term efficacy of ustekinumab for pCD.

Published
2021
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10. Impact of hydrostatic pressure, nonstoichiometry, and doping on trimeron lattice excitations in magnetite during axis switching

Author

Kołodziej, T., primary, Piętosa, J., additional, Puźniak, R., additional, Wiśniewski, A., additional, Król, G., additional, Kąkol, Z., additional, Biało, I., additional, Tarnawski, Z., additional, Ślęzak, M., additional, Podgórska, K., additional, Niewolski, J., additional, Gala, M. A., additional, Kozłowski, A., additional, Honig, J. M., additional, and Tabiś, W., additional

Published
2023
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11. New horizons in breast cancer: the promise of immunotherapy

Author

de la Cruz-Merino, L., Palazón-Carrión, N., Henao-Carrasco, F., Nogales-Fernández, E., Álamo-de la Gala, M., Vallejo-Benítez, A., Chiesa, M., Sánchez-Margalet, V., and GEICAM (Spanish Breast Cancer Research Group) and GÉTICA (Spanish Group for Cancer Immuno-Biotherapy)

Published
2019
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12. Modelos mentales erróneos y persistentes en programación: cuestionario realizado y datos crudos anonimizados

Author

Universidad de Alicante. Departamento de Ciencia de la Computación e Inteligencia Artificial, Gallego-Durán, Francisco J., Compañ, Patricia, Villagrá-Arnedo, Carlos-José, García Sánchez, Gala M., Satorre Cuerda, Rosana, Universidad de Alicante. Departamento de Ciencia de la Computación e Inteligencia Artificial, Gallego-Durán, Francisco J., Compañ, Patricia, Villagrá-Arnedo, Carlos-José, García Sánchez, Gala M., and Satorre Cuerda, Rosana

Abstract

Estos son los datos crudos y análisis realizados del artículo "Modelos mentales erróneos y persistentes en programación", presentado al congreso JENUI 2023. Incluyen el cuestionario con todas las preguntas realizadas a los estudiantes, y las respuestas completas anonimizadas. El estudio aborda el proceso de aprendizaje a través de la creación de modelos mentales, representaciones análogas a lo aprendido que permiten realizar predicciones y tomar decisiones. Se sostiene que un aprendizaje efectivo puede ser representado por la refinación de estos modelos para acercarlos a la realidad. La programación, en particular, presenta un desafío adicional, ya que no solo requiere la refinación de modelos mentales, sino también la habilidad para navegar entre múltiples modelos precisos en ambas direcciones, a fin de crear un programa que produzca los efectos deseados. El estudio propone un método iterativo para identificar modelos mentales incorrectos en la programación, a partir de hipótesis basadas en la experiencia docente y la recopilación de evidencia empírica. Esta metodología, aplicada en un grupo de estudiantes de cuarto curso de Ingeniería, permite no solo la identificación de modelos erróneos potenciales, sino también la detección de otros no previstos que requieren más investigación. Estos hallazgos apuntan a la necesidad de mejorar los procesos de enseñanza para ayudar a los estudiantes a desarrollar modelos mentales más precisos y efectivos en el campo de la programación.

Published
2023

13. Modelos mentales erróneos y persistentes en programación

Author

Universidad de Alicante. Departamento de Ciencia de la Computación e Inteligencia Artificial, Gallego-Durán, Francisco J., Compañ, Patricia, Villagrá-Arnedo, Carlos-José, García Sánchez, Gala M., Satorre Cuerda, Rosana, Universidad de Alicante. Departamento de Ciencia de la Computación e Inteligencia Artificial, Gallego-Durán, Francisco J., Compañ, Patricia, Villagrá-Arnedo, Carlos-José, García Sánchez, Gala M., and Satorre Cuerda, Rosana

