Publications by authors named "Mingyang Song"

277 Publications

Gluten intake and risk of digestive system cancers in three large prospective cohort studies.

Clin Gastroenterol Hepatol 2021 Nov 17. Epub 2021 Nov 17.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Electronic address:

Background & Aims: In patients with celiac disease, gluten triggers an immune reaction that damages small intestinal villi and may increase long-term risk of gastrointestinal cancer. However, the health impacts of gluten in the general population are understudied. We aimed to examine the association between gluten intake and risk of digestive system cancers among individuals without celiac disease.

Methods: We leveraged longitudinal data from three prospective cohorts, Nurses' Health Study (1984-2018, 73,166 women aged 65.1±10.8 years), Nurses' Health Study II (1991-2017, 90,423 women aged 49.1±8.2 years), and Health Professionals Follow-Up Study (1986-2016, 42,617 men aged 64.8±10.8 years). Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of digestive system cancers according to quintiles of gluten intake assessed from food frequency questionnaires.

Results: During 4,801,513 person-years of follow-up, we documented 6,231 incident digestive system cancer cases among three cohorts. After adjusting for a wide-range of risk factors, including body mass index, physical activity, diet quality, gluten intake was not associated with an increased risk of digestive system cancer, with a HR (95% CI) of 0.94 (0.87, 1.02) comparing the highest to the lowest quintile of gluten intake (p-trend=0.05). Similar null associations were found for individual digestive system cancers: oral cavity and oropharyngeal cancer, esophageal cancer, stomach cancer, small intestine cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, and liver cancer.

Conclusions: Gluten intake was not associated with risk of digestive system cancers in adults without celiac disease. Restricting dietary gluten is unlikely to be beneficial to the prevention of digestive system cancers in the general population.
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http://dx.doi.org/10.1016/j.cgh.2021.11.016DOI Listing
November 2021

Three novel alkaloids from Portulaca oleracea L. and their anti-inflammatory bioactivities.

Fitoterapia 2021 Nov 16;156:105087. Epub 2021 Nov 16.

School of The First Clinic, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, PR China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, PR China. Electronic address:

Three novel alkaloids, identified as (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxyphenyl)acrylamide (1), named oleracrylimide A, (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide (2), named oleracrylimide B, and (E)-N-((2R)-3-(2,5-dihydroxy-4-((3,4,5-trihydroxy-6-(((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxypropanoyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide (3), named oleracrylimide C were isolated from Portulaca oleracea L. and the structures of the three novel compounds were determined by 1D and 2D NMR, circular dichroism, and UHPLC-ESI-QTOF/MS spectroscopic methods. Moreover, the bioactivities of anti-inflammation of the three compounds were investigated via testing RAW 264.7 macrophage cell stimulated by Lipopolysaccharide.
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http://dx.doi.org/10.1016/j.fitote.2021.105087DOI Listing
November 2021

Reproducibility and validity of diet quality scores derived from food frequency questionnaires.

Am J Clin Nutr 2021 Nov 11. Epub 2021 Nov 11.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Diet quality scores (DQSs) are frequently used to study diet-disease relationships but the validity of these scores derived from food frequency questionnaires (FFQs) has rarely been evaluated.

Objective: To evaluate the validity and reproducibility of six commonly used DQSs derived from the FFQ, including the Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH) score, alternative Mediterranean Diet score (AMED), and three plant-based diet indices (overall, healthful, and unhealthful).

Design: This analysis included 1,394 participants from the Men's (n = 652) and Women's (n = 742) Lifestyle Validation Studies. Participants completed a 152-item FFQ at the beginning of the study and one year later, and completed two weighed 7-day dietary records (7DDRs) and donated two blood samples six-month apart between FFQ assessments. The reproducibility of the FFQs was evaluated by rank intraclass correlation coefficients (ICC). The validity was assessed by comparing FFQ-derived DQSs to those from the average of two 7DDRs using Spearman rank correlation coefficients deattenuated for random measurement error in the 7DDRs (rs). Further, we calculated the correlations between DQSs and plasma biomarkers of diet including fatty acids, folate, carotenoids, retinol, and alpha-and gamma-tocopherol.

Results: Six FFQ derived DQSs demonstrated moderate to high reproducibility (energy-adjusted ICCs = 0.61 to 0.84) and validity (energy-adjusted, deattenuated rs = 0.56 to 0.80) in both men and women. We consistently observed expected correlations between FFQ derived DQSs with plasma fatty acids, including long chain N-3 and trans fatty acids, most carotenoids, and gamma-tocopherol (rs>0.2).

Conclusions: Our study demonstrates the validity of the FFQ to evaluate overall diet quality using six commonly used DQSs. In addition, these DQSs have qualitatively demonstrated biological relevance as indicated by their correlations with circulating biomarkers.
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http://dx.doi.org/10.1093/ajcn/nqab368DOI Listing
November 2021

Association Between the Sulfur Microbial Diet and Risk of Colorectal Cancer.

JAMA Netw Open 2021 Nov 1;4(11):e2134308. Epub 2021 Nov 1.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.

Importance: Sulfur-metabolizing bacteria that reduce dietary sulfur to hydrogen sulfide have been associated with colorectal cancer (CRC). However, there are limited studies investigating the association between diet and sulfur-metabolizing bacteria in the development of CRC.

Objective: To develop a dietary score that correlates with gut sulfur-metabolizing bacteria and to examine its association with CRC risk.

