tbuckley/cabot-search huggingface dataset:
Inhibition of MLK3 decreases proliferation and increases antiproliferative activity of epidermal growth factor receptor (EGFR) inhibitor in pancreatic cancer cell lines
Authors: Sreenivasa Chandana, Cheryl Leece, Kathleen Gallo, Burra Madhukar, Barbara Conley
Journal: Cancer Research (2008)

2339  Rationale: Pancreatic cancer (PC) is associated with advanced presentation and poor survival. Currently approved therapies, including EGFR inhibitors, have minimal effect on patient survival. PCs have a high incidence of activated Ras, which may bypass inhibition of EGFR, resulting in resistance to EGFR inhibitors. Mixed lineage kinases (MLKs) are members of a large family of mitogen-activated protein kinase (MAPK) kinase kinases (MAPKKKs) that activate MAPK pathways, involving JNK, ERK 1/2 and p38 cell signaling pathways.1 MLK3 is required for proliferation of tumor cells with oncogenic kras mutations.2 The role of MLK3 in the pathophysiology and resistance to therapy of PC is not well known. Methods: The requirement of MLK3 for cell proliferation and survival of PC cell lines PANC 1 (gift of Dr. J. McCormick, Michigan State University) and MiaPaCa2 (ATCC), both of which have activating ras mutations, was investigated using RNA interference (siRNA) and MLK3 inhibitor K252a to inhibit the expression and activity of MLK3. Cells were also exposed to EGFR inhibitor Compound 56 at various concentrations. Proliferation was assessed with MTT after 48-72 h exposure. The effect of MLK3 inhibition on relevant cell signaling pathways was assessed by immunoblotting with activation-specific phosphoantibodies directed against MAPKs and the prosurvival kinase Akt. Results: MLK3 expression was significantly higher in PC cell lines than in a normal pancreatic epithelial cell line (gift of Dr. M. Tsao, Princess Margaret Hosp, Toronto). siRNA decreased MLK3 expression in both PC cell lines. K252a also significantly decreased MLK3 expression. Inhibition of MLK3 by siRNA or K252a was associated with decreased cell proliferation in both PC cell lines, with concurrent decrease in pERK and pAkt in PANC-1 cells and decreased pERK and pJNK in MiaPaCa2 cells. Concomitant exposure to MLK3 inhibitor and Compound 56 further inhibited cell proliferation and increased caspase 3 activity, compared to either agent alone. These results suggest that MLK3 plays an important role in survival and proliferation in PC cells with kras mutations and inhibition of MLK3 may enhance the effects of EGFR inhibitors in PC.
Long-term Cost-Effectiveness of Dexcom G6 Real-time Continuous Glucose Monitoring Versus Self-Monitoring of Blood Glucose in Patients With Type 1 Diabetes in the U.K.
Authors: Stéphane Roze, John Isitt, Jayne Smith-Palmer, Mehdi Javanbakht, Peter Lynch
Journal: Diabetes Care (2020)

A long-term health economic analysis was performed to establish the cost-effectiveness of real-time continuous glucose monitoring (RT-CGM) (Dexcom G6) versus self-monitoring of blood glucose (SMBG) alone in U.K.-based patients with type 1 diabetes (T1D).The analysis used the IQVIA CORE Diabetes Model. Clinical input data were sourced from the DIAMOND trial in adults with T1D. Simulations were performed separately in the overall population of patients with baseline HbA1c ≥7.5% (58 mmol/mol), and a secondary analysis was performed in patients with baseline HbA1c ≥8.5% (69 mmol/mol). The analysis was performed from the National Health Service health care payer perspective over a lifetime time horizon.In the overall population, G6 RT-CGM was associated with a mean incremental gain in quality-adjusted life expectancy of 1.49 quality-adjusted life years (QALYs) versus SMBG (mean [SD] 11.47 [2.04] QALYs versus 9.99 [1.84] QALYs). Total mean (SD) lifetime costs were also pounds sterling (GBP) 14,234 higher with RT-CGM (GBP 102,468 [35,681] versus GBP 88,234 [39,027]) resulting in an incremental cost-effectiveness ratio of GBP 9,558 per QALY gained. Sensitivity analyses revealed that the findings were sensitive to changes in the quality-of-life benefit associated with reduced fear of hypoglycemia and avoidance of fingerstick testing as well as the HbA1c benefit associated with RT-CGM use.For U.K.-based T1D patients, the G6 RT-CGM device is associated with significant improvements in clinical outcomes and, over patient lifetimes, is a cost-effective disease management option relative to SMBG on the basis of a willingness-to-pay threshold of GBP 20,000 per QALY gained.
Influenza Vaccination Is Associated With Reduced Cardiovascular Mortality in Adults With Diabetes: A Nationwide Cohort Study
Authors: Daniel Modin, Brian Claggett, Lars Køber, Morten Schou, Jens Ulrik Stæhr Jensen, Scott D. Solomon, Orly Vardeny, Filip Krag Knop, Susanne Dam Nielsen, Michael Fralick, Christian Torp-Pedersen, Gunnar Gislason, Tor Biering-Sørensen
Journal: Diabetes Care (2020)