Abstract

El aprendizaje implica la creación de representaciones mentales análogas a lo aprendido, conocidas como modelos mentales. Estos modelos nos permiten realizar predicciones y tomar decisiones. Cuanto más cercanos sean a la realidad, mejores serán nuestras predicciones y decisiones, lo que indica que refinar estos modelos puede representar un aprendizaje efectivo. La programación, además, requiere realizar el proceso inverso: a partir de los efectos deseados, crear un programa que los produzca. Este proceso, más complejo que simplemente refinar un modelo mental, demanda múltiples modelos precisos y habilidad asociativa para navegar entre ellos en ambas direcciones. Los profesores enseñamos sobre modelos conceptuales, que son abstracciones claramente definidas. Adquirir estos modelos implica generalizar y extraer patrones de numerosos ejemplos específicos. A menudo, los modelos mentales iniciales se vinculan a detalles circunstanciales de los ejemplos, tanto al ruido como a la señal. Aunque estos modelos sean erróneos, pueden funcionar razonablemente bien en algunas situaciones específicas, ser suficientes para aprobar y persistir en el tiempo. Esto podría explicar dificultades futuras en la programación. Este estudio busca identificar modelos mentales incorrectos en la programación. Proponemos un método iterativo que parte de hipótesis basadas en la experiencia docente y llega hasta la evidencia empírica. Este enfoque también permite descubrir nuevos modelos y refinar nuestro conocimiento. Presentamos su aplicación con estudiantes de cuarto curso y conceptos de primer curso. Nuestros resultados destacan modelos erróneos potenciales y sugieren otros no previstos que requieren más investigación., Learning involves creating mental representations analogous to what is learned, known as mental models. These models allow us to make predictions and decisions. The closer they are to reality, the better our predictions and decisions will be, indicating that effective learning consists of refining these models. Programming, on the other hand, requires carrying out the reverse process: from the desired effects, create a program that produces them. This process, more complex than merely refining a mental model, demands multiple accurate models and associative skills to navigate between them in both directions. Teachers instruct on conceptual models, which are clearly defined abstractions. Acquiring these models involves generalizing and extracting patterns from numerous specific examples. Consequently, initial mental models often link to circumstantial details of the examples, both to the noise and the signal. Although these models may be erroneous, they can work reasonably well in some specific situations, be sufficient to pass, and persist over time. This could explain future difficulties in programming. This study seeks to identify incorrect mental models in programming. We propose an iterative method that starts from hypotheses based on teaching experience and reaches empirical evidence. This approach also allows discovering new models and refining our knowledge. We present its application with fourth-year students and first-year concepts. Our results highlight potential erroneous models and suggest other unforeseen ones that require further investigation.

Published
2023

22. Initial Clinical Outcomes Using Placental Derived Tissue Grafts to Repair Anovaginal Fistula

Author

Gala M, Godoy-Brewer, Oluwafemi, Owodunni, Alyssa M, Parian, Leonardo, de Castro Duraes, Florin M, Selaru, and Susan, Gearhart

Abstract

Perianal fistula is a debilitating disease and challenging condition to treat. Recently, the use of stem cells has been shown to improve healing of fistulas.We wish to examine the use of an umbilical cord derived stem cell graft in a pilot study as a novel scaffold/stem inlay implanted into fistula repairs for anovaginal fistula to examine healing rates.This was a pilot study.This study took place in a colorectal surgery practice.Patients with anovaginal fistula were consented to participate. Cryopreserved umbilical cord tissue graft with viable cells was incorporated as an in-lay using a previously reported technique by the authors. Demographic data including history of prior repairs and inflammatory bowel disease were included. All patients were followed for a minimum of 6 weeks.The primary measures were safety and efficacy of novel stem cell graft in the treatment of anovaginal fistula.From 9/2017-9/2019, 15 patients underwent anovaginal fistula repair. Three of these patients underwent a second repair, for a total of 18 repairs. No patient was intentionally diverted while 3 patients presented for repair with a pre-existing stoma. The majority of repairs were previous repair failures (12, 67%) and seven repairs were performed on 5 patients with inflammatory bowel disease (IBD). Median follow-up was 30 weeks (6 - 104). The safety profile for cryopreserved umbilical cord tissue graft was excellent as no adverse events occurred. Overall complete healing rate was 39% and 12 (67%) repairs resulted in improvement of symptoms.This was a small pilot study.This is the largest series using cryopreserved umbilical cord graft for anovaginal fistula repair. The utilization of umbilical cord was safe and effective at closing defects. Randomized studies are necessary to determine added benefits over current standard of care. See Video Abstract at http://links.lww.com/DCR/B896.

Published
2022

27. Microsporidia infection in patients with autoimmune diseases

Author

Emad M. Eed, Yousry A. Hawash, Amany S. Khalifa, Ahmed M Khalifa, Osama Mahmoud Khalifa, Khadiga Ahmed Ismail, Saleh Alghamdi, Hatem K Althubiti, Taisir Saber, Khalaf F. Alsharif, and Gala M Alsofyani

