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The level of tumor and circulating CXCR1/2-expressing neutrophils and CXCR1/2 ligands correlate with poor patient outcomes, inversely correlate with tumoral lymphocyte content, and predict immune checkpoint inhibitor (ICI) treatment failure. Accordingly, CXCR2-selective and CXCR1/2 dual inhibitors exhibit activity both as single agents and in combination with ICI treatment in mouse tumor models. Based on such reports, clinical trials combining CXCR1/2 axis antagonists with ICI treatment for cancer patients are underway. It has been assumed that CXCR1/2 blockade impacts tumors by blocking neutrophil chemotaxis and reducing neutrophil content in tumors. Here, we show that while CXCR2 antagonism does slow tumor growth, it does not preclude neutrophil recruitment into tumor. Instead, CXCR1/2 inhibition alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes and rendering neutrophils incapable of suppressing lymphocyte proliferation. This is associated with decreased release of reactive oxygen species and Arginase-1 into the extracellular milieu. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications.
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Neutrófilos , Receptores de Interleucina-8A , Receptores de Interleucina-8B , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/metabolismo , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8A/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Animales , Ratones , Humanos , Infiltración Neutrófila/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Línea Celular Tumoral , Ratones Endogámicos C57BL , FemeninoRESUMEN
OBJECTIVE: We address the problem of finding brain connectivities that are associated with a clinical outcome or phenotype. METHODS: The proposed framework regresses a (scalar) clinical outcome on matrix-variate predictors which arise in the form of brain connectivity matrices. For example, in a large cohort of subjects we estimate those regions of functional connectivities that are associated with neurocognitive scores. We approach this high-dimensional yet highly structured estimation problem by formulating a regularized estimation process that results in a low-rank coefficient matrix having a sparse set of nonzero entries which represent regions of biologically relevant connectivities. In contrast to the recent literature on estimating a sparse, low-rank matrix from a single noisy observation, our scalar-on-matrix regression framework produces a data-driven extraction of structures that are associated with a clinical response. The method, called Sparsity Inducing Nuclear-Norm Estimator (SpINNEr), simultaneously constrains the regression coefficient matrix in two ways: a nuclear norm penalty encourages low-rank structure while an l1 norm encourages entry-wise sparsity. RESULTS: Our simulations show that SpINNEr outperforms other methods in estimation accuracy when the response-related entries (representing the brain's functional connectivity) are arranged in well-connected communities. SpINNEr is applied to investigate associations between HIV-related outcomes and functional connectivity in the human brain. CONCLUSION AND SIGNIFICANCE: Overall, this work demonstrates the potential of SpINNEr to recover sparse and low-rank estimates under scalar-on-matrix regression framework.
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Algoritmos , Encéfalo , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiologíaRESUMEN
The clinical management of patients with indeterminate pulmonary nodules is associated with unintended harm to patients and better methods are required to more precisely quantify lung cancer risk in this group. Here, we combine multiple noninvasive approaches to more accurately identify lung cancer in indeterminate pulmonary nodules. We analyzed 94 quantitative radiomic imaging features and 41 qualitative semantic imaging variables with molecular biomarkers from blood derived from an antibody-based microarray platform that determines protein, cancer-specific glycan, and autoantibody-antigen complex content with high sensitivity. From these datasets, we created a PSR (plasma, semantic, radiomic) risk prediction model comprising nine blood-based and imaging biomarkers with an area under the receiver operating curve (AUROC) of 0.964 that when tested in a second, independent cohort yielded an AUROC of 0.846. Incorporating known clinical risk factors (age, gender, and smoking pack years) for lung cancer into the PSR model improved the AUROC to 0.897 in the second cohort and was more accurate than a well-characterized clinical risk prediction model (AUROC = 0.802). Our findings support the use of a multi-omics approach to guide the clinical management of indeterminate pulmonary nodules.
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Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4+ T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.
