Publications by authors named "Xuehong Zhang"

392 Publications

Higher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality.

Nat Commun 2021 11 4;12(1):6388. Epub 2021 Nov 4.

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

The relationship between dietary factors and liver disease remains poorly understood. This study evaluated the associations of whole grain and dietary fiber intake with liver cancer risk and chronic liver disease mortality. The National Institutes of Health-American Association of Retired Persons Diet and Health Study cohort recruited 485, 717 retired U.S. participants in 1995-1996. Follow-up through 2011 identified 940 incident liver cancer cases and 993 deaths from chronic liver disease. Compared with the lowest, the highest quintile of whole grain intake was associated with lower liver cancer risk (Hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63-0.96) and chronic liver disease mortality (HR = 0.44, 95% CI: 0.35-0.55) in multivariable Cox models. Dietary fiber was also associated with lower liver cancer risk (HR = 0.69, 95% CI: 0.53-0.90) and chronic liver disease mortality (HR = 0.37, 95% CI: 0.29-0.48). Fiber from vegetables, beans and grains showed potential protective effect. Here, we show that higher intake of whole grain and dietary fiber are associated with lower risk of liver cancer and liver disease mortality.
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http://dx.doi.org/10.1038/s41467-021-26448-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568891PMC
November 2021

Proinflammatory and Hyperinsulinemic Dietary Patterns Are Associated With Specific Profiles of Biomarkers Predictive of Chronic Inflammation, Glucose-Insulin Dysregulation, and Dyslipidemia in Postmenopausal Women.

Front Nutr 2021 20;8:690428. Epub 2021 Sep 20.

Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.

Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer. EDIH was developed using plasma C-peptide, whereas EDIP was based on plasma C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha receptor 2 (TNF-αR2). We investigated whether these dietary patterns were associated with a broader range of relevant biomarkers not previously tested. In this cross-sectional study, we included 35,360 women aged 50-79 years from the Women's Health Initiative with baseline (1993-1998) fasting blood samples. We calculated EDIH and EDIP scores from baseline food frequency questionnaire data and tested their associations with 40 circulating biomarkers of insulin response/insulin-like growth factor (IGF) system, chronic systemic inflammation, endothelial dysfunction, lipids, and lipid particle size. Multivariable-adjusted linear regression was used to estimate the percent difference in biomarker concentrations per 1 standard deviation increment in dietary index. FDR-adjusted < 0.05 was considered statistically significant. Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) were significantly associated with altered concentrations of 25 of the 40 biomarkers examined. For EDIH, the percent change in biomarker concentration in the insulin-related biomarkers ranged from +1.3% (glucose) to +8% (homeostatic model assessment for insulin resistance) and -9.7% for IGF-binding protein-1. EDIH impacted inflammation and endothelial dysfunction biomarkers from +1.1% (TNF-αR2) to +7.8% (CRP) and reduced adiponectin by 2.4%; and for lipid biomarkers: +0.3% (total cholesterol) to +3% (triglycerides/total cholesterol ratio) while reducing high-density lipoprotein cholesterol by 2.4%. EDIP showed a similar trend of associations with most biomarkers, although the magnitude of association was slightly weaker for the insulin-related biomarkers and stronger for lipids and lipid particle size. Dietary patterns with high potential to contribute to insulin hypersecretion and to chronic systemic inflammation, based on higher EDIH and EDIP scores, were associated with an unfavorable profile of circulating biomarkers of glucose-insulin dysregulation, chronic systemic inflammation, endothelial dysfunction and dyslipidemia. The broad range of biomarkers further validates EDIH and EDIP as mechanisms-based dietary patterns for use in clinical and population-based studies of metabolic and inflammatory diseases.
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http://dx.doi.org/10.3389/fnut.2021.690428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488136PMC
September 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

Strain-controlled synthesis of ultrathin hexagonal GaTe/MoS heterostructure for sensitive photodetection.

iScience 2021 Sep 25;24(9):103031. Epub 2021 Aug 25.

Key Laboratory for Micro-Nano Physics and Technology of Hunan Province, College of Materials Science and Engineering, School of Physics and Electronics, Hunan University, Changsha, Hunan 410082, China.

Ultrathin hexagonal GaTe, with relatively high charge density, holds great potential in the field of optoelectronic devices. However, the thermodynamical stability limits it fabrications as well as applications. Here, by introducing two-dimensional MoS as the substrate, we successfully realized the phase-controlled synthesis of ultrathin h-GaTe, leading to high-quality h-GaTe/MoS heterostructures. Theoretical calculation studies reveal that GaTe with hexagonal phase is more thermodynamically stable on MoS templates, which can be attributed to the strain stretching and the formation energy reduction. Based on the achieved p-n heterostructures, optoelectronic devices are designed and probed, where remarkable photoresponsivity (32.5 A/W) and fast photoresponse speed (<50 μs) are obtained, indicating well-behaved photo-sensing behaviors. The study here could offer a good reference for the controlled growth of the relevant materials, and the achieved heterostructure will find promising applications in future integrated electronic and optoelectronic devices and systems.
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http://dx.doi.org/10.1016/j.isci.2021.103031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437799PMC
September 2021

Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner.

