We developed an assay to quantify LDL transcytosis across endothelial cells and discovered an unexpected role for SR-BI. Elucidating the mechanisms of LDL transcytosis may identify novel targets for the prevention or therapy of atherosclerosis.

Background Patients with metastatic breast cancer (MBC) are living longer, but development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population. Methods Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to: breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with HER2+, triple negative, and hormone receptor (HR)+/HER2- MBC; pooled overall estimates for incidence were calculated using random effects models. Results 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0 – 34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5 – 40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9 – 36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10 – 0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09 – 0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03 – 0.08) for patients with HR+/HER2- MBC. Conclusion There is high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.

Transcellular albumin transport occurs via caveolae that are abundant in lung microvascular endothelial cells. Stimulation of albumin transcytosis by proinflammatory mediators may contribute to alveolar protein leak in lung injury, yet the regulation of albumin transport and its underlying molecular mechanisms are so far incompletely understood. Here we tested the hypothesis that thrombin may stimulate transcellular albumin transport across lung microvascular endothelial cells in an acid-sphingomyelinase dependent manner. Thrombin increased the transport of fluorescently labeled albumin across confluent human lung microvascular endothelial cell (HMVEC-L) monolayers to an extent that markedly exceeds the rate of passive diffusion. Thrombin activated acid sphingomyelinase (ASM) and increased ceramide production in HMVEC-L, but not in bovine pulmonary artery cells, which showed little albumin transport in response to thrombin. Thrombin increased total caveolin-1 (cav-1) content in both whole cell lysates and lipid rafts from HMVEC-L, and this effect was blocked by inhibition of ASM or de novo protein biosynthesis. Thrombin-induced uptake of albumin into lung microvascular endothelial cells was confirmed in isolated-perfused lungs by real-time fluorescence imaging and electron microscopy of gold-labeled albumin. Inhibition of ASM attenuated thrombin-induced albumin transport both in confluent HMVEC-L and in intact lungs, whereas HMVEC-L treatment with exogenous ASM increased albumin transport and enriched lipid rafts in cav-1. Our findings indicate that thrombin stimulates transcellular albumin transport in an acid sphingomyelinase-dependent manner by inducing de novo synthesis of cav-1 and its recruitment to membrane lipid rafts.

Background Rapid and accurate identification of right ventricular (RV) dysfunction is essential for decreasing mortality associated with acute pulmonary embolism (PE), particularly for non-high-risk patients without hypotension on admission. This study aimed to develop a rapid and accurate tool for predicting the risk of RV dysfunction in non-high-risk patients with acute PE. Methods The medical records of non-high-risk patients with acute PE admitted to Shengjing Hospital of China Medical University between January 2011 and May 2020 were retrospectively analysed. The primary outcome of this study was RV dysfunction within 24 h after admission. The enrolled patients were randomized into training or validation sets as a ratio of 2:1. In the training set, a nomogram was developed, and the consistency was corroborated in the validation set. The areas under the receiver operating characteristic curves (AUCs) and 95% confidence intervals (CIs) were calculated. Results A total of 845 patients were enrolled, including 420 men and 425 women with an average age of 60.05 ± 15.43 years. Right ventricular dysfunction was identified in 240 patients (28.40%). The nomogram for RV dysfunction included N-terminal pro-brain natriuretic peptide, cardiac troponin I, and ventricular diameter ratios, which provided AUC values of 0.881 in the training dataset (95% confidence interval (CI): 0.868–0.898, p < 0.001) and 0.839 in the validation set (95% CI: 0.780–0.897, p < 0.001). The predictive tool was published as a web-based calculato (https://gaoyzcmu.shinyapps.io/APERVD/). Conclusions The combination of CT and laboratory parameters forms a predictive tool that may facilitate the identification of RV dysfunction in non-high-risk patients with acute PE.

Background. Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS). Materials and Methods. We conducted a retrospective analysis of women (≥ 18 years old) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT) or SRS to the brain at the Sunnybrook Odette Cancer Center, Toronto, Canada between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed, with subgroup analyses by breast cancer subtype.Results. Among 683 eligible patients, 153 (22.4%) had triple negative (TNBC), 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2-, and 61 (13.3%) had breast cancer of unknown subtype. The majority of patients received fist line WBRT (n=459, 67.2%) or SRS (n=126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (IQR 1.0-9.6 months) and 5.1 months (IQR 2.0-11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first line WBRT and HER2-subtype were independently prognostic for shorter OS. Conclusion. Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system-active systemic therapies warrant further investigation. The Oncologist 2021;9999:• • Implications for Practice: Although triple negative and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor (HR)+/HER2-breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, we propose that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery.

Background: Blood-based biomarkers (liquid biopsy) are increasingly used in precision oncology. Yet, little is known about cancer patients' perspectives in clinical practice. We explored patients' depth of preferences for liquid vs tissue biopsies and knowledge regarding the role of blood biomarkers on their cancer. Methods: Three interviewer-administered trade-off scenarios and a 54-item selfadministered questionnaire were completed by cancer outpatients across all disease sites at the Princess Margaret Cancer Centre. Results: Of 413 patients, 54% were female; median age was 61 (range 18-101) years. In trade-off scenario preference testing, 90% (n=372) preferred liquid over tissue biopsy at baseline; when wait times for their preferred test were increased from 2 weeks, patients tolerated an additional mean of 1.8 weeks (SD 2.1) for liquid biopsy before switching to tissue biopsy (with wait time 2 weeks). Patients also tolerated a 6.2% decrease (SD 8.8) in the chance that their preferred test would conclusively determine optimal treatment before switching from the baseline of 80%. 216 patients (58%) preferred liquid biopsy even with no chance of adverse events from tissue biopsy. Patients' knowledge of blood-based biomarkers related to their cancer was low (mean 23%); however, the majority viewed development of blood biomarkers as important. Conclusion: Patients had limited understanding of cancer-specific blood-based biomarkers, but 90% preferred liquid over tissue biopsies to assess biomarkers. There was little tolerance to wait longer for results, or for decreased test-conclusiveness. Developing accurate, low-risk tests for cancer diagnosis and management for blood biomarkers is therefore desirable to patients.

Von Hippel‐Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype–phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open‐access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co‐occurrences and genotype–phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants.

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