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Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ratones , Animales , Vancomicina , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Homólogo/efectos adversosRESUMEN
Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/patología , Autoanticuerpos , Procesamiento Proteico-PostraduccionalRESUMEN
Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator-penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R2 = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios Prospectivos , Medicina de Precisión , Farmacogenética , Metabolómica , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodosRESUMEN
Consumption of probiotics and/or yogurt could be a solution for restoring the balance of the gut microbiota. This study examined associations of regular intake of probiotic supplements or yogurt with the gut microbiota among a diverse population of older adults (N=1,861; 60-72 years). Fecal microbial composition was obtained from 16S rRNA gene sequencing (V1-V3 region). General Linear Models were used to estimate the associations of probiotic supplement or yogurt intake with microbiome measures adjusting for covariates. Compared to non-yogurt consumers (N=1,023), regular yogurt consumers (≥once/week, N=818) had greater Streptococcus (ß=0.29, P=0.0003) and lower Odoribacter (ß=-0.33, P<0.0001) abundance. The directions of the above associations were consistent across the five ethnic groups but stronger among Japanese Americans (Streptococcus: ß=0.56, P=0.0009; Odoribacter: ß=-0.62, P=0.0005). Regular intake of probiotic supplements (N=175) was not associated with microbial characteristics (i.e., alpha diversity and the abundance of 152 bacteria genera). Streptococcus is one of the predominant bacteria genera in yogurt products, which may explain the positive association between yogurt consumption and Streptococcus abundance. Our analyses suggest that changes in Odoribacter were independent of changes in Streptococcus abundance. Future studies may investigate whether these microbial genera and their sub-level species mediate potential pathways between yogurt consumption and health.
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Myeloid lineage cells suppress T cell viability through arginine depletion via arginase 1 (ARG1). Despite numerous studies exploring the mechanisms by which ARG1 perturbs lymphocyte function, the cellular populations responsible for its generation and release remain poorly understood. Here, we showed that neutrophil lineage cells and not monocytes or macrophages expressed ARG1 in human non-small cell lung cancer (NSCLC). Importantly, we showed that approximately 40% of tumor-associated neutrophils (TANs) actively transcribed ARG1 mRNA. To determine the mechanism by which ARG1 mRNA is induced in TANs, we utilized FPLC followed by MS/MS to screen tumor-derived factors capable of inducing ARG1 mRNA expression in neutrophils. These studies identified ANXA2 as the major driver of ARG1 mRNA expression in TANs. Mechanistically, ANXA2 signaled through the TLR2/MYD88 axis in neutrophils to induce ARG1 mRNA expression. The current study describes what we believe to be a novel mechanism by which ARG1 mRNA expression is regulated in neutrophils in cancer and highlights the central role that neutrophil lineage cells play in the suppression of tumor-infiltrating lymphocytes.
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Anexina A2 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Anexina A2/genética , Arginasa/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/metabolismo , ARN Mensajero , Espectrometría de Masas en Tándem , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismoRESUMEN
Studying the association of the brain's structure and function with neurocognitive outcomes requires a comprehensive analysis that combines different sources of information from a number of brain-imaging modalities. Recently developed regularization methods provide a novel approach using information about brain structure to improve the estimation of coefficients in the linear regression models. Our proposed method, which is a special case of the Tikhonov regularization, incorporates structural connectivity derived with Diffusion Weighted Imaging and cortical distance information in the penalty term. Corresponding to previously developed methods that inform the estimation of the regression coefficients, we incorporate additional information via a Laplacian matrix based on the proximity measure on the cortical surface. Our contribution consists of constructing a principled formulation of the penalty term and testing the performance of the proposed approach via extensive simulation studies and a brain-imaging application. The penalty term is constructed as a weighted combination of structural connectivity and proximity between cortical areas. Simulation studies mimic the real brain-imaging settings. We apply our approach to the study of data collected in the Human Connectome Project, where the cortical properties of the left hemisphere are found to be associated with vocabulary comprehension.