J Mol Cell Biol 2021 Sep 16. Epub 2021 Sep 16.

Center for Comparative Biomedicine, Ministry of Education Key Lab of Systems Biomedicine, State Key Laboratory of Oncogenes and Related Genes, Joint International Research Laboratory of Metabolic and Developmental Sciences, Institute of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

Clustered protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion proteins that are central for neurite self-avoidance and neuronal connectivity in the brain. Their downstream non-receptor tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2, also known as Ptk2b, Cakb, Raftk, Fak2, and Cadtk) is predominantly expressed in the hippocampus. We constructed Pyk2 null mouse lines and found that these mutant mice showed enhancement in contextual fear memory, without any change in auditory-cued and spatial-referenced learning and memory. In addition, by preparing Y402F mutant mice, we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner. Moreover, using high-throughput RNA sequencing, we found that immediate early genes, such as Npas4, cFos, Zif268/Egr1, Arc, and Nr4a1, were enhanced in Pyk2 null mice. We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics. Thus, we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2 null mice provide a model for understanding fear-related disorders. These findings have interesting implications regarding dysregulation of the Pcdh‒Pyk2 axis in neuropsychiatric disorders.
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http://dx.doi.org/10.1093/jmcb/mjab057DOI Listing
September 2021

Allele frequency deviation (AFD) as a new prognostic model to predict overall survival in lung adenocarcinoma (LUAD).

Cancer Cell Int 2021 Aug 26;21(1):451. Epub 2021 Aug 26.

Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.

Background: Lung adenocarcinoma (LUAD) remains one of the world's most known aggressive malignancies with a high mortality rate. Molecular biological analysis and bioinformatics are of great importance as they have recently occupied a large area in the studies related to the identification of various biomarkers to predict survival for LUAD patients. In our study, we attempted to identify a new prognostic model by developing a new algorithm to calculate the allele frequency deviation (AFD), which in turn may assist in the early diagnosis and prediction of clinical outcomes in LUAD.

Method: First, a new algorithm was developed to calculate AFD using the whole-exome sequencing (WES) dataset. Then, AFD was measured for 102 patients, and the predictive power of AFD was assessed using Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and area under the curve (AUC). Finally, multivariable cox regression analyses were conducted to evaluate the independence of AFD as an independent prognostic tool.

Result: The Kaplan-Meier analysis showed that AFD effectively segregated patients with LUAD into high-AFD-value and low-AFD-value risk groups (hazard ratio HR = 1.125, 95% confidence interval CI 1.001-1.26, p = 0.04) in the training group. Moreover, the overall survival (OS) of patients who belong to the high-AFD-value group was significantly shorter than that of patients who belong to the low-AFD-value group with 42.8% higher risk and 10% lower risk of death for both groups respectively (HR for death = 1.10; 95% CI 1.01-1.2, p = 0.03) in the training group. Similar results were obtained in the validation group (HR = 4.62, 95% CI 1.22-17.4, p = 0.02) with 41.6%, and 5.5% risk of death for patients who belong to the high and low-AFD-value groups respectively. Univariate and multivariable cox regression analyses demonstrated that AFD is an independent prognostic model for patients with LUAD. The AUC for 5-year survival were 0.712 and 0.86 in the training and validation groups, respectively.

Conclusion: AFD was identified as a new independent prognostic model that could provide a prognostic tool for physicians and contribute to treatment decisions.
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http://dx.doi.org/10.1186/s12935-021-02127-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390239PMC
August 2021

Trends in Consumption of Ultraprocessed Foods Among US Youths Aged 2-19 Years, 1999-2018.

JAMA 2021 08;326(6):519-530

Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.

Importance: The childhood obesity rate has been steadily rising among US youths during the past 2 decades. Increasing evidence links consumption of ultraprocessed foods to excessive calorie consumption and weight gain, but trends in the consumption of ultraprocessed foods among US youths have not been well characterized.

Objective: To characterize trends in the consumption of ultraprocessed foods among US youths.

Design, Setting, And Participants: Serial cross-sectional analysis using 24-hour dietary recall data from a nationally representative sample of US youths aged 2-19 years (n = 33 795) from 10 cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999-2000 to 2017-2018.

Exposures: Secular time.

Main Outcomes And Measures: Percentage of total energy consumed from ultraprocessed foods as defined by NOVA, an established food classification system that categorizes food according to the degree of food processing.

