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1.
Gut Microbes ; 16(1): 2399260, 2024.
Article in English | MEDLINE | ID: mdl-39239875

ABSTRACT

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.


Subject(s)
Amino Acids , Bacteria , Gastrointestinal Microbiome , Liver Cirrhosis , Liver , Animals , Humans , Liver Cirrhosis/microbiology , Liver Cirrhosis/metabolism , Mice , Amino Acids/metabolism , Bacteria/classification , Bacteria/metabolism , Bacteria/genetics , Bacteria/isolation & purification , Male , Liver/metabolism , Liver/pathology , Liver/microbiology , Female , Feces/microbiology , Mice, Inbred C57BL , Middle Aged , Fatty Liver/metabolism , Fatty Liver/microbiology , Disease Models, Animal , Metagenome , Adult
2.
Cancer Prev Res (Phila) ; 17(1): 1-5, 2024 01 04.
Article in English | MEDLINE | ID: mdl-38173395

ABSTRACT

The American College of Physicians (ACP) update of their standing guidance statement for colorectal-cancer screening in asymptomatic average-risk adults was recently published to assist clinicians with implementing evidence-based patient care. After assessing existing guideline literature, the ACP recommended five actions: consider not screening adults ages 45 to 49 years; stop screening adults older than 75 years; discuss benefits, harms, costs, availability, frequency, and patient values/preferences with patients prior to choosing a screening method; and when choosing, recommend biennial rather than annual use of a fecal immunochemical test or a guaiac fecal occult blood test and avoid recommending computed tomography colonography or stool DNA tests. While the ACP guidelines are rigorous, well-intended, and considerate of patients' input, their greatest impact may result from highlighting the need for researchers to help frontline clinicians to describe the risk, costs, and benefits/harms of various colorectal-cancer screening strategies in an effective, yet time-efficient, manner given the all-too-brief annual patient encounters. In the United States, reimbursement is still dependent on U.S. Preventive Services Task Force recommendations which are somewhat more liberal in contrast to the ACP's approach which strongly favors randomized, controlled trial evidence to guide the delivery of prevention and screening services to asymptomatic average-risk patients.


Subject(s)
Colorectal Neoplasms , Early Detection of Cancer , Adult , Humans , Colonography, Computed Tomographic , Colonoscopy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/prevention & control , Early Detection of Cancer/methods , Physicians , United States , Middle Aged , Aged , Practice Guidelines as Topic
3.
Clin Cancer Res ; 29(21): 4361-4372, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37724990

ABSTRACT

PURPOSE: Lynch syndrome (LS) is a hereditary condition with a high lifetime risk of colorectal and endometrial cancers. Exercise is a non-pharmacologic intervention to reduce cancer risk, though its impact on patients with LS has not been prospectively studied. Here, we evaluated the impact of a 12-month aerobic exercise cycling intervention in the biology of the immune system in LS carriers. PATIENTS AND METHODS: To address this, we enrolled 21 patients with LS onto a non-randomized, sequential intervention assignation, clinical trial to assess the effect of a 12-month exercise program that included cycling classes 3 times weekly for 45 minutes versus usual care with a one-time exercise counseling session as control. We analyzed the effects of exercise on cardiorespiratory fitness, circulating, and colorectal-tissue biomarkers using metabolomics, gene expression by bulk mRNA sequencing, and spatial transcriptomics by NanoString GeoMx. RESULTS: We observed a significant increase in oxygen consumption (VO2peak) as a primary outcome of the exercise and a decrease in inflammatory markers (prostaglandin E) in colon and blood as the secondary outcomes in the exercise versus usual care group. Gene expression profiling and spatial transcriptomics on available colon biopsies revealed an increase in the colonic mucosa levels of natural killer and CD8+ T cells in the exercise group that were further confirmed by IHC studies. CONCLUSIONS: Together these data have important implications for cancer interception in LS, and document for the first-time biological effects of exercise in the immune system of a target organ in patients at-risk for cancer.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Exercise , Endometrial Neoplasms/genetics , Gene Expression Profiling , Intestinal Mucosa/pathology
4.
Cancer Epidemiol Biomarkers Prev ; 32(10): 1338-1347, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37540502

