CausNet-partial : 'Partial Generational Orderings' based search for optimal sparse Bayesian networks via dynamic programming with parent set constraints.

Background: In our recent work, we developed a novel dynamic programming algorithm to find optimal Bayesian networks (BNs) with parent set constraints. This 'generational orderings' based dynamic programming search algorithm - CausNet - efficiently searches the space of possible BNs given the possible parent sets. The algorithm supports both continuous and categorical data, as well as continuous, binary and survival outcomes. In the present work, we develop a variant of CausNet - CausNet-partial - which searches the space of 'partial generational orderings', which further reduces the search space and is suited for finding smaller sparse optimal Bayesian networks; and can be applied to 1000s of variables. Results: We test this method both on synthetic and real data. Our algorithm performs better than three state-of-art algorithms that are currently used extensively to find optimal BNs. We apply it to simulated continuous data and also to a benchmark discrete Bayesian network ALARM, a Bayesian network designed to provide an alarm message system for patient monitoring. We first apply the original CausNet and then CausNet-partial varying the partial order from 5 to 2. CausNet-partial discovers small sparse networks with drastically reduced runtime as expected from theory. Conclusions: Our partial generational orderings based search for small optimal networks, is both an efficient and highly scalable approach for finding optimal sparse and small Bayesian Networks and can be applied to 1000s of variables. Using specifiable parameters - correlation, FDR cutoffs, in-degree, and partial order - one can increase or decrease the number of nodes and density of the networks. Availability of two scoring option - BIC and Bge - and implementation for survival outcomes and mixed data types makes our algorithm very suitable for many types of high dimensional data in a variety of fields.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value.

BACKGROUND: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes. METHODS: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. RESULTS: CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. CONCLUSIONS: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.

Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy.

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17µg/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy (ßPM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; ßNO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS (ßPM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 (ßNO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.

Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.

Background: Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. Method: To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women's Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. Results: On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43, -0.21]) and 0.12cm3 (95%CI=[-0.22, -0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29, -0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14, -0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. Conclusion: In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.

PURPOSE: Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy. MATERIALS AND METHODS: Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes. RESULTS: Restricting to RASWT patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square P = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square P < .001) and with single-agent cetuximab (68%, chi-square P = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab. CONCLUSION: These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.

ACDC: a general approach for detecting phenotype or exposure associated co-expression.

Background: Existing module-based differential co-expression methods identify differences in gene-gene relationships across phenotype or exposure structures by testing for consistent changes in transcription abundance. Current methods only allow for assessment of co-expression variation across a singular, binary or categorical exposure or phenotype, limiting the information that can be obtained from these analyses. Methods: Here, we propose a novel approach for detection of differential co-expression that simultaneously accommodates multiple phenotypes or exposures with binary, ordinal, or continuous data types. Results: We report an application to two cohorts of asthmatic patients with varying levels of asthma control to identify associations between gene co-expression and asthma control test scores. Results suggest that both expression levels and covariances of ADORA3, ALOX15, and IDO1 are associated with asthma control. Conclusion: ACDC is a flexible extension to existing methodology that can detect differential co-expression across varying external variables.

Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials.

Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Methods: Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n = 107; control cohort: FOLFIRI/cetuximab arm, n = 129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n = 163) trials, was genotyped using the OncoArray-500 K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. Findings: In the discovery cohort, patients with FASN rs4485435 any C allele (n = 21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n = 62) in multivariable (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR = 2.07, 95%CI: 1.15-3.74; p = 0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p = 0.017) on PFS. Interpretation: Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. Funding: This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

CausNet: generational orderings based search for optimal Bayesian networks via dynamic programming with parent set constraints.