Results: Dietary intake from youths were analyzed (weighted mean age, 10.7 years; 49.1% were girls). From 1999 to 2018, the estimated percentage of total energy from consumption of ultraprocessed foods increased from 61.4% to 67.0% (difference, 5.6% [95% CI, 3.5% to 7.7%]; P < .001 for trend), whereas the percentage of total energy from consumption of unprocessed or minimally processed foods decreased from 28.8% to 23.5% (difference, -5.3% [95% CI, -7.5% to -3.2%]; P < .001 for trend). Among the subgroups of ultraprocessed foods, the estimated percentage of energy from consumption of ready-to-heat and -eat mixed dishes increased from 2.2% to 11.2% (difference, 8.9% [95% CI, 7.7% to 10.2%]) and from consumption of sweet snacks and sweets increased from 10.7% to 12.9% (difference, 2.3% [95% CI, 1.0% to 3.6%]), but the estimated percentage of energy decreased for sugar-sweetened beverages from 10.8% to 5.3% (difference, -5.5% [95% CI, -6.5% to -4.5%]) and for processed fats and oils, condiments, and sauces from 7.1% to 4.0% (difference, -3.1% [95% CI, -3.7% to -2.6%]) (all P < .05 for trend). There was a significantly larger increase in the estimated percentage of energy from consumption of ultraprocessed foods among non-Hispanic Black youths (from 62.2% to 72.5%; difference, 10.3% [95% CI, 6.8% to 13.8%]) and Mexican American youths (from 55.8% to 63.5%; difference, 7.6% [95% CI, 4.4% to 10.9%]) than the increase among non-Hispanic White youths (from 63.4% to 68.6%; difference, 5.2% [95% CI, 2.1% to 8.3%]) (P = .04 for trends).

Conclusions And Relevance: Based on the NHANES cycles from 1999 to 2018, the estimated proportion of energy intake from consumption of ultraprocessed foods has increased among youths in the US and has consistently comprised the majority of their total energy intake.
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http://dx.doi.org/10.1001/jama.2021.10238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356071PMC
August 2021

Thermal Preparation and Application of a Novel Silicon Fertilizer Using Talc and Calcium Carbonate as Starting Materials.

Molecules 2021 Jul 26;26(15). Epub 2021 Jul 26.

College of Environmental Science and Engineering, Guilin University of Technology, 319 Yanshan Street, Guilin 541006, China.

The deficiency of available silicon (Si) incurred by year-round agricultural and horticultural practices highlights the significance of Si fertilization for soil replenishment. This study focuses on a novel and economical route for the synthesis of Si fertilizer via the calcination method using talc and calcium carbonate (CaCO) as starting materials. The molar ratio of talc to CaCO of 1:2.0, calcination temperature of 1150 °C and calcination time of 120 min were identified as the optimal conditions to maximize the available Si content of the prepared Si fertilizer. X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) characterizations elucidate the principles of the calcination temperature-dependent microstructure evolution of Si fertilizers, and the akermanite CaMg(SiO) and merwinite CaMg(SiO) were identified as the primary silicates products. The results of release and solubility experiments suggest the content of available metallic element and slow-release property of the Si fertilizer obtained at the optimum preparation condition (Si-OPC). The surface morphology and properties of Si-OPC were illuminated by the results of scanning electron microscope (SEM), surface area and nitrogen adsorption analysis. The acceleration action of CaCO in the decomposition process of talc was demonstrated by the thermogravimetry-differential scanning calorimetry (TG-DSC) test. The pot experiment corroborates that 5 g kg soil Si-OPC application sufficed to facilitate the pakchoi growth by providing nutrient elements. This evidence indicates the prepared Si fertilizer as a promising candidate for Si-deficient soil replenishment.
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http://dx.doi.org/10.3390/molecules26154493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347156PMC
July 2021

A male-ABCD algorithm for hepatocellular carcinoma risk prediction in HBsAg carriers.

Chin J Cancer Res 2021 Jun;33(3):352-363

State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Objective: Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults.

Methods: HBsAg-positive males of 35-69 years old (N=6,153) were included from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.

Results: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT (γ-glutamyl-transpeptidase), counts of platelets, white cells, concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91 (0.90-0.93), larger than existing models. At 1.5 points of risk score, 26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk, with positive prediction value of 22.85% and 12.35%, respectively.

Conclusions: Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.03.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286891PMC
June 2021

Evolution of Subfamily I.1 Lipases in Pseudomonas aeruginosa.

Curr Microbiol 2021 Sep 19;78(9):3494-3504. Epub 2021 Jul 19.

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.

The gram-negative Pseudomonas aeruginosa is an opportunistic human pathogen that contains two different types of strains: the "classical" and the "outlier". In the "classical" strain, its bacterial subfamily I.1 lipases, such as LipA and LipC in P. aeruginosa PAO1, play critical roles in its pathogenicity. However, less is known about the subfamily I.1 lipases in the "outlier" strain, nor the evolution paths of those lipases in both types of P. aeruginosa strains. Our genome-scale investigation on I.1 lipases across different bacterial strains demonstrates the presence of one LipA-like and one new type of I.1 lipase (LipC2) in those "outlier" strains. The related genomic islands analyses further suggest that the LipC counterpart gene in the "outlier" strain was lost by gene truncation. In addition, the evolutionary analyses also indicates the horizontal LipC2 gene transfer from other gammaproteobacterial species, as well as the horizontal LipA gene transfer between two different phyla, both suggesting that the gene transfer of bacterial I.1 lipases might occur in different taxonomical levels. Our results not only provide an evidence to understand the pathogenicity among different P. aeruginosa strains, but add to the knowledge of I.1 lipase evolution in bacteria.
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http://dx.doi.org/10.1007/s00284-021-02589-4DOI Listing
September 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

Adiposity, Adulthood Weight Change, and Risk of Incident Hepatocellular Carcinoma.