ABSTRACT

BACKGROUND: It is estimated that 6% to 20% of all cholangiocarcinoma (CCA) diagnoses are explained by primary sclerosing cholangitis (PSC), but the underlying risk factors in the absence of PSC are unclear. We examined associations of different risk factors with intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) in the United States. METHODS: We conducted a case-control study of 121 patients with ECC and 308 patients with ICC treated at MD Anderson Cancer Center between May 2014 and March 2020, compared with 1,061 healthy controls. Multivariable logistic regression analysis was applied to estimate the adjusted OR (AOR) and 95% confidence interval (CI) for each risk factor. RESULTS: Being Asian, diabetes mellitus, family history of cancer, and gallbladder stones were associated with higher odds of developing ICC and ECC. Each 1-unit increase in body mass index in early adulthood (ages 20-40 years) was associated with a decrease in age at diagnosis of CCA (6.7 months, P < 0.001; 6.1 months for ICC, P = 0.001; 8.2 months for ECC, P = 0.007). A family history of cancer was significantly associated with the risk of ICC and ECC development; the AORs (95% CI) were 1.11 (1.06-1.48) and 1.32 (1.01-2.00) for ICC and ECC, respectively. CONCLUSIONS: In this study, early adulthood onset of obesity was significantly associated with CCA and may predict early diagnosis at younger age than normal weight individuals. IMPACT: The study highlights the association between obesity and CCA, independent of PSC. There is a need to consider the mechanistic pathways of obesity in the absence of fatty liver and cirrhosis.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Cholangitis, Sclerosing , Humans , Adult , Infant , Case-Control Studies , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/epidemiology , Cholangitis, Sclerosing/pathology , Cholangiocarcinoma/epidemiology , Cholangiocarcinoma/etiology , Liver Cirrhosis/pathology , Risk Factors , Obesity/complications , Obesity/epidemiology , Obesity/pathology , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/epidemiology , Bile Duct Neoplasms/etiology
5.
Cancer Prev Res (Phila) ; 16(7): 365-367, 2023 07 05.
Article in English | MEDLINE | ID: mdl-37403656

ABSTRACT

Nearly all cancers have identifiable histologically defined precursors known as precancers. These precancers offer a window of opportunity to intercept the neoplastic process to prevent its development into invasive cancer. However, lack of knowledge regarding the evolution of precancers and the microenvironmental pressures shaping them precludes efforts to intercept them. Technological developments over the past decade have facilitated the study of precancers at a previously unattainable resolution. Calls for a national PreCancer Atlas effort incorporating these technologies were heeded in 2018, with the launch of the Human Tumor Atlas Network (HTAN) as part of the Beau Biden National Cancer Moonshot. Since then, five funded HTAN groups have focused their efforts on profiling precancers from breast, colon, skin, and lung. In this time, what progress has been made? What is next for HTAN and the field of premalignant biology? And are there lessons that individual investigators and the larger prevention field can learn from this initial effort to accelerate the development of novel early detection methods, risk prediction biomarkers, and interception agents? A special collection of invited reviews by experts in cancer evolution, systems biology, immunology, cancer genetics, preventive agent development, among other areas, attempts to answer these questions.


