An Anthropomorphic Diagnosis System of Pulmonary Nodules using Weak Annotation-Based Deep Learning.

Purpose: To develop an anthropomorphic diagnosis system of pulmonary nodules (PN) based on Deep learning (DL) that is trained by weak annotation data and has comparable performance to full-annotation based diagnosis systems. Methods: The proposed system uses deep learning (DL) models to classify PNs (benign vs. malignant) with weak annotations, which eliminates the need for time-consuming and labor-intensive manual annotations of PNs. Moreover, the PN classification networks, augmented with handcrafted shape features acquired through the ball-scale transform technique, demonstrate capability to differentiate PNs with diverse labels, including pure ground-glass opacities, part-solid nodules, and solid nodules. Results: The experiments were conducted on two lung CT datasets: (1) public LIDC-IDRI dataset with 1,018 subjects, (2) In-house dataset with 2740 subjects. Through 5-fold cross-validation on two datasets, the system achieved the following results: (1) an Area Under Curve (AUC) of 0.938 for PN localization and an AUC of 0.912 for PN differential diagnosis on the LIDC-IDRI dataset of 814 testing cases, (2) an AUC of 0.943 for PN localization and an AUC of 0.815 for PN differential diagnosis on the in-house dataset of 822 testing cases. These results demonstrate comparable performance to full annotation-based diagnosis systems. Conclusions: Our system can efficiently localize and differentially diagnose PNs even in resource-limited environments with good robustness across different grade and morphology sub-groups in the presence of deviations due to the size, shape, and texture of the nodule, indicating its potential for future clinical translation. Summary: An anthropomorphic diagnosis system of pulmonary nodules (PN) based on deep learning and weak annotation was found to achieve comparable performance to full-annotation dataset-based diagnosis systems, significantly reducing the time and the cost associated with the annotation. Key Points: A fully automatic system for the diagnosis of PN in CT scans using a suitable deep learning model and weak annotations was developed to achieve comparable performance (AUC = 0.938 for PN localization, AUC = 0.912 for PN differential diagnosis) with the full-annotation based deep learning models, reducing around 30%∼80% of annotation time for the experts.The integration of the hand-crafted feature acquired from human experts (natural intelligence) into the deep learning networks and the fusion of the classification results of multi-scale networks can efficiently improve the PN classification performance across different diameters and sub-groups of the nodule.

Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.

Does Tweeting Improve Citations? One-Year Results From the TSSMN Prospective Randomized Trial.

BACKGROUND: The Thoracic Surgery Social Media Network (TSSMN) is a collaborative effort of leading journals in cardiothoracic surgery to highlight publications via social media. This study aims to evaluate the 1-year results of a prospective randomized social media trial to determine the effect of tweeting on subsequent citations and nontraditional bibliometrics. METHODS: A total of 112 representative original articles were randomized 1:1 to be tweeted via TSSMN or a control (non-tweeted) group. Measured endpoints included citations at 1 year compared with baseline, as well as article-level metrics (Altmetric score) and Twitter analytics. Independent predictors of citations were identified through univariable and multivariable regression analyses. RESULTS: When compared with control articles, tweeted articles achieved significantly greater increase in Altmetric scores (Tweeted 9.4 ± 5.8 vs Non-tweeted 1.0 ± 1.8, P < .001), Altmetric score percentiles relative to articles of similar age from each respective journal (Tweeted 76.0 ± 9.1 percentile vs Non-tweeted 13.8 ± 22.7 percentile, P < .001), with greater change in citations at 1 year (Tweeted +3.1 ± 2.4 vs Non-Tweeted +0.7 ± 1.3, P < .001). Multivariable analysis showed that independent predictors of citations were randomization to tweeting (odds ratio [OR] 9.50; 95% confidence interval [CI] 3.30-27.35, P < .001), Altmetric score (OR 1.32; 95% CI 1.15-1.50, P < .001), open-access status (OR 1.56; 95% CI 1.21-1.78, P < .001), and exposure to a larger number of Twitter followers as quantified by impressions (OR 1.30, 95% CI 1.10-1.49, P < .001). CONCLUSIONS: One-year follow-up of this TSSMN prospective randomized trial importantly demonstrates that tweeting results in significantly more article citations over time, highlighting the durable scholarly impact of social media activity.

Siderophore-Assisted Dissolution of Iron(III) Hydroxide Oxides from Iron-Rich Fossil Matrices.

