tbuckley/cabot-search huggingface dataset:
Abstract A31: Tumor stroma in the development of acquired cancer therapy resistance
Authors: Jesus Gomez-Escudero, Eleni Maniati, Freddie Whiting, Jun Wang, Trevor Graham, Kairbaan Hodivala-Dilke
Journal: Cancer Research (2020)

Abstract Despite the onset of new treatment strategies, mortality rates for breast cancer are estimated at approximately 600,000 women per year, mostly due to acquired resistance to therapy. Chemotherapy, often combination therapy, includes DNA-damaging agents such as epirubicin, an epimer of doxorubicin. Although chemotherapy has been reported to reduce recurrence rates by 50% over two years, eight-year survival rates are approximately 30% and overall mortality is 20-25%. Studies aiming to overcome resistance to therapy have focused mainly on in vitro malignant cell assays. These have failed to deliver appropriate targets to overcome resistance because they have failed to account for the influence of the tumor microenvironment on chemoresistance. Published evidence indicates that resistance to therapy is not malignant cell-intrinsic, but instead depends on DNA-damaging chemotherapy-induced changes in paracrine signals from endothelial cells. Our current research has established that the doxorubicin treatment acutely affects endothelial cells with long-term effects on tumor cell resistance to therapy in vivo. Endothelial cells are heterogenous, and the effect of DNA damage on endothelial cell evolution and how this regulates malignant cell resistance to therapy is unknown. We have observed that orthotopic murine mammary tumors arising from the same source of primary mammary tumor cells show differential chemotherapy responses. RNA seq analysis of tumors after acute doxorubicin treatment reveal highest levels of differential transcript expression in endothelial cells compared with cancer-associated fibroblasts or malignant cells. In vitro assays show that conditioned media from tumor endothelial cells treated with chemotherapy can protect tumor cells from DNA damage and cell death. Current analysis now focuses on analyzing the complexity of endothelial cell regulation of tumor cell response to chemotherapy and how this could model clonal evolution of tumor cells. We aim to create a chemoresistance stromal evolution signature, to determine the individual components of this and commonalities between cancers and possible drug effects. Thus, our data could change the paradigm of drug resistance and define how stromal compartments regulate acquired resistance. Citation Format: Jesus Gomez-Escudero, Eleni Maniati, Freddie Whiting, Jun Wang, Trevor Graham, Kairbaan Hodivala-Dilke. Tumor stroma in the development of acquired cancer therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A31.
Missed Opportunities for Prevention of Congenital Syphilis — United States, 2018
Authors: Anne Kimball, Elizabeth Torrone, Kathryn Miele, Laura Bachmann, Phoebe Thorpe, Hillard Weinstock, Virginia Bowen
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Congenital syphilis is an infection with Treponema pallidum in an infant or fetus, acquired during pregnancy from a mother with untreated or inadequately treated syphilis. Congenital syphilis can cause miscarriage, stillbirth, or early infant death, and infected infants can experience lifelong physical and neurologic problems. Although timely identification and treatment of maternal syphilis during pregnancy can prevent congenital syphilis (1,2), the number of reported congenital syphilis cases in the United States increased 261% during 2013-2018, from 362 to 1,306. Among reported congenital syphilis cases during 2018, a total of 94 resulted in stillbirths or early infant deaths (3). Using 2018 national congenital syphilis surveillance data and a previously developed framework (4), CDC identified missed opportunities for congenital syphilis prevention. Nationally, the most commonly missed prevention opportunities were a lack of adequate maternal treatment despite the timely diagnosis of syphilis (30.7%) and a lack of timely prenatal care (28.2%), with variation by geographic region. Congenital syphilis prevention involves syphilis prevention for women and their partners and timely identification and treatment of pregnant women with syphilis. Preventing continued increases in congenital syphilis requires reducing barriers to family planning and prenatal care, ensuring syphilis screening at the first prenatal visit with rescreening at 28 weeks' gestation and at delivery, as indicated, and adequately treating pregnant women with syphilis (2). Congenital syphilis prevention strategies that implement tailored public health and health care interventions to address missed opportunities can have substantial public health impact.
Reconsidering Mycobacterium bovis as a proxy for zoonotic tuberculosis: a molecular epidemiological surveillance study
Authors: Shannon C Duffy, Sreenidhi Srinivasan, Megan A Schilling, Tod Stuber, Sarah N Danchuk, Joy S Michael, Manigandan Venkatesan, Nitish Bansal, Sushila Maan, Naresh Jindal, Deepika Chaudhary, Premanshu Dandapat, Robab Katani, Shubhada Chothe, Maroudam Veerasami, Suelee Robbe-Austerman, Nicholas Juleff, Vivek Kapur, Marcel A Behr
Journal: The Lancet Microbe (2020)