Cancer Prev Res (Phila) 2021 Oct 15;14(10):945-954. Epub 2021 Jul 15.

Harvard Medical School, Boston, Massachusetts.

Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980-2012) and 48,026 men (1986-2012), who recalled young-adult weight [age 18 years (women); 21 years (men)], and provided biennially updated information regarding weight, body mass index (BMI), and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable adjusted HRs (aHR) and 95% confidence intervals (CI). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood [continuous aHRs per each 1 unit = 1.05; 95% CI = 1.02-1.09 ( = 0.019), and 1.08; 95% CI = 1.06-1.10 ( = 0.004), respectively]. Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase = 1.03; 95% CI = 1.01-1.08; = 0.010), including after further adjusting for young-adult BMI ( = 0.010) and later-adult BMI ( = 0.008). Compared with adults with stable weight (±5 kg), the multivariable-aHRs with weight gain of 5-<10 kg, 10-<20 kg, and ≥20 kg were, 1.40 (95% CI = 0.67-2.16), 2.09 (95% CI = 1.11-3.95), and 2.61 (95% CI = 1.42-5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk. PREVENTION RELEVANCE: Our data suggest that maintaining a stable weight during adulthood, specifically by preventing weight gain, could represent an important public health strategy for the prevention of hepatocellular carcinoma.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492521PMC
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

Long-term Weight Changes and Risk of Rheumatoid Arthritis Among Women in a Prospective Cohort: A Marginal Structural Model Approach.

Rheumatology (Oxford) 2021 Jul 10. Epub 2021 Jul 10.

Division of Rheumatology, Inflammation, and Immunity, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115.

Objective: To examine the association of long-term weight change with rheumatoid arthritis (RA) risk in a large prospective cohort study.

Methods: The Nurses' Health Study (NHS) II started in 1989 (baseline); after exclusions, we studied 108,505 women 25-42 years old without RA. Incident RA was reported by participant and confirmed by medical record review. Body weight was reported biennially through 2015. We investigated two time-varying exposures: weight changes from baseline and from age 18; change was divided into 5 categories. We used a marginal structural model (MSM) approach to account for time-varying weight change and covariates.

Results: Over 2,583,266 person-years, with a median follow-up time of 25.3 years, 541 women developed RA. Compared to women with stable weight from baseline, weight change was significantly associated with increased RA risk [weight gain 2-<10 kg: RR = 1.98 (95% CI 1.38, 2.85); 10-<20 kg: RR = 3.28 (95% CI 2.20, 4.89); ≥20 kg: RR = 3.81 (95% CI 2.39, 6.07); and weight loss >2 kg: RR = 2.05 (95% CI 1.28, 3.28)]. Weight gain of 10 kg or more from age 18 compared with stable weight was also associated with increased RA risk [10-< 20 kg: RR = 2.12 (95% CI 1.37, 3.27), ≥20 kg: RR = 2.31 (95% CI 1.50, 3.56)]. Consistent findings were observed for seropositive and seronegative RA.

Conclusion: Long-term weight gain was strongly associated with increased RA risk in women, with weight gain of ≥ 20 kg associated with more than a three-fold increased RA risk. Maintenance of healthy weight may be a strategy to prevent or delay RA.
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http://dx.doi.org/10.1093/rheumatology/keab535DOI Listing
July 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 07 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Genetic Variation in the Mitochondrial Glycerol-3-Phosphate Acyltransferase Is Associated With Liver Injury.

Hepatology 2021 Dec 9;74(6):3394-3408. Epub 2021 Nov 9.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.

Background And Aims: Most of the genetic basis of chronic liver disease remains undiscovered.

Approach And Results: To identify genetic loci that modulate the risk of liver injury, we performed genome-wide association studies on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome-wide significance (P < 5 × 10 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol-3-phosphate acyltransferase (GPAM rs10787429) associated with increased levels of ALT (P = 1.4 × 10 ), AST (P = 3.6 × 10 ), ALP (P = 9.5 × 10 ), and total bilirubin (P = 2.9 × 10 ). This common genetic variant was also associated with an allele dose-dependent risk of alcohol-associated liver disease (odd ratio [OR] = 1.34, P = 2.6 × 10 ) and fatty liver disease (OR = 1.18, P = 5.8 × 10 ) by International Classification of Diseases, 10th Revision codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST (P = 7.1 × 10 and 3.95 × 10 , respectively), as well as between GPAM rs10787429 and weekly alcohol consumption in association with ALT, AST, and alcohol-associated liver disease (P = 4.0 × 10 , 1.6 × 10 , and 1.3 × 10 , respectively). Unlike previously described genetic variants that are associated with an increased risk of liver injury but confer a protective effect on circulating lipids, GPAM rs10787429 was associated with an increase in total cholesterol (P = 2.0 × 10 ), LDL cholesterol (P = 2.0 × 10 ), and HDL cholesterol (P = 6.6 × 10 ). Single-cell RNA-sequencing data demonstrated hepatocyte-predominant expression of GPAM in cells that co-express genes related to VLDL production (P = 9.4 × 10 ).