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Batch effects in microbiome data arise from differential processing of specimens and can lead to spurious findings and obscure true signals. Strategies designed for genomic data to mitigate batch effects usually fail to address the zero-inflated and over-dispersed microbiome data. Most strategies tailored for microbiome data are restricted to association testing or specialized study designs, failing to allow other analytic goals or general designs. Here, we develop the Conditional Quantile Regression (ConQuR) approach to remove microbiome batch effects using a two-part quantile regression model. ConQuR is a comprehensive method that accommodates the complex distributions of microbial read counts by non-parametric modeling, and it generates batch-removed zero-inflated read counts that can be used in and benefit usual subsequent analyses. We apply ConQuR to simulated and real microbiome datasets and demonstrate its advantages in removing batch effects while preserving the signals of interest.
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Microbiota , Microbiota/genética , Proyectos de InvestigaciónRESUMEN
Biomarker-guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration-time curve (AUC) of CY and its metabolites are time- and resource-intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time-varying differences in CY formation clearance to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY) and 24 h after the first dose of PT-CY (24-h post-CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT.
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Trasplante de Células Madre Hematopoyéticas , Humanos , Lipidómica , Hidroxilación , Ciclofosfamida/efectos adversos , LípidosRESUMEN
High-fiber plant foods contain lignans that are converted to bioactive enterolignans, enterolactone (ENL) and enterodiol (END) by gut bacteria. Previously, we conducted an intervention study to gain mechanistic insight into the potential chemoprotective effects of flaxseed lignan supplementation (secoisolariciresinol diglucoside; SDG) compared to a placebo in 42 men and women. Here, we expand on these analyses to further probe the impact of the microbial metabolite phenotype on host gene expression in response to lignan exposure. We defined metabolic phenotypes as high- or low-ENL excretion based on the microbial metabolism of SDG. RNA-seq was used to assess host gene expression in fecal exfoliated cells. Stratified by microbial ENL excretion, differentially expressed (DE) genes in high- and low-ENL excreter groups were compared. Linear discriminant analysis using the ENL phenotypes identified putative biomarker combinations of genes capable of discriminating the lignan treatment from the placebo. Following lignan intervention, a total of 165 DE genes in high-ENL excreters and 1450 DE genes in low-ENL excreters were detected. Functional analysis identified four common upstream regulators (master genes): CD3, IFNG, IGF1 and TNFRSF1A. Our findings suggest that the enhanced conversion of flaxseed lignan to ENL is associated with a suppressed inflammatory status.
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Lino , Lignanos , 4-Butirolactona , Estudios Cruzados , Suplementos Dietéticos , Femenino , Lino/metabolismo , Humanos , Lignanos/metabolismo , Lignanos/farmacología , Masculino , FenotipoRESUMEN
Background: The human gut microbiome (GM) has been observed to vary by race/ethnicity. Objective: Assess whether racial/ethnic GM variation is mediated by differences in diet. Design: Stool samples collected from 2013 to 2016 from 5267 healthy Multiethnic Cohort participants (age 59−98) were analyzed using 16S rRNA gene sequencing to estimate the relative abundance of 152 bacterial genera. For 63 prevalent genera (>50% in each ethnic group), we analyzed the mediation of GM differences among African Americans, Japanese Americans, Latinos, Native Hawaiians, and Whites by overall diet quality (Healthy Eating Index score (HEI-2015)) and intake amounts of 14 component foods/nutrients assessed from 2003 to 2008. For each significant mediation (p < 1.3 × 10−5), we determined the percent of the total ethnicity effect on genus abundance mediated by the dietary factor. Results: Ethnic differences in the abundance of 12 genera were significantly mediated by one or more of eight dietary factors, most frequently by overall diet quality and intakes of vegetables and red meat. Lower vegetable intake mediated differences in Lachnospira (36% in African Americans, 39% in Latinos) and Ruminococcus-1 (−35% in African Americans, −43% in Latinos) compared to Native Hawaiians who consumed the highest amount. Higher red meat intake mediated differences in Lachnospira (−41%) and Ruminococcus-1 (36%) in Native Hawaiians over African Americans, who consumed the least. Dairy and alcohol intakes appeared to mediate and counterbalance the difference in Bifidobacterium between Whites and Japanese Americans. Conclusions: Overall diet quality and component food intakes may contribute to ethnic differences in GM composition and to GM-related racial/ethnic health disparities.
