tbuckley/cabot-search huggingface dataset:
Abstract P1-10-15: <i>BRCA1</i> alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy
Authors: Mamoru Takada, Yasuhiko Kaneko, Masayuki Haruta, Shigenori Nagai, Kenichi Inoue, Katsunori Toduka, Masafumi Kurozumi, Hiroyuki Takei, Seishi Ogawa, Takeshi Nagashima, Takafumi Sangai, Hiroshi Fujimoto, Junta Sakakibara, Ryotaro Teranaka
Journal: Cancer Research (2020)

Abstract The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in germinal BRCA1- or BRCA2-mutation carriers. Since tumors with the phenotype have defects in the DNA damage repair pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who underwent diagnostic core-needle biopsy and received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. They had a tumor size of T1, T2, T3, or T4, a lymph node status of N0, N1, N2, or N3, and no distant metastasis (M0) at diagnosis, and were enrolled as subjects in this study. The methylation and/or loss or UPD of BRCA1 (termed BRCA1 alterations) and the loss or UPD of BRCA2 (termed BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, out of 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P&amp;lt;0.001 and P&amp;lt;0.001) and higher percentage of TP53 alterations (the loss or UPD and/or mutations) than those without (P&amp;lt;0.001 and P&amp;lt;0.001). Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4 or ERCC1/2 in tumors, patients with additional defects in DNA damage repair genes had worse OS (P=0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer. Citation Format: Mamoru Takada, Yasuhiko Kaneko, Masayuki Haruta, Shigenori Nagai, Kenichi Inoue, Katsunori Toduka, Masafumi Kurozumi, Hiroyuki Takei, Seishi Ogawa, Takeshi Nagashima, Takafumi Sangai, Hiroshi Fujimoto, Junta Sakakibara, Ryotaro Teranaka. BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-15.
Abstract ES7-2: The toll on health care providers
Authors: SH Giordano
Journal: Cancer Research (2020)

Abstract The Toll on Health Care Providers Challenging conversation between health care provider and patients and their families can contribute to provider’s burnout. A challenging interaction for a medical professional already overstretched by the healthcare system may increase levels of stress, anxiety and anger, which in turn will affect performance and communication. Burnout is a well-known work-related stress syndrome characterized by exhaustion, cynicism, and inefficiency. It is established that at least 50% of US physicians experience professional burnout with consequent negative impact on quality care, patient satisfaction, and overall institutional success. Cancer care professionals have experienced a drastically increase in the incidence of burnout over the past decade due to the emotionally demanding nature of their work and the ever-growing burden of administrative work. A recent Medscape report describes a burnout rate of 55% among female oncologist and 45% among male oncologist. Both individual physician level factors and organizational level factors contribute to oncologist burnout. We will discuss common driver factors and strategies to prevent and mitigate this public health problem. Many gaps in our knowledge on physician burnout remain, but effective individual and organizational interventions are crucial for the prevention and improvement of clinician well-being and need to be incorporated into oncology care. Citation Format: SH Giordano. The toll on health care providers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES7-2.
Using observational data to quantify bias of traveller-derived COVID-19 prevalence estimates in Wuhan, China
Authors: Rene Niehus, Pablo M De Salazar, Aimee R Taylor, Marc Lipsitch
Journal: The Lancet Infectious Diseases (2020)

The incidence of coronavirus disease 2019 (COVID-19) in Wuhan, China, has been estimated using imported case counts of international travellers, generally under the assumptions that all cases of the disease in travellers have been ascertained and that infection prevalence in travellers and residents is the same. However, findings indicate variation among locations in the capacity for detection of imported cases. Singapore has had very strong epidemiological surveillance and contact tracing capacity during previous infectious disease outbreaks and has consistently shown high sensitivity of case-detection during the COVID-19 outbreak.
Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts
Authors: Albert Gris-Oliver, Marta Palafox, Laia Monserrat, Fara Brasó-Maristany, Andreu Òdena, Mònica Sánchez-Guixé, Yasir H. Ibrahim, Guillermo Villacampa, Judit Grueso, Mireia Parés, Marta Guzmán, Olga Rodríguez, Alejandra Bruna, Caroline S. Hirst, Alan Barnicle, Elza C. de Bruin, Avinash Reddy, Gaia Schiavon, Joaquín Arribas, Gordon B. Mills, Carlos Caldas, Rodrigo Dienstmann, Aleix Prat, Paolo Nuciforo, Pedram Razavi, Maurizio Scaltriti, Nicholas C. Turner, Cristina Saura, Barry R. Davies, Mafalda Oliveira, Violeta Serra
Journal: Clinical Cancer Research (2020)

