tbuckley/cabot-search huggingface dataset:
TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers
Authors: Jocelyn Charlton, Eunmi J. Jung, Alexandra L. Mattei, Nina Bailly, Jing Liao, Eric J. Martin, Pay Giesselmann, Björn Brändl, Elena K. Stamenova, Franz-Josef Müller, Evangelos Kiskinis, Andreas Gnirke, Zachary D. Smith, Alexander Meissner
Journal: Nature Genetics (2020)
Multilingual Analysis of the Quality and Readability of Online Health Information on the Adverse Effects of Breast Cancer Treatments
Authors: Maia Fefer, Carolyn C. Lamb, Abra H. Shen, Peter Clardy, Vinayak Muralidhar, Phillip M. Devlin, Edward Christopher Dee
Journal: JAMA Surgery (2020)

This quality improvement study assesses the quality and readability of online health information that patients may encounter when seeking information on adverse effects of breast cancer treatment.
A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors
Authors: Zhaojun Qiu, Pengyan Fa, Tao Liu, Chandra B. Prasad, Shanhuai Ma, Zhipeng Hong, Ernest R. Chan, Hongbing Wang, Zaibo Li, Kai He, Qi-En Wang, Terence M. Williams, Chunhong Yan, Steven T. Sizemore, Goutham Narla, Junran Zhang
Journal: Cancer Research (2020)

Abstract There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non–small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC in vitro and in vivo and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors. Significance: This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
<i>Lactobacillus rhamnosus</i> probiotic prevents airway function deterioration and promotes gut microbiome resilience in a murine asthma model
Authors: Irina Spacova, Wannes Van Beeck, Sven Seys, Fien Devos, Jeroen Vanoirbeek, Jozef Vanderleyden, Jan Ceuppens, Mariya Petrova, Sarah Lebeer
Journal: Gut Microbes (2020)

Allergic asthma is a highly prevalent inflammatory disease of the lower airways, clinically characterized by airway hyperreactivity and deterioration of airway function. Immunomodulatory probiotic bacteria are increasingly being explored to prevent asthma development, alone or in combination with other treatments.In this study, wild-type and recombinant probiotic Lactobacillus rhamnosus GR-1 were tested as preventive treatment of experimental allergic asthma in mice. Recombinant L. rhamnosus GR-1 was designed to produce the major birch pollen allergen Bet v 1, to promote allergen-specific immunomodulation. Administration of wild-type and recombinant L. rhamnosus GR-1 prevented the development of airway hyperreactivity. Recombinant L. rhamnosus GR-1 also prevented elevation of airway total cell counts, lymphocyte counts and lung IL-1β levels, while wild-type L. rhamnosus GR-1 inhibited airway eosinophilia. Of note, a shift in gut microbiome composition was observed after asthma development, which correlated with the severity of airway inflammation and airway hyperreactivity. In the groups that received L. rhamnosus GR-1, this asthma-associated shift in gut microbiome composition was not observed, indicating microbiome-modulating effects of this probiotic.These data demonstrate that L. rhamnosus GR-1 can prevent airway function deterioration in allergic asthma. Bet v 1 expression by L. rhamnosus GR-1 further contributed to lower airway inflammation, although not solely through the expected reduction in T helper 2-associated responses, suggesting involvement of additional mechanisms. The beneficial effects of L. rhamnosus GR-1 correlate with increased gut microbiome resilience, which in turn is linked to protection of airway function, and thus further adds support to the existence of a gut-lung axis.
FRI0633-HPR PHYSICAL AND SOCIAL ACTIVITY OF PATIENTS SUFFERING FROM JUVENILE IDIOPATHIC ARTHRITIS
Authors: T. Shelepina
Journal: Annals of the Rheumatic Diseases (2020)

