tbuckley/cabot-search huggingface dataset:
Trecc: Re-challenge therapy with anti-EGFR in metastatic colorectal adenocarcinoma (mCRC).
Authors: Amanda Karani, Tiago Felismino, Lara Azevedo Diniz, Mariana Petaccia Macedo, Larissa Machado, Diogo De Brito Sales, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2019)

683 Background: Anti-EGFR plus chemotherapy (CT) promotes high response rates (RR) and median overall survival (OS) surpasses 30 months in RASwt/BRAFwt mCRC. After disease progression (PD), resistance mechanisms have been described. The aim of our study was to evaluate efficacy of anti-EGFR re-challenge (TRECC). Methods: We retrospectively analyzed a cohort of patients (pts) with mCRC. All pts had received anti-EGFR plus CT and were discontinued for different reasons. During the treatment, there was re-challenge with an anti-EGFR + CT. We aimed to evaluate progression-free survival (PFS) and OS after re-challenge and prognostic factors associated with PFS. Results: Sixty eight pts met the study criteria. Median follow-up after re-challenge was 39.3m. Discontinuation after first exposure was 25% due to PD; 75% for other reasons. Median anti-EGFR free interval was 10.5m. At re-challenge, main CT regime was: FOLFIRI 58.8%, Cetuximab and Panitumumab were used in 59 and 9 pts respectively. mPFS after re-challenge was 6.6m; mOS was 24.4m. Objective response rate (CR + PR) at re-challenge was 42.6%. In an univariate analysis, adverse prognostic factors related to PFS were: absence of objective response at 1st EGFR exposure (HR 2.12, CI:1.20-3.74 p = 0.009); PD as reason for 1st discontinuation (HR 3.44, CI:1.88-6.29 p &lt; 0.0001); re-challenge at fourth or later lines (HR 2,51, CI:1.49-4.23 p = 0.001); panitumumab use (HR 2.26 CI:1.18-5.54 p = 0.017). In a multivariate model, only PD as reason for 1st discontinuation remained statistically significant (HR = 2.63, CI:1.14-6.03 p = 0.022). mPFS was 3.3m and 8.4m and mOS was 7,5m and 33,4m in patients with PD as reason for 1st discontinuation and other reasons respectively. Conclusions: Re-challenge therapy is commonly used due to paucity of effective lines of treament for mCRC. In our analysis, pts that stopped 1st anti-EGFR therapy due to PD have shorter survival, suggesting these pts do not benefit from TRECC. However, interruption due to treatment holiday after PR/CR resulted in longer PFS. In conclusion, for a selected group of pts, TRECC could be considered a strategy of treatment. Due to the limited number of pts, our data should be evaluated in a prospective cohort of patients.
Robin Irvine Russell
Authors: Anna Dominiczak, Peter Mills
Journal: BMJ (2019)

Robin Irvine Russell, an internationally recognised consultant physician and gastroenterologist, head of department of gastroenterology at the Glasgow Royal Infirmary, and honorary professor at the University of Glasgow, died peacefully at the Prince and Princess of Wales Hospice in Glasgow on 21 November 2018, aged 81 years.

Born in Wishaw, Lanarkshire, on 21 December 1936, Robin became dux of Wishaw High School before graduating as a bachelor of medicine and surgery in 1960, a doctor of medicine in 1972, and a doctor of philosophy in 1976, all from the University of Glasgow.

From 1966 to 1968, Robin was a member of the scientific and medical staff at the …
Beta-cell sensitivity to insulinotropic gut hormones is reduced after gastric bypass surgery
Authors: Marzieh Salehi, Amalia Gastaldelli, David A D’Alessio
Journal: Gut (2019)