Current paleontological techniques to separate vertebrate fossils from encasing iron-rich cements by chemical means are limited by the low solubility of common iron(III) hydroxide oxides such as hematite and goethite. This study examines novel geochemical extractions capable of selectively dissolving iron(III) hydroxide oxides, in aqueous solutions of pH 9-11, without damaging fossilised bones or teeth (hydroxidecarbonate-apatite). This involves the siderophore ligands pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), and acetohydroxamic acid (aHA), whose coordination complexes with iron(III) show exceptionally high formation stability constants. The methods have been tested on natural hematite and fossil containing samples from the Riversleigh World Heritage Area in Australia. Both 0.01 mol dm-3 aHA and 0.001 mol dm-3 PIH at pH 9.7 were able to dissolve over 0.1 mmol dm-3 of the goethite coating bone fragments.

Trainee Thoracic Surgery Social Media Network: Early Experience With TweetChat-Based Journal Clubs.

BACKGROUND: Virtual journal clubs on Twitter (TweetChats) provide a platform to globally discuss publications. The Thoracic Surgery Social Media Network (TSSMN) is an organization that focuses on bringing social media attention to key publications in cardiothoracic surgery. TSSMN recently formed a Trainee Group with the goal of conducting chats covering key topics in cardiothoracic surgical training. The aim of this study was to characterize the pilot experience of this group. METHODS: The TSSMN trainee group held 3 TweetChats during the study period between 2017 and 2018. Each TweetChat was a structured discussion of 2 to 4 publications. The number of tweets, participants, most popular tweets, and impressions was assessed for each of the TweetChats. RESULTS: The 3 TweetChats had a mean of 40 participants (range, 36-45), generating an average of 497 tweets (range, 451-526) with a mean of 809,746 impressions (range, 591,814-1,140,000). Fruitful discussions on the topics of simulation in surgery, assessment of resident autonomy, and development of optimal organizational cultures to maximize team performance were held. CONCLUSIONS: Twitter is a useful tool to collaborate and disseminate information. The 3 TweetChats organized by TSSMN trainee delegates generated approximately 1500 tweets with 2 million impressions. By these metrics, the feasibility of a trainee-led TSSMN TweetChat was confirmed.

Social Media Improves Cardiothoracic Surgery Literature Dissemination: Results of a Randomized Trial.

BACKGROUND: The Thoracic Surgery Social Media Network (TSSMN) represents a collaborative effort of leading journals in cardiothoracic surgery to highlight publications via social media, specifically Twitter. We conducted a prospective randomized trial to determine the effect of scheduled tweeting on nontraditional bibliometrics of dissemination. METHODS: A total of 112 representative original articles (2017-2018) were selected and randomized 1:1 to an intervention group to be tweeted via TSSMN or a control (non-tweeted) group. Four articles per day were tweeted by TSSMN delegates for 14 days. Primary endpoints included change in article-level metrics (Altmetric) score pre-tweet and post-tweet compared with the control group. Secondary endpoints included change in Twitter analytics day 1 post-tweet and day 7 post-tweet for each article compared with baseline. RESULTS: Tweeting via TSSMN significantly improved article Altmetric scores (pre-tweet 1 vs post-tweet 8; P < .001), Mendeley reads (pre-tweet 1 vs post-tweet 3; P < .001), and Twitter impressions (day 1 post-tweet 1599 vs day 7 post-tweet 2296; P < .001). Subgroup analysis demonstrates that incorporating photos into the tweets trended toward increased link clicks to the full-text article (P = .08) whereas tweeting at 1 pm Eastern Standard Time and 9 pm Eastern Standard Time generated the highest and lowest audience reach (P = .022), respectively. Articles published in adult cardiac surgery achieved the highest change in Altmetric score (P = .028) and Mendeley reads (P = .028), and were more likely to be retweeted (P = .042) than were those published on education, general thoracic surgery, and congenital surgery. CONCLUSIONS: Social media highlights of scholarly literature via TSSMN Twitter activity improves article Altmetric scores, Mendeley reads, and Twitter analytics, with dissemination to a greater audience.

Intracellular speciation of gold nanorods alters the conformational dynamics of genomic DNA.

Gold nanorods are one of the most widely explored inorganic materials in nanomedicine for diagnostics, therapeutics and sensing1. It has been shown that gold nanorods are not cytotoxic and localize within cytoplasmic vesicles following endocytosis, with no nuclear localization2,3, but other studies have reported alterations in gene expression profiles in cells following exposure to gold nanorods, via unknown mechanisms4. In this work we describe a pathway that can contribute to this phenomenon. By mapping the intracellular chemical speciation process of gold nanorods, we show that the commonly used Au-thiol conjugation, which is important for maintaining the noble (inert) properties of gold nanostructures, is altered following endocytosis, resulting in the formation of Au(I)-thiolates that localize in the nucleus5. Furthermore, we show that nuclear localization of the gold species perturbs the dynamic microenvironment within the nucleus and triggers alteration of gene expression in human cells. We demonstrate this using quantitative visualization of ubiquitous DNA G-quadruplex structures, which are sensitive to ionic imbalances, as an indicator of the formation of structural alterations in genomic DNA.