Conclusions: Genetic variation in GPAM is associated with susceptibility to liver injury. GPAM may represent a therapeutic target in chronic liver disease.
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http://dx.doi.org/10.1002/hep.32038DOI Listing
December 2021

Inhibition of lncRNA plays a protective role in hypoxia-ischemia-reoxygenation-induced myocardial injury by regulating miR-335 and RASA1 expression.

Mol Med Rep 2021 Aug 24;24(2). Epub 2021 Jun 24.

Department of Cardiology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China.

Long non‑coding (lnc)RNAs serve a role in a number of diseases, including different types of cancer and acute myocardial infarction. The aim of the present study was to investigate the protective role of lncRNA small nucleolar RNA host gene 8 in hypoxia‑ischemia‑reoxygenation (HI/R)‑induced myocardial injury and its potential mechanism of action. Cell viability, proliferation, creatine kinase myocardial band, cell apoptosis and protein expression levels were determined by Cell Counting Kit‑8 assay, EdU assay, ELISA, flow cytometry and western blotting, respectively. The association between and microRNA (miR)‑335 was confirmed using a dual‑luciferase reporter gene assay. The effects of the miR‑335 inhibitor transfections had on increasing apoptosis and decreasing H9C2 cell viability were reversed in cells co‑transfected with small interfering (si)RNA. Furthermore, it was found that miR‑335 could regulate RAS p21 protein activator 1 (RASA1) expression and that transfection with siRNA downregulated RASA1 expression. Silencing of RASA1 protected against HI/R‑induced H9C2 cell injury. However, siRNA did not further reduce apoptosis, demonstrating that may act through RASA1, and RASA1 may mediate the protection of siRNA in HI/R myocardial injury. Thus, inhibition of lncRNA alleviated HI/R‑induced myocardial damage by regulating miR‑335 and RASA1.
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http://dx.doi.org/10.3892/mmr.2021.12236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240175PMC
August 2021

Discovery and Features of an Alkylating Signature in Colorectal Cancer.

Cancer Discov 2021 Oct 17;11(10):2446-2455. Epub 2021 Jun 17.

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

Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations p.G12D, p.G13D, and p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression. SIGNIFICANCE: Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target p.G12D/p.G13D..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487940PMC
October 2021

Lon protease downregulates phenazine-1-carboxamide biosynthesis by degrading the quorum sensing signal synthase PhzI and exhibits negative feedback regulation of Lon itself in Pseudomonas chlororaphis HT66.

Mol Microbiol 2021 08 21;116(2):690-706. Epub 2021 Jun 21.

State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Pseudomonas chlororaphis HT66 exhibits strong antagonistic activity against various phytopathogenic fungi due to its main antibiotic phenazine-1-carboxamide (PCN). PCN gene cluster consists of phzABCDEFG, phzH, phzI, and phzR operons. phzABCDEFG transcription is activated by the PhzI/R quorum sensing system. Deletion of the lon gene encoding an ATP-dependent protease resulted in significant enhancement of PCN production in strain HT66. However, the regulatory pathway and mechanism of Lon on PCN biosynthesis remain unknown. Here, lon mutation was shown to significantly improve antimicrobial activity of strain HT66. The N-acyl-homoserine lactone synthase PhzI mediates the negative regulation of PCN biosynthesis and phzABCDEFG transcription by Lon. Western blot showed that PhzI protein abundance and stability were significantly enhanced by lon deletion. The in vitro degradation assay suggested that Lon could directly degrade PhzI protein. However, Lon with an amino acid replacement (S -A) could not degrade PhzI protein. Lon-recognized region was located within the first 50 amino acids of PhzI. In addition, Lon formed a new autoregulatory feedback circuit to modulate its own degradation by other potential proteases. In summary, we elucidated the Lon-regulated pathway mediated by PhzI during PCN biosynthesis and the molecular mechanism underlying the degradation of PhzI by Lon in P. chlororaphis HT66.
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http://dx.doi.org/10.1111/mmi.14764DOI Listing
August 2021

A seven-gene prognostic signature predicts overall survival of patients with lung adenocarcinoma (LUAD).

Cancer Cell Int 2021 Jun 6;21(1):294. Epub 2021 Jun 6.

Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.

Background: Lung adenocarcinoma (LUAD) is one of the most common types in the world with a high mortality rate. Despite advances in treatment strategies, the overall survival (OS) remains short. Our study aims to establish a reliable prognostic signature closely related to the survival of LUAD patients that can better predict prognosis and possibly help with individual monitoring of LUAD patients.

Methods: Raw RNA-sequencing data were obtained from Fudan University and used as a training group. Differentially expressed genes (DEGs) for the training group were screened. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate cox regression analysis were conducted to identify the candidate prognostic genes and construct the risk score model. Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic power and performance of the signature. Moreover, The Cancer Genome Atlas (TCGA-LUAD) dataset was further used to validate the predictive ability of prognostic signature.

