The impact of statin use before intensive care unit admission on patients with acute kidney injury after cardiac surgery.

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious complication after cardiac surgery. The influence of statin use before surgery on the renal outcome of patients undergoing cardiac surgery is controversial. The purpose of this study was to evaluate the effect of statins on postoperative renal outcomes in patients undergoing cardiac surgery. Methods: We included CSA-AKI patients in the Medical Information Mart for Intensive Care (MIMIC)-IV database and were divided into statin group and non-statin group according to whether they used statins before entering intensive care units (ICU). The main outcomes were hospitalization and 30-day mortality, and the secondary outcomes were 60-day mortality and 90-day mortality. We used propensity score matching (PSM) to adjust for confounding factors. The 95% confidence interval (CI) and risk ratio (RO) were calculated by the COX proportional regression model. At the same time, stratified analysis was used to explore whether the relationship between the statins use before intensive care units and mortality was different in each subgroup and whether the relationship between different doses of Atorvastatin and mortality was different. Result: We identified 675 pre-ICU statin users and 2095 non-statin users. In the COX proportional regression model, pre-ICU statin use was associated with decreased in-hospital (HR = 0.407, 95%confidence interval 0.278-0.595, p < 0.001) and 30-day mortality (HR = 0.407, 95%CI 0.279-0.595, p < 0.001). The survival rate of patients who took statins before entering ICU was significantly higher than that of those who did not use statins at 30 days, 60 days and 90 days. There is a significant interaction between patients with aged>65 years (HR = 0.373, 95%CI 0.240-0.581, p < 0.001), Acute kidney injury grade I (HR = 0.244, 95%CI 0.118-0.428, p < 0.001), and without post-myocardial infarction syndrome (HR = 0.344, 95%CI 0.218-0.542, p < 0.001). The mortality in hospital and 60 days of CSA-AKI patients treated with ≥80 mg Atorvastatin before operation was significantly reduced (p < 0.05). Conclusion: The pre-ICU statin use was significantly associated with decreased risk in hospital and 30-day mortality. The preoperative use of ≥80 mg Atorvastatin may improve the prognosis of CSA-AKI.

Analysis of proteome and post-translational modifications of 2-hydroxyisobutyrylation reveals the glycolysis pathway in oral adenoid cystic carcinoma.

PURPOSE: Oral adenoid cystic carcinoma (OACC) has high rates of both local-regional recurrence and distant metastasis. The objective of this study is to investigate the impact of Khib on OACC and its potential as a targeted therapeutic intervention. EXPERIMENTAL DESIGN: We investigated the DEPs (differentially expressed proteins) and DHMPs between OACC-T and OACC-N using LC-MS/MS-based quantitative proteomics and using several bioinformatics methods, including GO enrichment analysis, KEGG pathway analysis, subcellular localization prediction, MEA (motif enrichment analysis), and PPI (protein-protein interaction networks) to illustrate how Khib modification interfere with OACC evolution. RESULTS: Compared OACC-tumor samples (OACC-T) with the adjacent normal samples (OACC-N), there were 3243 of the DEPs and 2011 Khib sites were identified on 764 proteins (DHMPs). DEPs and DHMPs were strongly associated to glycolysis pathway. GAPDH of K254, ENO of K228, and PGK1 of K323 were modified by Khib in OACC-T. Khib may increase the catalytic efficiency to promote glycolysis pathway and favor OACC progression. CONCLUSIONS AND CLINICAL RELEVANCE: Khib may play a significant role in the mechanism of OACC progression by influencing the enzyme activity of the glycolysis pathway. These findings may provide new therapeutic options of OACC.

Integrated CO2 capture and reverse water-gas shift reaction over CeO2-CaO dual functional materials.