Recent influenza infection is associated with an increased risk of atherothrombotic events, including acute myocardial infarction (AMI) and stroke. Little is known about the association between influenza vaccination and cardiovascular outcomes in patients with diabetes.We used nationwide register data to identify patients with diabetes in Denmark during nine consecutive influenza seasons in the period 2007-2016. Diabetes was defined as use of glucose-lowering medication. Patients who were not 18-100 years old or had ischemic heart disease, heart failure, chronic obstructive lung disease, cancer, or cerebrovascular disease were excluded. Patient exposure to influenza vaccination was assessed before each influenza season. We considered the outcomes of death from all causes, death from cardiovascular causes, and death from AMI or stroke. For each season, patients were monitored from December 1 until April 1 the next year.A total of 241,551 patients were monitored for a median of four seasons (interquartile range two to eight seasons) for a total follow-up of 425,318 person-years. The vaccine coverage during study seasons ranged from 24% to 36%. During follow-up, 8,207 patients died of all causes (3.4%), 4,127 patients died of cardiovascular causes (1.7%), and 1,439 patients died of AMI/stroke (0.6%). After adjustment for confounders, vaccination was significantly associated with reduced risks of all-cause death (hazard ratio [HR] 0.83, P < 0.001), cardiovascular death (HR 0.84, P < 0.001), and death from AMI or stroke (HR 0.85, P = 0.028) and a reduced risk of being admitted to hospital with acute complications associated with diabetes (diabetic ketoacidosis, hypoglycemia, or coma) (HR 0.89, P = 0.006).In patients with diabetes, influenza vaccination was associated with a reduced risk of all-cause death, cardiovascular death, and death from AMI or stroke. Influenza vaccination may improve outcome in patients with diabetes.
Hospital admissions with acute coronary syndromes during the COVID-19 pandemic in German cardiac care units
Authors: Thorsten Kessler, Tobias Graf, Ingo Hilgendorf, Konstantinos Rizas, Eimo Martens, Constantin von zur Mühlen, Peter Kraemer, Roza Meyer-Saraei, Franz-Josef Neumann, Christoph Bode, Karl-Ludwig Laugwitz, Steffen Massberg, Heribert Schunkert, Joachim Weil, Adnan Kastrati, Hendrik B Sager
Journal: Cardiovascular Research (2020)
Aberrant Clonal Hematopoiesis of the Erythroid and Myeloid Lineages in a Lentivirally Barcoded Rhesus Macaque
Authors: Diego A Espinoza, Chuanfeng Wu, Xing Fan, Di Yang, Idalia Montano Yabe, Selami Demirci, So Gun Hong, Aylin Bonifacino, Allen Krouse, Mark Metzger, Rong Lu, Katherine R Calvo, John F Tisdale, Xiaolin Wu, Suk See De Ravin, Harry L Malech, Robert E Donahue, Cynthia E Dunbar
Journal: Blood (2017)
Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers
Authors: Peter Izmirly, Mimi Kim, Deborah M. Friedman, Nathalie Costedoat-Chalumeau, Robert Clancy, Joshua A. Copel, Colin K.L. Phoon, Bettina F. Cuneo, Rebecca E. Cohen, Kimberly Robins, Mala Masson, Benjamin J. Wainwright, Noel Zahr, Amit Saxena, Jill P. Buyon
Journal: Journal of the American College of Cardiology (2020)
Intrinsic regulation of c-Met induction by STAT3 in nasopharyngeal cancer (NPC): a point for therapeutic intervention for aggressive NPC
Authors: Vivian Lui, Elaine Wong, Daisy Yau, Sze Chuen Wong, Money Lam, Sai-Wah Tsao, Nathalie Wong, Kwok Lo, Chin Chan, Laura Stabile, Jill Siegfried, Anthony Chan
Journal: Cancer Research (2007)

