tbuckley/cabot-search huggingface dataset:
Chronic Allergen Stimulation Yields T cell Dysfunction in Obese Asthmatics
Authors: Sarah E. Henrickson, Bertram Bengsch, Sasikanth Manne, Kaitlin C. O'Boyle, Ramin S. Herati, Laura A. Vella, Scott E. Hensley, Joshua R. Rabinowitz, Susan Coffin, E. John Wherry
Journal: Journal of Allergy and Clinical Immunology (2018)
Targeted Retinal Photocoagulation for Diabetic Macular Edema with Peripheral Retinal Nonperfusion
Authors: David M. Brown, William C. Ou, Tien P. Wong, Rosa Y. Kim, Daniel E. Croft, Charles C. Wykoff
Journal: Ophthalmology (2018)

To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME).Phase I/II prospective, randomized, controlled clinical trial.Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus.Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1-disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated.Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered.At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters (P = 0.20) and mean CRT improved 302 and 152 μm (P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10-34) and 27.1 (range, 12-36), with 73% (362/496) and 80% (433/538) of PRN injections administered (P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively (P = 0.30).In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone.
Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors
Authors: Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt– van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Journal: Nature Medicine (2018)
Digital healthcare: regulating the revolution
Authors: Rishi Duggal, Ingrid Brindle, Jessamy Bagenal
Journal: BMJ (2018)

Abstract  The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. We report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks ERCC1 DNA-binding elements and restricts access to the XPF catalytic site. Binding of a model DNA junction separates the XPF helical and ERCC1 (HhH)2 domains, promoting activation. Using these structural data, we propose a model for a 5’-NER incision complex involving XPF-ERCC1-XPA and a DNA junction substrate. Structure-function data suggest xeroderma pigmentosum patient mutations often compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation.
Results from the 208-Week (4-Year) Follow-up of RESPONSE Trial, a Phase 3 Study Comparing Ruxolitinib (Rux) with Best Available Therapy (BAT) for the Treatment of Polycythemia Vera (PV)
Authors: Jean-Jacques Kiladjian, Srdan Verstovsek, Martin Griesshammer, Tamás Masszi, Simon Durrant, Francesco Passamonti, Claire N. Harrison, Fabrizio Pane, Pierre Zachee, Keita Kirito, Carlos Besses, Masayuki Hino, Ana Ines Varela, Carole B. Miller, Elisa Rumi, Vittorio Rosti, Igor Wolfgang Blau, Ruben A Mesa, Tuochuan Dong, Nathalie Francillard, Mary Laughlin, Alessandro M. Vannucchi
Journal: Blood (2017)
Doctors from overseas are missing out on dyslexia screening, researchers find
Authors: Abi Rimmer
Journal: BMJ (2018)

Doctors from outside the UK are not being screened for dyslexia before they sit UK exams, researchers have found.1

Research published in the Postgraduate Medical Journal looked at pass rates for the applied knowledge test (AKT)—a computer based component of the Membership of the Royal College of General Practitioners examination.

It showed that, while dyslexia was not associated with pass rates, doctors who failed the exam and then …
Abstract P084: Cardiovascular Disease Burden in African Americans: The Jackson Heart Study
Authors: Yuan-I Min, Pramod Anugu, Kenneth Butler, Adolfo Correa, Tara Hartley, Stanford Mwasongwe, Arnita Norwood, Mario Sims, Valerie Wallace, Wei Wang, Karen Winters
Journal: Circulation (2016)