Design, Setting, And Participants: This prospective cohort study included data from the Health Professionals Follow-up Study (1986-2014), Nurses' Health Study (1984-2016), and Nurses' Health Study II (1991-2017). Participants were US male health professionals and female registered nurses who were free of inflammatory bowel disease and cancer at baseline, with a subsample of participants who provided stool samples from 2012 to 2014. Statistical analysis was conducted from September 1, 2020, to June 1, 2021.

Exposure: A dietary pattern, assessed by a food-frequency questionnaire, that most correlated with 43 sulfur-metabolizing bacteria identified through taxonomic and functional profiling of gut metagenome data.

Main Outcomes And Measures: Incident CRC.

Results: Among 214 797 participants comprising 46 550 men (mean [SD] age at baseline, 54.3 [9.7] years) and 168 247 women (mean [SD] age at baseline, 43.0 [9.2] years), 3217 incident cases of CRC (1.5%) were documented during 5 278 048 person-years of follow-up. The sulfur microbial diet, developed in a subsample of 307 men (mean [SD] age, 70.5 [4.3] years) and 212 women (mean [SD] age, 61.0 [3.8] years), was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. After adjustment for other risk factors, greater adherence to the sulfur microbial diet was associated with an increased risk of CRC, with a hazard ratio (HR) of 1.27 (95% CI, 1.12-1.44) comparing the highest vs the lowest quintile of the diet score (linear trend of diet score quintiles; P < .001 for trend). When assessed by anatomical subsites, greater adherence to the sulfur microbial diet was positively associated with distal CRC (HR, 1.25; 95% CI, 1.05-1.50; P = .02 for trend) but not proximal colon cancer (HR, 1.13; 95% CI, 0.93-1.39; P = .19 for trend).

Conclusions And Relevance: Adherence to the sulfur microbial diet was associated with an increased risk of CRC, suggesting a potential mediating role of sulfur-metabolizing bacteria in the associaton between diet and CRC. Further research is needed to confirm these findings and to determine the underlying mechanisms.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.34308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590167PMC
November 2021

Secure Outsourcing of Matrix Determinant Computation under the Malicious Cloud.

Sensors (Basel) 2021 Oct 14;21(20). Epub 2021 Oct 14.

School of Computer Science and Engineering, Sun Yat-sen University, Guangzhou 510006, China.

Computing the determinant of large matrix is a time-consuming task, which is appearing more and more widely in science and engineering problems in the era of big data. Fortunately, cloud computing can provide large storage and computation resources, and thus, act as an ideal platform to complete computation outsourced from resource-constrained devices. However, cloud computing also causes security issues. For example, the curious cloud may spy on user privacy through outsourced data. The malicious cloud violating computing scripts, as well as cloud hardware failure, will lead to incorrect results. Therefore, we propose a secure outsourcing algorithm to compute the determinant of large matrix under the malicious cloud mode in this paper. The algorithm protects the privacy of the original matrix by applying row/column permutation and other transformations to the matrix. To resist malicious cheating on the computation tasks, a new verification method is utilized in our algorithm. Unlike previous algorithms that require multiple rounds of verification, our verification requires only one round without trading off the cheating detectability, which greatly reduces the local computation burden. Both theoretical and experimental analysis demonstrate that our algorithm achieves a better efficiency on local users than previous ones on various dimensions of matrices, without sacrificing the security requirements in terms of privacy protection and cheating detectability.
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http://dx.doi.org/10.3390/s21206821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539666PMC
October 2021

Chronic Constipation as a Risk Factor for Colorectal Cancer: Results From a Nationwide, Case-Control Study.

Clin Gastroenterol Hepatol 2021 Oct 20. Epub 2021 Oct 20.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. Electronic address:

Background & Aims: Prolonged colon transit times may increase the contact time between potential carcinogens in the stool and the colonic mucosa. Nonetheless, previous studies have yielded conflicting results connecting chronic constipation with the risk of colorectal cancer (CRC). We examined the association between chronic constipation and later CRC.

Methods: In this nationwide case-control study, we identified 41,299 CRC cases by colorectal biopsy in Sweden between July 2007 and December 2016 and matched them to 203,181 age- and sex-matched controls from the general population. We compared odds of earlier chronic constipation (defined as ≥2 laxative prescriptions in the Prescribed Drug Register with ≥6 months between the first and last prescription) between CRC cases and controls using logistic regression. In separate analyses, we compared odds of earlier constipation between CRC cases and sibling comparators, but also examined earlier risk of having an inpatient/outpatient specialty diagnosis of chronic constipation before CRC.

Results: Overall, 3943 patients with CRC met our criteria for chronic constipation before CRC. The crude proportion of chronic constipation in CRC patients was 9.5% compared with 8.8% in controls. After multivariable adjustment, there was a modest association between chronic constipation and later CRC (odds ratio [OR], 1.10; 95% CI, 1.06-1.14) that vanished using sibling comparators to control for residual confounding (OR, 1.04; 95% CI, 0.97-1.13). In a sensitivity analysis of 126,650 CRC patients diagnosed from 1989 to 2016, we found no association with earlier chronic constipation diagnosed in inpatient/outpatient specialty clinics (OR, 0.88; 95% CI, 0.75-1.04).

Conclusions: In a nationwide case-control study, chronic constipation was not associated with later CRC.
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http://dx.doi.org/10.1016/j.cgh.2021.10.024DOI Listing
October 2021

Unrestrained eating behavior and risk of mortality: A prospective cohort study.