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Microbioma Gastrointestinal , Anciano , Anciano de 80 o más Años , Asiático , Ingestión de Alimentos , Humanos , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Población BlancaRESUMEN
The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug-metabolizing enzymes that metabolize CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY), and 24 h after the first dose of PT-CY (24-h post-CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre-CY time point, no EMCs were associated at FDR less than 0.1. At pre-HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre-graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24-h post-CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.
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Trasplante de Células Madre Hematopoyéticas , Área Bajo la Curva , Ciclofosfamida/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Hidroxilación , Receptores de TrasplantesRESUMEN
BACKGROUND: Results from observational studies suggest high diet quality favorably influences the human gut microbiome. Fruit and vegetable consumption is often a key contributor to high diet quality. OBJECTIVE: To evaluate measures of gut bacterial diversity and abundance in relation to serum biomarkers of fruit and vegetable intake. DESIGN: Secondary analysis of cross-sectional data. PARTICIPANTS AND SETTING: Men and women from Los Angeles, CA, and Hawai'i who participated in the Multiethnic Cohort-Adiposity Phenotype Study from 2013 to 2016 (N = 1,709). MAIN OUTCOME MEASURES: Gut microbiome diversity and composition in relation to dietary biomarkers. STATISTICAL ANALYSIS: Carotenoid (beta carotene, alpha carotene, cryptoxanthins, lutein, lycopene, and zeaxanthin), tocopherol (α, ß + γ, and δ), and retinol concentrations were assessed in serum. The α and ß diversity and composition of the gut microbiome were classified based on 16S rRNA gene sequencing of bacterial DNA from self-collected fecal samples. Global differences in microbial community profiles in relation dietary biomarkers were evaluated using multivariable permutational analysis of variance. Associations of α diversity (Shannon index), ß diversity (weighted and unweighted UniFrac) with center log-ratio-transformed phyla and genera abundances were evaluated using linear regression, adjusted for covariates. RESULTS: Increasing total carotenoid, beta carotene, alpha carotene, cryptoxanthin, and lycopene concentrations were associated with higher gut bacterial diversity (Shannon Index) (P < 0.001). Total tocopherol, α-tocopherol, and δ-tocopherol concentrations contributed significantly to more than 1% of the microbiome variation in gut bacterial community: total tocopherol: 1.74%; α-tocopherol: 1.70%; and δ-tocopherol: 1.16% (P < 0.001). Higher total carotenoid was associated with greater abundance of some genera relevant for microbial macronutrient metabolism (P < 0.001). CONCLUSIONS: Objective biomarkers of fruit and vegetable intake, particularly carotenoids, were favorably associated with gut bacterial composition and diversity in this multiethnic population. These observations provide supportive evidence that fruit and vegetable intake is related to gut bacterial composition; more work is needed to elucidate how this influences host health.
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Carotenoides/sangre , Dieta/normas , Frutas , Microbioma Gastrointestinal , Tocoferoles/sangre , Verduras , Vitamina A/sangre , Anciano , Biomarcadores/sangre , Estudios Transversales , Etnicidad , Femenino , Hawaii , Humanos , Los Angeles , Masculino , Persona de Mediana EdadRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.
