Deep learning features encode interpretable morphologies within histological images.

Convolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture). While many studies have incorporated CNN features into predictive models, there has been little empirical study of their properties. We show such features can be construed as abstract morphological genes ( mones ) with strong independent associations to biological phenotypes. Many mones are specific to individual cancer types, while others are found in multiple cancers especially from related tissue types. We also observe that mone-mone correlations are strong and robustly preserved across related cancers. Importantly, linear mone-based classifiers can very accurately separate 38 distinct classes (19 tumor types and their adjacent normals, AUC = [Formula: see text] for each class prediction), and linear classifiers are also highly effective for universal tumor detection (AUC = [Formula: see text]). This linearity provides evidence that individual mones or correlated mone clusters may be associated with interpretable histopathological features or other patient characteristics. In particular, the statistical similarity of mones to gene expression values allows integrative mone analysis via expression-based bioinformatics approaches. We observe strong correlations between individual mones and individual gene expression values, notably mones associated with collagen gene expression in ovarian cancer. Mone-expression comparisons also indicate that immunoglobulin expression can be identified using mones in colon adenocarcinoma and that immune activity can be identified across multiple cancer types, and we verify these findings by expert histopathological review. Our work demonstrates that mones provide a morphological H&E decomposition that can be effectively associated with diverse phenotypes, analogous to the interpretability of transcription via gene expression values. Our work also demonstrates mones can be interpreted without using a classifier as a proxy

Prognostic Implications of Resistive Reserve Ratio in Patients With Coronary Artery Disease.

Background Resistive reserve ratio is a thermodilution-based index which integrates both coronary flow and pressure. Resistive reserve ratio represents the vasodilatory capacity of interrogated vessels including both epicardial coronary artery and microvascular circulation. We evaluated the prognostic potential of resistive reserve ratio compared with pressure-derived index (fractional flow reserve [FFR]) or flow-derived index (coronary flow reserve [CFR]). Methods and Results A total of 1245 patients underwent coronary pressure and flow measurement using pressure-temperature wire. Resistive reserve ratio was calculated by CFR adjusted using the ratio between resting and hyperemic distal coronary pressure ([resting mean transit time/hyperemic mean transit time]×[resting distal coronary pressure/hyperemic distal coronary pressure]). Clinical outcome was assessed by patient-oriented composite outcome (POCO), a composite of any death, myocardial infarction, and revascularization at 5 years. At 5 years, the cumulative incidence of POCO was significantly different according to quartiles of resistive reserve ratio (9.9%, 11.3%, 17.2%, and 22.7% in quartiles 1 to 4, respectively, log rank P0.80 or patients with CFR>2.0. (FFR>0.80 group: 14.8% versus 6.0%; log rank P=0.001; CFR>2.0 group: 13.5% versus 7.1%; log rank P=0.045). Adding resistive reserve ratio into the model for 5-year POCO showed significantly higher global Chi square value than FFR or CFR (P<0.001, respectively, for FFR and CFR). Resistive reserve ratio <3.5 was significantly associated with the risk of POCO at 5 years in multivariable model (adjusted hazard ratio 1.597, 95% CI, 1.098-2.271, P=0.014). Conclusions Resistive reserve ratio, which integrated both coronary flow and pressure, showed incremental prognostic implications in patients with coronary artery disease undergoing elective percutaneous coronary intervention guided by invasive physiologic evaluation. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03690713.S

Blood transfusions may adversely affect survival outcomes of patients with lung cancer: a systematic review and meta-analysis

BackgroundDespite common use in clinical practice, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. The purpose of the current study is to perform an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients.MethodsWe searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to November 2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I2 test. Publication bias was explored via funnel plot and trim-and-fill analyses.ResultsWe included 23 cohort studies with 12,175 patients (3,027 cases and 9,148 controls) for meta-analysis. Among these records, 22 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.35, 95% CI: 1.14-1.61, P&lt;0.001, I2=0%) and DFS (HR=1.46, 95% CI: 1.15-1.86, P=0.001, I2=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI: 1.07-1.49, P=0.006; DFS: HR=1.35, 95% CI: 1.08-1.69, P=0.008).ConclusionsBlood transfusions were associated with decreased survival of patients with lung cancer

Adipokine Resistin Is a Key Player to Modulate Monocytes, Endothelial Cells, and Smooth Muscle Cells, Leading to Progression of Atherosclerosis in Rabbit Carotid Artery