Clin Nutr 2021 11 17;40(11):5419-5429. Epub 2021 Sep 17.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background & Aims: Unrestrained eating behavior has been thought to be a proxy for diet frequency, timing, and caloric intake. We investigated the association of unrestrained eating with mortality risk in the Nurses' Health Study prospectively.

Methods: During follow-up (1994-2016), 21,953 deaths were documented among 63,999 eligible participants in analyses of eating anything at any time, 22,120 deaths were documented among 65,839 participants in analyses of no concern with figure change. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results: Eating anything at any time was associated with an increased mortality from cancer (overall HR, 95%CI: 1.07, 1.00-1.13; driven by gastrointestinal tract cancer: 1.30, 1.10-1.54) and respiratory disease (1.16, 1.05-1.29), and decreased cardiovascular disease-specific mortality (0.92, 0.86-0.99), compared to those without this behavior; however, no association was observed between this behavior and all-cause mortality (1.02, 0.99-1.05). Women who reported having no concern with figure change experienced higher risk of mortality from all-cause (1.08, 1.05-1.11), cancer (1.08, 1.02-1.14), and respiratory disease (1.18, 1.08-1.30), compared to those not reporting this behavior. Their combined effect was associated with a higher all-cause (1.09, 1.04-1.14), cancer-specific (overall: 1.18, 1.09-1.28; gastrointestinal tract cancer: 1.36, 1.08-1.71; lung cancer: 1.09; 1.04-1.14), and respiratory disease-specific (1.30, 1.13-1.50) mortality, and was inversely associated with cardiovascular disease-specific mortality (0.88, 0.80-0.98), compared to those exhibiting the opposite.

Conclusions: Unrestrained eating was associated with increased risk of all-cause, cancer-specific (particularly for gastrointestinal tract cancer and lung cancer), and respiratory disease-specific mortality, and decreased risk of cardiovascular disease-specific mortality.
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http://dx.doi.org/10.1016/j.clnu.2021.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571025PMC
November 2021

Gallstone Disease and Risk of Conventional Adenomas and Serrated Polyps: A Prospective Study.

Cancer Epidemiol Biomarkers Prev 2021 Oct 7. Epub 2021 Oct 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Gallstone disease has been associated with colorectal cancer and some form of polyps, although the findings are inconclusive. It remains unknown whether gallstone disease influences the initiation of colorectal cancer.

Methods: We prospectively assessed the association of gallstone disease with risk of colorectal cancer precursors, including conventional adenomas and serrated polyps, in the Nurses' Health Study (1992-2012), the Nurses' Health Study II (1991-2011), and the Health Professionals Follow-up Study (1992-2012). Gallstone diseases were assessed using biennial follow-up questionnaires. Self-reported polyp diagnosis was confirmed by review of medical records. Logistic regression models were used to calculate the ORs with adjustment for smoking and other potential confounders.

Results: Among participants who had undergone a total of 323,832 endoscopies, 16.5% had gallstone disease and 11.3% received cholecystectomy. We documented 1,724, 1,212, and 1,943 cases of conventional adenomas and 1,470, 1,090, and 1,643 serrated polyps in patients with gallstones, cholecystectomy, and either of them, respectively. The OR for adenomas was 1.00 [95% confidence interval (CI): 0.95-1.06] for gallstones, 0.99 (95% CI: 0.93-1.06) for cholecystectomy, and 1.00 (95% CI: 0.95-1.05) for either exposure. The corresponding ORs for serrated polyps were 0.98 (95% CI: 0.92-1.04), 0.99 (95% CI: 0.93-1.06), and 0.97(95% CI: 0.92-1.03), respectively.

Conclusions: Gallstone disease is not associated with colorectal polyps.

Impact: Patients with gallstones appear to have similar risk of colorectal polyps compared with those without and may therefore follow average-risk colorectal cancer screening guidelines.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0515DOI Listing
October 2021

Association of nut consumption with risk of total cancer and 5 specific cancers: evidence from 3 large prospective cohort studies.

Am J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: The associations between nut consumption and cancer risk have not been extensively investigated.

Objectives: We aimed to examine the associations between nut consumption, especially specific types of nuts (peanut, tree nut, walnut, and tree nut other than walnut), and cancer risk.

Methods: Nut consumption was assessed by FFQ at baseline and updated every 2-4 y in the Nurses' Health Study (1980-2014), the Nurses' Health Study II (1991-2015), and the Health Professionals Follow-up Study (1986-2018). We examined the associations between the intake of total and specific types of nuts and risk of total cancer and common cancers, including lung, colorectal, breast, bladder, and aggressive prostate cancer. Cox proportional-hazards models were used to obtain the HRs and 95% CIs in each cohort as well as pooled.

Results: During 5,873,671 person-years of follow-up in 180,832 women and 45,560 men, we documented 44,561 incident cancer cases. As compared with nonconsumers, the pooled multivariable HRs of total nut consumption for ≥5 times/wk were 0.99 (95% CI: 0.94, 1.04; P-trend = 0.54) for total cancer, 0.88 (95% CI: 0.74, 1.04; P-trend = 0.18) for lung cancer, 1.07 (95% CI: 0.92, 1.26; P-trend = 0.89) for colorectal cancer, 0.90 (95% CI: 0.71, 1.14; P-trend = 0.65) for bladder cancer, 0.96 (95% CI: 0.85, 1.08; P-trend = 0.36) for breast cancer, and 1.18 (95% CI: 0.92, 1.51; P-trend = 0.52) for aggressive prostate cancer.