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Adiposidad/fisiología , Bacterias/clasificación , Microbioma Gastrointestinal/fisiología , Enfermedad del Hígado Graso no Alcohólico/etnología , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Anciano , Bacterias/aislamiento & purificación , Estudios Transversales , Endotoxinas/metabolismo , Humanos , Inflamación/patología , Hígado/patología , Masculino , Persona de Mediana Edad , Obesidad/patología , ARN Ribosómico 16S/genética , Factores de RiesgoRESUMEN
As past usual diet quality may affect gut microbiome (GM) composition, we examined the association of the Healthy Eating Index (HEI)-2015 assessed 21 and 9 years before stool collection with measures of fecal microbial composition in a subset of the Multiethnic Cohort. A total of 5936 participants completed a validated quantitative FFQ (QFFQ) at cohort entry (Q1, 1993-1996), 5280 at follow-up (Q3, 2003-2008) and 1685 also at a second follow-up (Adiposity Phenotype Study (APS), 2013-2016). All participants provided a stool sample in 2013-2016. Fecal microbial composition was obtained from 16S rRNA gene sequencing (V1-V3 regions). HEI-2015 scores were computed based on each QFFQ. Using linear regression adjusted for relevant covariates, we calculated associations of HEI-2015 scores with gut microbial diversity and 152 individual genera. The mean HEI-2015 scores increased from Q1 (67 (sd 10)) to Q3 (71 (sd 11)) and APS (72 (sd 10)). Alpha diversity assessed by the Shannon Index was significantly higher with increasing tertiles of HEI-2015. Of the 152 bacterial genera tested, seven (Anaerostipes, Coprococcus_2, Eubacterium eligens, Lachnospira, Lachnospiraceae_ND3007, Ruminococcaceae_UCG-013 and Ruminococcus_1) were positively and five (Collinsella, Parabacteroides, Ruminiclostridium_5, Ruminococcus gnavus and Tyzzerella) were inversely associated with HEI-2015 assessed in Q1, Q3 and APS. The estimates of change per unit of the HEI-2015 score associated with the abundance of these twelve genera were consistent across the three questionnaires. The quality of past diet, assessed as far as â¼20 years before stool collection, is equally predictive of GM composition as concurrently assessed diet, indicative of the long-term consistency of this relation.
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BACKGROUND: The gut microbiome may play a role in inflammation associated with type 2 diabetes (T2D) development. This cross-sectional study examined its relation with glycemic status within a subset of the Multiethnic Cohort (MEC) and estimated the association of circulating bacterial endotoxin (measured as plasma lipopolysaccharide-binding protein (LBP)) with T2D, which may be mediated by C-reactive protein (CRP). METHODS: In 2013-16, cohort members from five ethnic groups completed clinic visits, questionnaires, and stool and blood collections. Participants with self-reported T2D and/or taking medication were considered T2D cases. Those with fasting glucose >125 and 100-125 mg/dL were classified as undiagnosed (UT2D) and pre-diabetes (PT2D) cases, respectively. We characterized the gut microbiome through 16S rRNA gene sequencing and measured plasma LBP and CRP by standard assays. Linear regression was applied to estimate associations of the gut microbiome community structure and LBP with T2D status adjusting for relevant confounders. RESULTS: Among 1,702 participants (59.9-77.4 years), 735 (43%) were normoglycemic (NG), 506 (30%) PT2D, 154 (9%) UT2D, and 307 (18%) T2D. The Shannon diversity index decreased (ptrend = 0.05), while endotoxin, measured as LBP, increased (ptrend = 0.0003) from NG to T2D. Of 10 phyla, Actinobacteria (ptrend = 0.007), Firmicutes (ptrend = 0.003), and Synergistetes (ptrend = 0.02) were inversely associated and Lentisphaerae (ptrend = 0.01) was positively associated with T2D status. Clostridium sensu stricto 1, Lachnospira, and Peptostreptococcaceae were less, while Escherichia-Shigella and Lachnospiraceae were more abundant among T2D patients, but the associations with Actinobacteria, Clostridium sensu stricto 1, and Escherichia-Shigella may be due metformin use. PT2D/UT2D values were closer to NG than T2D. No indication was detected that CRP mediated the association of LBP with T2D. CONCLUSIONS: T2D but not PT2D/UT2D status was associated with lower abundance of SCFA-producing genera and a higher abundance of gram-negative endotoxin-producing bacteria suggesting that the gut microbiome may contribute to chronic systemic inflammation and T2D through bacterial translocation.