Results: A prognostic signature consisting of seven prognostic-related genes was constructed using the training group. The 7-gene prognostic signature significantly grouped patients in high and low-risk groups in terms of overall survival in the training cohort [hazard ratio, HR = 8.94, 95% confidence interval (95% CI)] [2.041-39.2]; P = 0.0004), and in the validation cohort (HR = 2.41, 95% CI [1.779-3.276]; P < 0.0001). Cox regression analysis (univariate and multivariate) demonstrated that the seven-gene signature is an independent prognostic biomarker for predicting the survival of LUAD patients. ROC curves revealed that the 7-gene prognostic signature achieved a good performance in training and validation groups (AUC = 0.91, AUC = 0.7 respectively) in predicting OS for LUAD patients. Furthermore, the stratified analysis of the signature showed another classification to predict the prognosis.

Conclusion: Our study suggested a new and reliable prognostic signature that has a significant implication in predicting overall survival for LUAD patients and may help with early diagnosis and making effective clinical decisions regarding potential individual treatment.
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http://dx.doi.org/10.1186/s12935-021-01975-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183047PMC
June 2021

Liquid-Metal-Assisted Growth of Vertical GaSe/MoS p-n Heterojunctions for Sensitive Self-Driven Photodetectors.

ACS Nano 2021 Jun 26;15(6):10039-10047. Epub 2021 May 26.

Key Laboratory for Micro-Nano Physics and Technology of Hunan Province, College of Materials Science and Engineering, School of Physics and Electronics, and State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan 410082, P.R. China.

van der Waals (vdW) vertical p-n junctions based on two-dimensional (2D) materials have shown great potential in flexible, self-driven, high-efficiency electronic and optoelectronic applications. However, due to the complex nucleation dynamics, the controllable synthesis of vertical heterostructures remains a daunting challenge. Here, we report the controlled growth of vertical GaSe/MoS p-n heterojunctions a liquid gallium (Ga)-assisted chemical vapor deposition method. The growth mechanism can be interpreted by theoretical calculations based on the Burton-Cabrera-Frank theory. By analyzing the diffusion barriers and the Ehrlich-Schwoebel barriers of adatoms, we found that the growth modes between vertical and lateral can be precisely switched by means of adjusting the amount of Ga. Based on the achieved high-quality vertical GaSe/MoS p-n heterojunctions, photosensing devices are further designed and systematically investigated. Upon light illumination, prominent photovoltaic effects with large open-circuit voltage (0.61 V) and broadband detection capability from 375 to 633 nm are observed, which can further be employed for self-powered photodetection with high responsivity (900 mA/W) and fast response speed (5 ms). The developed liquid-metal-assisted strategy provides an effective method for controllable synthesis of vdW heterostructures and will give impetus to their applications in high-performance optoelectronic device.
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http://dx.doi.org/10.1021/acsnano.1c01643DOI Listing
June 2021

Association of bowel movement frequency and laxative use with risk of hepatocellular carcinoma in US women and men.

Int J Cancer 2021 10 4;149(8):1529-1535. Epub 2021 Jun 4.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abnormal bowel movements have been related to a variety of hepatocellular carcinoma (HCC) risk factors such as dyslipidemia, diabetes and altered metabolism of bile acids and gut microbiota. However, little is known about whether bowel movement frequency affects the risk of developing HCC. We followed 88 123 women in the Nurses' Health Study (NHS) and 28 824 men in the Health Professionals Follow-up Study (HPFS) for up to 24 years. The Cox proportional hazards regression model was used to calculate multivariable hazard ratios (HRs) and confidence intervals (95%CI). We documented 101 incident HCC cases. Compared to those with daily bowel movements, participants with bowel movement more than once per day had a multivariable HR of 1.93 (95%CI: 1.18 to 3.16) in the pooled cohorts. For the same comparison, the positive association appeared stronger for men (2.72, 95% CI: 1.14 to 6.44) than for women (1.63, 95% CI: 0.87 to 3.06) but there was no statistically significant heterogeneity by sex (P-value = .31). We found null associations between bowel movement every 2 days or less and the risk of HCC (HR = 1.05, 95%CI: 0.62 to 1.79). The HR (95%CI) for participants who used laxatives regularly relative to those who never used laxatives was 1.00 (0.64 to 1.55). Our results suggest participants with bowel movement more than once daily is associated with a higher risk of developing HCC compared to those with daily bowel movements. These findings need to be confirmed and potential mechanisms underlying this association need to be elucidated.
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http://dx.doi.org/10.1002/ijc.33699DOI Listing
October 2021

The global regulator Hfq exhibits far more extensive and intensive regulation than Crc in Pseudomonas protegens H78.

Mol Plant Pathol 2021 Aug 8;22(8):921-938. Epub 2021 May 8.