Conclusions: In 3 large prospective cohorts, frequent nut consumption was not associated with risk of total cancer and common individual cancers.
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http://dx.doi.org/10.1093/ajcn/nqab295DOI Listing
September 2021

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Cancer Immunol Immunother 2021 Sep 16. Epub 2021 Sep 16.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Ave., EBRC Room 404A, Boston, MA, 02115, USA.

Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset,"  ≥ 55 "later onset").

Methods: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.

Results: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14HLA-DR cells (P = 0.015), and CD3CD4FOXP3 cells (P = 0.039).

Conclusions: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.
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http://dx.doi.org/10.1007/s00262-021-03056-6DOI Listing
September 2021

Is Colorectal Cancer Screening Absolutely Beneficial for Older Adults?

JAMA Oncol 2021 Nov;7(11):1728-1729

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston.

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http://dx.doi.org/10.1001/jamaoncol.2021.4155DOI Listing
November 2021

Ultra-processed Foods and Risk of Crohn's Disease and Ulcerative Colitis: A Prospective Cohort Study.

Clin Gastroenterol Hepatol 2021 Aug 28. Epub 2021 Aug 28.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background & Aims: The rising incidence of inflammatory bowel disease in regions undergoing Westernization has coincided with the increase in ultra-processed food (UPF) consumption over the past few decades. We aimed to examine the association between consumption of UPFs and the risk of Crohn's disease (CD) and ulcerative colitis (UC).

Methods: We performed a prospective cohort study of 3 nationwide cohorts of health professionals in the United States-the Nurses' Health Study (1986-2014), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2012). We employed Cox proportional hazards models with adjustment for confounders to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CD and UC according to self-reported consumption of UPFs.

Results: The study included 245,112 participants. Over 5,468,444 person-years of follow-up, we documented 369 incident cases of CD and 488 incident cases of UC. The median age at diagnosis was 56 years (range, 29-85 years). Compared with participants in the lowest quartile of simple updated UPF consumption, those in the highest quartile had a significantly increased risk of CD (HR, 1.70; 95% CI, 1.23-2.35; P = .0008). Among different UPF subgroups, ultra-processed breads and breakfast foods; frozen or shelf-stable ready-to-eat/heat meals; and sauces, cheeses, spreads, and gravies showed the strongest positive associations with CD risk (HR per 1 standard deviation increase in intake, 1.18 [95% CI, 1.07-1.29], 1.11 [95% CI, 1.01-1.22], and 1.14 [95% CI, 1.02-1.27], respectively). There was no consistent association between UPF intake and UC risk.

Conclusions: Higher UPF intake was associated with an increased risk of incident CD. Further studies are needed to identify specific contributory dietary components.
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http://dx.doi.org/10.1016/j.cgh.2021.08.031DOI Listing
August 2021

Diagnostic yield of endoscopy in irritable bowel syndrome: A nationwide prevalence study 1987-2016.

Eur J Intern Med 2021 Aug 19. Epub 2021 Aug 19.

Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, United States; Department of Paediatrics, Örebro University Hospital, Sweden. Electronic address:

Introduction: Symptoms of irritable bowel syndrome (IBS) are common reasons for endoscopic procedures. We examined the yield of colonoscopy and upper endoscopy in IBS for several organic diseases.

Methods: Matched population-based prevalence study in Sweden. We identified 21,944 participants diagnosed with IBS from 1987 to 2016 undergoing colonoscopy with a biopsy from all of Sweden's 28 pathology departments within 6 months of diagnosis. We compared prevalence of histopathology-proven diagnoses of inflammatory bowel disease (IBD), colorectal cancer, precancerous polyps, and microscopic colitis between patients recently diagnosed with IBS and matched controls without IBS (n = 81,101) undergoing colonoscopy. We also compared prevalence of celiac disease between patients diagnosed with IBS (n = 9,965) and matched controls (n = 45,584) undergoing upper endoscopy with biopsy. IBS patients were also compared to their siblings. Conditioned logistic regression estimated adjusted odds ratios (aORs).

Results: Biopsy-proven IBD was seen in 1.6% of IBS and in 5.9% of controls (aOR=0.21; 95%CI=0.19-0.24). The prevalence of precancerous polyps was 4.1% vs. 13.0% (aOR=0.28; 95%CI=0.26-0.30), colorectal cancer 0.8% vs. 6.3% (aOR=0.17; 95%CI=0.14-0.20) and celiac disease 1.9% vs. 3.4% (aOR=0.54; 95%CI=0.47-0.63). Conversely, the prevalence of microscopic colitis was 2.9% vs. 1.7% (aOR=1.77; 95%CI=1.61-1.95), with higher prevalence in older patients and patients with IBS with diarrhea. Yield of colonoscopy for precancerous polyps, colorectal cancer, and microscopic colitis increased by age. Our findings were consistent using unaffected siblings as the comparator group.

Discussion: The diagnostic yield of upper endoscopy and colonoscopy for organic disease is low in patients with a first-time diagnosis of IBS, though increases with age.
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http://dx.doi.org/10.1016/j.ejim.2021.08.001DOI Listing
August 2021

Survival Outcome and Clinicopathologicl analysis of Homeobox gene cluster-embedded LncRNAs in Human Cancers: A Systematic Review and Meta-analysis.