Background: African Americans (AA) bear an excess burden of CVD compared to Whites. This burden persists when socioeconomic status (SES) and other known CVD risk factors are considered. One limitation to studies of Black-White disparities in CVD is that population subgroups with lower SES may be over-represented among AA compared to Whites. We aimed to quantify CVD burden in the Jackson Heart Study (JHS), an exclusively AA cohort with a balanced representation of SES. Methods: Baseline distributions of SES indicators in 5,301 JHS participants were compared to the US 2000 Census data. Baseline prevalence of myocardial infarction (MI), stroke and hypertension were compared to the National Health and Nutrition Examination Survey (NHANES) data collected during a comparable time period as the JHS baseline exam (2000-2004) (population reference including all races). Indirect standardization methods based on population age and sex specific prevalence were used to calculate the expected prevalence of MI, stroke and hypertension in the JHS. Standardized prevalence ratios (SPR) was calculated by dividing the observed by the expected prevalence. An SPR greater than 1 indicates excess burden. Results: Compared to national data, JHS participants were more likely to have some college education (61% vs. 52%) or a bachelor’s degree (32% vs. 24%), were more likely to hold management or professional occupations (36% vs. 34%), but had somewhat lower income, which could be in part due to a higher proportion (64%) of women in the JHS cohort. The observed baseline prevalence of MI, stroke and hypertension in JHS was 5.5%, 4.4% and 60.1%. The SPR for MI, stroke and hypertension were 1.05 (95% CI 0.88, 1.25), 1.39 (95% CI 1.12, 1.69) and 1.51 (1.42, 1.60) for men. The corresponding values for women were 1.61 (95% CI 1.37, 1.89), 1.33 (95% CI 1.12, 1.57) and 1.43 (95% CI 1.37, 1.50). Further analyses evaluating CVD risk factors (smoking, weight, physical activity, serum cholesterol, blood pressure and diabetes) found excess burden in overweight/obesity, physical inactivity, elevated blood pressure (≥140/90 mmHg), and diabetes among JHS participants compared to the population reference. Conclusions: We found an excess burden for stroke and hypertension in men, and an excess burden for MI, stroke and hypertension in women in the JHS. We also found an excess burden for CVD risk factors in the JHS cohort. Despite comparable SES between JHS and US population, we found an excess burden of CVD and CVD risk factors in this AA cohort.
Bone marrow stromal cells activate Stat3 and confer resistance to Bcr-Abl inhibitors in K562 CML cells
Authors: Nadine Bewry, Rajesh Nair, Mike Emmons, William Dalton, Lori Hazlehurst
Journal: Cancer Research (2008)

2454   Imatinib mesylate (IM) represents a potent molecularly targeted therapy against the oncogenic tyrosine kinase Bcr-Abl. Although IM has shown considerable efficacy against chronic myeloid leukemia (CML), treatment with IM is not curative and overtime most CML patients become refractory to further treatment. Acquired resistance to IM has been associated with mutations within the kinase domain of Bcr-Abl as well as over-expression of drug transporters. However,  in vitro  resistance models do not consider the role of the tumor microenvironment in the emergence of the drug resistant phenotype. The predominant microenvironment of CML is the bone marrow. This microenvironment is a rich source of both soluble factors and extracellular matrixes, which may influence drug response. To address the influence of the bone marrow microenvironment on IM sensitivity we utilized an  in vitro  co-culture bone marrow stroma model. Using a transwell system we demonstrated that soluble factors secreted by the HS-5 bone marrow stroma cell line were sufficient to cause resistance to apoptosis induced by IM. We subsequently determined that HS-5 conditioned media (CM) protects K562 CML cells from apoptosis induced by IM. We also determined that CM increases clonogenic survival following treatment with IM. Finally, culturing K562 cells in CM derived from HS-5 cells inhibits apoptosis induced by the second generation Bcr-Abl kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825). These data suggest that more potent Bcr-Abl inhibitors will not overcome resistance associated with the bone marrow microenvironment. HS-5 cells are reported to express several cytokines and growth factors known to activate Stat3. Given its crucial role in the survival of hematopoietic cells, we asked whether 1) CM derived from HS-5 cells can activate Stat3 in K562 cells and 2) does activation of Stat3 confer resistance to Bcr-Abl inhibitors. In this report we show that exposure of K562 cells to CM caused an increased Y705 phosphorylation of Stat3. Furthermore, using a siRNA approach, we found that reducing Stat3 expression sensitized K562 cells cultured in CM to apoptosis induced by IM (p
Abstract 11731: Oligogenic Familial Hypercholesterolemia, LDL Cholesterol, and Coronary Artery Disease
Authors: Hayato Tada, Masa-aki Kawashiri, Akihiro Nomura, Ryota Teramoto, Kazuyoshi Hosomichi, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, Atsushi Tajima, Masakazu Yamagishi
Journal: Circulation (2017)

Background: The concept of severe familial hypercholesterolemia (FH) was introduced with the aim of identifying individuals at an extremely high-risk for coronary artery disease (CAD) among those w...
Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ß1 secretion
Authors: Yu Ren, Huan-huan Jia, Yi-qi Xu, Xuan Zhou, Xiao-hui Zhao, Yun-fei Wang, Xin Song, Zhi-yan Zhu, Ting Sun, Yan Dou, Wei-ping Tian, Xiu-lan Zhao, Chun-sheng Kang, Mei Mei
Journal: Molecular Cancer (2018)