Abstract Purpose: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor–positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. Experimental Design: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. Results: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. Conclusions: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
Liver transplantation in Rio de Janeiro, Brazil: A retrospective cohort study
Authors: Victor Diniz, Monica Martins, José Cardoso, Mariana Abrahão, Caio Wierzchon, Munique Siqueira, Eduardo Fernandes, Camila Kyt, Maria Monachesi, Camila Girão, Ronaldo Andrade, Camilla Cesar, Felipe Mello, Leandro Pimentel
Journal: International Journal of Surgery (2020)
COVID-19 threatens health systems in sub-Saharan Africa: the eye of the crocodile
Authors: Elijah Paintsil
Journal: Journal of Clinical Investigation (2020)

The threat of coronavirus disease 2019 to health systems in sub-Saharan Africa (SSA) can be compared metaphorically to a lake in Africa infested with a bask of crocodiles and the saying "the eye of the crocodile."In the lake, only the eyes of the crocodile appear on the surface while the rest of the body is submerged in water.In this Viewpoint, the eyes and the body of the crocodile represent the public health preparedness and health systems, respectively, in SSA.SSA has had multiple epidemics, including, in the last 3 decades, HIV and Ebola virus.Interestingly, HIV, Ebola virus, and SARS-CoV-2 are all of zoonotic origin.HIV resulted from cross-species transfer of simian immunodeficiency virus from chimpanzees, found in eastern and central Africa, to humans (1).Ebola virus was discovered in humans during concurrent outbreaks in the Democratic Republic of Congo and the Sudan in 1976 (2, 3).It is believed that bats are the natural hosts of Ebola virus.SARS-CoV-2 also originated from bats found in caves in China.Although HIV and Ebola originated in Africa, SARS-CoV-2 was imported from China.This Viewpoint discusses the potential impact of the COVID-19 epidemic on already-fragile health systems in SSA and forecasts lessons likely to be learned from COVID-19 in SSA.
Long noncoding RNA BANCR predicts poor clinical outcome in periampullary tumors
Authors: Fuat Aksoy, Halit Ziya Dundar, Secil Ak Aksoy, Berrin Tunca, Pinar Tasar, Yilmaz Ozen, Gulsah Cecener, Unal Egeli, Nesrin Ugras, Omer Yerci, Ekrem Kaya
Journal: International Journal of Surgery (2020)
Whole-Exome Sequencing Analysis of the Progression from Non–Low-Grade Ductal Carcinoma<i>In Situ</i>to Invasive Ductal Carcinoma
Authors: Fresia Pareja, David N. Brown, Ju Youn Lee, Arnaud Da Cruz Paula, Pier Selenica, Rui Bi, Felipe C. Geyer, Andrea Gazzo, Edaise M. da Silva, Mahsa Vahdatinia, Anthe A. Stylianou, Lorenzo Ferrando, Hannah Y. Wen, James B. Hicks, Britta Weigelt, Jorge S. Reis-Filho
Journal: Clinical Cancer Research (2020)

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease.Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods.DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed.Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.
Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity
Authors: Faheem Farooq, Peter J. Mogayzel, Sophie Lanzkron, Carlton Haywood, John J. Strouse
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Sickle cell disease (SCD) and cystic fibrosis (CF) are severe autosomal recessive disorders associated with intermittent disease exacerbations that require hospitalizations, progressive chronic organ injury, and substantial premature mortality. Research funding is a limited resource and may contribute to health care disparities, especially for rare diseases that disproportionally affect economically disadvantaged groups. <h3>Objective</h3> To compare disease-specific funding between SCD and CF and the association between funding and research productivity. <h3>Design, Setting, and Participants</h3> This cross-sectional study examined federal and foundation funding, publications indexed in PubMed, clinical trials registered in ClinicalTrials.gov, and new drug approvals from January 1, 2008, to December 31, 2018, in an estimated US population of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF. <h3>Main Outcomes and Measures</h3> Federal and foundation funding, publications indexed in PubMed, clinical trial registrations, and new drug approvals. <h3>Results</h3> From 2008 through 2018, federal funding was greater per person with CF compared with SCD (mean [SD], $2807 [$175] vs $812 [$147];<i>P</i> &lt; .001). Foundation expenditures were greater for CF than for SCD (mean [SD], $7690 [$3974] vs $102 [$13.7];<i>P</i> &lt; .001). Significantly more research articles (mean [SD], 1594 [225] vs 926 [157];<i>P</i> &lt; .001) and US Food and Drug Administration drug approvals (4 vs 1) were found for CF compared with SCD, but the total number of clinical trials was similar (mean [SD], 27.3 [6.9] vs 23.8 [6.3];<i>P</i> = .22). <h3>Conclusions and Relevance</h3> The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.
Targeting JAK/STAT pathway in Takayasu’s arteritis
Authors: Paul Régnier, Alexandre Le Joncour, Anna Maciejewski-Duval, Anne-Claire Desbois, Cloé Comarmond, Michelle Rosenzwajg, David Klatzmann, Patrice Cacoub, David Saadoun
Journal: Annals of the Rheumatic Diseases (2020)