Achieving carbon neutrality is one of the most important tasks to meet the environmental challenges due to excessive CO2 emissions. Integrated CO2 capture and utilization (ICCU) represents an effective process for direct utilization of CO2-contained exhaust gas (e.g. flue gas), in which converting the captured CO2 into CO via reverse water-gas shift (RWGS) reaction is a promising route. The dual functional materials (DFMs), containing CO2 adsorbents and catalysts, are widely applied to achieve ICCU. The conventional active metals (Ni, Fe, etc.)-based DFMs and non-transition metal DFMs (e.g. CaO) are restricted by low CO selectivity, catalytic efficiency or CO generation in the CO2 capture step. To address the above obstructs in the application of DFMs, the metal oxides-based DFMs, MOx-CaO (M = Al, Ce, Ti or Zr), are synthesized and evaluated. The CeO2-CaO outperformed the other metal oxides-based DFMs and possessed significantly improved catalytic performance. It is found that 33% CeO2-CaO DFM displayed approximately 49% CO2 conversion and approximately 100% CO selectivity in integrated CO2 capture and reverse water-gas shift reaction (ICCU-RWGS) at 650°C, while CaO-alone only achieved approximately 20% CO2 conversion at the same condition. The surface basicity of CeO2 is revealed to contribute to the improved catalytic performance by enhancing CO2 chemisorption and activation in the hydrogenation step. Furthermore, CeO2-CaO material possessed excellent cycle stability in 20 cycles ICCU-RWGS, achieving a sustainable and high-efficient performance in CO2 conversion and CO selectivity.

A validation of models for prediction of pathogenic variants in mismatch repair genes.

PURPOSE: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer. METHODS: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance. RESULTS: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+. CONCLUSION: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.

MicroRNA-506 has a suppressive effect on the tumorigenesis of nonsmall-cell lung cancer by regulating tubby-like protein 3.

MicroRNA-506 (miR-506), a miRNA, has been proven to act as a tumor suppressor gene in nonsmall-cell lung cancer (NSCLC); Tubby-like protein 3 (TULP3) is a potential target gene of miR-506. This study investigates whether miR-506 can prevent NSCLC progression by mediating TULP3. In vivo and in vitro experiments were performed to explore the function and potential regulatory relationship of miR-506 and TULP3 in NSCLC. Our results revealed that miR-506 is high expression in NSCLC cell lines, and the overexpression of miR-506 could inhibit cell viability and enhance cell apoptosis in H1299 and A549 cells. Pro-apoptotic related protein (cytochrome C, Bax, and cleaved caspase-9) expression increased while anti-apoptotic related protein (BCL-2 and BCL-XL) expression decreased after miR-506 was overexpression. Meanwhile, the overexpression of miR-506 could notably downregulate TULP3. Additionally, silence of TULP3 inhibited cell viability and promoted cell apoptosis. At the same time, pro-apoptotic related protein expression was promoted while anti-apoptotic related protein expression was inhibited. Furthermore, TULP3 overexpression could markedly reverse the inhibitory effect of miR-506 on the proliferation and induction of mitochondrial apoptosis in H1299 and A549 cells. In vivo tumor formation experiments also exhibited consistent results indicating that the functions of TULP3 might be correlated with the promotion of tumorigenesis. In conclusion, we firstly found that miR-506 can be involved in the processes of NSCLC and exert a suppressive effect on tumorigenesis by regulating TULP3 expression.

Theophylline and dexamethasone in combination reduce inflammation and prevent the decrease in HDAC2 expression seen in monocytes exposed to cigarette smoke extract.

Lung and systemic inflammation are associated with impaired lung function and increased mortality in patients with chronic obstructive pulmonary disease (COPD). Theophylline and glucocorticoids have been shown to have an anti-inflammatory effect in some respiratory diseases. However, corticosteroid insensitivity is a major barrier to the anti-inflammatory management of COPD. This study aimed to explore whether a combined treatment of theophylline and dexamethasone (Dex) could decrease cigarette smoke extract (CSE)-induced inflammation via prevention of a reduction in histone deacetylase 2 (HDAC2) expression and through inhibition of the PI3K/Akt pathway, which may be related to corticosteroid sensitivity. The half-maximal inhibitory concentration (IC50) of Dex (IC50-Dex) was used to as a marker of corticosteroid sensitivity. IC50-Dex was determined through observation of Dex inhibition of tumor necrosis factor-α (TNF-α)-induced interleukin (IL)-8 release. Using reverse transcription quantitative PCR and western blotting, U937 cells treated with CSE were assessed for HDAC2 expression levels and phosphorylation levels of Akt. Theophylline and Dex pre-treatment was shown to significantly reduce the CSE-induced release of IL-8 and TNF-α. The combination of theophylline and Dex pretreatment also reversed corticosteroid insensitivity in CSE-induced U937 cells and inhibited the PI3K/AKT pathway to a greater extent than theophylline treatment alone. CSE-treated U937 cells showed a reduction in HDAC2 mRNA and protein expression compared with the control group. However, this effect was reduced after pre-incubation with the combined therapy or theophylline alone. In conclusion, pretreatment with theophylline and Dex decreased CSE-induced inflammation via inhibition of the PI3K/Akt pathway and increase in HDAC2 protein expression.