Background: Juvenile Idiopathic Artritis (JIA) is a chronic, disabling disease of a childhood age that significantly limits the patient’s capabilities and affects the life quality. Modern drug therapies can prevent most of the negative consequences of the disease and maintain satisfactory functional abilities of patients. Objectives: to examine the nature of the daily physical and social activities of patients suffering from JIA. Methods: the study included 236 patients aged from 4 to 17 years old undergoing in-patient treatment. Among them, 146 (62%) - polyarthritis and spreading oligoarthritis, including 13 (5.5%) - with damage to the eyes, persistent oligoarthritis - 60 (25%), including 26 (11%) with damage to the eyes, systemic JIA 22 (16%), enthesitis-associated 8 (3%). The patients were divided into the following age groups: pre-school age (4-6 years old) – 26 patients (11%), primary school age (7-10 years old) - 54 patients (23%); an average school age (11-12 years old) – 49 patients (21%), senior school age (13-15 years old) -52 patients (22%), youth (16-17 years old) -55 patients (23%). The assessment methods: collection of their pharmacological history, questioning (with an author’s questionnaire) the parents of children aged from 4 to 10 years and older patients themselves, VAS pain evaluation, a CHAQ questionnaire. Results: 10 (4%) patients received NSAID, 88 (38%) patients - synthetic basic anti-inflammatory drugs, biological therapy - 133 (56%), 5 patients (2%) did not receive any drug therapy. An average value of the VAS pain evaluation: 2.5 cm, the CHAQ functional insufficiency is low: 137 patients (58%), medium insufficiency in 88 patients (37%), a severe one in 11 patients (5%). Children’s educational institutions were regularly visited by 199 (85%) patients, leisure activities were enjoyed by 90 (38%) patients; at that, the highest rate of leisure activities was recorded for the age group 112-12 years (67% of the entire group), daily walks were recorded in 172 (73%) patients, doing homework on a regular basis by 155 (66%) patients, regular doing exercises of therapeutic gymnastics recorded in 55 (24%) patients. Conclusion: The social activity of patients suffering from JIA can be estimated as satisfactory, while their physical activity as inadequate. An adequate social and physical activation of patients with JIA being in the remission status is required. This can be facilitated by educational programs for patients and their parents, a joint discussion of issues on the social and physical activity of patients and their parents with rheumatologists and rehabilitation therapy specialists. Acknowledgments: I thank senior researcher, E. S. Fedorov MD for his help in completing the work and preparing abstracts Disclosure of Interests: None declared
THU0443 SEASONAL VARIATIONS AND ASSOCIATED FACTORS OF GOUT ATTACKS: A PROSPECTIVE MULTICENTER STUDY IN SOUTH KOREA
Authors: H. J. Choi, K. W. Moon, H. O. Kim, Y. A. Lee, S. J. Hong, J. Y. Jung, H. A. Kim, C. H. Suh, Y. J. Ha, I. J. Kim, J. Lee, E. K. Park, S. G. Lee, M. R. Seo, H. J. Baek, S. T. Choi, J. S. Song
Journal: Annals of the Rheumatic Diseases (2020)

Background: Gout shows a seasonal variation that widely differs among geographic areas, and we previously reported a seasonal effect on gout in Korea. However, we had no information regarding changes in diet and had only limited laboratory data because this was a retrospective study in patients receiving a urate-lowering therapy. Therefore, we designed this prospective study to elucidate the seasonality and associated factors of gout attacks in Korea. Objectives: To evaluate the seasonality and associated factors of the incidence of gout attacks in Korea. Methods: We prospectively enrolled patients with gout attacks who were treated at nine rheumatology clinics between January 2015 and July 2018 and followed them for 1-year. Demographic data, clinical and laboratory features, and meteorological data including seasonality were collected. Results: Two hundred-five patients (males, 94.1%) were enrolled. The proportion of patients with initial gout attacks was 46.8% (n = 96). The mean age, body mass index, attack duration, and serum uric acid level at enrollment were 50.5 years, 26.1, 10.2 days, and 7.3 mg/dL, respectively. Gout attacks were most common during spring (43.4%, P &lt; 0.001) and in March (23.4 %, P &lt; 0.001). A similar pattern of seasonality was observed in the group with initial gout attacks. Alcohol was the most common provoking factor (39.0%), particularly during summer (50.0%). The mean diurnal temperature change on the day of the attack was highest in the spring (10.3°C), followed by winter (9.1°C), summer (8.1°C), and fall (8.0°C) ( P = 0.027). The mean change in humidity between the 2 consecutive days (the day before and the day of the attack) was significantly different among the seasons (3.4%, spring; 0.2%, summer; 0.4%, fall; -3.9%, winter; P = 0.015). One hundred twenty-five (61%) patients completed 1-year follow-up (51% in the initial attack group). During the follow-up period, 51 gout flares developed (18 in the initial attack group). No significant seasonal variation in the follow-up flares was found. Conclusion: In this prospective study, the most common season and month of gout attacks in Korea were spring and March, respectively. Alcohol was the most common provoking factor, particularly during summer. Diurnal temperature changes on the day of the attack and humidity changes from the day before the attack to the day of the attack were associated with gout attack in our cohort. References: [1]Choi HJ, Lee CH, Lee JH et al. Seasonality of gout in Korea: a multicenter study. J Korean Med Sci 2015;30:240-4. Disclosure of Interests: : None declared
Abstract IA22: Tumor-educated platelets for the detection of cancer
Authors: Thomas Wurdinger
Journal: Clinical Cancer Research (2020)