2149  Overexpression of c-Met, a key player in cancer invasion and metastasis, is believed to be involved in the malignant progression of nasopharyngeal cancer (NPC). The mechanism for its overexpression in human cancers remains unclear. Hepatocyte growth factor (HGF), the ligand of c-Met, activates downstream signaling of c-Met, as well as inducing upregulation of c-Met expression in some epithelial cancers. This HGF-induced c-Met upregulation may further augment the invasiveness of c-Met-overexpressing cancers. Here, we hypothesize that STAT3, an intrinsic downstream signaling molecule of c-Met, is crucial for the regulation of HGF-induced c-Met overexpression in NPC. In NPC cell lines (e.g. HONE-1 and HK1), HGF induced a dose-dependent expression of c-Met precursor protein at 48 hrs, with a maximal induction at 50 ng/ml of HGF. To investigate the involvement of STAT3 in regulating c-Met expression, two representative NPC cell lines, HONE-1 and CNE-2, were transfected with STAT3 siRNA. Specific downregulation of STAT3 by STAT3 siRNA (300 pmoles), but not control siRNA, was accompanied by significant inhibition of c-Met expression in both NPC cell lines up to day 4 post-transfection. Both c-Met protein and mRNA expression was inhibited up to 70% (by Western blotting and quantitative RT-PCR, respectively). Treatment of HONE-1 and CNE-2 cells with a STAT3 inhibitor, JSI-124 (Curcubitacin I), also resulted in significant inhibition of HGF-induced c-Met protein expression (>50% inhibition) at 48 hrs. The contribution of two other major downstream signaling molecules of c-Met in c-Met regulation was found to be less significant, as activation of AKT by transfection with an activated AKT mutant (myr-AKT1) did not alter c-Met expression up to day 3, and treatment with a MEK-1/-2 inhibitor (U0126, at 20 μM, for 48 hrs) reduced c-Met protein expression by only 30 %. Our novel finding indicates that STAT3 serves as a major intrinsic regulator of c-Met expression in NPC. Therefore, targeting such an intrinsic regulator, STAT3, (and most likely, targeting MAPK as well), may offer additional advantages to current c-Met targeting strategies by attenuating both c-Met induction, as well as, c-Met signaling.This is supported by our finding that: 1) HGF-induced NPC proliferation was completely and efficiently abrogated by targeting STAT3 (by JSI-124 at 200nM for 48 hrs), 2) HGF-induced cell motility and migration (by wound healing and cell scattering assays) was significantly inhibited by JSI-124 (200nM, 24 hrs) in HONE-1. Our findings may have broad implications for various cancers and provide a model for efficient c-Met targeting in cancer.  Financial Support: Start-up fund, Department of Clinical Oncology, CUHK (to VWYL)
Kinetics of viral load and antibody response in relation to COVID-19 severity
Authors: Yanqun Wang, Lu Zhang, Ling Sang, Feng Ye, Shicong Ruan, Bei Zhong, Tie Song, Abeer N. Alshukairi, Rongchang Chen, Zhaoyong Zhang, Mian Gan, Airu Zhu, Yongbo Huang, Ling Luo, Chris Ka Pun Mok, Manal M. Al Gethamy, Haitao Tan, Zhengtu Li, Xiaofang Huang, Fang Li, Jing Sun, Yanjun Zhang, Liyan Wen, Yuming Li, Zhao Chen, Zhen Zhuang, Jianfen Zhuo, Chunke Chen, Lijun Kuang, Junxiang Wang, Huibin Lv, Yongliang Jiang, Min Li, Yimin Lin, Ying Deng, Lan Tang, Jieling Liang, Jicheng Huang, Stanley Perlman, Nanshan Zhong, Jingxian Zhao, J.S. Malik Peiris, Yimin Li, Jincun Zhao
Journal: Journal of Clinical Investigation (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.
Circulating tumor cells: Ready for translation?
Authors: Zoi Diamantopoulou, Francesc Castro-Giner, Nicola Aceto
Journal: The Journal of Experimental Medicine (2020)