Objective Postprandial hyperinsulinaemia after Roux-en Y gastric bypass (GB) has been attributed to rapid nutrient flux from the gut, and an enhanced incretin effect. However, it is unclear whether surgery changes islet cell responsiveness to regulatory factors. This study tested the hypothesis that β-cell sensitivity to glucagon like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) is attenuated after GB. Design Ten non-diabetic subjects with GB, and 9 body mass index (BMI)-matched and age-matched non-surgical controls (CN) with normal glucose tolerance had blood glucose clamped at ~7.8 mM on three separate days. Stepwise incremental infusions of GLP-1 (15, 30, 60, 120 and 300 ng/LBkg/h), GIP (75, 150, 300, 600 and 1200 ng/LBkg/h) or saline were administered from 90 to 240 min and insulin secretion measured. Results GB subjects had similar fasting glucose levels but lower fasting insulin compared with CN, likely due to increased insulin clearance. The average insulin secretion rates (ISRs) to 7.8 mM glucose were ~30% lower in GB relative to CN subjects. However, incretin-stimulated ISRs, adjusted for insulin sensitivity and glucose-stimulated insulin secretion, were even more attenuated in the GB subjects, by threefold to fourfold (AUC ISR(90−240 min) during GLP-1 and GIP: 47±8 and 44±12 nmol in GB and 116±16 and 161±44 in CN; p&lt;0.01). Conclusion After GB, the sensitivity of insulin secretion to both glucose and incretins is diminished.
Bronchoalveolar Lavage Findings In Patients With Asthma, Wheezing Or Chronic Pneumopathy At A Pediatric Referral Center In Colombia
Authors: Milena Villamil-Osorio, María Alejandra Bejarano-Melo, Oscar Correa-Jimenez, Maria J. Gutierrez, Oscar Ramirez-Camacho, Juliana Caceres-Montejo, Carlos Rodríguez-Martínez, Sonia Restrepo-Gualteros
Journal: Journal of Allergy and Clinical Immunology (2019)
EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia
Authors: Sebastian Stasik, Jan Moritz Middeke, Michael Kramer, Christoph Rollig, Alwin Krämer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Ralph Naumann, Björn Steffen, Volker Kunzmann, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W Krause, Regina Herbst, Mathias Hänel, Norbert Frickhofen, Richard Noppeney, Ulrich Kaiser, Claudia D. Baldus, Martin Kaufmann, Zdenek Racil, Uwe Platzbecker, Wolfgang E. Berdel, Jiri Mayer, Hubert Serve, Carsten Müller-Tidow, Gerhard Ehninger, Martin Bornhäuser, Johannes Schetelig, Christian Thiede
Journal: Blood (2018)
Abstract P010: Obesity Status in Younger Age, 39-year Weight Change and Physical Performance in Older Age: the Chicago Healthy Aging Study (CHAS)
Authors: Thanh Huyen T Vu, Mercedes R Carnethon, Kiang Liu, Donald M Lloyd-Jones, Godwin I Ogbole, Daniel B Garside, Martha L Daviglus
Journal: Circulation (2017)

Background: Obesity is associated with serious medical complications and impaired quality of life. In older adults, obesity can aggravate the age-related decline in physical performance and lead to other forms of disability. However, the association of obesity status and weight change over decades with physical performance in older age has not been well studied. Methods: In 1,325 men and women who were initially examined in 1967-73 and re-examined in 2007-10 in the CHAS study, we stratified by baseline BMI and categorized weight change over 39 years (categories in table footnote). At follow-up (FU) when participants were ages 65+, muscle strength (hand grip) and performance [4m gait speed and Short Physical Performance Battery (SPPB)] were measured. We used multivariate logistic regression analysis to determine the association of baseline obesity status and weight change categories with categorized low strength and performance measures adjusted for baseline (BL) CVD risk status, FU age, sex, race, education, ankle-brachial index, SBP, total cholesterol, smoking status, diabetes, and cholesterol and BP medication use. Results: The mean age at baseline was 33 and at FU was 71, 28% were women and 9% were black. At follow-up, 10.3 % had SPPB score ≤ 8, 8.4 % had gait speed on 4 meter course &lt; 0.8 m/s, and 23.8 % had low sex-specific handgrip strength (&lt;18kg for women, &lt;30kg for men). As compared with those who were normal weight at baseline with minimal weight change (-10lbs to 20lbs), participants who were overweight initially and gained the most weight (&gt; 20lbs) were more likely to have a low SPPB score, gait speed &lt;0.8 m/s, or sex-specific handgrip strength (ORs: 4.55, 4.58, and 1.86, respectively). Weight loss &gt; 10 lbs is associated with SPPB score, and can be seen among those with BL BMI &lt;25 kg/m 2 but not among those with BL BMI ≥ 25 kg/m 2 . Conclusion: Obesity and overweight in younger age and significant weight gain over time are each associated with poor physical performance in older age.
Continuous alternative to freeze drying: Manufacturing of cyclodextrin-based reconstitution powder from aqueous solution using scaled-up electrospinning
Authors: Panna Vass, Balázs Démuth, Attila Farkas, Edit Hirsch, Edina Szabó, Brigitta Nagy, Sune K. Andersen, Tamás Vigh, Geert Verreck, István Csontos, György Marosi, Zsombor K. Nagy
Journal: Journal of Controlled Release (2019)