BACKGROUND: Finding a globally optimal Bayesian Network using exhaustive search is a problem with super-exponential complexity, which severely restricts the number of variables that can feasibly be included. We implement a dynamic programming based algorithm with built-in dimensionality reduction and parent set identification. This reduces the search space substantially and can be applied to large-dimensional data. We use what we call 'generational orderings' based search for optimal networks, which is a novel way to efficiently search the space of possible networks given the possible parent sets. The algorithm supports both continuous and categorical data, as well as continuous, binary and survival outcomes. RESULTS: We demonstrate the efficacy of our algorithm on both synthetic and real data. In simulations, our algorithm performs better than three state-of-art algorithms that are currently used extensively. We then apply it to an Ovarian Cancer gene expression dataset with 513 genes and a survival outcome. Our algorithm is able to find an optimal network describing the disease pathway consisting of 6 genes leading to the outcome node in just 3.4 min on a personal computer with a 2.3 GHz Intel Core i9 processor with 16 GB RAM. CONCLUSIONS: Our generational orderings based search for optimal networks is both an efficient and highly scalable approach for finding optimal Bayesian Networks and can be applied to 1000 s of variables. Using specifiable parameters-correlation, FDR cutoffs, and in-degree-one can increase or decrease the number of nodes and density of the networks. Availability of two scoring option-BIC and Bge-and implementation for survival outcomes and mixed data types makes our algorithm very suitable for many types of high dimensional data in a variety of fields.

Breast cancer and neurotransmitters: emerging insights on mechanisms and therapeutic directions.

Exploring the relationship between various neurotransmitters and breast cancer cell growth has revealed their likely centrality to improving breast cancer treatment. Neurotransmitters play a key role in breast cancer biology through their effects on the cell cycle, epithelial mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment and other pathways. Neurotransmitters and their receptors are vital to the initiation, progression and drug resistance of cancer and progress in our biological understanding may point the way to lower-cost and lower-risk antitumor therapeutic strategies. This review discusses multiple neurotransmitters in the context of breast cancer. It also discusses risk factors, repurposing of pharmaceuticals impacting neurotransmitter pathways, and the opportunity for better integrated models that encompass exercise, the intestinal microbiome, and other non-pharmacologic considerations. Neurotransmitters' role in breast cancer should no longer be ignored; it may appear to complicate the molecular picture but the ubiquity of neurotransmitters and their wide-ranging impacts provide an organizing framework upon which further understanding and progress against breast cancer can be based.

Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study.

BACKGROUND: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours. METHODS: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ2 or Fisher's exact tests. Antitumour immune response within the tumour environment was predicted by analysing the infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The Kaplan-Meier method and the log-rank test were used to evaluate the impact of gene alterations on the efficacy of immune checkpoint inhibitors in MSS gastrointestinal cancers from the CARIS database, a Memorial Sloan Kettering Cancer Center cohort, and a Peking University Cancer Hospital cohort. FINDINGS: MSS-TMB-H was observed in 1600 (3·29%) of 48 606 tumours, dMMR/MSI-H in 2272 (4·67%), and MSS-TMB-L in 44 734 (92·03%). Gene mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair antitumour immune response despite TMB-H, while mutations in 16 other genes (CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1) were related to TMB-H with enhanced antitumour immune response independent of dMMR/MSI-H, constructing a predictive model (modified TMB [mTMB]) for immune checkpoint inhibitor efficacy. Patients with any mutation in the mTMB gene signature, in comparison with patients with mTMB wildtype tumours, showed a superior survival benefit from immune checkpoint inhibitors in MSS gastrointestinal cancers in the CARIS cohort (n=95, median overall survival 18·77 months [95% CI 17·30-20·23] vs 7·03 months [5·73-8·34]; hazard ratio 0·55 [95% CI 0·31-0·99], p=0·044). In addition, copy number amplification in chromosome 11q13 (eg, CCND1, FGF genes) was more prevalent in MSS-TMB-H tumours than in the dMMR/MSI-H or MSS-TMB-L subgroups. INTERPRETATION: Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs. FUNDING: US National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Gene Gregg Pancreas Research Fund, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Victoria and Philip Wilson Research Fund, Fong Research Project, Ming Hsieh Research Fund, Shanghai Sailing Program, China National Postdoctoral Program for Innovative Talents, China Postdoctoral Science Foundation, National Natural Science Foundation of China.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.