BackgroundZoonotic tuberculosis is defined as human infection with Mycobacterium bovis. Although globally, India has the largest number of human tuberculosis cases and the largest cattle population, in which bovine tuberculosis is endemic, the burden of zoonotic tuberculosis is unknown. The aim of this study was to obtain estimates of the human prevalence of animal-associated members of the Mycobacterium tuberculosis complex (MTBC) at a large referral hospital in India.MethodsWe did a molecular epidemiological surveillance study of 940 positive mycobacteria growth indicator tube (MGIT) cultures, collected from patients visiting the outpatient department at Christian Medical College (Vellore, India) with suspected tuberculosis between Oct 1, 2018, and March 31, 2019. A PCR-based approach was applied to subspeciate cultures. Isolates identified as MTBC other than M tuberculosis or as inconclusive on PCR were subject to whole-genome sequencing (WGS), and phylogenetically compared with publicly available MTBC sequences from south Asia. Sequences from WGS were deposited in the National Center for Biotechnology Information Sequence Read Archive, accession number SRP226525 (BioProject database number PRJNA575883).FindingsThe 940 MGIT cultures were from 548 pulmonary and 392 extrapulmonary samples. A conclusive identification was obtained for all 940 isolates; wild-type M bovis was not identified. The isolates consisted of M tuberculosis (913 [97·1%] isolates), Mycobacterium orygis (seven [0·7%]), M bovis BCG (five [0·5%]), and non-tuberculous mycobacteria (15 [1·6%]). Subspecies were assigned for 25 isolates by WGS, which were analysed against 715 MTBC sequences from south Asia. Among the 715 genomes, no M bovis was identified. Four isolates of cattle origin were dispersed among human sequences within M tuberculosis lineage 1, and the seven M orygis isolates from human MGIT cultures were dispersed among sequences from cattle.InterpretationM bovis prevalence in humans is an inadequate proxy of zoonotic tuberculosis. The recovery of M orygis from humans highlights the need to use a broadened definition, including MTBC subspecies such as M orygis, to investigate zoonotic tuberculosis. The identification of M tuberculosis in cattle also reinforces the need for One Health investigations in countries with endemic bovine tuberculosis.FundingBill & Melinda Gates Foundation, Canadian Institutes for Health Research.
What Is a Normal Blood Pressure?
Authors: Daniel W. Jones
Journal: JAMA Cardiology (2020)

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Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis
Authors: Dong Chen, Zhiliang Duan, Wenhua Zhou, Weiwei Zou, Shengwei Jin, Dezhou Li, Xinyu Chen, Yongchao Zhou, Lan Yang, Yanjun Zhang, Sujan Shresta, Jinsheng Wen
Journal: The Journal of Experimental Medicine (2020)

Cross-reactive anti-flaviviral immunity can influence the outcome of infections with heterologous flaviviruses. However, it is unclear how the interplay between cross-reactive antibodies and T cells tilts the balance toward pathogenesis versus protection during secondary Zika virus (ZIKV) and Japanese encephalitis virus (JEV) infections. We show that sera and IgG from JEV-vaccinated humans and JEV-inoculated mice cross-reacted with ZIKV, exacerbated lethal ZIKV infection upon transfer to mice, and promoted viral replication and mortality upon ZIKV infection of the neonates born to immune mothers. In contrast, transfer of CD8+ T cells from JEV-exposed mice was protective, reducing the viral burden and mortality of ZIKV-infected mice and abrogating the lethal effects of antibody-mediated enhancement of ZIKV infection in mice. Conversely, cross-reactive anti-ZIKV antibodies or CD8+ T cells displayed the same pathogenic or protective effects upon JEV infection, with the exception that maternally acquired anti-ZIKV antibodies had no effect on JEV infection of the neonates. These results provide clues for developing safe anti-JEV/ZIKV vaccines.
Response to Discussion: ‘Which specific modes of exercise training are most effective for treating low back pain? Network meta-analysis’
Authors: Daniel L Belavy, Patrick J Owen, Clint T Miller, Niamh L Mundell, Scott D Tagliaferri, Helena Brisby, Steven J Bowe
Journal: British Journal of Sports Medicine (2020)

