tbuckley/cabot-search huggingface dataset:
Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk
Authors: M Tohen, J Castillo, R J Baldessarini, C Zarate, J C Kando
Journal: American Journal of Psychiatry (1995)

The purpose of this study was to determine the occurrence of leukopenia and other blood dyscrasias associated with psychiatric use of carbamazepine and valproate.Rates of WBC counts of 3,000-4,000/mm3 (moderate leukopenia) and < 3,000/mm3 (severe leukopenia), platelet counts of < 100,000/mm3, and hematocrit < 30% were identified among 2,228 treated patients at risk among 11,720 patients admitted to McLean Hospital over 4 years (1989-1993). Patients who received carbamazepine or valproate and had a blood dyscrasia not associated with a relevant medical condition were compared to patients treated with imipramine or desipramine.Of 977 patients treated with carbamazepine, 2.1% experienced leukopenia (16 moderate cases, five severe). Time to 50% risk was 16 days, and recovery occurred within about 6 days after carbamazepine was stopped. For 1,251 patients given valproate, the occurrence of leukopenia was 0.4% (three moderate cases, two severe). The occurrence of leukopenia in 1,031 patients given the tricyclic antidepressants was 0.3% (two moderate cases, one severe). The observed occurrence of moderate leukopenia with carbamazepine was 6.9 and 7.3 times higher than that with valproate and antidepressants, respectively.Severe blood dyscrasias were uncommon in psychiatric patients given carbamazepine and were about as rare with valproate as with imipramine or desipramine. Most important, in this cohort of 2,228 patients exposed to carbamazepine and valproate, there were no life-threatening cases.
A phase II prospective study of EGFR-TKI for Asian patients with EGFR-mutant non-squamous, non-small cell lung cancer
Authors: Jia-Juan Hsieh, John Chang, Ping-Tsung Chen, Hung-Ming Wang, Yun-Chung Cheung, Jen-Shi Chen, Cheng-Hsu Wang, Chih-Hung Chen, Kun-Yun Yeh, Shiu-Feng Huang, Li-Ying Ou
Journal: Cancer Research (2007)

3523  Background:   The correlation of EGFR mutations with the treatment response was strong in many retrospective studies. However, no prospective studies have been reported. We conducted this prospective to evaluate the efficacy of EGFR-TKI for patients with EGFR-mutant non-small cell lung cancer (NSCLC).  Methods:  Patients with histologically proven non-squamous NSCLC were enrolled only if the fresh tumor samples were EGFR mutant except T790M. Eligible patients were treated with either Iressa 250 mg QD or Tarceva 150 mg QD. CXR was taken every week for 4 weeks. CT scan was done at baseline, day 14 and day 56. Response was evaluated according to RECIST criteria. Mutation analysis of the EGFR gene was performed by PCR amplification and sequencing. Chromotography was reviewed by 2 investigators with manual and BLAST software.  Results:  Sixteen patients were enrolled up to November, 2006. 7 (43.7%) of 16 mutations were exon 19 deletion, 7 (43.7%) exon 21 L858R missense mutation, 1 (6.3%) exon 18 missense mutation (E709K and G719A), and 1 (6.3%) exon 20 duplication (P772_V774dup). 14 (87.5%) of 16 evaluable patients achieved a partial response, 1 with L858R (6.3%) stable disease, and 1 with exon 20 duplication (6.3%) progressive disease. Grade 1 or 2 skin rash and diarrhea were seen in 57.1% and 14.3%, respectively.  Conclusions:  We prospectively demonstrated an extremely high and dramatic response rate of EGFR-TKI in Asian patients with EGFR-mutant NSCLC.
Gluten-Free Diet Reduces Symptoms, Particularly Diarrhea, in Patients With Irritable Bowel Syndrome and Antigliadin IgG
Authors: María Inés Pinto-Sanchez, Andrea Nardelli, Rajka Borojevic, Giada De Palma, Natalia Causada Calo, Justin McCarville, Alberto Caminero, Daniel Basra, Alexa Mordhorst, Ekatherina Ignatova, Suzanne Hansen, Melanie Uhde, Gary L Norman, Joseph A Murray, Edgardo Smecuol, David Armstrong, Julio C Bai, Detlef Schuppan, Stephen M Collins, Armin Alaedini, Paul Moayyedi, Elena F Verdu, Premysl Bercik
Journal: Clinical Gastroenterology and Hepatology (2020)
Covid-19: England to test 150 000 people every two weeks to track local outbreaks
Authors: Jacqui Wise
Journal: BMJ (2020)