The aims of this study were to evaluate electrospinning as a continuous alternative to freeze drying in the production of a reconstitution injection dosage form, and to prove that aqueous electrospinning can be realized with a high production rate at room temperature. High-speed electrospinning with a novel continuous cyclone collection was used to manufacture a formulation of the poorly water-soluble antifungal voriconazole (VOR) with sulfobutylether-β-cyclodextrin (SBE-β-CD). The freeze-dried, marketed product of this drug substance, Vfend® also contains SBE-β-CD as excipient. SBE-β-CD acted as a ‘quasi-polymer’, and it could be electrospun despite its low molecular mass (2163 Da). According to X-ray diffraction and differential scanning calorimetry, no traces of crystalline VOR were detectable in the fibers. Furthermore, Raman mapping and energy dispersive spectroscopy measurements showed a uniform distribution of amorphous VOR in the fibers. Reconstitution tests carried out with ground fibrous powder showed complete dissolution resulting in a clear solution after 30 s (similarly to Vfend®). The high productivity rate (~240 g/h) achieved using high-speed electrospinning makes this scaled-up, continuous and flexible manufacturing process capable of fulfilling the technological and capacity requirements of the pharmaceutical industry. This work shows that aqueous high-speed electrospinning, being a continuous and high-throughput process, is an economically viable production alternative to freeze drying.
Does This Patient Have a Severe Snake Envenomation?
Authors: Charles J. Gerardo, João R. N. Vissoci, C. Scott Evans, David L. Simel, Eric J. Lavonas
Journal: JAMA Surgery (2019)

Venomous snakebite severity ranges from an asymptomatic dry bite to severe envenomation and death. The clinical evaluation aids in prognosis and is essential to determine the risks and potential benefits of antivenom treatment.To identify historical features, clinical examination findings, basic laboratory testing, and clinical grading scales that will risk-stratify patients with pit viper snake envenomation for severe systemic envenomation, severe tissue injury, and/or severe hematologic venom effects.We conducted a structured search of PubMed (1966-October 3, 2017) and Embase database (1980-October 3, 2017) to identify English-language studies that evaluated clinical features predictive of severe envenomation.We included studies that evaluated the test performance of at least 1 clinical finding with an acceptable reference standard of severe envenomation for venomous snakes of the Western Hemisphere. Only studies involving the most common subfamily, Crotalinae (pit vipers), were evaluated. Seventeen studies with data were available for abstraction.The clinical features assessed and severity outcome measures were extracted from each original study. We assessed severity in 3 categories: systemic toxicity, tissue injury, and hematologic effects. Differences were resolved by author consensus.The pooled prevalence of severe systemic envenomation was 14% (95% CI, 9%-21%). The pooled prevalence of severe tissue injury and severe hematologic venom effects were 14% (95% CI, 12%-16%) and 18% (95% CI, 8%-27%), respectively. Factors increasing the likelihood of severe systemic envenomation included the time from bite to care of 6 or more hours (likelihood ratio [LR], 3.4 [95% CI, 1.1-6.4]), a patient younger than 12 years (LRs, 3.2 [95% CI, 1.5-7.1] and 2.9 [95% CI, 1.3-6.2]), large snake size (LR, 3.1 [95% CI, 1.5-5.7]), and ptosis (LRs, 1.4 [95% CI, 1.0-2.1] and 3.8 [95% CI, 1.8-8.3]). Envenomation by the genus Agkistrodon (copperhead and cottonmouth), as opposed to rattlesnakes, decreased the likelihood of severe systemic envenomation (LR, 0.28 [95% CI, 0.10-0.78]). Initial hypofibrinogenemia (LR, 5.1 [95% CI, 1.7-15.0]) and thrombocytopenia (LR, 3.7 [95% CI, 1.9-7.3]) increased the likelihood of severe hematologic venom effects. Other clinical features from history, physical examination, or normal laboratory values were not discriminative.Clinical features can identify patients at increased risk of severe systemic envenomation and severe hematologic venom effects, but there are few features that are associated with severe tissue injury or can confidently exclude severe envenomation. Physicians should monitor patients closely and be wary of progression from nonsevere to a severe envenomation and have a low threshold to escalate therapy as needed.
Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) Vs. Standard Intensive Chemotherapy (hyper-CVAD) As Frontline Therapy for Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL): A Propensity Score Analysis
Authors: Koji Sasaki, Hagop M. Kantarjian, Nicholas J Short, Farhad Ravandi, Maria Khouri, Guillermo Garcia-Manero, Naval G. Daver, Tapan M. Kadia, Marina Y. Konopleva, Nitin Jain, Ghayas C. Issa, Jovitta Jacob, Rebecca E. Garris, Musa Yilmaz, Philip A. Thompson, Patrice Nasnas, Naveen Pemmaraju, Jorge E. Cortes, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2018)
Enterovirus Persistence in Cardiac Cells of Patients With Idiopathic Dilated Cardiomyopathy Is Linked to 5’ Terminal Genomic RNA-Deleted Viral Populations With Viral-Encoded Proteinase Activities
Authors: Alexis Bouin, Paul-Antoine Gretteau, Michel Wehbe, Fanny Renois, Yohan N’Guyen, Nicolas Lévêque, Michelle N. Vu, Steven Tracy, Nora M. Chapman, Patrick Bruneval, Paul Fornes, Bert L. Semler, Laurent Andreoletti
Journal: Circulation (2019)