The communication between carcinoma associated fibroblasts (CAFs) and cancer cells facilitate tumor metastasis. In this study, we further underlying the epigenetic mechanisms of CAFs feed the cancer cells and the molecular mediators involved in these processes. MCF-7 and MDA-MB-231 cells were treated with CAFs culture conditioned medium, respectively. Cytokine antibody array, enzyme-linked immunosorbent assay, western blotting and immunofluorescence were used to identify the key chemokines. Chromatin immunoprecipitation and luciferase reporter assay were performed to explore the transactivation of target LncRNA by CAFs. A series of in vitro assays was performed with RNAi-mediated knockdown to elucidate the function of LncRNA. An orthotopic mouse model of MDA-MB-231 was conducted to confirm the mechanism in vivo. Here we reported that TGF-β1 was top one highest level of cytokine secreted by CAFs as revealed by cytokine antibody array. Paracrine TGF-β1 was essential for CAFs induced EMT and metastasis in breast cancer cells, which is a crucial mediator of the interaction between stromal and cancer cells. CAF-CM significantly enhanced the HOTAIR expression to promote EMT, whereas treatment with small-molecule inhibitors of TGF-β1 attenuated the activation of HOTAIR. Most importantly, SMAD2/3/4 directly bound the promoter site of HOTAIR, located between nucleotides -386 and -398, -440 and -452, suggesting that HOTAIR was a directly transcriptional target of SMAD2/3/4. Additionally, CAFs mediated EMT by targeting CDK5 signaling through H3K27 tri-methylation. Depletion of HOTAIR inhibited CAFs-induced tumor growth and lung metastasis in MDA-MB-231 orthotopic animal model. Our findings demonstrated that CAFs promoted the metastatic activity of breast cancer cells by activating the transcription of HOTAIR via TGF-β1 secretion, supporting the pursuit of the TGF-β1/HOTAIR axis as a target in breast cancer treatment.
O<sub>2</sub>-generating MnO<sub>2</sub> nanoparticles for enhanced photodynamic therapy of bladder cancer by ameliorating hypoxia
Authors: Tingsheng Lin, Xiaozhi Zhao, Sheng Zhao, Hang Yu, Wenmin Cao, Wei Chen, Hui Wei, Hongqian Guo
Journal: Theranostics (2018)

Photodynamic therapy (PDT) is an emerging effective treatment for cancer. However, the great promise of PDT for bladder cancer therapy has not yet been realized because of tumor hypoxia. To address this challenge, we fabricated O2-generating HSA-MnO2-Ce6 NPs (HSA for human serum albumin, Ce6 for chlorin e6, and NPs for nanoparticles) to overcome tumor hypoxia and thus enhance the photodynamic effect for bladder cancer therapy. Methods: The HSA-MnO2-Ce6 NPs were prepared. We investigated the O2 generation of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study, and dual-modal imaging of NPs were demonstrated. Therapeutic efficacy of NPs for bladder cancer was evaluated. Results: HSA-MnO2-Ce6 NPs had an excellent performance in generating O2in vitro upon reaction with H2O2 at endogenous levels. Moreover, 1O2 generation was increased two-fold by using HSA-MnO2-Ce6 NPs instead of HSA-Ce6 NPs in the presence of H2O2 under 660 nm laser irradiation. In vitro cell viability assays showed that HSA-MnO2-Ce6 NPs themselves were non-toxic but greatly enhanced PDT effects on bladder cancer cells under laser irradiation. In vivo near-infrared (NIR) fluorescence and magnetic resonance (MR) imaging suggested the excellent bladder tumor-targeting property of HSA-MnO2-Ce6 NPs. O2 content in orthotopic bladder cancer was increased 3.5-fold after injection of HSA-MnO2-Ce6 NPs as compared with pre-injection. Given the excellent tumor-targeting ability and negligible toxicity, HSA-MnO2-Ce6 NPs were then used to treat orthotopic bladder cancer by PDT. The PDT with HSA-MnO2-Ce6 NPs showed remarkably improved therapeutic efficacy and significantly prolonged lifetime of mice as compared with controls. Conclusion: This study not only demonstrated the great potential of HSA-MnO2-Ce6 NPs for bladder cancer photodynamic ablation but also provided a new therapeutic strategy to overcoming tumor hypoxia.
Abstract 14999: Functional Assessment of Community-Based Automated External Defibrillators
Authors: Josh Matzke, Erica Sutton, Stuart Crawford, Jamie Heimroth, Brad S Sutton
Journal: Circulation (2016)

Introduction: The use of automated external defibrillators (AEDs) coupled with bystander CPR has been shown to significantly improve mortality for out-of-hospital cardiac arrest. However, ongoing m...
Tumor necrosis factor family member <scp>LIGHT</scp> acts with <scp>IL</scp>‐1β and <scp>TGF</scp>‐β to promote airway remodeling during rhinovirus infection
Authors: A. K. Mehta, T. Doherty, D. Broide, M. Croft
Journal: Allergy (2018)