State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

The biocontrol rhizobacterium Pseudomonas protegens H78 can produce a large array of antimicrobial secondary metabolites, including pyoluteorin (Plt), 2,4-diacetylphloroglucinol (DAPG), and pyrrolnitrin (Prn). Our preliminary study showed that the biosynthesis of antibiotics including Plt is activated by the RNA chaperone Hfq in P. protegens H78. This prompted us to explore the global regulatory mechanism of Hfq, as well as the catabolite repression control (Crc) protein in H78. The antimicrobial capacity of H78 was positively controlled by Hfq while slightly down-regulated by knockout of crc. Similarly, cell growth of H78 was significantly impaired by deletion of hfq and slightly inhibited by knockout of crc. Transcriptomic profiling revealed that hfq mutation resulted in significant down-regulation of 688 genes and up-regulation of 683 genes. However, only 113 genes were significantly down-regulated and 105 genes up-regulated by the crc mutation in H78. Hfq positively regulated the expression of gene clusters involved in secondary metabolism (plt, prn, phl, hcn, and pvd), the type VI secretion system, and aromatic compound degradation. However, Crc only positively regulated the biosynthesis of Plt but not other antibiotics. Hfq also regulated expression of genes involved in oxidative phosphorylation and flagellar biogenesis. In addition, Hfq and Crc activated transcription of crcY/Z sRNAs by feedback. In summary, Hfq processes far more extensive and intensive regulatory capacity than Crc and shows small cross-regulation with Crc in H78. This study lays the foundation for clarifying the Hfq and/or Crc-dependent global regulatory network and improving antibiotic production by genetic engineering in P. protegens.
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http://dx.doi.org/10.1111/mpp.13070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295515PMC
August 2021

Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment.

J Immunother Cancer 2021 04;9(4)

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

Background: Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.

Methods: We used multiplexed immunofluorescence combined with digital image analysis to identify CD14 monocytic and CD15 granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1-Q4) of myeloid cell densities. Immune cell-tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.

Results: Higher intraepithelial ( =0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal ( <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14HLA-DR cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14HLA-DR cells were associated with higher colorectal cancer-specific mortality ( =0.0003; HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15 cells were located closer to tumor cells than CD14 cells, and CD14HLA-DR cells were closer to tumor than CD14HLA-DR cells (p<0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14HLA-DR cell versus CD14HLA-DR cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality ( <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).

Conclusions: Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14HLA-DR and immature CD14HLA-DR monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.
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http://dx.doi.org/10.1136/jitc-2020-002297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098931PMC
April 2021

Tumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis.

Cancers (Basel) 2021 Apr 22;13(9). Epub 2021 Apr 22.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 ( = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively ( = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.
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http://dx.doi.org/10.3390/cancers13092016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122644PMC
April 2021

Postdiagnostic dairy products intake and colorectal cancer survival in US males and females.

Am J Clin Nutr 2021 06;113(6):1636-1646

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

Background: To evaluate the association between postdiagnostic dairy intake and survival among patients with colorectal cancer (CRC).

Methods: This study analyzed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Postdiagnostic dairy intake and other dietary and lifestyle factors were obtained from validated questionnaires. Individual dairy items including milk, cheese, yogurt, and so on were reported, and total, high-fat, and low-fat dairy intakes were derived.

Results: A total of 1753 eligible CRC cases were identified until 2012, from which 703 deaths were documented after a median follow-up time of 8.2 y, and 242 were due to CRC. Overall, when comparing those who consumed 21+ servings/wk with <7 servings/wk, postdiagnostic total dairy intake did not show significant associations with CRC-specific mortality (HR: 1.35; 95% CI: 0.85, 2.13) or overall mortality (HR: 1.28; 95% CI: 0.98, 1.67). However, high-fat dairy, including whole milk and cream cheese, was positively associated with overall mortality (HR: 1.33; 95% CI: 1.08, 1.65) but not significantly with CRC-specific mortality (HR: 1.31; 95% CI: 0.91, 1.90) when comparing those who consumed 10.5+ servings/wk with <3.5 servings/wk. For the same comparison, low-fat dairy, including skim or nonfat milk and cottage cheese, was inversely associated with overall mortality (HR: 0.74; 95% CI: 0.59, 0.92) but not CRC-specific mortality (HR: 0.91; 95% CI: 0.63, 1.29).

Conclusions: Total dairy products intake did not show significant association with CRC-specific or overall mortality. However, high intake of high-fat dairy products was associated with increased mortality, whereas low-fat dairy was associated with lower risk of overall mortality.
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http://dx.doi.org/10.1093/ajcn/nqab059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244033PMC
June 2021

Dietary Fats, Serum Cholesterol and Liver Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Studies.

Cancers (Basel) 2021 Mar 30;13(7). Epub 2021 Mar 30.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

To quantify the associations between dietary fats and their major components, as well as serum levels of cholesterol, and liver cancer risk, we performed a systematic review and meta-analysis of prospective studies. We searched PubMed, Embase, and Web of Science up to October 2020 for prospective studies that reported the risk estimates of dietary fats and serum cholesterol for liver cancer risk. We carried out highest versus lowest intake or level and dose-response analyses. Higher intake of dietary saturated fatty acids (SFA) was associated with a higher liver cancer risk in both category analysis (relative risk [RR] = 1.34, 95% confidence interval [CI]: 1.06, 1.69) and dose-response analysis (RR = 1.04, 95%CI: 1.01, 1.07). Higher serum total cholesterol was inversely associated with liver cancer but with large between-studies variability (RR = 0.72, 95%CI: 0.69, 0.75, I = 75.3%). The inverse association was more pronounced for serum high-density lipoprotein (HDL) cholesterol (RR = 0.42, 95%CI: 0.27, 0.64). Higher intake of dietary SFA was associated with higher risk of liver cancer while higher serum levels of cholesterol and HDL were associated with a lower risk of liver cancer with high between-studies variability.
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http://dx.doi.org/10.3390/cancers13071580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037522PMC
March 2021

[Development and high yield strategies of microbial-derived antibiotics in agriculture].