Inflammasome activation restrains the intracellular Neospora caninum proliferation in bovine macrophages.

Neospora caninum is an intracellular parasite that causes neosporosis in cattle. Bovine neosporosis is considered a major cause of bovine abortion worldwide. Rapid replication of N. caninum tachyzoites within host cells is responsible for the acute phase of N. caninum infection. Evidence shows that the host immune response plays an essential role in recognizing and regulating the replication of invading pathogens. Nucleotide-binding oligomerization domain receptors (NLRs) are a class of cytoplasmic sensors that can sense pathogens and induce the formation of the inflammasome complex. Activation of the inflammasome promotes restriction of microbial replication. Our previous study revealed NLRP3 inflammasome activation in N. caninum-infected murine macrophages. However, the role of inflammasome activity in N. caninum-infected bovine cells is unknown. To address this question, a bovine peritoneal macrophage cell line was used to investigate the role of inflammasome activation in regulating intracellular N. caninum replication. The results showed that inflammasome mediated activation of caspase-1 occurs in N. caninum-infected bovine macrophages, and caspase-1-dependent cell death was considered to be induced in N. caninum-infected bovine macrophages because N. caninum induced cell death decreased following pretreatment with zVAD-fmk and VX765. Meanwhile, the inhibition of caspase-1 in N. caninum-infected bovine macrophages led to the presence of more parasites in the parasitophorous vacuole. In contrast, inflammasome activation induced by ATP treatment in N. caninum-infected bovine macrophages contributed to the clearance of N. caninum. In addition, pyroptotic cell supernatant collected from ATP-stimulated bovine macrophages also impaired the ability of this parasite to infect new cells. In conclusion, this study is the first report on the role of the bovine inflammasome in restraining intracellular N. caninum replication and suggests that the bovine inflammasome may be a potential target for future development of drugs or vaccines against N. caninum infection in cattle.

Bayesian analysis on meta-analysis of case-control studies accounting for within-study correlation.

In retrospective studies, odds ratio is often used as the measure of association. Under independent beta prior assumption, the exact posterior distribution of odds ratio given a single 2 × 2 table has been derived in the literature. However, independence between risks within the same study may be an oversimplified assumption because cases and controls in the same study are likely to share some common factors and thus to be correlated. Furthermore, in a meta-analysis of case-control studies, investigators usually have multiple 2 × 2 tables. In this article, we first extend the published results on a single 2 × 2 table to allow within study prior correlation while retaining the advantage of closed-form posterior formula, and then extend the results to multiple 2 × 2 tables and regression setting. The hyperparameters, including within study correlation, are estimated via an empirical Bayes approach. The overall odds ratio and the exact posterior distribution of the study-specific odds ratio are inferred based on the estimated hyperparameters. We conduct simulation studies to verify our exact posterior distribution formulas and investigate the finite sample properties of the inference for the overall odds ratio. The results are illustrated through a twin study for genetic heritability and a meta-analysis for the association between the N-acetyltransferase 2 (NAT2) acetylation status and colorectal cancer.

Tracking the dynamic seroma cavity using fiducial markers in patients treated with accelerated partial breast irradiation using 3D conformal radiotherapy.

PURPOSE: The purpose of the present study was to perform an analysis of the changes in the dynamic seroma cavity based on fiducial markers in early stage breast cancer patients treated with accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy (3D-CRT). METHODS: A prospective, single arm trial was designed to investigate the utility of gold fiducial markers in image guided APBI using 3D-CRT. At the time of lumpectomy, four to six suture-type gold fiducial markers were sutured to the walls of the cavity. Patients were treated with a fractionation scheme consisting of 15 fractions with a fractional dose of 333 cGy. Treatment design and planning followed NSABP∕RTOG B-39 guidelines. During radiation treatment, daily kV imaging was performed and the markers were localized and tracked. The change in distance between fiducial markers was analyzed based on the planning CT and daily kV images. RESULTS: Thirty-four patients were simulated at an average of 28 days after surgery, and started the treatment on an average of 39 days after surgery. The average intermarker distance (AiMD) between fiducial markers was strongly correlated to seroma volume. The average reduction in AiMD was 19.1% (range 0.0%-41.4%) and 10.8% (range 0.0%-35.6%) for all the patients between simulation and completion of radiotherapy, and between simulation and beginning of radiotherapy, respectively. The change of AiMD fits an exponential function with a half-life of seroma shrinkage. The average half-life for seroma shrinkage was 15 days. After accounting for the reduction which started to occur after surgery through CT simulation and treatment, radiation was found to have minimal impact on the distance change over the treatment course. CONCLUSIONS: Using the marker distance change as a surrogate for seroma volume, it appears that the seroma cavity experiences an exponential reduction in size. The change in seroma size has implications in the size of the CTV, PTV, and percent of normal breast tissue irradiated when using 3D-CRT.