Covid-19: England to test 150 000 people every two weeks to track local outbreaks Jacqui WiseThe Office for National Statistics (ONS) is to expand its infection survey to 150 000 people a fortnight in England by October, up from the current 28 000, in order to provide more information about the spread of covid-19 infection within the community and help to identify local outbreaks. 11 Office for National Statistics.Huge expansion of ONS led testing study will provide new insight into spread of covid-19 across the UK.18 August 2020.
Covid-19: Deaths in England and Wales are lowest since pandemic began
Authors: Shaun Griffin
Journal: BMJ (2020)

Deaths from covid-19 in England and Wales dipped to their lowest in 20 weeks in the first week of August, latest figures from the Office of National Statistics (ONS) show.Of the deaths registered, 152 (1.7%) mentioned covid-19-down from 193 the previous week. 1 Wales and the north west of England were the only regions where deaths were increasing.All other areas of England saw a reduction in fatalities.The latest findings from the monthly covid-19 infection survey conducted in England show that between 26 April and 2 August only 28% of 165 people who tested positive for SARS-CoV-2 or virus antibodies reported symptoms around the time of their test. 2 James Naismith, of the Rosalind Franklin Institute at the University of Oxford, said, "While this is good news, since for the vast majority covid-19 is not a serious illness, it makes it much harder to spot its spread."There was also some provisional evidence of a higher level of previous infection among people from ethnic minorities.Around 4.8% of people identifying as white tested positive for antibodies compared with 11.1% of people from all other ethnic groups.The previous infection survey report showed higher covid-19 infection rates in those working in patient or resident facing health and social care roles.The latest report suggests, however, that in more recent periods the heightened risk of infection for patient facing healthcare workers has reduced compared with those not in these roles.
Abstract 346: Cardiac Diagnoses and Initial Presentation to the Emergency Department May Be Associated With Hospital Mortality Among Hospitalized Pediatric Patients Who Experience Medical Emergency Team Events
Authors: Rebecca J Piasecki, Mona N Bahouth, Chakra Budhathoki, Heather M Newton, Jordan M Duval-Arnould, Cheryl R Dennison Himmelfarb, Elizabeth A HUNT
Journal: Circulation (2019)