Circulating tumor cells are tumor-derived pioneers responsible for the metastatic spread of cancer. Here, we outline recent discoveries, challenges, and future trends for circulating tumor cell investigations, arguing that the time is coming for translation of this work into clinical practice.
P-360 EGFR-inhibitors in metastatic wild-type RAS colorectal cancer: Experience of the oncology department of Mohammed VI University Hospital in Marrakech
Authors: H. Jouihri, K. Cisse, K. Lakloumi, K. El Bouaouidi, S. El Ouarzazi, M. Kaakoua, M. Elfadli, R. Belbaraka
Journal: Annals of Oncology (2020)
Organisations for patients with cancer feel the brunt of COVID-19 pandemic
Authors: Roxanne Nelson
Journal: The Lancet Oncology (2020)

The ongoing COVID-19 pandemic has disrupted all facets of cancer care, from delaying diagnoses and treatment to halting clinical trials and biomedical research. Patient organisations have not been spared from the impact, with all aspects of their work affected, and in some cases, their very viability.
O-8 Atezolizumab + bevacizumab vs sorafenib for unresectable hepatocellular carcinoma: Results from older adults enrolled in IMbrave150
Authors: D. Li, H. Toh, P. Merle, K. Tsuchiya, S. Hernandez, H. Shao, S. Mulla, B. Ding, M. Kudo
Journal: Annals of Oncology (2020)
The neighbourhood natural environment is associated with asthma in children: A birth cohort study
Authors: João Cavaleiro Rufo, Inês Paciência, Elaine Hoffimann, André Moreira, Henrique Barros, Ana Isabel Ribeiro
Journal: Allergy (2020)

A lower exposure to the natural environment has been hypothesized to adversely affect the human microbiome and its immunomodulatory capacity. However, the underlying effects of this hypothesis are still not understood. We aimed to evaluate the effect of early-life exposure to greenness and species richness on the development of allergic diseases and asthma in children.A longitudinal study was conducted comprising 1050 children from a population-based birth cohort recruited in Portugal. Residential normalized difference vegetation index (NDVI) and species richness index (SRI) were assessed at baseline to estimate their association with allergic diseases and asthma at the ages of 4 and 7.Significant predisposing associations were observed between the exposure to species richness at baseline and the onset of asthma and wheezing at the age of 7. Children living in neighbourhoods surrounded by high levels of SRI were at a significantly higher risk developing allergic sensitization(OR [95% CI] = 2.00 [1.04:3.86] at age 4; 2.35 [1.20:4.63] at age 7). Living surrounded by greener environments was significantly associated with a lower prevalence of asthma and rhinitis at the age of 7(0.41 [0.18:0.97] and 0.37 [0.15:0.93], respectively).Living in close proximity to a greener environment at birth has a protective effect on the development of allergic diseases and asthma at the age of 7. Conversely, living in neighbourhoods with a high number of fauna species appears to be associated with a higher risk for allergy, asthma and wheezing.
P-233 Metformin combined with irinotecan in patients with refractory colorectal cancer: A phase 2 trial
Authors: A. Bragagnoli, R. Araujo, M. Ferraz, F. Comar, K. Abdalla, F. Santos, L. Dos Santos, F. Cárcano, J. Carvalheira, J. Lima
Journal: Annals of Oncology (2020)
Insufficient Calorie Intake Worsens Post-Discharge Quality of Life and Increases Readmission Burden in Heart Failure
Authors: Feriha Bilgen, Peiyu Chen, Armella Poggi, Joanna Wells, Erika Trumble, Stephen Helmke, Sergio Teruya, Tonimarie Catalan, Hannah R. Rosenblum, Maria L. Cornellier, Wahida Karmally, Mathew S. Maurer, Scott L. Hummel
Journal: JACC Heart Failure (2020)
P-6 Perioperative FLOT: Tolerability, pathological response rates, and the role of adjuvant phase
Authors: E. Ozden, U. Isik, Y. Cakmak, H. Uslu, M. Tosun, E. Sahin, M. Kaypak, D. Cabuk, U. Kefeli, K. Uygun
Journal: Annals of Oncology (2020)
The impact of aircraft noise on vascular and cardiac function in relation to noise event number: a randomized trial
Authors: Frank P Schmidt, Johannes Herzog, Boris Schnorbus, Mir Abolfazl Ostad, Larissa Lasetzki, Omar Hahad, Gianna Schäfers, Tommaso Gori, Mette Sørensen, Andreas Daiber, Thomas Münzel
Journal: Cardiovascular Research (2020)