Objectives We investigated the effects of human resistin on atherosclerotic progression and clarified its underlying mechanisms. Background Resistin is an adipokine first identified as a mediator of insulin resistance in murine obesity models. But, its role in human pathology is under debate. Although a few recent studies suggested the relationship between resistin and atherosclerosis in humans, the causal relationship and underlying mechanism have not been clarified. Methods We cloned rabbit resistin, which showed 78% identity to human resistin at the complementary deoxyribonucleic acid level, and its expression was examined in 3 different atherosclerotic rabbit models. To evaluate direct role of resistin on atherosclerosis, collared rabbit carotid arteries were used. Histological and cell biologic analyses were performed. Results Rabbit resistin was expressed by macrophages of the plaque in the 3 different atherosclerotic models. Periadventitial resistin gene transfer induced macrophage infiltration and expression of various inflammatory cytokines, resulting in the acceleration of plaque growth and destabilization. In vitro experiments elucidated that resistin increased monocyte-endothelial cell adhesion by upregulating very late antigen-4 on monocytes and their counterpart vascular cell adhesion molecule-1 on endothelial cells. Resistin augmented monocyte infiltration in collagen by direct chemoattractive effect as well as by enhancing migration toward monocyte chemotactic protein-1. Administration of connecting segment-1 peptide, which blocks very late antigen-4 x vascular cell adhesion molecule-1 interaction, ameliorated neointimal growth induced by resistin in vivo. Conclusions Our results indicate that resistin aggravates atherosclerosis by stimulating monocytes, endothelial cells, and vascular smooth muscle cells to induce vascular inflammation. These findings provide the first insight on the causal relationship between resistin and atherosclerosis. (J Am Coll Cardiol 2011;57:99-109) (C) 2011 by the American College of Cardiology FoundationDong B, 2008, ARTERIOSCL THROM VAS, V28, P1270, DOI 10.1161/ATVBAHA.108.164715Rader DJ, 2008, NATURE, V451, P904, DOI 10.1038/nature06796Maiellaro K, 2007, CARDIOVASC RES, V75, P640, DOI 10.1016/j.cardiores.2007.06.023Lubos E, 2007, ATHEROSCLEROSIS, V193, P121, DOI 10.1016/j.atherosclerosis.2006.05.039Xu WB, 2006, BIOCHEM BIOPH RES CO, V351, P376, DOI 10.1016/j.bbrc.2006.10.051Mu H, 2006, CARDIOVASC RES, V70, P146, DOI 10.1016/j.cardiores.2006.01.015Jung HS, 2006, CARDIOVASC RES, V69, P76, DOI 10.1016/j.cardiores.2005.09.015Yu YH, 2005, CIRC RES, V96, P1042, DOI 10.1161/01.RES.0000165803.47776.38Bokarewa M, 2005, J IMMUNOL, V174, P5789Hansson GK, 2005, NEW ENGL J MED, V352, P1685Reilly MP, 2005, CIRCULATION, V111, P932, DOI 10.1161/01.CIR.0000155620.10387.43Calabro P, 2004, CIRCULATION, V110, P3335, DOI 10.1161/01.CIR.0000147825.97879.E7Patel SD, 2004, SCIENCE, V304, P1154Degawa-Yamauchi M, 2003, J CLIN ENDOCR METAB, V88, P5452, DOI 10.1210/jc.2002-021808Lee JH, 2003, J CLIN ENDOCR METAB, V88, P4848, DOI 10.1210/jc.2003-030519Verma S, 2003, CIRCULATION, V108, P736, DOI 10.1161/01.CIR.0000084503.91330.49Fain JN, 2003, BIOCHEM BIOPH RES CO, V300, P674, DOI 10.1016/S0006-291X(02)02864-4Okamoto Y, 2002, CIRCULATION, V106, P2767, DOI 10.1161/01.CIR.0000042707.50032.19Sartore S, 2001, CIRC RES, V89, P1111, DOI 10.1161/hh2401.100844Steppan CM, 2001, NATURE, V409, P307, DOI 10.1038/35053000Steppan CM, 2001, P NATL ACAD SCI USA, V98, P5022001, JAMA, V285, P2486Festa A, 2000, CIRCULATION, V102, P42Doran AC, 2008, ARTERIOSCL THROM VAS, V28, P812, DOI 10.1161/ATVBAHA.107.159327Ross R, 1999, NEW ENGL J MED, V340, P115Friedman JM, 1998, NATURE, V395, P763Kolodgie FD, 1996, ARTERIOSCL THROM VAS, V16, P1454MOLOSSI S, 1995, J CLIN INVEST, V95, P2601MAY MJ, 1993, J CELL SCI, V106, P109HOTAMISLIGIL GS, 1993, SCIENCE, V259, P87

M-CSF from Cancer Cells Induces Fatty Acid Synthase and PPARβ/δ Activation in Tumor Myeloid Cells, Leading to Tumor Progression

We investigate crosstalk between cancer cells and stromal myeloid cells. We find that Lewis lung carcinoma cells significantly induce PPARβ/δ activity in myeloid cells in vitro and in vivo. Myeloid cell-specific knockout of PPARβ/δ results in impaired growth of implanted tumors, and this is restored by adoptive transfer of wild-type myeloid cells. We find that IL-10 is a downstream effector of PPARβ/δ and facilitates tumor cell invasion and angiogenesis. This observation is supported by the finding that the CD11blowIL-10+ pro-tumoral myeloid cell is scarcely detected in tumors from myeloid-cell-specific PPARβ/δ knockout mice, where vessel densities are also decreased. Fatty acid synthase (FASN) is shown to be an upstream regulator of PPARβ/δ in myeloid cells and is induced by M-CSF secreted from tumor cells. Our study gives insight into how cancer cells influence myeloid stromal cells to get a pro-tumoral phenotype

Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials

<div><p>Background</p><p>There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI.</p><p>Methods and Results</p><p>Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I² = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I² = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I² = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein.</p><p>Conclusions</p><p>High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.</p></div