Subjects
Diarrhea, Male, 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Immunology, lcsh:QR1-502, Polymerase Chain Reaction, Microbiology, Gastroenterology, lcsh:Microbiology, law.invention, Feces, 03 medical and health sciences, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), law, Immunity, Internal medicine, Microsporidiosis, medicine, Humans, Immunology and Allergy, In patient, autoimmune diseases, Prospective Studies, 030212 general & internal medicine, Polymerase chain reaction, General Immunology and Microbiology, biology, Tumor Necrosis Factor-alpha, business.industry, Intracellular parasite, biology.organism_classification, Microsporidium, Infectious Diseases, Case-Control Studies, Microsporidia, microsporidia, tumor necrosis factor alpha antagonists, Female, Tumor necrosis factor alpha, medicine.symptom, business
Abstract

Purpose: Microsporidium is a spore-forming intracellular parasite that affects a wide range of hosts including humans. The tumor necrosis factor alpha (TNF-α) plays a key role in the immunity to infection with microsporidia. Recently, the TNF-α antagonists have proven successful in treating variable autoimmune diseases. In the current study, we aimed to investigate the impact of using TNF-α antagonists as a therapeutic regimen in the prevalence of infections with microsporidia. Materials and Methods: Diarrheal patients with distinct autoimmune diseases (n = 100) were assigned to the study. Patients taking anti-TNF-α medications (n = 60) were allocated to Group 1A and those undergoing non-TNF-α inhibitor treatment (n = 40) to Group 1B. Furthermore, patients with diarrhea without autoimmune disorders (n = 20) were allocated as controls. Stool specimens, 3 per patient, were collected and microscopically examined for microsporidia spores. A microsporidia-specific stool polymerase chain reaction was used to confirm the microscopic findings. Results: Microsporidia infection was identified in 28.3% (17/60), 10% (4/40), and in 5% (1/20) of patients in Group 1A, Group 1B, and in the control group, respectively. Overall, infection was significantly high in cases compared to the controls and in patients receiving TNF-α antagonists compared to patients not given TNF-α inhibitors (P < 0.05). Finally, infection was significantly higher in cases treated with TNF-α antagonists for ≥2 months compared to cases treated for

Published
2020

28. Gas Chromatography-Tandem Mass Spectrometry Method for Selective Detection of 2-Nitropropane in Mainstream Cigarette Smoke

Author

Clifford H. Watson, Roberto Bravo Cardenas, Juliana Giraldo Junco, Liza Valentin-Blasini, and Gala M. Chapman

Subjects
volatile organic compound, Chromatography, Gas Chromatography/Tandem Mass Spectrometry, General interest, gas chromatography, 010401 analytical chemistry, 2-nitropropane, Plant culture, 010501 environmental sciences, tobacco, 01 natural sciences, Article, SB1-1110, 0104 chemical sciences, Cigarette smoke, mass spectrometry, 0105 earth and related environmental sciences
Abstract

Summary Although 2-nitropropane is a potentially harmful compound present in cigarette smoke, there are few fully-validated, modern methods to quantitate it in mainstream cigarette smoke. We developed an isotope dilution gas chromatography-tandem mass spectrometry (ID-GC-MS/MS) method for the detection of 2-nitropropane in mainstream cigarette smoke. The vapor fraction of mainstream cigarette smoke was collected in inert polyvinyl fluoride gas sampling bags and extracted with hexanes containing isotopically labeled internal standard, then purified and concentrated via solid-phase extraction using a normal phase silica adsorbent and a 100% dichloromethane eluant. This method is sensitive enough to measure vapor phase 2-nitro-propane concentrations in the nanogram range, with a 19 ng per cigarette method limit of detection. Product variability estimated from the analysis of 15 cigarette products yielded relative standard deviations ranging from 5.4% to 15.7%, and estimates of precision from two quality control products yielded relative standard deviations of 9.49% and 14.9%. Under the Health Canada Intense smoking regimen, 2-nitropropane in machine-generated mainstream smoke from 15 cigarette products ranged from 98.3 to 363 ng per cigarette.

Published
2019
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33. Ustekinumab is effective for perianal fistulising Crohn's disease: a real-world experience and systematic review with meta-analysis

Author

Gala M Godoy Brewer, George Salem, Muhammad A Afzal, Berkeley N Limketkai, Zadid Haq, Maryam Tajamal, Joanna Melia, Mark Lazarev, Florin M Selaru, and Alyssa M. Parian

Subjects
Gastroenterology, gastrointestinal fistulae, Crohn Disease, inflammatory bowel disease, Crohn's colitis, Quality of Life, Humans, Rectal Fistula, Ustekinumab, Prospective Studies, anal, Retrospective Studies, Anorectal Disease
Abstract