We recently published1 a network meta-analysis (NMA) on the effect of different modes of exercise training in patients with chronic non-specific low back pain in the British Journal of Sports Medicine . We respond here to the questions posed by Maher et al .2

The authors of the letter commented that potential effect-modifying covariates need more investigation (evaluation of transitivity). As per NMA guidelines,3 we investigated potential effect-modifying covariates. Baseline pain and disability are commonly4–6 identified as key predictors of prognosis and treatment outcome for back pain. In our NMA,1 we presented these analyses in Supplemental Figure 2 of the original manuscript. These potential effect-modifying covariates (baseline pain, baseline disability) did not differ across the groups investigated. There might be many opinions7 on how to assess potential effect-modifying covariates and how to account for them in an NMA, as yet there is no consensus. Our analyses and reporting were based on current practices for NMA.3

The authors of the letter noted that forest plots/league tables were not provided. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines state that forest plots and/or league tables ‘may be considered’ but are not required.8 9 The comment reflects a different view …
Quantifying the importance of the key sites on haemagglutinin in determining the selection advantage of influenza virus: Using A/H3N2 as an example
Authors: Shi Zhao, Jingzhi Lou, Lirong Cao, Zigui Chen, Renee WY Chan, Marc KC Chong, Benny CY Zee, Paul KS Chan, Maggie H Wang
Journal: Journal of Infection (2020)
AB0075 SYNOVIAL TISSUE MACROPHAGES ARE DOMINANTLY ALTERNATIVELY ACTIVATED IN PATIENTS WITH MATURE OSTEOARTHRITIS
Authors: G. Laskarin, T. Kehler, D. Legović, V. Šantić, B. Ćurko-Cofek, V. Drvar, M. Rogoznica, D. Rukavina
Journal: Annals of the Rheumatic Diseases (2020)

Background: Macrophages are abundant inflammatory cell type in the synovial membrane of knee osteoarthritis (OA) (1). Their quantity is associated with radiographic severity of knee OA and joint symptoms (2), while their functions are set in response to micro-environmental signals (3). Classically activated macrophages M1 support T helper 1 (Th1) driven pro-inflammatory reactions, while alternatively activated macrophages M2 strengthen Th2 inflammatory processes (3). Objectives: To investigate activation status of synovial tissue macrophages in patients with mature OA in terms of M1 / M2 polarization. Methods: Synovial tissue samples (6) with abundant lymphocyte infiltration were obtained during aloarthroplasty. Double immunofluorescence labeling was performed on paraffin-embedded synovial tissue sections using primary rabbit anti-macrophage CD68 mAb in combination with mouse anti-human antibodies directed toward CD3, arginase-1, TNF-alpha and IL-15. CD206 and CD163 were single labelled. Results: CD68+ macrophages mostly co-expressed arginase-1 (4/6 samples), indicating their M2 orientation. Macrophages were placed in lining synovial tissue and nearby tissue-resident CD3+ cells. M2 markers CD206 and CD163 were found in the area of macrophage interaction with T cells. CD68+ cells co-expressing TNF-alpha or IL-15 M1 markers were in minority in these synovial tissues. Lymphocyte infiltration was less abundant in remaining (2/6) synovial tissue samples. Conclusion: Mature synovial tissue macrophages, equipped dominantly with arginase-1 are M2 oriented and might support Th2 immune response in surrounding T cells. References: [1]Grieshaber-Bouyer R, Kämmerer T, Rosshirt N, Nees TA, Koniezke P, Tripel E, Schiltenwolf M, Kirsch J, Hagmann S, Moradi B. Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip and Knee Osteoarthritis. J Clin Med. 2019;8(10):piiE1631. [2]Haraden CA, Huebner JL, Hsueh MF, Li YJ, Kraus VB. Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation. Arthritis Res Ther. 2019;21(1):146. [3]Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013;8(11):e80908. Acknowledgments: University of Rijeka supported the research by the grants No. Uni-ri-biomed-18-110 and No. Uni-ri-biomed-18-160. Disclosure of Interests: None declared
Detecting changes in quality‐of‐life over time in patients with peripheral vascular malformations: the OVAMA project
Authors: M.M. Lokhorst, S.E.R. Horbach, M. Waner, T.M. O, C.J.M. Vleuten, L.B. Mokkink, C.M.A.M. Horst, P.I. Spuls
Journal: British Journal of Dermatology (2020)