Subject(s)
Precancerous Conditions , Humans , Precancerous Conditions/pathology , Biology
6.
Cancer Prev Res (Phila) ; 15(11): 777-784, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35969832

ABSTRACT

The human papillomavirus (HPV) vaccine was indicated for the prevention of vulvovaginal cancers in 2008, but its impact on the incidence of vulvar cancers within the US is unknown. To determine this, we conducted a secondary analysis of 88,942 vulvar cancer cases among women 20+ years old using the US Cancer Statistics 2001-2018 databases. Data were stratified by tumor behavior (in situ or invasive), age (20-44, 45-64, 65+ years old), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic), and US census region (Northeast, South, Midwest, West), and incidence rates and average annual percentage changes (AAPC) were calculated by group. Reversing previous trends, the incidence of vulvar carcinoma in situ significantly decreased between 2001 and 2018 among women from all age groups, races/ethnicities, and regions (combined AAPC,  -4.3; 95% confidence interval (CI), -4.7 to -3.8). The incidence of invasive vulvar squamous cell carcinoma decreased significantly among 20- to 44-year-old women (AAPC, -0.8; 95% CI, -1.3 to -0.3), but significantly increased among those 45 to 64 (AAPC, 2.3; 95% CI, 1.8-2.8) and 65+ years old (AAPC, 1.2; 95% CI, 1.1-1.4). Regardless of tumor behavior, incidence was highest among non-Hispanic Whites and the Midwest region. Overall, the significant declines in vulvar carcinoma in situ among all ages, as well as invasive vulvar cancer among younger women, are encouraging and complement other recent data suggesting HPV vaccinations are already reducing anal and cervical cancer incidence. Over time, further declines in vulvar carcinoma incidence are likely as uptake and completion rates of the HPV vaccine increase in the US. PREVENTION RELEVANCE: We found evidence that HPV vaccinations likely contributed to a decrease in the incidences of vulvar carcinoma in situ and invasive vulvar carcinoma among 20- to 44-year-old women between 2001 and 2018. Our data add to the growing evidence that HPV vaccinations are reducing the incidence of HPV-related anogenital cancers.


Subject(s)
Alphapapillomavirus , Carcinoma in Situ , Papillomavirus Infections , Papillomavirus Vaccines , Uterine Cervical Neoplasms , Vulvar Neoplasms , United States/epidemiology , Female , Humans , Young Adult , Adult , Vulvar Neoplasms/epidemiology , Vulvar Neoplasms/prevention & control , Vulvar Neoplasms/complications , Papillomavirus Vaccines/therapeutic use , Incidence , Papillomavirus Infections/complications , Papillomavirus Infections/epidemiology , Papillomavirus Infections/prevention & control , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/pathology , Carcinoma in Situ/epidemiology , Carcinoma in Situ/prevention & control , Vaccination
7.
mSystems ; 7(3): e0003322, 2022 06 28.
Article in English | MEDLINE | ID: mdl-35477306

ABSTRACT

Mexican Americans have a high prevalence of diabetes and burden of diabetes-related complications, highlighting the need for novel preventive strategies and noninvasive predictors of diabetes risk tailored to this population. Changes in the gut microbiome have the potential to predict diabetes. Here, we aimed to identify alterations in the gut microbiome associated with diabetes in the high-risk population of Mexican Americans in South Texas. Stool samples were collected from 216 subjects from the population-based Cameron County Hispanic Cohort. Among them, 75 had type 2 diabetes. Taxonomic and functional profiling of the stool samples were assessed by 16S and shotgun metagenomic sequencing, and the influence of genetic factors was explored. The gut microbiome of subjects with diabetes was enriched with proinflammatory Proteobacteria members (Enterobacteriaceae, Escherichia-Shigella) and depleted of butyrate-producing Clostridiales members (Faecalibacterium prausnitzii, Peptostreptococcaceae, and Clostridium sensu stricto 1). The accompanying metagenomic changes in subjects with diabetes suggested dysregulated amino acid metabolism, reduced galacturonate and glucuronate catabolism (correlating with Faecalibacterium prausnitzii abundance), and enriched heme biosynthesis (correlating with Enterobacteriaceae abundance). Polymorphism rs7129790 near MMP27 was strongly associated with high Proteobacteria abundance and was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. In conclusion, Mexican Americans in South Texas with diabetes display distinct gut microbiome and metagenomic signatures. These signatures may have utility in risk modeling and disease prevention in this high-risk population. IMPORTANCE The gut microbiome composition varies across ethnicities and geographical locations, yet studies on diabetes-associated microbiome changes specific to high-risk Mexican Americans are lacking. Here, we aimed to identify specific alterations associated with diabetes in this population, as well as host genetic factors that may explain increased disease susceptibility in this ethnic group. Using samples from a population-based cohort of Mexican Americans with a high prevalence of obesity and diabetes, we confirmed findings from studies on other ethnicities that suggested promotion of a chronic proinflammatory environment, loss of butyrate production, and compromised intestinal barrier integrity. High abundance of proinflammatory Proteobacteria was associated with a polymorphism that was more frequent in this cohort and in individuals of Mexican ancestry than in Europeans. Validation of microbiome-based risk models for diabetes should be evaluated in prospective cohort studies.