Expert Rev Mol Diagn 2021 Nov 2;21(11):1211-1221. Epub 2021 Sep 2.

Department of Epidemiology, School of Public Health, China Medical University, Liaoning, PR China.

Objective: The ectopic expression of Homeobox (HOX) gene cluster-embedded long non-coding RNAs (LncRNAs) have been involved several carcinogenic development and progressions. This meta-analysis aimed to summarize the LncRNAs to validate the functions and the prognostic values in several kinds of cancer.

Methods: The retrospective study was conducted to analyze the association between HOX gene-related LncRNAs and the survival outcomes. Cochran's Q and I test were used for calculated heterogeneity, and I > 50%, P < 0.05 was conformed to the random effect model. Publication bias was indicated by Begg's and Egger's test.

Results: Total 15,315 patients extracting from 121 studies focused on assessing the association between LncRNAs and the survival outcomes and 12,110 participants were enrolled to address the clinicopathological features. The results demonstrated that the overexpression of HOX gene cluster-embedded LncRNAs revealed notable association among tumor size (pooled OR = 1.80), lymph node metastasis (LNM) stage (pooled OR = 3.00), tumor node metastasis (TNM) stage (pooled OR = 2.86), histological differentiation (pooled OR = 1.59) and distant metastasis (pooled OR = 2.49). Additionally, the up-regulated LncRNAs predicted a poor prognosis in overall survival (pooled HR = 1.95, 95%CI = 1.86-2.04), and also disclosed worse prognosis among the stratified analysis included HOX clusters, LncRNAs, ethnicity, and tumor classification (pooled HRs >1).

Conclusion: In summary, the findings proved that HOX gene cluster-embedded LncRNAs acted as potential biomarkers for clinical treatment of several tumors and the overexpression might be a candidate hallmark for prognosis outcome.
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http://dx.doi.org/10.1080/14737159.2021.1970536DOI Listing
November 2021

The CRCbiome study: a large prospective cohort study examining the role of lifestyle and the gut microbiome in colorectal cancer screening participants.

BMC Cancer 2021 Aug 18;21(1):930. Epub 2021 Aug 18.

Department of Research, Cancer Registry of Norway, Oslo, Norway.

Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions.

Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50-74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period.

Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

Trial Registration: ClinicalTrials.gov Identifier: NCT01538550 .
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http://dx.doi.org/10.1186/s12885-021-08640-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371800PMC
August 2021

Genetic Obesity Variants and Risk of Conventional Adenomas and Serrated Polyps.

Dig Dis Sci 2021 Aug 17. Epub 2021 Aug 17.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Higher body mass index (BMI) is associated with increased risk of colorectal cancer. How genetically predicted BMI may be associated with colorectal cancer precursors is unknown.

Aims: Our objective was to quantify the association of genetically predicted and measured BMI with risk of colorectal cancer precursors.

Methods: We evaluated the association of genetically predicted and measured BMI with risk of conventional adenomas, serrated polyps, and synchronous polyps among 27,426 participants who had undergone at least one lower gastrointestinal endoscopy in the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study. Genetic risk score was derived from 97 BMI-related single nucleotide polymorphisms. Multivariable logistic regression evaluated each polyp subtype compared to non-polyps.

Results: For conventional adenomas, the OR per 2-kg/m increase was 1.03 (95% CI, 1.01-1.04) for measured BMI and 0.98 (95% CI, 0.88-1.10) for genetically predicted BMI; for serrated polyps, the OR was 1.06 (95% CI, 1.04-1.08) and 1.04 (95% CI, 0.90-1.20), respectively; for synchronous polyps, the OR was 1.10 (95% CI, 1.07-1.13) and 1.09 (95% CI, 0.89-1.34), respectively. Genetically predicted BMI was associated with synchronous polyps in women (OR = 1.37, 95% CI: 1.05-1.79).

Conclusion: Genetically predicted BMI was not associated with colorectal cancer precursor lesions. The confidence intervals were wide and encompassed those for measured BMI, indicating that null findings may be due to insufficient power.
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http://dx.doi.org/10.1007/s10620-021-07193-xDOI Listing
August 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Association of mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma.

Oncoimmunology 2021 2;10(1):1956173. Epub 2021 Aug 2.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, and mutations. mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22-2.75; = .004]. mutation was statistically-insignificantly ( = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03-2.31). -mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than -wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) ( = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.
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http://dx.doi.org/10.1080/2162402X.2021.1956173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331006PMC
October 2021

The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men.

Clin Transl Gastroenterol 2021 08 1;12(8):e00338. Epub 2021 Aug 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Introduction: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.).

Methods: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012).

Results: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers.

Discussion: Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.
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http://dx.doi.org/10.14309/ctg.0000000000000338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323793PMC
August 2021

Race, ethnicity, community-level socioeconomic factors, and risk of COVID-19 in the United States and the United Kingdom.

EClinicalMedicine 2021 Aug 17;38:101029. Epub 2021 Jul 17.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, 15th Floor, Boston, MA 02114, USA.

Background: There is limited prior investigation of the combined influence of personal and community-level socioeconomic factors on racial/ethnic disparities in individual risk of coronavirus disease 2019 (COVID-19).

Methods: We performed a cross-sectional analysis nested within a prospective cohort of 2,102,364 participants from March 29, 2020 in the United States (US) and March 24, 2020 in the United Kingdom (UK) through December 02, 2020 via the COVID Symptom Study smartphone application. We examined the contribution of community-level deprivation using the Neighborhood Deprivation Index (NDI) and the Index of Multiple Deprivation (IMD) to observe racial/ethnic disparities in COVID-19 incidence. ClinicalTrials.gov registration: NCT04331509.