Background: Group B enteroviruses are common causes of acute myocarditis, which can be a precursor of chronic myocarditis and dilated cardiomyopathy, leading causes of heart transplantation. To date, the specific viral functions involved in the development of dilated cardiomyopathy remain unclear. Methods: Total RNA from cardiac tissue of patients with dilated cardiomyopathy was extracted, and sequences corresponding to the 5’ termini of enterovirus RNAs were identified. After next-generation RNA sequencing, viral cDNA clones mimicking the enterovirus RNA sequences found in patient tissues were generated in vitro, and their replication and impact on host cell functions were assessed on primary human cardiac cells in culture. Results: Major enterovirus B populations characterized by 5’ terminal genomic RNA deletions ranging from 17 to 50 nucleotides were identified either alone or associated with low proportions of intact 5’ genomic termini. In situ hybridization and immunohistological assays detected these persistent genomes in clusters of cardiomyocytes. Transfection of viral RNA into primary human cardiomyocytes demonstrated that deleted forms of genomic RNAs displayed early replication activities in the absence of detectable viral plaque formation, whereas mixed deleted and complete forms generated particles capable of inducing cytopathic effects at levels distinct from those observed with full-length forms alone. Moreover, deleted or full-length and mixed forms of viral RNA were capable of directing translation and production of proteolytically active viral proteinase 2A in human cardiomyocytes. Conclusions: We demonstrate that persistent viral forms are composed of B-type enteroviruses harboring a 5’ terminal deletion in their genomic RNAs and that these viruses alone or associated with full-length populations of helper RNAs could impair cardiomyocyte functions by the proteolytic activity of viral proteinase 2A in cases of unexplained dilated cardiomyopathy. These results provide a better understanding of the molecular mechanisms that underlie the persistence of EV forms in human cardiac tissues and should stimulate the development of new therapeutic strategies based on specific inhibitors of the coxsackievirus B proteinase 2A activity for acute and chronic cardiac infections.
The Role of Imaging of Flow Patterns by 4D Flow MRI in Aortic Stenosis
Authors: Julio Garcia, Alex J. Barker, Michael Markl
Journal: JACC. Cardiovascular imaging (2019)

Aortic valve stenosis (AS) is the most prevalent valvular heart disease in developed countries and is associated with the development of severe secondary complications such as aortic dilatation and aneurysm. Emerging evidence suggests that the modified hemodynamic environment associated with AS can cause altered flow patterns in the ascending aorta associated with aortic wall remodeling and development of aortopathy. Recent advances in magnetic resonance imaging (MRI) allow for the comprehensive visualization and quantification of in vivo aortic flow pattern dynamics. In particular, the technique of 4-dimensional flow MRI offers the opportunity to derive advanced hemodynamic measures such as vorticity and helicity, wall shear stress, flow displacement, pressure gradients, viscous energy loss, and turbulent kinetic energy. This review introduces 4-dimensional flow MRI for blood flow visualization and quantification of hemodynamic metrics in the setting of aortic valve disease, with a focus on AS and associated secondary aortopathy.
Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience
Authors: Marie-Anne Couturier, Xavier Thomas, Francoise Huguet, Céline Berthon, Célestine Simand, Yosr Hicheri, Mathilde Hunault, Patrice Chevallier
Journal: Blood (2018)
Abstract 12246: Combination of Oral Anti-coagulation With Single Versus Dual Anti-platelet Agents Post Percutaneous Coronary Intervention and Atrial Fibrillation-Challenging the Conventional Approach: A Meta Analysis
Authors: Safi U Khan, Muhammad U Khan, Ahmad N Lone, Shilpa Pedapati, Abhishek Mishra, Edo Kaluski
Journal: Circulation (2017)