Subject(s)
Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Humans , Butyrates , Diabetes Mellitus, Type 2/epidemiology , Enterobacteriaceae , Gastrointestinal Microbiome/genetics , Mexican Americans/genetics , Prospective Studies , Texas/ethnology
8.
Cancer ; 128 Suppl 4: 861-874, 2022 02 15.
Article in English | MEDLINE | ID: mdl-35133659

ABSTRACT

Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case-control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.


Subject(s)
Biomarkers, Tumor , Neoplasms , Case-Control Studies , Early Detection of Cancer , Humans , Neoplasms/diagnosis , Proteomics
9.
Hepatology ; 75(4): 955-967, 2022 04.
Article in English | MEDLINE | ID: mdl-34633706

ABSTRACT

BACKGROUND AND AIMS: Hispanics are disproportionately affected by NAFLD, liver fibrosis, cirrhosis, and HCC. Preventive strategies and noninvasive means to identify those in this population at high risk for liver fibrosis, are urgently needed. We aimed to characterize the gut microbiome signatures and related biological functions associated with liver fibrosis in Hispanics and identify environmental and genetic factors affecting them. APPROACH AND RESULTS: Subjects of the population-based Cameron County Hispanic Cohort (CCHC; n = 217) were screened by vibration-controlled transient elastography (FibroScan). Among them, 144 (66.7%) had steatosis and 28 (13.0%) had liver fibrosis. The gut microbiome of subjects with liver fibrosis was enriched with immunogenic commensals (e.g., Prevotella copri, Holdemanella, Clostridiaceae 1) and depleted of Bacteroides caccae, Parabacteroides distasonis, Enterobacter, and Marinifilaceae. The liver fibrosis-associated metagenome was characterized by changes in the urea cycle, L-citrulline biosynthesis and creatinine degradation pathways, and altered synthesis of B vitamins and lipoic acid. These metagenomic changes strongly correlated with the depletion of Parabacteroides distasonis and enrichment of Prevotella and Holdemanella. Liver fibrosis was also associated with depletion of bacterial pathways related to L-fucose biosynthesis. Alcohol consumption, even moderate, was associated with high Prevotella abundance. The single-nucleotide polymorphisms rs3769502 and rs7573751 in the NCK adaptor protein 2 (NCK2) gene positively associated with high Prevotella abundance. CONCLUSION: Hispanics with liver fibrosis display microbiome profiles and associated functional changes that may promote oxidative stress and a proinflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high-risk population.


Subject(s)
Carcinoma, Hepatocellular , Gastrointestinal Microbiome , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Bacteroidetes , Carcinoma, Hepatocellular/complications , Gastrointestinal Microbiome/genetics , Hispanic or Latino/genetics , Humans , Liver Cirrhosis/complications , Liver Neoplasms/complications , Non-alcoholic Fatty Liver Disease/complications
10.
Cancer Epidemiol Biomarkers Prev ; 30(9): 1643-1651, 2021 09.
Article in English | MEDLINE | ID: mdl-34155064