Findings: Compared with non-Hispanic White participants, the risk for a positive COVID-19 test was increased in the US for non-Hispanic Black (multivariable-adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.18-1.47) and Hispanic participants (OR, 1.42; 95% CI, 1.33-1.52) and in the UK for Black (OR, 1.17; 95% CI, 1.02-1.34), South Asian (OR, 1.39; 95% CI, 1.30-1.49), and Middle Eastern participants (OR, 1.38; 95% CI, 1.18-1.61). This elevated risk was associated with living in more deprived communities according to the NDI/IMD. After accounting for downstream mediators of COVID-19 risk, community-level deprivation still mediated 16.6% and 7.7% of the excess risk in Black compared to White participants in the US and the UK, respectively.

Interpretation: Our results illustrate the critical role of social determinants of health in the disproportionate COVID-19 risk experienced by racial and ethnic minorities.
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http://dx.doi.org/10.1016/j.eclinm.2021.101029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285255PMC
August 2021

Physical activity and the risk of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related mortality in South Korea: a nationwide cohort study.

Br J Sports Med 2021 Jul 22. Epub 2021 Jul 22.

Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea (the Republic of)

Purpose: To determine the potential associations between physical activity and risk of SARS-CoV-2 infection, severe illness from COVID-19 and COVID-19 related death using a nationwide cohort from South Korea.

Methods: Data regarding 212 768 Korean adults (age ≥20 years), who tested for SARS-CoV-2, from 1 January 2020 to 30 May 2020, were obtained from the National Health Insurance Service of South Korea and further linked with the national general health examination from 1 January 2018 to 31 December 2019 to assess physical activity levels. SARS-CoV-2 positivity, severe COVID-19 illness and COVID-19 related death were the main outcomes. The observation period was between 1 January 2020 and 31 July 2020.

Results: Out of 76 395 participants who completed the general health examination and were tested for SARS-CoV-2, 2295 (3.0%) were positive for SARS-CoV-2, 446 (0.58%) had severe illness from COVID-19 and 45 (0.059%) died from COVID-19. Adults who engaged in both aerobic and muscle strengthening activities according to the 2018 physical activity guidelines had a lower risk of SARS-CoV-2 infection (2.6% vs 3.1%; adjusted relative risk (aRR), 0.85; 95% CI 0.72 to 0.96), severe COVID-19 illness (0.35% vs 0.66%; aRR 0.42; 95% CI 0.19 to 0.91) and COVID-19 related death (0.02% vs 0.08%; aRR 0.24; 95% CI 0.05 to 0.99) than those who engaged in insufficient aerobic and muscle strengthening activities. Furthermore, the recommended range of metabolic equivalent task (MET; 500-1000 MET min/week) was associated with the maximum beneficial effect size for reduced risk of SARS-CoV-2 infection (aRR 0.78; 95% CI 0.66 to 0.92), severe COVID-19 illness (aRR 0.62; 95% CI 0.43 to 0.90) and COVID-19 related death (aRR 0.17; 95% CI 0.07 to 0.98). Similar patterns of association were observed in different sensitivity analyses.

Conclusion: Adults who engaged in the recommended levels of physical activity were associated with a decreased likelihood of SARS-CoV-2 infection, severe COVID-19 illness and COVID-19 related death. Our findings suggest that engaging in physical activity has substantial public health value and demonstrates potential benefits to combat COVID-19.
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http://dx.doi.org/10.1136/bjsports-2021-104203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300550PMC
July 2021

Unrestrained eating behavior and risk of digestive system cancers: a prospective cohort study.

Am J Clin Nutr 2021 11;114(5):1612-1624

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: Unrestrained eating behavior, as a potential proxy for diet frequency, timing, and caloric intake, has been questioned as a plausible risk factor for digestive system cancers, but epidemiological evidence remains sparse.

Objectives: We investigated prospectively the associations between unrestrained eating behavior and digestive system cancer risk.

Methods: Participants in the Nurses' Health Study who were free of cancer and reported dietary information in 1994 were followed for ≤18 y. Cox models were used to estimate HRs and 95% CIs for unrestrained eating (eating anything at any time, no concern with figure change, or both) and risk of digestive system cancers.

Results: During follow-up, 2064 digestive system cancer cases were documented among 70,450 eligible participants in analyses of eating anything at any time, In total, 2081 digestive system cancer cases were documented among 72,468 eligible participants in analyses of no concern with figure change. In fully adjusted analyses, women with the behavior of eating anything at any time had a higher risk of overall digestive system cancer (HR: 1.22; 95% CI: 1.10, 1.35), overall gastrointestinal tract cancer ((HR: 1.33; 95% CI: 1.18, 1.50), buccal cavity and pharynx cancer (HR: 1.50; 95% CI: 1.02, 2.21), esophageal cancer (HR: 1.62; 95% CI: 1.01, 2.62), small intestine cancer (HR: 1.92; 95% CI: 1.02,3. 59), and colorectal cancer (HR: 1.20; 95% CI: 1.04, 1.38), and a non-statistically significant increased risk of stomach cancer (HR: 1.54; 95% CI: 0.96,2.48), compared with women without this behavior. No statistically significant association was observed for pancreatic cancer and liver and gallbladder cancer. The combined effect of eating anything at any time and having no concern with figure change was associated with a significantly increased risk of overall digestive system cancer (HR: 1.27; 95% CI: 1.10, 1.46), overall gastrointestinal tract cancer (HR: 1.45; 95% CI: 1.23, 1.71), and colorectal cancer (HR: 1.34; 95% CI: 1.11, 1.63), compared with women exhibiting the opposite.