Takayasu's arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK.We analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK.Transcriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients.JAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.
Covid-19: death rate is 0.66% and increases with age, study estimates
Authors: Elisabeth Mahase
Journal: BMJ (2020)

19: death rate is 0.66% and increases with age, study estimates Elisabeth MahaseThe BMJThe overall death rate from covid-19 has been estimated at 0.66%, rising sharply to 7.8% in people aged over 80 and declining to 0.0016% in children aged 9 and under.
Siamese neural networks for continuous disease severity evaluation and change detection in medical imaging
Authors: Matthew D. Li, Ken Chang, Ben Bearce, Connie Y. Chang, Ambrose J. Huang, J. Peter Campbell, James M. Brown, Praveer Singh, Katharina V. Hoebel, Deniz Erdoğmuş, Stratis Ioannidis, William E. Palmer, Michael F. Chiang, Jayashree Kalpathy-Cramer
Journal: npj Digital Medicine (2020)

Using medical images to evaluate disease severity and change over time is a routine and important task in clinical decision making. Grading systems are often used, but are unreliable as domain experts disagree on disease severity category thresholds. These discrete categories also do not reflect the underlying continuous spectrum of disease severity. To address these issues, we developed a convolutional Siamese neural network approach to evaluate disease severity at single time points and change between longitudinal patient visits on a continuous spectrum. We demonstrate this in two medical imaging domains: retinopathy of prematurity (ROP) in retinal photographs and osteoarthritis in knee radiographs. Our patient cohorts consist of 4861 images from 870 patients in the Imaging and Informatics in Retinopathy of Prematurity (i-ROP) cohort study and 10,012 images from 3021 patients in the Multicenter Osteoarthritis Study (MOST), both of which feature longitudinal imaging data. Multiple expert clinician raters ranked 100 retinal images and 100 knee radiographs from excluded test sets for severity of ROP and osteoarthritis, respectively. The Siamese neural network output for each image in comparison to a pool of normal reference images correlates with disease severity rank (ρ = 0.87 for ROP and ρ = 0.89 for osteoarthritis), both within and between the clinical grading categories. Thus, this output can represent the continuous spectrum of disease severity at any single time point. The difference in these outputs can be used to show change over time. Alternatively, paired images from the same patient at two time points can be directly compared using the Siamese neural network, resulting in an additional continuous measure of change between images. Importantly, our approach does not require manual localization of the pathology of interest and requires only a binary label for training (same versus different). The location of disease and site of change detected by the algorithm can be visualized using an occlusion sensitivity map-based approach. For a longitudinal binary change detection task, our Siamese neural networks achieve test set receiving operator characteristic area under the curves (AUCs) of up to 0.90 in evaluating ROP or knee osteoarthritis change, depending on the change detection strategy. The overall performance on this binary task is similar compared to a conventional convolutional deep-neural network trained for multi-class classification. Our results demonstrate that convolutional Siamese neural networks can be a powerful tool for evaluating the continuous spectrum of disease severity and change in medical imaging.
Actinomycin D downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma
Authors: Jessica T Taylor, Stuart Ellison, Alina Pandele, Shaun Wood, Erica Nathan, Gabriella Forte, Helen Parker, Egor Zindy, Mark Elvin, Alan Dickson, Kaye J Williams, Konstantina Karabatsou, Martin McCabe, Catherine McBain, Brian W Bigger
Journal: Neuro-Oncology (2020)

Abstract Background Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.