Sheng Wu Gong Cheng Xue Bao 2021 Mar;37(3):1032-1041

State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

The development of high-efficiency, low-toxicity, and low-residue green pesticides is the main trend of pesticide research, and the microbial-derived antibiotics are one of the essential parts of green pesticides and play a significant role in agriculture. With the development of microbial genomics technology, metabolic engineering, high-throughput screening and other technologies, the research on new microbial-derived antibiotics has entered a new stage in agriculture. Here we briefly summarize the types of new microbial-derived antibiotics developed in agriculture over the past decade. We also introduce the research strategies for high-yield breeding and fermentation of antibiotic-producing strains in agriculture. This review may provide references for the future development of agricultural antibiotics.
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http://dx.doi.org/10.13345/j.cjb.200643DOI Listing
March 2021

Simple Sugar and Sugar-Sweetened Beverage Intake During Adolescence and Risk of Colorectal Cancer Precursors.

Gastroenterology 2021 07 19;161(1):128-142.e20. Epub 2021 Mar 19.

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

Background & Aims: Recent increasing trends in early-onset colorectal cancer (CRC) strongly supports that early-life diet is involved in CRC development. However, data are lacking on the relationship with high sugar intake during early life.

Methods: We prospectively investigated the association of adolescent simple sugar (fructose, glucose, added sugar, total sugar) and sugar-sweetened beverage (SSB) intake with CRC precursor risk in 33,106 participants of the Nurses' Health Study II who provided adolescent dietary information in 1998 and subsequently underwent lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data.

Results: During follow-up, 2909 conventional adenomas (758 high-risk) and 2355 serrated lesions were identified (mean age at diagnoses, 52.2 ± 4.3 years). High sugar and SSB intake during adolescence was positively associated with risk of adenoma, but not serrated lesions. Per each increment of 5% of calories from total fructose intake, multivariable ORs were 1.17 (95% CI, 1.05-1.31) for total and 1.30 (95% CI, 1.06-1.60) for high-risk adenoma. By subsite, ORs were 1.12 (95% CI, 0.96-1.30) for proximal, 1.24 (95% CI, 1.05-1.47) for distal, and 1.43 (95% CI, 1.10-1.86) for rectal adenoma. Per 1 serving/day increment in SSB intake, ORs were 1.11 (95% CI, 1.02-1.20) for total and 1.30 (95% CI, 1.08-1.55) for rectal adenoma. Contrary to adolescent intake, sugar and SSB intake during adulthood was not associated with adenoma risk.

Conclusions: High intake of simple sugars and SSBs during adolescence was associated with increased risk of conventional adenoma, especially rectal adenoma.
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http://dx.doi.org/10.1053/j.gastro.2021.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238879PMC
July 2021

Association of folate intake and colorectal cancer risk in the postfortification era in US women.

Am J Clin Nutr 2021 07;114(1):49-58

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

Background: Folate may play a preventive role in the early stages of colorectal carcinogenesis, but long latencies may be needed to observe a reduction in colorectal cancer (CRC) incidence. In addition, concerns have been raised about the potential for cancer promotion with excessive folate intake, especially after the mandatory folic acid fortification in the United States in 1998.

Objective: We aimed to examine the association between folate intake in different chemical forms and CRC risk, especially in the postfortification era in the United States.

Design: We prospectively followed 86,320 women from the Nurses' Health Study (1980-2016). Folate intake was collected by validated food frequency questionnaires. CRC was self reported and confirmed by review of medical records. The association between the folate intake and CRC risk was assessed using Cox proportional hazards regression.

Results: We documented 1988 incident CRC cases during follow-up. Analyzing folate intake as a continuous variable, greater total folate intake 12-24 y before diagnosis was associated with lower risk of CRC (per increment of 400 dietary folate equivalents (DFE)/d, HR: 0.93, 95% CI: 0.85, 1.01 for 12-16 y; HR: 0.83, 95% CI: 0.75, 0.92 for 16-20 y; and HR: 0.87, 95% CI: 0.77, 0.99 for 20-24 y); and greater synthetic folic acid intake 16-24 y before diagnosis was also associated with a lower CRC risk (per increment of 400 DFE/d, HR: 0.91, 95% CI: 0.84, 0.99 for 16-20 y and HR: 0.91, 95% CI: 0.83-1.01 for 20-24 y). In the postfortification period (1998-2016), intake of total or specific forms of folate was not associated with CRC risk, even among multivitamin users.

Conclusions: Folate intake, both total and from synthetic forms, was associated with a lower risk of overall CRC after long latency periods. There was no evidence that high folate intake in the postfortification period was related to increased CRC risk in this US female population.
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http://dx.doi.org/10.1093/ajcn/nqab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246607PMC
July 2021
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