Abstract Blood-based “liquid biopsies” provide a means for minimally invasive molecular diagnostics, overcoming limitations of tissue acquisition. Early detection of cancer, clinical cancer diagnostics, and companion diagnostics are regarded as important applications of liquid biopsies. It has been reported that tumor-educated platelets (TEPs) may enable blood-based cancer diagnostics. Platelets have emerged as central players in the systemic and local responses to tumor growth. Confrontation of platelets with tumor cells via transfer of tumor-associated biomolecules (“education”) is an emerging concept and can result in the sequestration of biomolecules. Moreover, external stimuli induce specific splicing of pre-mRNAs in circulating platelets. Platelets are considered to undergo queue-specific splice events in response to signals released by cancer cells and the tumor microenvironment, such as stromal and immune cells. The combination of specific splice events in response to external signals and the capacity of platelets to directly ingest (spliced) circulating mRNA can provide TEPs with a highly dynamic mRNA repertoire, with potential applicability to cancer diagnostics. We determined the diagnostic potential of TEPs by mRNA sequencing of platelet samples. Blood platelet samples of &amp;gt;1,000 patients with cancer covering multiple tumor types and healthy donors were analyzed. Healthy donors and early- and late-stage cancer patients were distinguished by a self-learning support vector machine (SVM) algorithm, using a set of spliced platelet transcripts with moderate to high expression. These results suggest that blood platelets may advance blood-based “liquid biopsies,” including for the detection of stage I-II tumors. Citation Format: Thomas Wurdinger. Tumor-educated platelets for the detection of cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA22.
Combination checkpoint blockade for metastatic cutaneous malignancies in kidney transplant recipients
Authors: Megan H Trager, Shana M Coley, Geoffrey Dube, Shaheer Khan, Matthew Ingham, Faramarz H Samie, Larisa J Geskin, Diana McDonnell, Daniel Brouder, Yvonne Saenger, Richard Carvajal
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection. Case presentations Here we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course. Conclusions These cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease. Trial Registration number NCT03816332 .
Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea
Authors: Jun Ho Jang, Youjin Kim, Silvia Park, Kihyun Kim, Seok Jin Kim, Won Seog Kim, Chul Won Jung, Jeeyun Lee, Se-Hoon Lee
Journal: PLoS Medicine (2020)

Background Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. Methods and findings We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90–1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. Conclusions Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. Trial registration Clinicaltrials.gov NCT02599012
Abstract B08: Tumor-educated platelets for early prostate cancer diagnosis, and therapy stratification in patients with metastasized castration resistant prostate cancer
Authors: Lee-Ann Tjon-Kon-Fat, Linda Köhn, Myron Best, Marie Lundholm, Thomas Wurdinger, Anders Widmark, Camilla Thellenberg-Karlsson, Pernilla Wikström, Jonas Nilsson
Journal: Clinical Cancer Research (2020)