ABSTRACT

BACKGROUND: Hispanics in South Texas have high rates of hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Liver fibrosis severity is the strongest predictive factor of NAFLD progression to HCC. We examined the association between free fatty acids (FA) and advanced liver fibrosis or HCC in this population. METHODS: We quantified 45 FAs in plasma of 116 subjects of the Cameron County Hispanic Cohort, 15 Hispanics with HCC, and 56 first/second-degree relatives of Hispanics with HCC. Liver fibrosis was assessed by FibroScan. RESULTS: Advanced liver fibrosis was significantly associated with low expression of very long chain (VLC) saturated FAs (SFA), odd chain SFAs, and VLC n-3 polyunsaturated FAs [PUFA; AOR; 95% confidence interval (CI), 10.4 (3.7-29.6); P < 0.001; 5.7 (2.2-15.2); P < 0.001; and 3.7 (1.5-9.3); P = 0.005]. VLC n3-PUFAs significantly improved the performance of the noninvasive markers for advanced fibrosis - APRI, FIB-4, and NFS. Plasma concentrations of VLC SFAs and VLC n-3 PUFAs were further reduced in patients with HCC. Low concentrations of these FAs were also observed in relatives of patients with HCC and in subjects with the PNPLA3 rs738409 homozygous genotype. CONCLUSIONS: Low plasma concentrations of VLC n-3 PUFAs and VLC SFAs were strongly associated with advanced liver fibrosis and HCC in this population. Genetic factors were associated with low concentrations of these FAs as well. IMPACT: These results have implications in identifying those at risk for liver fibrosis progression to HCC and in screening this population for advanced fibrosis. They also prompt the evaluation of VLC n-3 PUFA or VLC SFA supplementation to prevent cirrhosis and HCC.


Subject(s)
Carcinoma, Hepatocellular/blood , Fatty Acids/blood , Liver Cirrhosis/blood , Liver Neoplasms/blood , Non-alcoholic Fatty Liver Disease/blood , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/etiology , Cohort Studies , Disease Progression , Female , Hispanic or Latino , Humans , Liver Cirrhosis/etiology , Male , Non-alcoholic Fatty Liver Disease/complications , Risk Factors , Texas
11.
Support Care Cancer ; 29(1): 97-105, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32314052

ABSTRACT

BACKGROUND: Optimal hepatitis C virus (HCV) screening strategies for cancer patients have not been established. We compared the performance of selective HCV screening strategies. METHODS: We surveyed patients presenting for first systemic anticancer therapy during 2013-2014 for HCV risk factors. We estimated the prevalence of positivity for HCV antibody (anti-HCV) and examined factors associated with anti-HCV status using Fisher's exact test or Student's t test. Sensitivity was calculated for screening patients born during 1945-1965, patients with ≥ 1 other risk factor, or both cohorts ("combined screening"). RESULTS: We enrolled 2122 participants. Median age was 59 years (range, 18-91); 1138 participants were women. Race/ethnicity distribution was white non-Hispanic, 76% (n = 1616); Hispanic, 11% (n = 233); black non-Hispanic, 8% (n = 160); Asian, 4% (n = 78); and other, 2% (n = 35). Primary cancer distribution was non-liver solid tumor, 78% (n = 1664); hematologic cancer, 20% (n = 422); and liver cancer, 1% (n = 28). Prevalence of anti-HCV was 1.93% (95% CI, 1.39%-2.61%). Over 28% of patients with detectable HCV RNA were unaware of infection. Factors significantly associated with anti-HCV positivity included less than a bachelor's degree, birth in 1945-1965, chronic liver disease, injection drug use, and blood transfusion or organ transplant before 1992. A total of 1315 participants (62%), including 39 of 41 with anti-HCV, reported ≥ 1 risk factor. Sensitivity was 80% (95% CI, 65-91%) for birth-cohort-based, 68% (95% CI, 52-82%) for other-risk-factor-based, and 95% (95% 83-99%) for combined screening. CONCLUSION: Combined screening still missed 5% of patients with anti-HCV. These findings favor universal HCV screening to identify all HCV-infected cancer patients.