Conclusions: Unrestrained eating behavior was independently associated with increased risk of gastrointestinal tract cancers. The potential importance of unrestrained eating behavior modification in preventing gastrointestinal tract cancers should be noted.
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http://dx.doi.org/10.1093/ajcn/nqab235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588850PMC
November 2021

The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors.

Gastroenterology 2021 Nov 14;161(5):1423-1432.e4. Epub 2021 Jul 14.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Electronic address:

Background & Aims: Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (HS), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking.

Methods: We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses' Health Study II (1991-2015), a prospective cohort study with dietary assessment every 4 years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats, foods previously linked to CRC development, and low in mixed vegetables and legumes. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: We documented 2911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (OR, 1.31; 95% CI, 1.10-1.56, P = .02), but not serrated lesions. Compared with the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (OR, 1.65 for villous/tubulovillous histology; 95% CI, 1.12-2.43; P = .04). Similar trends for early-onset adenoma were observed based on diet consumed during adolescence. In contrast, no clear association for adenomas was identified after age 50.

Conclusions: Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.
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http://dx.doi.org/10.1053/j.gastro.2021.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545755PMC
November 2021

Adherence to the World Cancer Research Fund/American Institute for Cancer Research Cancer Prevention Recommendations and Colorectal Cancer Survival.

Cancer Epidemiol Biomarkers Prev 2021 Oct 16;30(10):1816-1825. Epub 2021 Jul 16.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Patients with cancer are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors.

Methods: We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer-specific and overall mortality among 1,491 patients with colorectal cancer in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted HRs and 95% confidence intervals (CI).

Results: During a median follow-up of 7.92 years, there were 641 deaths (179 colorectal cancer-specific deaths). Patients in the highest quartile of the post-diagnostic WCRF/AICR lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR = 0.76, 95% CI: 0.49-1.18) of colorectal cancer-specific mortality and a 37% lower risk (HR = 0.63, 95% CI: 0.50-0.78) of overall mortality compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both colorectal cancer-specific and overall mortality for the same comparison (colorectal cancer-specific: HR = 0.50, 95% CI: 0.32-0.79; overall: HR = 0.59, 95% CI: 0.47-0.75). The post-diagnostic WCRF/AICR diet score was not statistically significantly associated with either colorectal cancer-specific or overall mortality.

Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in patients with colorectal cancer.

Impact: This study provides support for patients with colorectal cancer to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for patients with cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492523PMC
October 2021

Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates.

J Natl Cancer Inst 2021 Jul 15. Epub 2021 Jul 15.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Background: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates.

Methods: Utilizing the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence [for CD68, CD86, IRF5, MAF, and MRC1 (CD206)] combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability-weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias due to tissue data availability. All statistical tests were 2-sided.

Results: During follow-up of 131,144 participants (3,648,370 person-years), we documented 3,092 incident colorectal cancer cases including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity=.003). Compared to never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for ≥40 pack-years (Ptrend=.004). In contrast, pack-years smoked were not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend>.009, with the α level of 0.005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages.

Conclusions: The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
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http://dx.doi.org/10.1093/jnci/djab142DOI Listing
July 2021

CoSMeD: a user-friendly web server to estimate 5-year survival probability of left-sided and right-sided colorectal cancer patients using molecular data.

Bioinformatics 2021 Jul 14. Epub 2021 Jul 14.

Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

Summary: Colorectal cancer is a heterogeneous disease with diverse prognoses between left-sided and right-sided patients; therefore, it is necessary to precisely evaluate the survival probability of side-specific colorectal cancer patients. Here, we collected multi-omics data from The Cancer Genome Atlas (TCGA) program, including gene expression, DNA methylation, and microRNA (miRNA) expression. Specificity measure (SPM) and robust likelihood-based survival analysis were used to identify 6 left-sided and 28 right-sided prognostic biomarkers. Compared to the performance of clinical prognostic models, the addition of these biomarkers could significantly improve the discriminatory ability and calibration in predicting side-specific 5-year survival for colorectal cancer. Additional dataset derived from Gene Expression Omnibus (GEO) was used to validate the prognostic value of side-specific genes. Finally, we constructed colorectal cancer side-specific molecular database (CoSMeD), a user-friendly interface for estimating side-specific colorectal cancer 5-year survival probability, which can lay the basis for personalized management of left-sided and right-sided colorectal cancer patients.

Availability And Implementation: CoSMeD is freely available at https://mulongdu.shinyapps.io/cosmed.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab523DOI Listing
July 2021

Changes in Lifestyle Factors After Endoscopic Screening: A Prospective Study in the United States.

Clin Gastroenterol Hepatol 2021 Jul 10. Epub 2021 Jul 10.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Endoscopic screening and adherence to a healthy lifestyle are major avenues for colorectal cancer (CRC) prevention. We investigated changes in lifestyles after endoscopic screening.