DEAD box 1 (DDX1) expression predicts for local control and overall survival in early stage, node-negative breast cancer.

BACKGROUND: DEAD box 1 (DDX1) is an RNA helicase with a number of roles, including translation initiation, RNA splicing and modification, and possibly DNA double-strand break repair. Amplification of DDX1 expression has been implicated in tumors including neuroblastoma, Wilms tumor, retinoblastoma, and testicular carcinoma. The purpose of this study was to evaluate the prognostic significance of DDX1 expression in patients with breast cancer treated with breast-conserving therapy. METHODS: Paraffin-embedded specimens from 282 women with node-negative stage 1 and 2 breast cancer treated with breast-conserving surgery and radiation therapy were constructed into tissue microarrays and stained for DDX1. The molecular profiles were correlated with clinicopathologic factors and overall, local, and distant metastatic-free survival. RESULTS: DDX1 positivity was identified in 142 (50%) patients. The median age at diagnosis was 53 years. Eighty percent of the patients had T1 disease; 11% were HER2neu-positive, and 18% had triple-negative disease. DDX1 negativity was strongly associated with triple-negative phenotype (P = .01). DDX1 positivity was found to be associated with improved local relapse-free survival (96% vs 85%, P = .0233), distant metastatic-free survival (95% vs 85%, P = .0320), and overall survival (92% vs 84%, P = .0474) at 10 years. CONCLUSIONS: Node-negative, early stage breast cancer patients with high levels of DDX1 were found to have a significant improvement in local control, distant metastatic-free survival, and overall survival compared with patients with low levels of DDX1.

Comparison of radiation-induced fatigue across 3 different radiotherapeutic methods for early stage breast cancer.

BACKGROUND: Radiation-induced fatigue is a common side effect of breast cancer radiotherapy (RT). This study compares the induction and persistence of radiation-induced fatigue in accelerated partial breast irradiation (APBI), accelerated hypofractionated RT, and standard whole breast RT. METHODS: Eighty patients were treated with a novel, 3-week accelerated regimen with 333 centigrays (cGy) for 15 fractions to 4995 cGy; of these, 45 were treated using APBI, whereas 35 patients were treated using accelerated hypofractionated RT. These patients were matched with patients receiving 200 cGy for 30 fractions using standard whole breast irradiation. Fatigue score, using Common Terminology Criteria for Adverse Events version 4.0, was obtained at 5 time points: consultation before RT, first on-treatment visit, halfway through treatment, last on-treatment visit, and first follow-up. RESULTS: Maximum fatigue and average fatigue since treatment were calculated. Maximum fatigue was 1.5, 2.4, and 2.3, and average fatigue was 0.46, 0.81, and 0.92 for the APBI, accelerated hypofractionated RT, and standard whole breast RT groups, respectively. The accelerated schedules did not have significantly less fatigue than standard whole breast RT at first on-treatment visit. Maximum fatigue in APBI was reduced compared with standard whole breast RT. Accelerated hypofractionated RT had fatigue trajectory similar to standard whole breast RT. Multivariate analysis found that increased age and whole breast treatment are associated with more fatigue. Chemotherapy, hormone therapy, race, and T stage were not significant predictors of maximum fatigue. Results were similar for average fatigue, except that magnitudes were smaller. CONCLUSIONS: Field sizes and age in breast RT were positively associated with maximum radiation-induced fatigue. Accelerated hypofractionated RT and standard whole breast RT had similar fatigue trajectories compared with APBI, which reduced fatigue at all times.

Accumulation of driver and passenger mutations during tumor progression.

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small--0.004 ± 0.0004--and has major implications for experimental cancer research.

Cancer-specific high-throughput annotation of somatic mutations: computational prediction of driver missense mutations.