Subject(s)
Hepacivirus/immunology , Hepatitis C Antibodies/blood , Hepatitis C/diagnosis , Liver Neoplasms/drug therapy , Mass Screening/methods , Adolescent , Adult , Black or African American/statistics & numerical data , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Hepatitis C/ethnology , Hispanic or Latino/statistics & numerical data , Humans , Male , Middle Aged , Prevalence , RNA, Viral/blood , Risk Factors , White People/statistics & numerical data , Young Adult
12.
Cancer Prev Res (Phila) ; 14(2): 241-252, 2021 02.
Article in English | MEDLINE | ID: mdl-32998941

ABSTRACT

Colorectal cancer is the second most common cancer in Brazil. Yet, a nationally organized colorectal screening program is not implemented. Barretos Cancer Hospital (BCH) is one of the largest Brazilian institution that cares for underserved patients. BCH developed a fecal immunochemical test (FIT)-based organized colorectal cancer screening program to improve colorectal cancer outcomes.This study aims to present the quality/performance measures of the first 2 years of the FIT-based colorectal cancer screening program and its impact on the colorectal cancer disease stage. Between 2015 and 2017, a total of 6,737 individuals attending the Outpatient Department of Prevention or the Mobile Unit of BCH, which visits 18 cities of Barretos county, ages 50 to 65 years, were personally invited by a health agent/nurse practitioner. Exclusion criteria were personal history of colorectal cancer, adenomatous polyps, inflammatory bowel disease, and colonoscopy, or flexible sigmoidoscopy performed in the past 5 years. European Union (EU) guidelines for colorectal cancer screening programs were evaluated. Overall, 92.8% returned the FIT, with an inadequate examination rate of 1.5%. Among the 6,253 adequately tested, 12.5% had a positive result. The colonoscopy compliance and completion rates were 84.6 and 98.2%, respectively. The PPVs were 60.0%, 16.5%, and 5.6% for adenoma, advanced adenoma, and cancer, respectively. Stage distribution of screen-detected cancers shows earlier stages than clinically diagnosed colorectal cancer cancers reported at BCH and Brazilian cancer registries. Our colorectal cancer screening program achieved desirable quality metrics, aligned with the EU guidelines. The observed shift toward earlier colorectal cancer stages suggests an exciting opportunity to improve colorectal cancer-related cancers in Brazil.


Subject(s)
Cancer Care Facilities/statistics & numerical data , Colorectal Neoplasms/diagnosis , Early Detection of Cancer/statistics & numerical data , Health Plan Implementation/statistics & numerical data , Aged , Brazil/epidemiology , Cancer Care Facilities/organization & administration , Cancer Care Facilities/standards , Colonoscopy/standards , Colonoscopy/statistics & numerical data , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/prevention & control , Female , Humans , Incidence , Male , Middle Aged , Neoplasm Staging/statistics & numerical data , Occult Blood , Patient Compliance/statistics & numerical data , Practice Guidelines as Topic , Prospective Studies , Registries/statistics & numerical data
14.
Cancer Res ; 79(24): 6079-6083, 2019 12 15.
Article in English | MEDLINE | ID: mdl-31658978

ABSTRACT

E-cigarettes have the ability to deliver nicotine in a manner that is similar to, and, theoretically, safer than, combusted tobacco. However, these devices are extremely heterogeneous and regulation has struggled to keep up with their rapid evolution. A compilation of early data suggest that e-cigarettes may contain numerous toxic substances, including known carcinogens. However, there are few data available on the short- and long-term health effects of e-cigarettes, including any potential effect on cancer risk. Until more is known, e-cigarettes should not be considered a safe alternative to combusted tobacco use.


