Key Results: Three Chinese radiologists had a sensitivity of 72%, 72% and 94% and specificity of 94%, 88% and 24% in differentiating 219 COVID-19 from 205 non-COVID-19 pneumonia.  Four United States radiologists had a sensitivity of 93%, 83%, 73% and 73% and specificity of 100%, 93%, 93% and 100%.  The most discriminating features for COVID-19 pneumonia included a peripheral distribution (80% vs. 57%, p<0.001), ground-glass opacity (91% vs. 68%, p<0.001) and vascular thickening (58% vs. 22%, p<0.001). Manuscript type: original researchThe total number of words of the manuscript, including entire text from title page to tables and references: 4364 This copy is for personal use only. To order printed copies, contact reprints@rsna.org I n P r e s s Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT Summary: Radiologists had high specificity but moderate sensitivity in differentiating COVID-19 from viral pneumonia on chest CT. Key Results:  Three Chinese radiologists had sensitivities of 72%, 72% and 94% and specificities of 94%, 88% and 24% in differentiating 219 COVID-19 from 205 non-COVID-19 pneumonia.  Four United States radiologists had sensitivities of 93%, 83%, 73% and 73% and specificities of 100%, 93%, 93% and 100%.  The most discriminating features for COVID-19 pneumonia included a peripheral distribution (80% vs. 57%, p<0.001), ground-glass opacity (91% vs. 68%, p<0.001) and vascular thickening (58% vs. 22%, p<0.001). Abstract Background: Despite its high sensitivity in diagnosing COVID-19 in a screening population, chest CT appearances of COVID 19 pneumonia are thought to be non-specific. Purpose: To assess the performance of United States (U.S.) and Chinese radiologists in differentiating COVID-19 from viral pneumonia on chest CT. Methods: A total of 219 patients with both positive COVID-19 by RT-PCR and abnormal chest CT findings were retrospectively identified from 7 Chinese hospitals in Hunan Providence, China from January 6 to February 20, 2020. A total of 205 patients with positive Respiratory Pathogen Panel for viral pneumonia and CT findings consistent with or highly suspicious for pneumonia by original radiology interpretation within 7 days of each other were identified from Rhode Island Hospital in Providence, RI. Three Chinese radiologists blindly reviewed all chest CTs (n=424) to differentiate COVID-19 from viral pneumonia. A sample of 58 age-matched cases was randomly selected and evaluated by 4 U.S. radiologists in a similar fashion. Different CT features were recorded and compared between the two groups. Results: For all chest CTs, three Chinese radiologists correctly differentiated COVID-19 from non-COVID-19 pneumonia 83% (350/424), 80% (338/424), and 60% (255/424) of the time, respectively. The seven radiologists had sensitivities of 80%, 67%, 97%, 93%, 83%, 73% and 70% and specificities of 100%, 93%, 7%, 100%, 93%, 93%, 100%. Compared to non-COVID-19 pneumonia, COVID-19 pneumonia was more likely to have a peripheral distribution (80% vs. 57%, p...

AI assistance improved radiologists' performance in distinguishing COVID-19 from pneumonia of other etiology on chest CT. Key Results: An AI model had higher test accuracy (96% vs 85%, p<0.001), sensitivity (95% vs 79%, p<0.001), and specificity (96% vs 88%, p=0.002) than radiologists. In an independent test set, our AI model achieved an accuracy of 87%, sensitivity of 89% and specificity of 86%. With AI assistance, the radiologists achieved a higher average accuracy (90% vs 85%, p<0.001), sensitivity (88% vs 79%, p<0.001) and specificity (91% vs 88%, p=0.001). AbstractBackground: COVID-19 and pneumonia of other etiology share similar CT characteristics, contributing to the challenges in differentiating them with high accuracy.Purpose: To establish and evaluate an artificial intelligence (AI) system in differentiating COVID-19 and other pneumonia on chest CT and assess radiologist performance without and with AI assistance.Methods: 521 patients with positive RT-PCR for COVID-19 and abnormal chest CT findings were retrospectively identified from ten hospitals from January 2020 to April 2020. 665 patients with non-COVID-19 pneumonia and definite evidence of pneumonia on chest CT were retrospectively selected from three hospitals between 2017 and 2019. To classify COVID-19 versus other pneumonia for each patient, abnormal CT slices were input into the EfficientNet B4 deep neural network architecture after lung segmentation, followed by two-layer fully-connected neural network to pool slices together.Our final cohort of 1,186 patients (132,583 CT slices) was divided into training, validation and test sets in a 7:2:1 and equal ratio. Independent testing was performed by evaluating model performance on separate hospitals. Studies were blindly reviewed by six radiologists without and then with AI assistance.Results: Our final model achieved a test accuracy of 96% (95% CI: 90-98%), sensitivity 95% (95% CI: 83-100%) and specificity of 96% (95% CI: 88-99%) with Receiver Operating Characteristic (ROC) AUC of 0.95 and Precision-Recall (PR) AUC of 0.90. On independent testing, our model achieved an accuracy of 87% (95% CI: 82-90%), sensitivity of 89% (95% CI: 81-94%) and specificity of 86% (95% CI: 80-90%) with ROC AUC of 0.90 and PR AUC of 0.87. Assisted by the models' probabilities, the radiologists achieved a higher average test accuracy (90% vs. 85%, ∆=5, p<0.001), sensitivity (88% vs. 79%, ∆=9, p<0.001) and specificity (91% vs. 88%, ∆=3, p=0.001).

Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with the ryanodine receptor RYR1 and promotes calcium release from the endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer.

Background Chest x-ray is a relatively accessible, inexpensive, fast imaging modality that might be valuable in the prognostication of patients with COVID-19. We aimed to develop and evaluate an artificial intelligence system using chest x-rays and clinical data to predict disease severity and progression in patients with COVID-19. Methods We did a retrospective study in multiple hospitals in the University of Pennsylvania Health System in Philadelphia, PA, USA, and Brown University affiliated hospitals in Providence, RI, USA. Patients who presented to a hospital in the University of Pennsylvania Health System via the emergency department, with a diagnosis of COVID-19 confirmed by RT-PCR and with an available chest x-ray from their initial presentation or admission, were retrospectively identified and randomly divided into training, validation, and test sets (7:1:2). Using the chest x-rays as input to an EfficientNet deep neural network and clinical data, models were trained to predict the binary outcome of disease severity (ie, critical or non-critical). The deep-learning features extracted from the model and clinical data were used to build time-to-event models to predict the risk of disease progression. The models were externally tested on patients who presented to an independent multicentre institution, Brown University affiliated hospitals, and compared with severity scores provided by radiologists. Findings 1834 patients who presented via the University of Pennsylvania Health System between March 9 and July 20, 2020, were identified and assigned to the model training (n=1285), validation (n=183), or testing (n=366) sets. 475 patients who presented via the Brown University affiliated hospitals between March 1 and July 18, 2020, were identified for external testing of the models. When chest x-rays were added to clinical data for severity prediction, area under the receiver operating characteristic curve (ROC-AUC) increased from 0·821 (95% CI 0·796–0·828) to 0·846 (0·815–0·852; p<0·0001) on internal testing and 0·731 (0·712–0·738) to 0·792 (0·780–0 ·803; p<0·0001) on external testing. When deep-learning features were added to clinical data for progression prediction, the concordance index (C-index) increased from 0·769 (0·755–0·786) to 0·805 (0·800–0·820; p<0·0001) on internal testing and 0·707 (0·695–0·729) to 0·752 (0·739–0·764; p<0·0001) on external testing. The image and clinical data combined model had significantly better prognostic performance than combined severity scores and clinical data on internal testing (C-index 0·805 vs 0·781; p=0·0002) and external testing (C-inde 0·752 vs 0·715; p<0·0001). Interpretation In patients with COVID-19, artificial intelligence based on chest x-rays had better prognostic performance than clinical data or radiologist-derived severity scores. Using artificial intelligence, chest x-rays can augment clinical data i...

Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSC), which are critical for tumor recurrence and metastasis. Here, we demonstrate that hypoxia-inducible factor (HIF)-1-dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Chemotherapy increased DUSP9 expression and decreased DUSP16 expression in a HIF1-dependent manner, leading to inhibition of ERK and activation of p38 signaling pathways, respectively. Inhibition of ERK caused transcriptional induction of the pluripotency factor Nanog through decreased inactivating phosphorylation of FoxO3, while activation of p38 stabilized Nanog and Klf4 mRNA through increased inactivating phosphorylation of RNA-binding protein ZFP36L1, both of which promoted specification of the BCSC phenotype. Inhibition of HIF1 or p38 signaling blocked chemotherapy-induced pluripotency factor expression and BCSC enrichment. These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC. These findings provide a molecular mechanism that may account for the increased relapse rate of women with TNBC who are treated with cytotoxic chemotherapy and suggest that combining chemotherapy with an inhibitor of HIF1 or p38 activity may increase patient survival. .

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