Abstract One in every ten men diagnosed with prostate cancer will have metastases at some point, causing the high mortality of prostate cancer. Only earlier diagnosis has the chance to save those lives. However, correct therapy stratification may prolong the life of the patients without severely reducing the quality of life, thereby possibly turning a deadly disease into a chronic disease. For this to happen, we need predictive biomarkers that can be employed to longitudinally follow the disease in order to identify vulnerabilities and to monitor acquired resistance for personalized medicine. Using the platelet-enriched fraction of a blood sample, we here show that we can use the ability of platelets to sequester material during circulation to provide information derived from the tumor. This information could be used for early detection of prostate cancer. By using the platelet test in combination with PSA measurements, we may be able to rule out a majority of the false negatives associated with the PSA test. Furthermore, the platelet platform can be used in synergy with other biomarker sources such as circulating tumor DNA or protein biomarkers, providing the possibility to predict and monitor outcome of abiraterone therapy, and providing alternatives to the nonfunctional therapy by guiding therapy switching, in metastatic castration-resistant patients. Citation Format: Lee-Ann Tjon-Kon-Fat, Linda Köhn, Myron Best, Marie Lundholm, Thomas Wurdinger, Anders Widmark, Camilla Thellenberg-Karlsson, Pernilla Wikström, Jonas Nilsson. Tumor-educated platelets for early prostate cancer diagnosis, and therapy stratification in patients with metastasized castration resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B08.
Carcinocythemia—Cancer cell leukemia
Authors: Preetesh Jain, Xiaohong Iris Wang
Journal: American Journal of Hematology (2020)

A 60-year-old man presented with a one-week history of fatigue and bilateral lower extremity pain. Physical examination was normal. Work up revealed anemia (hemoglobin 8.4 g/dL), WBC 4.2 K/uL, platelets 55 K/uL, MCV 83 fL and PSA levels 1872 ng/L. Peripheral blood smear showed normocytic, normochromic anemia and thrombocytopenia. Atypical cells with irregular nuclear contour were also noted (A) and blasts or dysplasia was absent. MRI spine showed severe lumbar spinal canal narrowing and compression of the cauda equina nerve roots. CT scan showed pelvic/retroperitoneal lymphadenopathy and pleural effusions. Tc 99 m-labeled bone scan confirmed diffuse bone metastases. Bone marrow (BM) touch preparation demonstrated clusters of atypical cells with hyperchromatic nuclei (B). BM was replaced by atypical cells (C). The large atypical cells were positive for pancytokeratin and PSA (D-E). Immunophenotyping did not show any aberrant B or T cells. A diagnosis of carcinocythemia (carcinoma cell leukemia)1, 2 due to disseminated prostate cancer was rendered. The patient was treated with a combination of radiation therapy, systemic anti-androgen therapy, and had remarkable improvement in his clinical symptoms, anemia, and pancytopenia. Dissemination of prostate cancer in peripheral blood is extremely rare. Early recognition of this differential in patients with pancytopenia can expedite patient management. All authors have reviewed and approved the manuscript and do not have any disclosures/conflicts of interest related to this manuscript. Preetesh Jain and Xiaohong Iris Wang collected and analyzed hematopathology and wrote the paper. Preetesh Jain managed the patient.
Imbalance between Tolerant and Cytotoxic Functional Subsets of NK Cells in a JAK2V617F Myeloproliferative Neoplasm Model
Authors: Thiago Mantello Bianco, Adriana Queiroz Arantes, Izabela Aparecida Lopes, Priscila Santos Scheucher, Cleide Araújo Silva, Ann Mullally, Susumu S Kobayashi, Eduardo Magalhães Rego, Lorena Lobo Figueiredo-Pontes
Journal: Blood (2017)
Hypertonic saline for fluid resuscitation in ICU patients post-cardiac surgery (HERACLES): a double-blind randomized controlled clinical trial
Authors: Carmen A. Pfortmueller, Manuel Kindler, Noelle Schenk, Anna S. Messmer, Benjamin Hess, Laura Jakob, Stefanie Wenger, Jan Waskowski, Patrick Zuercher, Frederik Stoehr, Stephan M. Jakob, Lars Englberger, Joerg C. Schefold
Journal: Intensive Care Medicine (2020)
Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial
Authors: Jean-Yves Blay, César Serrano, Michael C Heinrich, John Zalcberg, Sebastian Bauer, Hans Gelderblom, Patrick Schöffski, Robin L Jones, Steven Attia, Gina D'Amato, Ping Chi, Peter Reichardt, Julie Meade, Kelvin Shi, Rodrigo Ruiz-Soto, Suzanne George, Margaret von Mehren
Journal: The Lancet Oncology (2020)