Subject(s)
Carcinogens/toxicity , Electronic Nicotine Delivery Systems/standards , Neoplasms/etiology , Nicotine/toxicity , Smoking/adverse effects , Humans , Smoking/legislation & jurisprudence
15.
Oncotarget ; 10(39): 3939-3951, 2019 Jun 11.
Article in English | MEDLINE | ID: mdl-31231471

ABSTRACT

Germline mutations in the tumor suppressor Adenomatous Polyposis Coli (APC) define Familial Adenomatous Polyposis (FAP), the genetic predisposition to developing adenomatous polyps. Recent sequencing of FAP adenomas have challenged established dogma that APC mutations alone represent the adenoma mutational landscape because recurrent somatic mutations in non-WNT pathway genes were also discovered. In particular, one of these novel genes, CNOT3, presented E20K and E70K mutations that are predicted to be deleterious in silico. We utilized zebrafish embryos to determine if these mutations affect CNOT3 function and perform novel biology in an APC-dependent pathway in vivo. Human CNOT3 (hCNOT3) and E20K mRNA injection rescued zebrafish cnot3a knockdown lordosis phenotype while E70K did not. In the FAP apcmcr zebrafish model, we show that ctbp1, but not retinoic acid, regulates cnot3a expression. Injection of hCNOT3 and E20K, but not E70K, to homozygous apcmcr zebrafish initiated gut differentiation while cnot3a knockdown in wildtype embryos led to decreased intestinal development and differentiation. Finally, targeted sequencing of 37 additional FAP adenomas revealed CNOT3 mutations in 20% of these samples. Overall, our work supports a mechanism where CTBP1 regulates CNOT3 and that overall CNOT3 perturbation could work in concert with germline APC mutations in advancing adenomas to a more transformed state prior to progression to adenocarcinoma.

16.
EBioMedicine ; 42: 296-303, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30905849

ABSTRACT

BACKGROUND: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. METHODS: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis. FINDINGS: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. INTERPRETATION: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. FUND: Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant.


Subject(s)
Cell Transformation, Neoplastic/genetics , Lung/metabolism , Lung/pathology , Precancerous Conditions/genetics , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Alleles , Allelic Imbalance , Chromosomal Instability , Disease Progression , Female , Genetic Heterogeneity , Genome-Wide Association Study , Haplotypes , Humans , Hyperplasia , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Models, Statistical , Mutation , Neoplasm Staging , Phylogeny , Polymorphism, Single Nucleotide , Young Adult
17.
Angew Chem Int Ed Engl ; 58(13): 4179-4183, 2019 03 22.
Article in English | MEDLINE | ID: mdl-30680862

ABSTRACT

Hyperpolarized magnetic resonance spectroscopy enables quantitative, non-radioactive, real-time measurement of imaging probe biodistribution and metabolism in vivo. Here, we investigate and report on the development and characterization of hyperpolarized acetylsalicylic acid (aspirin) and its use as a nuclear magnetic resonance (NMR) probe. Aspirin derivatives were synthesized with single- and double-13 C labels and hyperpolarized by dynamic nuclear polarization with 4.7 % and 3 % polarization, respectively. The longitudinal relaxation constants (T1 ) for the labeled acetyl and carboxyl carbonyls were approximately 30 seconds, supporting in vivo imaging and spectroscopy applications. In vitro hydrolysis, transacetylation, and albumin binding of hyperpolarized aspirin were readily monitored in real time by 13 C-NMR spectroscopy. Hyperpolarized, double-labeled aspirin was well tolerated in mice and could be observed by both 13 C-MR imaging and 13 C-NMR spectroscopy in vivo.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Aspirin/pharmacokinetics , Carbon Isotopes/analysis , Serum Albumin, Bovine/metabolism , Acetylation , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Aspirin/chemistry , Hydrolysis , Male , Mice , Tissue Distribution
18.
Cancer Prev Res (Phila) ; 11(12): 735-778, 2018 12.
Article in English | MEDLINE | ID: mdl-30530635

ABSTRACT

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1ß, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative.