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Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/patología , Microbioma Gastrointestinal/fisiología , Anciano , Bacterias/genética , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Humanos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/microbiología , Estado Prediabético/patología , ARN Ribosómico 16S/genéticaRESUMEN
One of the challenging problems in neuroimaging is the principled incorporation of information from different imaging modalities. Data from each modality are frequently analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method, generalized ridgified Partially Empirical Eigenvectors for Regression (griPEER), to estimate associations between the brain structure features and a scalar outcome within the generalized linear regression framework. griPEER improves the regression coefficient estimation by providing a principled approach to use external information from the structural brain connectivity. Specifically, we incorporate a penalty term, derived from the structural connectivity Laplacian matrix, in the penalized generalized linear regression. In this work, we address both theoretical and computational issues and demonstrate the robustness of our method despite incomplete information about the structural brain connectivity. In addition, we also provide a significance testing procedure for performing inference on the estimated coefficients. Finally, griPEER is evaluated both in extensive simulation studies and using clinical data to classify HIV+ and HIV- individuals.
L'un des défis en imagerie cérébrale consiste à établir les principes pour incorporer de l'information provenant de différentes modalités d'imagerie. Les données de chaque modalité sont fréquemment analysées séparément, exploitant par exemple des techniques de réduction de la dimension, ce qui conduit à une perte d'information mutuelle. Les auteurs proposent une nouvelle méthode de régularisation, griPEER (ou par vecteurs propres ridgifiés partiellement empiriques généralisés pour la régression) afin d'estimer l'association entre des caratéristiques de structures du cerveau et une variable réponse scalaire dans le cadre d'une régression linéaire généralisée. Les griPEER améliorent l'estimation des coefficients de régression en établissant les principes d'une approche permettant d'utiliser des informations externes de connectivité des structures du cerveau. À cet effet, les auteurs ajoutent au modèle de régression pénalisée généralisé un terme de pénalité dérivé de la matrice laplacienne de connectivité structurelle. Les auteurs résolvent des problèmes théoriques et calculatoires, puis démontrent la robustesse de leur méthode lorsque l'information à propos de la connectivité du cerveau est incomplète. De plus, ils présentent une procédure de test d'hypothèse permettant de l'inférence au sujet des paramètres estimés. Finalement, les auteurs évaluent les griPEER dans de vastes études de simulation et en utilisant des données cliniques afin de classifier les individus en VIH+ et VIH−.
RESUMEN
Busulfan-based conditioning is the most commonly used high-dose conditioning regimen for allogeneic hematopoietic cell transplant (HCT). The alkylating agent busulfan has a narrow therapeutic index, with busulfan doses personalized to a target plasma exposure (targeted busulfan). Using a global pharmacometabonomics approach, we sought to identify novel biomarkers of relapse or acute graft versus host disease (GVHD) in a cohort of 84 patients receiving targeted busulfan before allogeneic HCT. A total of 763 endogenous metabolomic compounds (EMCs) were quantitated in 230 longitudinal blood samples before, during, and shortly after intravenous busulfan administration. We performed both univariate linear regression and pathway enrichment analyses using global testing. The cysteine/methionine pathway and the glycine, serine, and threonine metabolism pathway were most associated with relapse. The latter be explained by the fact that glutathione S-transferases conjugate both busulfan and glutathione, which contains glycine as a component. The d-arginine and d-ornithine metabolism pathway and arginine and proline metabolism pathway were most associated with acute GVHD. None of these associations were significant after correcting for false discovery rate (FDR) with a strict cutoff of FDR-adjusted p < 0.1. Although larger studies are needed to substantiate these findings, the results show that EMCs may be used as predictive biomarkers in HCT patients.