Novel Airway and Ventilator Management of Tracheobronchial Disruption After Blunt Trauma.

Tracheobronchial injuries can be difficult to diagnose and manage, especially in the presence of polytrauma. A 50-year-old woman presented as a Level I trauma activation after being struck by a motor vehicle. Initial evaluation demonstrated intracranial hemorrhage and multiple chest injuries, including multilevel bilateral rib fractures, pneumomediastinum, and concern for tracheobronchial injury. After initial stabilization, bronchoscopy was performed and demonstrated an injury to the carina. We report a novel airway and ventilation strategy in the setting of concomitant tracheobronchial injury after severe blunt chest trauma in which extracorporeal support is contraindicated.

The interplay between cell signalling and the mevalonate pathway in cancer.

The mevalonate (MVA) pathway is an essential metabolic pathway that uses acetyl-CoA to produce sterols and isoprenoids that are integral to tumour growth and progression. In recent years, many oncogenic signalling pathways have been shown to increase the activity and/or the expression of MVA pathway enzymes. This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.

Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P < 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.

Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings.

Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001). Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the most frequently seen in humans and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextransulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.

MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer.

Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor "bystander" effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.

Suppression of Her2/Neu mammary tumor development in mda-7/IL-24 transgenic mice.

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2+ breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.

Validation of a molecular and pathological model for five-year mortality risk in patients with early stage lung adenocarcinoma.

INTRODUCTION: The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality. METHODS: Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome. RESULTS: The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12-1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10). CONCLUSIONS: This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.

Fatty acid synthase plays a role in cancer metabolism beyond providing fatty acids for phospholipid synthesis or sustaining elevations in glycolytic activity.

Fatty acid synthase is over-expressed in many cancers and its activity is required for cancer cell survival, but the role of endogenously synthesized fatty acids in cancer is unknown. It has been suggested that endogenous fatty acid synthesis is either needed to support the growth of rapidly dividing cells, or to maintain elevated glycolysis (the Warburg effect) that is characteristic of cancer cells. Here, we investigate both hypotheses. First, we compared utilization of fatty acids synthesized endogenously from (14)C-labeled acetate to those supplied exogenously as (14)C-labeled palmitate in the culture medium in human breast cancer (MCF-7 and MDA-MB-231) and untransformed breast epithelial cells (MCF-10A). We found that cancer cells do not produce fatty acids that are different from those derived from exogenous palmitate, that these fatty acids are esterified to the same lipid and phospholipid classes in the same proportions, and that their distribution within neutral lipids is not different from untransformed cells. These results suggest that endogenously synthesized fatty acids do not fulfill a specific function in cancer cells. Furthermore, we observed that cancer cells excrete endogenously synthesized fatty acids, suggesting that they are produced in excess of requirements. We next investigated whether lipogenic activity is involved in the maintenance of high glycolytic activity by culturing both cancer and non-transformed cells under anoxic conditions. Although anoxia increased glycolysis 2-3 fold, we observed no concomitant increase in lipogenesis. Our results indicate that breast cancer cells do not have a specific qualitative or quantitative requirement for endogenously synthesized fatty acids and that increased de novo lipogenesis is not required to sustain elevations in glycolytic activity induced by anoxia in these cells.

mda-7/IL-24 expression inhibits breast cancer through upregulation of growth arrest-specific gene 3 (gas3) and disruption of ß1 integrin function.

Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of ß1 integrin with fibronectin. A mutated GAS3, which is unable to bind ß1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of ß1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of ß1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10(-9)), and the incidence of metastases is significantly reduced in patients with HER2(+) breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-ß1integrin-fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.

Role of sp transcription factors in the regulation of cancer cell metabolism.

Cancer cells exhibit altered metabolism characterized by the generation of adenosine triphosphate by glycolysis and generation of fatty acids by de novo synthesis. The majority of genes involved in these pathways have binding sites for specificity protein (Sp) transcription factors in their promoters. Studies showing that Sp transcription factors, particularly Sp1, are involved in the regulation in cancer cells of hexokinase, pyruvate kinase, lactate dehydrogenase, fatty acid synthase, and hypoxia-inducible factor-1α are reviewed. Glycolysis and lipogenesis in cancers are also known to be stimulated by the constitutive activation of the PI3K/Akt signaling pathway. Evidence is presented for the notion that Sp transcription factors may act in concert with Akt to regulate the abnormal metabolism of cancer cells.