Subject(s)
Biomedical Research/trends , Neoplasms/prevention & control , Obesity/epidemiology , Primary Prevention/organization & administration , Biomedical Research/organization & administration , Congresses as Topic , Health Plan Implementation , Health Status Disparities , Humans , Neoplasms/ethnology , Neoplasms/etiology , Obesity/complications , Primary Prevention/methods , Primary Prevention/trends , Public Health/statistics & numerical data , Public Health/trends , Societies, Medical/organization & administration , Societies, Medical/trends , Societies, Scientific/organization & administration , Societies, Scientific/trends , United States/epidemiology
19.
J Glob Oncol ; 4: 1-11, 2018 09.
Article in English | MEDLINE | ID: mdl-30241245

ABSTRACT

According to the Pan American Health Organization, noncommunicable diseases, including cancer, are the leading causes of preventable and premature death in the Americas. Governments and health care systems in Latin America face numerous challenges as a result of increasing morbidity and mortality from cancer. Multiple international organizations have recognized the need for collaborative action on and technical support for cancer research and control in Latin America. The Center for Global Health at the US National Cancer Institute (NCI-CGH) is one entity among many that are working in the region and has sought to develop a strategy for working in Latin America that draws on and expands the collaborative potential of engaged, skilled, and diverse partners. NCI-CGH has worked toward developing and implementing initiatives in collaboration with global partners that share the common objectives of building a global cancer research community and translating research results into evidence-informed policy and practice. Both objectives are complementary and synergistic and are additionally supported by an overarching strategic framework that is focused on partnerships and science diplomacy. This work highlights the overall strategy for NCI-CGH engagement in Latin America through partnerships and diplomacy, and highlights selected collaborative efforts that are aimed at improving cancer outcomes in the region.


Subject(s)
Diplomacy , International Cooperation , Neoplasms/epidemiology , Neoplasms/prevention & control , Research , Animals , Capital Financing , Global Health , Health Planning , Humans , Latin America/epidemiology , Public Health Surveillance , Research/economics , Research/legislation & jurisprudence , Research/organization & administration
20.
Cancer Metastasis Rev ; 37(2-3): 439-454, 2018 09.
Article in English | MEDLINE | ID: mdl-30112590

ABSTRACT

Platelets can serve as "first responders" in cancer and metastasis. This is partly due to bioactive lipid metabolism that drives both platelet and cancer biology. The two primary eicosanoid metabolites that maintain platelet rapid response homeostasis are prostacyclin made by endothelial cells that inhibits platelet function, which is counterbalanced by thromboxane produced by platelets during activation, aggregation, and platelet recruitment. Both of these arachidonic acid metabolites are inherently unstable due to their chemical structure. Tumor cells by contrast predominantly make more chemically stable prostaglandin E2, which is the primary bioactive lipid associated with inflammation and oncogenesis. Pharmacological, clinical, and epidemiologic studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs), which target cyclooxygenases, can help prevent cancer. Much of the molecular and biological impact of these drugs is generally accepted in the field. Cyclooxygenases catalyze the rate-limiting production of substrate used by all synthase molecules, including those that produce prostaglandins along with prostacyclin and thromboxane. Additional eicosanoid metabolites include lipoxygenases, leukotrienes, and resolvins that can also influence platelets, inflammation, and carcinogenesis. Our knowledge base and technology are now progressing toward identifying newer molecular and cellular interactions that are leading to revealing additional targets. This review endeavors to summarize new developments in the field.


Subject(s)
Blood Platelets/metabolism , Lipid Metabolism , Neoplasms/etiology , Neoplasms/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Biomarkers , Blood Platelets/drug effects , Epoprostenol/metabolism , Glucose/metabolism , Humans , Immunomodulation , Inflammation/complications , Inflammation/etiology , Inflammation/metabolism , Lipid Metabolism/drug effects , Lipoxygenase/metabolism , Metabolic Networks and Pathways/drug effects , Mixed Function Oxygenases/metabolism , Neoplasms/pathology , Neoplasms/prevention & control , Prostaglandin-Endoperoxide Synthases/metabolism , Prostaglandins/metabolism , Receptors, Prostaglandin/metabolism , Thromboxane-A Synthase/antagonists & inhibitors , Thromboxane-A Synthase/metabolism
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