BackgroundPerianal Crohn’s disease (pCD) is a debilitating complication affecting up to 30% of Crohn’s disease (CD) population, leading to increased morbidity, mortality and decreased quality of life. Despite the growing armamentarium of medications for luminal CD, their efficacy in pCD remains poorly studied.AimTo determine the efficacy of ustekinumab, a biologic approved for luminal CD, in pCD through a retrospective cohort study and systematic review.MethodsA retrospective cohort study on patients with CD with active perianal fistulae treated with ustekinumab from September 2013 to August 2019 was performed to determine perianal fistula response and remission at 6 and 12 months after ustekinumab induction. A systematic review was performed to further establish rates of fistula response and remission with ustekinumab.ResultsAt 6 months, 48.1% (13/27) patients achieved fistula response with none achieving fistula remission on provider exam, and 59.3% (16/27) achieved patient-reported symptomatic improvement with 3.7% (1/27) achieving symptomatic remission. At 1 year, on provider exam, 55.6% (5/9) had fistula response with none achieving fistula remission, and 100% (9/9) had symptomatic improvement with 22.2% (2/9) achieving symptomatic remission. There were no major safety signals during 1-year follow-up. The systematic review of 25 studies found 44% (92/209) of patients with active perianal fistulas had a clinical response within 6 months of follow-up, and 53.9% (85/152) of patients with 12 months of follow-up achieved clinical response.ConclusionUstekinumab presents a safe and effective therapy for treatment of pCD. Prospective, randomised trials are needed to further elucidate long-term efficacy of ustekinumab for pCD.

Published
2021

34. Quantification of nitromethane in mainstream smoke using gas chromatography and tandem mass spectrometry

Author

Roberto Bravo Cardenas, Gala M. Chapman, Clifford H. Watson, Juliana Giraldo Junco, and Liza Valentin-Blasini

Subjects
Health, Toxicology and Mutagenesis, Nitromethane, 010501 environmental sciences, Toxicology, Mass spectrometry, 01 natural sciences, Mainstream smoke, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, RA1190-1270, Volatile organic compound, Sidestream smoke, 0105 earth and related environmental sciences, ComputingMethodologies_COMPUTERGRAPHICS, chemistry.chemical_classification, Smoke, Detection limit, Chromatography, GC–MS/MS, Regular Article, Tobacco analysis, chemistry, Toxicology. Poisons, Sample collection, Gas chromatography, 030217 neurology & neurosurgery
Abstract

Graphical abstract, Highlights • A novel method was developed to detect nitromethane in cigarette smoke. • The method is sensitive, accurate, and fit for high-throughput applications. • The new method was used to quantify nitromethane in smoke from 10 cigarette brands. • Differences were observed depending on tobacco types used., Nitromethane is a volatile organic compound categorized as a Group 2B carcinogen by the International Agency for Research on Cancer. It has been detected in mainstream cigarette smoke, but few reliable methods have been reported for accurate quantification. We developed, a sensitive, selective, fully validated method for the targeted determination of nitromethane in mainstream tobacco smoke in ten U.S. domestic brands and two quality control materials (3R4F and CM6). The vapor phase portion of machine-generated cigarette mainstream smoke, under modified ISO 3308:2000 regime (ISO) and modified intense regime (HCI), from single cigarettes was collected using airtight polyvinylfluoride sampling bags. The bags’ contents were extracted using methanol containing an isotopically labeled internal standard followed by gas chromatography-tandem mass spectrometry. This approach is sufficiently sensitive to measure nitromethane levels in the nanogram range, with a method limit of detection of 72.3 ng/cig. Within-product variability estimated from the replicate analysis of 10 products ranged from 4.6%–16.3% (n = 6) over the two different smoking regimes, and method reproducibility estimated from two products used as quality control materials (3R4F and CM6) yielded intermediate precision values ranging from 16.6 to 20.8% (n = 20). Under HCI, nitromethane yields in machine-generated cigarette smoke from ten different domestic cigarette products ranged from 3.2 to 12 μg/cig; under ISO yields ranged from 1.6 to 4.9 μg/cig under standardized smoking machine conditions. Nitromethane yields are related to both the smoke regime (blocking of vent holes, puff duration and puff volume) and the heterogeneity of tobacco mixtures. This method provides a selective and fully validated technique to accurately quantify nitromethane in mainstream cigarette smoke, with minimal waste generation. It is an improvement over previous methods with regards to specificity, throughput, and simplicity of the sample collection process.