Abstract Aims Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (Leq), is an adequate indicator of the cardiovascular impact induced by different noise patterns. Methods and results In a randomized crossover study, we exposed 70 individuals with established cardiovascular disease or increased cardiovascular risk to two aircraft noise scenarios and one control scenario. Polygraphic recordings, echocardiography, and flow-mediated dilation (FMD) were determined for three study nights. The noise patterns consisted of 60 (Noise60) and 120 (Noise120) noise events, respectively, but with comparable Leq, corresponding to a mean value of 45 dB. Mean value of noise during control nights was 37 dB. During the control night, FMD was 10.02 ± 3.75%, compared to 7.27 ± 3.21% for Noise60 nights and 7.21 ± 3.58% for Noise120 nights (P &amp;lt; 0.001). Sleep quality was impaired after noise exposure in both noise scenario nights (P &amp;lt; 0.001). Serial echocardiographic assessment demonstrated an increase in the E/E′ ratio, a measure of diastolic function, within the three exposure nights, with a ratio of 6.83 ± 2.26 for the control night, 7.21 ± 2.33 for Noise60 and 7.83 ± 3.07 for Noise120 (P = 0.043). Conclusions Nighttime exposure to aircraft noise with similar Leq, but different number of noise events, results in a comparable worsening of vascular function. Adverse effects of nighttime aircraft noise exposure on cardiac function (diastolic dysfunction) seemed stronger the higher number of noise events.
AB0919 WHAT IS LOWER EXTREMITY ENTHESEAL INVOLVEMENT IN ACUTE GOUT ATTACK? AN ULTRASOUND-STUDY
Authors: H. Cao, G. Xu, J. Lin
Journal: Annals of the Rheumatic Diseases (2020)

Background: Articular involvement in acute gout attack is extremely common and mainly characterized by arthritis, which are usually transient, severe, reversible and well responsive to treatment. The involvement of tendons and entheses in lower extremity in monosodium urate-related disease through US (ultrasound) assessment have been described 1,2 . US findings in gout raising the hypothesis that entheseal involvement could be a missing target in the clinical evaluation of gout patients. Objectives: To evaluate by ultrasound (US) the frequency and characteristics of lower extremity entheseal involvement in acute gout attack patients. Methods: US assessment were performed by independent rheumatologist on 31 patients with acute gout attack. Presence of lower extremity entheseal involvement were evaluated by grey-scale (GS) and power Doppler (PD). US assessment contain quadriceps, patellar and Achilles tendons, and plantar fascia entheses according to the OMERACT definitions. Results: US revealed one or more abnormalities in at least one enthesis in 22 out of 31 gout patients (71.0%) and 47 out of 310 entheses (15.2%). Among the affected entheses, the patellar insertion of quadriceps tendon was most commonly involved (57.4%) during acute gout attack, followed by the calcaneal insertion of the Achilles tendon (17.0%) and distal insertion of the patellar tendon (14.9%). The proximal insertion of the patellar tendon and calcaneal insertion of the plantar fascia were involved in 8.5% and 2.1%, respectively. Bone erosions and osteophytes were found in affected entheses (10.6% and 25.5%, respectively). Conclusion: Our study identifies that lower extremity entheseal involvement is a missing target in the evaluation of patients with acute gout attack. US plays a key role in the assessment of both clinical and subclinical enthesitis in gout patients. References: [1]Pineda C, Amezcua-Guerra LM, Solano C, et al. Joint and Tendon Subclinical Involvement Suggestive of Gouty Arthritis in Asymptomatic Hyperuricemia: an Ultrasound Controlled Study. J Rheumatol. 2011;38(6):1195-1195. [2]Carroll M, Dalbeth N, Allen B, et al. Ultrasound Characteristics of the Achilles Tendon in Tophaceous Gout: A Comparison with Age- and Sex-matched Controls. J Rheumatol. 2017;44(10):1487-1492. Disclosure of Interests: None declared