Rhinovirus (RV) can exacerbate allergen-driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma-like features in childhood without prior allergen exposure.We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling.We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL-1β and TGF-β, each previously shown to contribute to lung remodeling driven by allergen.Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT-deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT-deficient mice. Furthermore, neutralizing IL-1β or TGF-β also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV.Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen-associated airway remodeling.
Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC).
Authors: Josep Tabernero, Ignacio Melero, Willeke Ros, Guillem Argiles, Aurelien Marabelle, Maria E. Rodriguez-Ruiz, Joan Albanell, Emiliano Calvo, Victor Moreno, James M. Cleary, Joseph Paul Eder, Vaios Karanikas, Said Bouseida, Federico Sandoval, Daniel Sabanes, Sasha Sreckovic, Herbert Hurwitz, Luis G. Paz-Ares, Jose M. Saro Suarez, Neil Howard Segal
Journal: Journal of Clinical Oncology (2017)

3002 Background: CEA CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. In preclinical models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and upregulates PD-1/PD-L1. Methods: Intwo ongoing dose-escalation phase I studies, RO6958688 is given as monotherapy (S1) i.v. QW or in combination (QW) with atezolizumab 1200 mg Q3W (S2) in adult patients (pts) with advanced CEA+ solid tumors. In S1, 80 pts (mCRC: 68) were treated at dose levels from 0.05 mg to 600 mg; in S2, 38 pts (mCRC: 28) from 5 mg to 160 mg. In S1, a Bayesian logistic regression model with overdose control guided dose escalation. Data cutoff 25.01.17. Results: At doses ≥60mg (36 pts in S1; 10 in S2), CT scans revealed tumor inflammation within days of first dose, consistent with the mode of action of RO6958688. 2 (5%) pts in S1 (both microsatellite stable (MSS) and 2 (20%; 1 MSS) in S2 had a partial response (RECIST v1.1). Preliminary tumor size reduction ( &gt; -10% and &lt; -30% [stable disease]) was observed in 4 (11%) additional pts in S1 and 5 (50%) in S2. At week 4-6 FDG PET scan assessment, 10 (28%) pts with mCRC in S1 and 6 (60%) in S2 had a metabolic partial response (EORTC criteria). At all doses in S1, the most common related AEs were pyrexia (56.3%), infusion related reaction (IRR, 50%) and diarrhea (40%). The most common grade ≥ 3 (G3) related AEs were IRR (16.3%) and diarrhea (5%). 5 patients experienced DLTs: G3 dyspnea, G3 diarrhea, G3 hypoxia, G4 colitis and G5 respiratory failure (G4-5 at 600mg). DLT events were likely associated with tumor lesion inflammation. In S2, there was no evidence of new or additive toxicities, with 1 DLT at 160 mg (G3 transient increase of ALT in a patient with liver metastases). PK/PD data are reported separately. Conclusions: Evidence of antitumor activity was observed with RO6958688 monotherapy in ongoing dose escalation. Activity appeared to be enhanced with doses in combination with atezolizumab, with a manageable safety profile. Updated data will be presented. Clinical trial information: NCT02324257 and NCT02650713.
Durable prostate cancer control in a randomized trial of optimal timing of dose escalated (76 Gy) radiation and 6 months ADT in prostate cancer
Authors: S. Malone, L. Eapen, None C.E., W. Kendal, J. Craig, R. Macrae, G. Perry, J. Bowen, S. Morgan, O. Holmes, S. Grimes
Journal: Annals of Oncology (2017)
Cardiac macrophages promote diastolic dysfunction
Authors: Maarten Hulsmans, Hendrik B. Sager, Jason D. Roh, María Valero-Muñoz, Nicholas E. Houstis, Yoshiko Iwamoto, Yuan Sun, Richard M. Wilson, Gregory Wojtkiewicz, Benoit Tricot, Michael T. Osborne, Judy Hung, Claudio Vinegoni, Kamila Naxerova, David E. Sosnovik, Michael R. Zile, Amy D. Bradshaw, Ronglih Liao, Ahmed Tawakol, Ralph Weissleder, Anthony Rosenzweig, Filip K. Swirski, Flora Sam, Matthias Nahrendorf
Journal: The Journal of Experimental Medicine (2018)

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia
Authors: Julia C. Gutjahr, Eva Szenes, Lisa Tschech, Daniela Asslaber, Michaela Schlederer, Simone Roos, Xiaobing Yu, Tamara Girbl, Christina Sternberg, Alexander Egle, Fritz Aberger, Ronen Alon, Lukas Kenner, Richard Greil, Veronique Orian-Rousseau, Tanja N. Hartmann
Journal: Blood (2018)
Elderly Hodgkin Lymphoma - Multicenter Retrospective Data Analysis from the Czech Hodgkin Lymphoma Registry
Authors: Alice Sýkorová, Heidi Mocikova, Vit Prochazka, Marie Lukasova, Pavla Stepankova, David Belada, Katerina Klaskova, Lubica Gaherova, Karel Chroust, Jana Markova
Journal: Blood (2017)