Published
2020

35. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author

Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, Peters, U, Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, and Peters, U

Abstract

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Published
2021

40. DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Author

Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, S, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A, Landi, S, Pardini, B, Corrado, A, Paolicchi, E, Cugliari, G, Berndt, S, Bezieau, S, Bien, SA, Brenner, H, Caan, BJ, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Cotterchio, M, Gala, M, Gallinger, SJ, Haile, RW, Harrison, TA, Hayes, RB, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, J, Jenkins, MA, Le Marchand, L, Lin, Y, Lindor, NM, Nan, H, Newcomb, PA, Ogino, S, Potter, JD, Schoen, RE, Slattery, ML, White, E, Vodickova, L, Vymetalkova, V, Vodicka, P, Gemignani, F, Peters, U, Naccarati, A, and Landi, S

Abstract

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Published
2020

41. Effect of low-dose and standard-dose aspirin on PGE2 biosynthesis among individuals with colorectal adenomas: A randomized clinical trial

Author

Drew, D. A., Schuck, M. M., Magicheva-Gupta, M. V., Stewart, K. O., Gilpin, K. K., Miller, P., Parziale, M. P., Pond, E. N., Takacsi-Nagy, O., Zerjav, D. C., Chin, S. M., Krems, J. M., Meixell, D., Joshi, A. D., Ma, W., Colizzo, F. P., Carolan, P. J., Nishioka, N. S., Staller, K., Richter, J. M., Khalili, H., Gala, M. K., Garber, J. J., Chung, D. C., Yarze, J. C., Zukerberg, L., Petrucci, Giovanna, Rocca, Bianca, Patrono, Carlo, Milne, G. L., Wang, M., Chan, A. T., Petrucci G. (ORCID:0000-0002-9280-3673), Rocca B. (ORCID:0000-0001-8304-6423), Patrono C., Drew, D. A., Schuck, M. M., Magicheva-Gupta, M. V., Stewart, K. O., Gilpin, K. K., Miller, P., Parziale, M. P., Pond, E. N., Takacsi-Nagy, O., Zerjav, D. C., Chin, S. M., Krems, J. M., Meixell, D., Joshi, A. D., Ma, W., Colizzo, F. P., Carolan, P. J., Nishioka, N. S., Staller, K., Richter, J. M., Khalili, H., Gala, M. K., Garber, J. J., Chung, D. C., Yarze, J. C., Zukerberg, L., Petrucci, Giovanna, Rocca, Bianca, Patrono, Carlo, Milne, G. L., Wang, M., Chan, A. T., Petrucci G. (ORCID:0000-0002-9280-3673), Rocca B. (ORCID:0000-0001-8304-6423), and Patrono C.

Abstract

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N 1⁄4 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8–12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 = 14.6 (mean = S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (=4.7 = 14.8) compared with no decrease (0.8 = 11.8) in the placebo group (P 1⁄4 0.015; mean duration of treatment 1⁄4 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P 1⁄4 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Published
2020

43. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, J.R. Bien, S.A. Harrison, T.A. Kang, H.M. Chen, S. Schmit, S.L. Conti, D.V. Qu, C. Jeon, J. Edlund, C.K. Greenside, P. Wainberg, M. Schumacher, F.R. Smith, J.D. Levine, D.M. Nelson, S.C. Sinnott-Armstrong, N.A. Albanes, D. Alonso, M.H. Anderson, K. Arnau-Collell, C. Arndt, V. Bamia, C. Banbury, B.L. Baron, J.A. Berndt, S.I. Bézieau, S. Bishop, D.T. Boehm, J. Boeing, H. Brenner, H. Brezina, S. Buch, S. Buchanan, D.D. Burnett-Hartman, A. Butterbach, K. Caan, B.J. Campbell, P.T. Carlson, C.S. Castellví-Bel, S. Chan, A.T. Chang-Claude, J. Chanock, S.J. Chirlaque, M.-D. Cho, S.H. Connolly, C.M. Cross, A.J. Cuk, K. Curtis, K.R. de la Chapelle, A. Doheny, K.F. Duggan, D. Easton, D.F. Elias, S.G. Elliott, F. English, D.R. Feskens, E.J.M. Figueiredo, J.C. Fischer, R. FitzGerald, L.M. Forman, D. Gala, M. Gallinger, S. Gauderman, W.J. Giles, G.G. Gillanders, E. Gong, J. Goodman, P.J. Grady, W.M. Grove, J.S. Gsur, A. Gunter, M.J. Haile, R.W. Hampe, J. Hampel, H. Harlid, S. Hayes, R.B. Hofer, P. Hoffmeister, M. Hopper, J.L. Hsu, W.-L. Huang, W.-Y. Hudson, T.J. Hunter, D.J. Ibañez-Sanz, G. Idos, G.E. Ingersoll, R. Jackson, R.D. Jacobs, E.J. Jenkins, M.A. Joshi, A.D. Joshu, C.E. Keku, T.O. Key, T.J. Kim, H.R. Kobayashi, E. Kolonel, L.N. Kooperberg, C. Kühn, T. Küry, S. Kweon, S.-S. Larsson, S.C. Laurie, C.A. Le Marchand, L. Leal, S.M. Lee, S.C. Lejbkowicz, F. Lemire, M. Li, C.I. Li, L. Lieb, W. Lin, Y. Lindblom, A. Lindor, N.M. Ling, H. Louie, T.L. Männistö, S. Markowitz, S.D. Martín, V. Masala, G. McNeil, C.E. Melas, M. Milne, R.L. Moreno, L. Murphy, N. Myte, R. Naccarati, A. Newcomb, P.A. Offit, K. Ogino, S. Onland-Moret, N.C. Pardini, B. Parfrey, P.S. Pearlman, R. Perduca, V. Pharoah, P.D.P. Pinchev, M. Platz, E.A. Prentice, R.L. Pugh, E. Raskin, L. Rennert, G. Rennert, H.S. Riboli, E. Rodríguez-Barranco, M. Romm, J. Sakoda, L.C. Schafmayer, C. Schoen, R.E. Seminara, D. Shah, M. Shelford, T. Shin, M.-H. Shulman, K. Sieri, S. Slattery, M.L. Southey, M.C. Stadler, Z.K. Stegmaier, C. Su, Y.-R. Tangen, C.M. Thibodeau, S.N. Thomas, D.C. Thomas, S.S. Toland, A.E. Trichopoulou, A. Ulrich, C.M. Van Den Berg, D.J. van Duijnhoven, F.J.B. Van Guelpen, B. van Kranen, H. Vijai, J. Visvanathan, K. Vodicka, P. Vodickova, L. Vymetalkova, V. Weigl, K. Weinstein, S.J. White, E. Win, A.K. Wolf, C.R. Wolk, A. Woods, M.O. Wu, A.H. Zaidi, S.H. Zanke, B.W. Zhang, Q. Zheng, W. Scacheri, P.C. Potter, J.D. Bassik, M.C. Kundaje, A. Casey, G. Moreno, V. Abecasis, G.R. Nickerson, D.A. Gruber, S.B. Hsu, L. Peters, U.

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2019

44. Evolution of the terrestrial vertebrate diversity of Marie-Galante Island (French West-Indies) during the last 40 000 years

Author

Bochaton, C., Bailon, S., GALA, M., COCHARD, D., Royer, A., Stoetzel, E., Lenoble, A., Archéozoologie, archéobotanique : sociétés, pratiques et environnements (AASPE), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Histoire naturelle de l'Homme préhistorique (HNHP), Muséum national d'Histoire naturelle (MNHN)-Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] [Dijon] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), International Palaeontological Association, Millan-Brun, Anne-Lise, Laboratoire Départemental de Préhistoire du Lazaret (LDPL), Département des Alpes-Maritimes, Centre d'Applications et de Recherches en TELédétection (CARTEL), Université de Sherbrooke [Sherbrooke], Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université de Perpignan Via Domitia (UPVD), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SHS.ARCHEO] Humanities and Social Sciences/Archaeology and Prehistory, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Marie-Galante Island (Guadeloupe, French West-Indies) has recently been the object of several paleontological investigations in order to characterize the evolution of its terrestrial vertebrate paleobiodiversity during the last 40 000 years. This paper consists in a synthesis these recently obtained results obtained by crossed studies of several large vertebrate fossil assemblages (mammal, bird, squamate, and amphibian) collected in Late Pleistocene and Holocene deposits. Our work reveals apreviously inconspicuous now-extinct Pleistocene and Holocene vertebrate biodiversity. We observed that this past diversity was recently modified to become very different from what it is nowadays. Indeed, while a small number of extinction or extirpation events can be related to the Pleistocene-Holocene climatic transition, the faunal community of the island is nearly completely modified during the last millenaries. These modifications include the arrival of several exogenous taxa, and an extinction/extirpation rate of native species between 54% and 100% depending of taxa.Our results suggest that human impact was the main factor driving the evolution of the island terrestrial faunal diversity. We also demonstrate a possible impact of Pre-Columbian human populations on the faunal diversity of Marie-Galante Island which however remains minor in respect to the overwhelming modifications possibly related to the European colonization and subsequent anthropization of the island.