Introduction: Current American Heart Association guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and P2Y receptor antagonists after percutaneous coronary intervention (PCI) with stent implantation or acute coronary syndrome (ACS). Up to 10 % of these patients have atrial fibrillation (AF) requiring prolonged oral anticoagulation (OAC). Hypothesis: The Superiority of triple therapy [(TT): OAC + DAPT] compared to combination OAC and single antiplatelet agent (OAC+SAP) in patients with coronary stenting or ACS and AF stems from non- randomized studies (NRS); and contradict the results of randomized controlled trials (RCTs). Methods: Eight studies including three RCTs and 5 NRS were extracted using MEDLINE, EMBASE and Cochrane Library(Inception-December 2016). Outcomes are stratified based on study designs and estimates are reported as random effects odds ratio (OR) with 95% confidence interval (CI). Results: In RCTs restricted analysis, the risk of major bleeding was significantly lower in...
Emicizumab for the Treatment of Acquired Hemophilia_A: Lessons Learned from 4 Very Different Cases
Authors: Paul Knoebl, Wolfgang R. Sperr, Peter Schellongowski, Thomas Staudinger, Petra Jilma-Stohlawetz, Peter Quehenberger, Silvia Koder, Cihan Ay, Karoline V. Gleixner
Journal: Blood (2018)
Noncommercial US Funders’ Policies on Trial Registration, Access to Summary Results, and Individual Patient Data Availability
Authors: Evelyn P. Whitlock, Kelly M. Dunham, Kimberly DiGioia, Emily Lazowick, Theresa C. Gleason, David Atkins
Journal: JAMA Network Open (2019)

Incomplete information about existing research is an underlying cause of research waste. National and international initiatives and requirements have been launched to address this issue.To characterize current clinical trial transparency policies among the largest noncommercial US funders and examine whether the policies are concordant with international funders.This retrospective review of public information used methods developed for documenting funder policies internationally; 2 researchers searched each funder's website and Google between May and November 2018 to locate trial transparency policies for 10 top US funders. Key informants at each funding organization were contacted by email and given 3 or more weeks to review and confirm or correct the findings. Nonresponders were contacted 2 or more additional times. Descriptive statistics were calculated to summarize the findings. The study was conducted using publicly available policy information with findings confirmed by funder representatives where possible. Participants included top 10 noncommercial US health research funders with the highest reported investment in health research (2013 dollars) who fund clinical trials. Data analysis was conducted from November 6, 2018, to November 23, 2018.Availability of policies addressing each of the 3 key trial transparency domains as specified by the World Health Organization in 2017.Independent assessment by 2 investigators of availability (yes or no) of a policy addressing registration for trials, sharing of summary results, and individual participant data sharing activities; requirements (yes, no, or supportive statement) of these policies in terms of completeness, timeliness, public access, and provision of additional technical or financial support to meet data sharing requirements; description (yes or no) of internal monitoring for policy adherence.All 10 funders acknowledged the outreach. One funder who indicated that less than 1% of their research funding goes to clinical trials was removed. Six (67%) of the remaining 9 top US funders have a publicly available written policy for all 3 major trial transparency domains. The most comprehensive trial transparency practice among US funders addresses summary results sharing as follows: 8 of 9 US funders (89%) have a policy, 5 of 9 US funders (56%) require reporting of summary results within 1 year, and 6 of 9 US funders (67%) monitor compliance with their summary results sharing policy. For clinical trial registration, 7 of 9 US funders (78%) have a policy and 5 of 9 US funders (56%) require registration and monitor trial registration to measure adherence to the policy.In this study, overall the proportion of US funders with policies and practices to support trial transparency in this sample was similar or compared favorably with the larger international sample of noncommercial funders recently reported.
IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation
Authors: Daniela Impellizzieri, Frederike Ridder, Miro E. Raeber, Cecilie Egholm, Janine Woytschak, Antonios G.A. Kolios, Daniel F. Legler, Onur Boyman
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 19930: Inflammatory Cytokine Oncostatin M Induces Endothelial Activation in vitro and in APOE*3Leiden.CETP Mice
Authors: Daniëlle van Keulen, Marianne G Pouwer, Gerard Pasterkamp, Alain J van Gool, Maarten D Sollewijn Gelpke, Hans M Princen, Dennie Tempel
Journal: Circulation (2017)

Introduction: Endothelial activation is involved in all stages of atherosclerosis development. Upon endothelial activation, the endothelial barrier becomes more permeable and starts recruiting immu...
Sinusoids as Drivers of Liver Development: More Than Simple Chemistry
Authors: Ana C. Maretti‐Mira, Laurie D. DeLeve
Journal: Hepatology (2019)

Maretti‐Mira, Ana C. Ph.D.1; DeLeve, Laurie D. M.D., Ph.D., F.A.A.S.L.D.1Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information