Citations

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. Methods: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. Results: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. Conclusions: We identified 38 candidates of protein biomarkers for PDAC risk. Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Abstract Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 μL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated ( P < 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-β1, TGF-β receptor type I, and TGF-β receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and −9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration ( P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-β1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-β1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

AbstractThere is increasing interest in health care organizations functioning as learning health systems (LHSs) to improve the quality and efficiency of health care delivery while generating new knowledge. Individuals must be trained in associated concepts and competencies and subsequently positioned (or embedded) within the delivery system for maximum effect as they perform their scholarship. Potential researchers within LHSs come from many different training backgrounds; therefore, each LHS scholar requires a goal‐directed plan tailored to his or her needs. There are few tools available to guide development, training, or evaluation of individuals interested in becoming leaders of research in LHSs. In this paper, we present a newly developed tool for guiding the training of such researchers, the Learning Health Systems Competency Appraisal Inventory (LHS‐CAI). The LHS‐CAI is modeled after the Clinical Research Appraisal Index (CRAI) used within Clinical and Translational Science Award sites across the United States. The LHS‐CAI is a tool for trainees at all levels to use with their mentors in an interactive manner. The tool can then identify areas in which more training is needed and at what level to ensure success as a researcher within LHSs. We further modified the CRAI format to better leverage the LHS‐CAI as a key part of an LHS scholar's individual development plan. To implement the LHS‐CAI, we have identified key points within the Minnesota Learning Health System Mentored Career Development Program (MN‐LHS) at which assessment of expertise for each competency would be useful to LHS scholars, mentors, and program leaders. Scholars in this program come from various clinical and academic backgrounds but are all targeting their career trajectories toward leading embedded LHS research. They will reevaluate their expertise upon completion of the program, with comparison to baseline serving as a key program evaluation tool. The LHS‐CAI is currently being implemented with the first cohort of scholars in the MN‐LHS program.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

AbstractBackgroundThe 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN).MethodsThe summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience.ResultsThe current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence‐based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω‐3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation.ConclusionsThis article provides a set of expert consensus statements to complement formal PN guideline recommendations.