Published
2018

46. Evolution of myeloid-derived suppressor cells and objective response rate in relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) patients after receiving immunotherapy

Author

Cortegana, C Jiménez, primary, Carrión, N Palazón, additional, Fernández, E Nogales, additional, García, M A Nieto, additional, Margalet, V Sánchez, additional, de la Gala, M D C Álamo, additional, de Ilárduya, M Suengas Martínez, additional, Burgos, E Montilla, additional, Fernández, I Araújo, additional, Carrasco, F Henao, additional, García-Sancho, A Martín, additional, Carnicero, F., additional, Herranz, E Rios, additional, de la Cruz Vicente, F., additional, Fernández, R., additional, Dominguez, A Rueda, additional, and de la Cruz Merino, L., additional

Published
2019
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47. Postoperative Transitional Care Needs in the Elderly

Author

Shubhada Sansgiry, Sonia T. Orcutt, Daniel A. Anaya, Linda T. Li, Courtney J. Balentine, David H. Berger, Aanand D. Naik, Gala M. Barden, Avo Artinyan, and Daniel Albo

Subjects
Male, medicine.medical_specialty, Multivariate analysis, Context (language use), Cohort Studies, Internal medicine, Outcome Assessment, Health Care, Odds Ratio, medicine, Humans, Transitional care, Survival analysis, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, Postoperative Care, Health Services Needs and Demand, business.industry, Retrospective cohort study, Odds ratio, Continuity of Patient Care, Survival Analysis, Confidence interval, Surgery, Logistic Models, Multivariate Analysis, Regression Analysis, Female, Colorectal Neoplasms, business, Follow-Up Studies, Cohort study
Abstract

OBJECTIVE To characterize transitional care needs (TCNs) after colorectal cancer (CRC) surgery and examine their association with age and impact on overall survival (OS). BACKGROUND TCNs after cancer surgery represent additional burden for patients and are associated with higher short-term mortality. They are not well-characterized in CRC patients, particularly in the context of a growing elderly population, and their effect on long-term survival is unknown. METHODS A retrospective cohort study of CRC patients (N = 486) having curative surgery at a tertiary referral center (2002-2011) was conducted. Outcomes included TCNs (home health or nonhome destination at discharge) and OS. Patients were compared on the basis of age: young (