The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.

fdrci: FDR confidence interval selection and adjustment for large-scale hypothesis testing.

Motivation: Approaches that control error by applying a priori fixed discovery thresholds such as 0.05 limit the ability of investigators to identify and publish weak effects even when evidence suggests that such effects exist. However, current false discovery rate (FDR) estimation methods lack a principled approach for post hoc identification of discovery thresholds other than 0.05. Results: We describe a flexible approach that hinges on the precision of a permutation-based FDR estimator. A series of discovery thresholds are proposed, and an FDR confidence interval selection and adjustment technique is used to identify intervals that do not cover one, implying that some discoveries are expected to be true. We report an application to a transcriptome-wide association study of the MAVERICC clinical trial involving patients with metastatic colorectal cancer. Several genes are identified whose predicted expression is associated with progression-free or overall survival. Availability and implementation: Software is provided via the CRAN repository (https://cran.r-project.org/web/packages/fdrci/index.html). Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial.

BACKGROUND: Reactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We analyzed genomic and clinical data from FIRE-3, a phase III trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes. RESULTS: In total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129; FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06-5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03). CONCLUSION: TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies.

Genetic variants involved in the cGAS-STING pathway predict outcome in patients with metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.

BACKGROUND: The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer. METHODS: Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival. RESULTS: In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06-4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35-6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23-2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97-4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22-3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92-5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE. CONCLUSION: These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer.

Ambient air pollution exposure and increasing depressive symptoms in older women: The mediating role of the prefrontal cortex and insula.

Exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) have been associated with the emergence of depressive symptoms in older adulthood, although most studies used cross-sectional outcome measures. Elucidating the brain structures mediating the adverse effects can strengthen the causal role between air pollution and increasing depressive symptoms. We evaluated whether smaller volumes of brain structures implicated in late-life depression mediate associations between ambient air pollution exposure and changes in depressive symptoms. This prospective study included 764 community-dwelling older women (aged 81.6 ± 3.6 in 2008-2010) from the Women's Health Initiative Memory Study (WHIMS) Magnetic Resonance Imaging study (WHIMS-MRI; 2005-06) and WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO; 2008-16). Three-year average annual mean concentrations (scaled by interquartile range [IQR]) of ambient PM2.5 (in µg/m3; IQR = 3.14 µg/m3) and NO2 (in ppb; IQR = 7.80 ppb) before WHIMS-MRI were estimated at participants' addresses via spatiotemporal models. Mediators included structural brain MRI-derived grey matter volumes of the prefrontal cortex and structures of the limbic-cortical-striatal-pallidal-thalamic circuit. Depressive symptoms were assessed annually by the 15-item Geriatric Depression Scale. Structural equation models were constructed to estimate associations between exposure, structural brain volumes, and depressive symptoms. Increased exposures (by each IQR) were associated with greater annual increases in depressive symptoms (ßPM2.5 = 0.022; 95% Confidence Interval (CI) = 0.003, 0.042; ßNO2 = 0.019; 95% CI = 0.001, 0.037). The smaller volume of prefrontal cortex associated with exposures partially mediated the associations of increased depressive symptoms with NO2 (8%) and PM2.5 (13%), and smaller insula volume associated with NO2 contributed modestly (13%) to the subsequent increase in depressive symptoms. We demonstrate the first evidence that the smaller volumes of the prefrontal cortex and insula may mediate the subsequent increases in depressive symptoms associated with late-life exposures to NO2 and PM2.5.

Air quality improvement and cognitive decline in community-dwelling older women in the United States: A longitudinal cohort study.

BACKGROUND: Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. METHODS AND FINDINGS: We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (ß = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (ß = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (ßPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 µg/m3 reduction, 95% CI: 0.001, 0.05; ßNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (ßPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 µg/m3 reduction, 95% CI: 0.02, 0.12; ßNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. CONCLUSIONS: In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Association of improved air quality with lower dementia risk in older women.

Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 µg/m3, 95% CI 0.71-0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71-0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 µg/m3, 95% CI 0.98-1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women.

Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

BACKGROUND: The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS: In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS: TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.