Methods: We drew data from 76,303 pairs of time- and age-matched individuals who had and had not, respectively, reported first time endoscopic screening, in the 3 cohorts (Nurses' Health Study I and II and the Health Professionals Follow-up Study). Detailed information was collected every 2-4 years on endoscopy screening, 12 lifestyle factors (including smoking, physical activity, regular use of aspirin/nonsteroidal anti-inflammatory drugs, body weight, and 8 dietary factors), and adherence to a healthy lifestyle based on a score defined by 5 major lifestyle factors (smoking, alcohol, body weight, physical activity, and diet). We assessed changes in lifestyle from pre- to post-screening periods for the matched pairs. We also conducted subgroup analysis according to screening findings (negative, low- and high-risk polyps, and CRC).

Results: Endoscopic screening was associated with higher prevalence of adherence to a healthy lifestyle (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04-1.16). The association strengthened with the severity of the screening findings, with an OR of 1.09 (95% CI, 1.03-1.15) for negative screening, 1.19 (95% CI, 1.07-1.33) for low-risk polyps, 1.42 (95% CI, 1.14-1.77) for high-risk polyps, and 1.55 (95% CI, 1.17-2.05) for CRC. The individual lifestyle factors and diet showed modest change.

Conclusions: Endoscopic screening was associated with a modest improvement in healthy lifestyles, particularly in individuals with more severe endoscopic findings. Further efforts of integrating lifestyle medicine into the screening setting are needed, to better leverage the teachable moment in improving CRC prevention.
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http://dx.doi.org/10.1016/j.cgh.2021.07.014DOI Listing
July 2021

Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors.

Gastroenterology 2021 Oct 7;161(4):1208-1217.e9. Epub 2021 Jul 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background & Aims: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50.

Methods: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model.

Results: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878).

Conclusions: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.
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http://dx.doi.org/10.1053/j.gastro.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463427PMC
October 2021

Obesity, Adiposity, and Risk of Symptomatic Gallstone Disease According to Genetic Susceptibility.

Clin Gastroenterol Hepatol 2021 Jul 2. Epub 2021 Jul 2.

Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background & Aims: Adiposity has been consistently associated with gallstone disease risk. We aimed to characterize associations of anthropometric measures (body mass index [BMI], recent weight change, long-term weight change, waist circumference, and waist-to-hip ratio) with symptomatic gallstone disease according to strata of gallstone disease polygenic risk score (PRS).

Methods: We conducted analysis among 34,626 participants with available genome-wide genetic data within 3 large, prospective, U.S. cohorts-the Nurses' Health Study (NHS), Health Professionals Follow-Up Study, and NHS II. We characterized joint associations of PRS and anthropometric measures and tested for interactions on the relative and absolute risk scales.

Results: Women in the highest BMI and PRS categories (BMI ≥30 kg/m and PRS ≥1 SD above mean) had odds ratio for gallstone disease of 5.55 (95% confidence interval, 5.29 to 5.81) compared with those in the lowest BMI and PRS categories (BMI <25 kg/m and PRS <1 SD below the mean). The corresponding odds ratio among men was 1.65 (95% confidence interval, 1.02 to 2.29). Associations for BMI did not vary within strata of PRS on the relative risk scale. On the absolute risk scale, the incidence rate difference between obese and normal-weight individuals was 1086 per 100,000 person-years within the highest PRS category, compared with 666 per 100,000 person-years in the lowest PRS category, with strong evidence for interaction with the ABCG8 locus.

Conclusions: While maintenance of a healthy body weight reduces gallstone disease risk among all individuals, risk reduction is higher among the subset with greater genetic susceptibility to gallstone disease.
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http://dx.doi.org/10.1016/j.cgh.2021.06.044DOI Listing
July 2021

Associations between body shape across the life course and adulthood concentrations of sex hormones in men and pre- and postmenopausal women: a multicohort study.

Br J Nutr 2021 Jun 30:1-10. Epub 2021 Jun 30.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The objective was to investigate associations between life-course adiposity and sex hormone concentrations: trajectory of adiposity from age 5 to 40 (premenopausal)/60 (postmenopausal women and men) in relation to levels of oestrone (E1), oestradiol (E2), sex hormone-binding globulins (SHBG), testosterone in 4801 premenopausal and 6019 postmenopausal women in the Nurses' Health Study (NHS) and NHS II, and 2431 men in the Health Professionals Follow-up Study. We used group-based trajectory models to identify groups within each cohort based on recalled somatotypes and reported BMI. Multivariate linear regression models were used to compare sex hormone concentration across different trajectory groups. The mean age at blood draw was 64·1 ± 8·1 years for men, 59·4 ± 6·0 for postmenopausal and 44·1 ± 4·6 for premenopausal women. In men, compared with the medium-stable group, lean-marked increase and medium increase groups had lower levels of SHBG (percentage difference: -17 and -9 %) and testosterone (-15 and -13 %). In postmenopausal women, compared with the medium-stable group, lean-marked increase and medium increase groups had higher levels of E1 (21 and 34 %) and E2 (45 and 68 %) but lower level of SHBG (-29 and -35 %). In premenopausal women, compared with the lean-moderate increase group, medium-stable/increase and heavy-stable/increase groups had lower levels of SHBG (-6 and -28 %). Attained adulthood adiposity and middle-life weight gain were associated with lower SHBG and testosterone in men, higher E1 and E2 and lower SHBG in postmenopausal women, and lower SHBG in premenopausal women. The study indicates the importance of maintaining a healthy body weight throughout life course for homoeostasis of sex hormones.
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http://dx.doi.org/10.1017/S0007114521001732DOI Listing
June 2021
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