Published
2015
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48. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, J.R. Bien, S.A. Harrison, T.A. Kang, H.M. Chen, S. Schmit, S.L. Conti, D.V. Qu, C. Jeon, J. Edlund, C.K. Greenside, P. Wainberg, M. Schumacher, F.R. Smith, J.D. Levine, D.M. Nelson, S.C. Sinnott-Armstrong, N.A. Albanes, D. Alonso, M.H. Anderson, K. Arnau-Collell, C. Arndt, V. Bamia, C. Banbury, B.L. Baron, J.A. Berndt, S.I. Bézieau, S. Bishop, D.T. Boehm, J. Boeing, H. Brenner, H. Brezina, S. Buch, S. Buchanan, D.D. Burnett-Hartman, A. Butterbach, K. Caan, B.J. Campbell, P.T. Carlson, C.S. Castellví-Bel, S. Chan, A.T. Chang-Claude, J. Chanock, S.J. Chirlaque, M.-D. Cho, S.H. Connolly, C.M. Cross, A.J. Cuk, K. Curtis, K.R. de la Chapelle, A. Doheny, K.F. Duggan, D. Easton, D.F. Elias, S.G. Elliott, F. English, D.R. Feskens, E.J.M. Figueiredo, J.C. Fischer, R. FitzGerald, L.M. Forman, D. Gala, M. Gallinger, S. Gauderman, W.J. Giles, G.G. Gillanders, E. Gong, J. Goodman, P.J. Grady, W.M. Grove, J.S. Gsur, A. Gunter, M.J. Haile, R.W. Hampe, J. Hampel, H. Harlid, S. Hayes, R.B. Hofer, P. Hoffmeister, M. Hopper, J.L. Hsu, W.-L. Huang, W.-Y. Hudson, T.J. Hunter, D.J. Ibañez-Sanz, G. Idos, G.E. Ingersoll, R. Jackson, R.D. Jacobs, E.J. Jenkins, M.A. Joshi, A.D. Joshu, C.E. Keku, T.O. Key, T.J. Kim, H.R. Kobayashi, E. Kolonel, L.N. Kooperberg, C. Kühn, T. Küry, S. Kweon, S.-S. Larsson, S.C. Laurie, C.A. Le Marchand, L. Leal, S.M. Lee, S.C. Lejbkowicz, F. Lemire, M. Li, C.I. Li, L. Lieb, W. Lin, Y. Lindblom, A. Lindor, N.M. Ling, H. Louie, T.L. Männistö, S. Markowitz, S.D. Martín, V. Masala, G. McNeil, C.E. Melas, M. Milne, R.L. Moreno, L. Murphy, N. Myte, R. Naccarati, A. Newcomb, P.A. Offit, K. Ogino, S. Onland-Moret, N.C. Pardini, B. Parfrey, P.S. Pearlman, R. Perduca, V. Pharoah, P.D.P. Pinchev, M. Platz, E.A. Prentice, R.L. Pugh, E. Raskin, L. Rennert, G. Rennert, H.S. Riboli, E. Rodríguez-Barranco, M. Romm, J. Sakoda, L.C. Schafmayer, C. Schoen, R.E. Seminara, D. Shah, M. Shelford, T. Shin, M.-H. Shulman, K. Sieri, S. Slattery, M.L. Southey, M.C. Stadler, Z.K. St and Huyghe, J.R. Bien, S.A. Harrison, T.A. Kang, H.M. Chen, S. Schmit, S.L. Conti, D.V. Qu, C. Jeon, J. Edlund, C.K. Greenside, P. Wainberg, M. Schumacher, F.R. Smith, J.D. Levine, D.M. Nelson, S.C. Sinnott-Armstrong, N.A. Albanes, D. Alonso, M.H. Anderson, K. Arnau-Collell, C. Arndt, V. Bamia, C. Banbury, B.L. Baron, J.A. Berndt, S.I. Bézieau, S. Bishop, D.T. Boehm, J. Boeing, H. Brenner, H. Brezina, S. Buch, S. Buchanan, D.D. Burnett-Hartman, A. Butterbach, K. Caan, B.J. Campbell, P.T. Carlson, C.S. Castellví-Bel, S. Chan, A.T. Chang-Claude, J. Chanock, S.J. Chirlaque, M.-D. Cho, S.H. Connolly, C.M. Cross, A.J. Cuk, K. Curtis, K.R. de la Chapelle, A. Doheny, K.F. Duggan, D. Easton, D.F. Elias, S.G. Elliott, F. English, D.R. Feskens, E.J.M. Figueiredo, J.C. Fischer, R. FitzGerald, L.M. Forman, D. Gala, M. Gallinger, S. Gauderman, W.J. Giles, G.G. Gillanders, E. Gong, J. Goodman, P.J. Grady, W.M. Grove, J.S. Gsur, A. Gunter, M.J. Haile, R.W. Hampe, J. Hampel, H. Harlid, S. Hayes, R.B. Hofer, P. Hoffmeister, M. Hopper, J.L. Hsu, W.-L. Huang, W.-Y. Hudson, T.J. Hunter, D.J. Ibañez-Sanz, G. Idos, G.E. Ingersoll, R. Jackson, R.D. Jacobs, E.J. Jenkins, M.A. Joshi, A.D. Joshu, C.E. Keku, T.O. Key, T.J. Kim, H.R. Kobayashi, E. Kolonel, L.N. Kooperberg, C. Kühn, T. Küry, S. Kweon, S.-S. Larsson, S.C. Laurie, C.A. Le Marchand, L. Leal, S.M. Lee, S.C. Lejbkowicz, F. Lemire, M. Li, C.I. Li, L. Lieb, W. Lin, Y. Lindblom, A. Lindor, N.M. Ling, H. Louie, T.L. Männistö, S. Markowitz, S.D. Martín, V. Masala, G. McNeil, C.E. Melas, M. Milne, R.L. Moreno, L. Murphy, N. Myte, R. Naccarati, A. Newcomb, P.A. Offit, K. Ogino, S. Onland-Moret, N.C. Pardini, B. Parfrey, P.S. Pearlman, R. Perduca, V. Pharoah, P.D.P. Pinchev, M. Platz, E.A. Prentice, R.L. Pugh, E. Raskin, L. Rennert, G. Rennert, H.S. Riboli, E. Rodríguez-Barranco, M. Romm, J. Sakoda, L.C. Schafmayer, C. Schoen, R.E. Seminara, D. Shah, M. Shelford, T. Shin, M.-H. Shulman, K. Sieri, S. Slattery, M.L. Southey, M.C. Stadler, Z.K. St

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 −8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Published
2019

49. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, Gruber, SB, Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, and Gruber, SB

Abstract

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: T

Published
2019

50. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, Peters, U, Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, and Peters, U

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Published
2019

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