Large-scale sequencing of cancer genomes has uncovered thousands of DNA alterations, but the functional relevance of the majority of these mutations to tumorigenesis is unknown. We have developed a computational method, called Cancer-specific High-throughput Annotation of Somatic Mutations (CHASM), to identify and prioritize those missense mutations most likely to generate functional changes that enhance tumor cell proliferation. The method has high sensitivity and specificity when discriminating between known driver missense mutations and randomly generated missense mutations (area under receiver operating characteristic curve, >0.91; area under Precision-Recall curve, >0.79). CHASM substantially outperformed previously described missense mutation function prediction methods at discriminating known oncogenic mutations in P53 and the tyrosine kinase epidermal growth factor receptor. We applied the method to 607 missense mutations found in a recent glioblastoma multiforme sequencing study. Based on a model that assumed the glioblastoma multiforme mutations are a mixture of drivers and passengers, we estimate that 8% of these mutations are drivers, causally contributing to tumorigenesis.

Random Effects Models in a Meta-Analysis of the Accuracy of Two Diagnostic Tests Without a Gold Standard.

In studies of the accuracy of diagnostic tests, it is common that both the diagnostic test itself and the reference test are imperfect. This is the case for the microsatellite instability test, which is routinely used as a prescreening procedure to identify individuals with Lynch syndrome, the most common hereditary colorectal cancer syndrome. The microsatellite instability test is known to have imperfect sensitivity and specificity. Meanwhile, the reference test, mutation analysis, is also imperfect. We evaluate this test via a random effects meta-analysis of 17 studies. Study-specific random effects account for between-study heterogeneity in mutation prevalence, test sensitivities and specificities under a nonlinear mixed effects model and a Bayesian hierarchical model. Using model selection techniques, we explore a range of random effects models to identify a best-fitting model. We also evaluate sensitivity to the conditional independence assumption between the microsatellite instability test and the mutation analysis by allowing for correlation between them. Finally, we use simulations to illustrate the importance of including appropriate random effects and the impact of overfitting, underfitting, and misfitting on model performance. Our approach can be used to estimate the accuracy of two imperfect diagnostic tests from a meta-analysis of multiple studies or a multicenter study when the prevalence of disease, test sensitivities and/or specificities may be heterogeneous among studies or centers.

TRAB: testing whether mutation frequencies are above an unknown background.

To rigorously determine whether a gene or a set of genes have alterations that are involved in carcinogenesis requires a comparison of the prevalence of identified changes to a control mutation frequency present in tumor DNA. To facilitate this task, we develop a testing approach and the associated R library, called TRAB, that evaluates whether the frequency of somatic mutation in a given gene is higher than that observed in a control group of genes. Specifically, we test the null hypothesis that the frequency belongs to a control population of frequencies, against the alternative hypothesis that the frequency is higher. Mutation frequencies in the control group are themselves allowed to be variable. TRAB computes the a posteriori probability and the Bayes factor for the hypothesis using a hierarchical Bayesian approach.

Multiple diseases in carrier probability estimation: accounting for surviving all cancers other than breast and ovary in BRCAPRO.

Mendelian models can predict who carries an inherited deleterious mutation of known disease genes based on family history. For example, the BRCAPRO model is commonly used to identify families who carry mutations of BRCA1 and BRCA2, based on familial breast and ovarian cancers. These models incorporate the age of diagnosis of diseases in relatives and current age or age of death. We develop a rigorous foundation for handling multiple diseases with censoring. We prove that any disease unrelated to mutations can be excluded from the model, unless it is sufficiently common and dependent on a mutation-related disease time. Furthermore, if a family member has a disease with higher probability density among mutation carriers, but the model does not account for it, then the carrier probability is deflated. However, even if a family only has diseases the model accounts for, if the model excludes a mutation-related disease, then the carrier probability will be inflated. In light of these results, we extend BRCAPRO to account for surviving all non-breast/ovary cancers as a single outcome. The extension also enables BRCAPRO to extract more useful information from male relatives. Using 1500 families from the Cancer Genetics Network, accounting for surviving other cancers improves BRCAPRO's concordance index from 0.758 to 0.762 (p=0.046), improves its positive predictive value from 35 to 39 per cent (p<10(-6)) without impacting its negative predictive value, and improves its overall calibration, although calibration slightly worsens for those with carrier probability<10 per cent.

Breast cancer risk among male BRCA1 and BRCA2 mutation carriers.

Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).