Vascular malformations are a group of rare congenital (present at birth) vessel anomalies. Mostly visible as a bumpy mass different in colour from normal skin, they can cause disfigurement of the face or body. Patients often experience pain, physical impairment, bleeding, and psycho‐social problems, leading to an overall poor quality of life. Thus, a main goal of treatment is improving their quality of life. Quality of life is measured with questionnaires, which are filled in by patients. To determine if a patient's quality of life improved or worsened after treatment, it is crucial that the questionnaire can detect changes over time. Never has a quality of life questionnaire been studied if it can detect changes in patients with vascular malformations. Consequently, it is impossible to evaluate if current treatments actually improve these patients’ quality of life. This study, from the Netherlands and U.S.A., aimed to find out if two widely used quality of life questionnaires, the ‘SF‐36’ and ‘Skindex‐29’, were able to detect changes in patients with vascular malformations. Sixty‐seven patients filled in the two questionnaires at two points in time. One group received treatment in between, and another group did not. When filling in the two questionnaires for the second time, patients were also asked if they experienced changes in aspects of quality of life. To deem the questionnaires as able to detect changes, a certain correlation was expected between the experienced change, and change in the scores of the questionnaires. For both questionnaires, the expected correlation was not found. The authors concluded that other questionnaires must be identified or developed to correctly detect changes in quality of life in patients with vascular malformations. This is a summary of the study: Responsiveness of quality‐of‐life measures in patients with peripheral vascular malformations: the OVAMA project
Effect of dose modifications on response to duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma in the DUO trial
Authors: Nicole Lamanna, Marco Montilo, Arpad Illes, Gabriel Etienne, Julio Delgado, Bryone J Kuss, Constantine S Tam, Fritz Offner, Francesc Bosch, Matthew S Davids, Ulrich Jaeger, Paolo Ghia, Florence Cymalista, David T Weaver, Stephanie Lustgarten, Hagop Youssoufian, Stephan Stilgenbauer, Ian W Flinn
Journal: American Journal of Hematology (2019)
Rammya Mathew: We must not be guided by bad science on covid-19
Authors: Rammya Mathew
Journal: BMJ (2020)

The covid-19 pandemic has forced the scientific world to make a huge number of decisions in an unimaginably short time. At the mercy of this new virus, and in our haste to respond, has bad science resurfaced and adversely influenced decision making, at both policy and practice level?

In the early stages of the pandemic we didn’t always separate anecdote from evidence. Concerns about NSAIDs spread quickly, and oral steroids were unnecessarily withheld from patients exacerbating with asthma or chronic obstructive pulmonary disorder. Information now travels more quickly than ever, but reliable and false information both spread at …
Abstract IA13: Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer
Authors: Yibin Kang
Journal: Cancer Research (2020)

Abstract Breast cancer remains a significant health concern worldwide. Integrative genomic analysis of clinical breast cancer samples identified Metadherin (MTDH) as a driver gene that promotes breast cancer initiation, progression, and treatment resistance. Using genetically engineered mouse models, we found that MTDH sustains breast cancer progression and metastasis via interacting with SND1, and acute Mtdh loss inhibits breast cancer development. Using a structure-based small-molecule screen, we obtained a serial of MTDH/SND1 inhibitors. Treatments of the compounds suppress breast tumor growth and metastasis and sensitize breast cancer to chemotherapy by sensitizing cancer cells to stress-induced apoptosis. This series of studies illustrates the use of mouse models to validate clinically relevant novel therapeutic targets for breast cancer and illustrates the functional mechanism of driver genes in cancer progression and metastasis. Citation Format: Yibin Kang. Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA13.
Pattern of liver injury in adult patients with COVID-19: a retrospective analysis of 105 patients
Authors: Qi Wang, Hong Zhao, Li-Gai Liu, Yan-Bin Wang, Ting Zhang, Ming-Hui Li, Yan-Li Xu, Gui-Ju Gao, Hao-Feng Xiong, Ying Fan, Ying Cao, Rui Ding, Jing-Jing Wang, Cheng Cheng, Wen Xie
Journal: Military Medical Research (2020)

Recent studies reported that patients with coronavirus disease-2019 (COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) have been shown.This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild group (n = 79) and severe group(n = 26). We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined.56.2% (59/105) of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4% (96/105) cases the level of ALT, AST or TBil ≤3 fold of the upper limit of normal reference range (ULN). The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group (P < 0.05). The percentage of the patients with elevated both ALT and AST was 12.7% (10/79) in mild cases vs. 46.2% (12/26) in severe cases (P = 0.001). 34.6% (9/26) severe group patients started to have abnormal ALT after admission, and 73.3% (77/105) of all patients had normal ALT before discharge.Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3 × ULN, but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.