Introduction: There is a paucity of data regarding the association of pediatric patient characteristics with hospital mortality and transfer to higher levels of care following medical emergency team (MET) events. Objective: To explore associations of patient characteristics with hospital mortality and transfer to higher levels of care among pediatric patients who experienced a MET event during an admission. Methods: This retrospective observational study included data from patients aged ≤17 years admitted to an urban, tertiary hospital who experienced a MET event between 2014 and 2017. Data specific to the initial MET event for a patient were included for analysis. Multiple logistic regression models were used to test associations between patient characteristics (age, race, sex, ethnicity, timing of MET event, primary admission diagnosis, receiving care on specialized units) and each outcome separately. Results: Of the 366 patients eligible for inclusion, 11% (41 of 366) experienced hospital mortality, and 59% (216 of 366) were transferred to higher levels of care following MET events. Hospital mortality was lower among those who received emergency department care within 24 hours before the MET event compared to patients who did not (OR=0.17; 95% CI=0.04-0.82). Hospital mortality was higher among those with cardiac-related primary admission diagnoses compared to patients with noncardiac-related diagnoses (OR=3.44; 95% CI=1.04-11.39), and among those of unknown race compared to white patients (OR=3.14; 95% CI=1.17-8.48). No patient characteristics were associated with transfers to higher levels of care. Conclusions: While MET events may cause concern about failures to triage patients to appropriate levels of care upon admission, we observed that patients admitted from the emergency department within 24 hours before their MET event were more likely to survive to discharge. Higher hospital mortality following MET events was observed among patients with cardiac diagnoses and those of unknown race; more research is needed to understand how processes and documentation of care are related to these patients. Further study of how these characteristics and other potential confounding factors are associated with MET events and outcomes is warranted.
BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition
Authors: Marco H. Hofmann, Michael Gmachl, Juergen Ramharter, Fabio Savarese, Daniel Gerlach, Joseph R. Marszalek, Michael P. Sanderson, Dirk Kessler, Francesca Trapani, Heribert Arnhof, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Andreas Zoephel, Szu-Chin Fu, Jessica L. Teh, Jark Böttcher, Nikolai Pototschnig, Franziska Schachinger, Katharina Schipany, Simone Lieb, Christopher P. Vellano, Jonathan C. O'Connell, Rachel L. Mendes, Jurgen Moll, Mark Petronczki, Timothy P. Heffernan, Mark Pearson, Darryl B. McConnell, Norbert Kraut
Journal: Cancer Discovery (2020)

Abstract KRAS is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors. Significance: To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D. See related commentary by Zhao et al., p. 17. This article is highlighted in the In This Issue feature, p. 1
High dosage of methylprednisolone as a rescue, second-line treatment in COVID-19 patients who failed to respond to tocilizumab
Authors: Edoardo Conticini, Federico Franchi, David Bennett, Serafina Valente, Maria A Mazzei, Elena Bargagli, Luca Volterrani, Sabino Scolletta, Bruno Frediani
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the article by Ramiro et al 1 about a cohort of patients affected by severe COVID-19 pneumonia. The authors evidenced the efficacy of 5 days of methylprednisolone (MP) (a single bolus of 250 mg, followed by 80 mg on days 2–5) plus, in case of insufficient response, tocilizumab (TCZ) 8 mg/kg, in reducing mortality and preventing invasive ventilation (IV).

As the massive lung damage during COVID-19 pneumonia is thought to be caused by an aberrant inflammatory response mediated by a massive release of inflammatory cytokines and chemokines, the use of biological immunosuppressants has been widely proposed. The rationale supporting their use is not only an antiviral effect,2 but the selective anti-inflammatory role and the capability of interrupting the cytokine cascade eventually responsible for lung failure.

TCZ, a monoclonal antibody directed against interleukin 6 (IL-6) receptor, was the first biological drug administered in a Chinese cohort of patients. Despite preliminary promising data, recent reviews and meta-analysis did not find statistically significant differences, in terms of mortality, intensive care unit (ICU) admission and requiring of IV, between patients treated with TCZ and …
Plasma Levels of Endothelial Cell Protein C Receptor Are Elevated in Patients With Sepsis and Systemic Lupus Erythematosus: Lack of Correlation With Thrombomodulin Suggests Involvement of Different Pathological Processes
Authors: Shinichiro Kurosawa, D.J. Stearns-Kurosawa, Craig W. Carson, Armando D' Angelo, Patrizia Della Valle, Charles T. Esmon
Journal: Blood (1998)
What lies beneath: poking a hole in the diagnosis
Authors: Natalya Kozlova, Anna Rozenshtein, Soumya Mikkilineni, Yevgeniy Linnik, Oleg Epelbaum
Journal: Thorax (2020)

A man aged 77 years was referred to the emergency department (ED) of our hospital by his primary physician for evaluation of dyspnoea and hypoxaemia. On presentation to the ED, he reported 2 months of progressively worsening dyspnoea and non-productive cough. He also endorsed weight loss and fatigue. He had been prescribed a recent course of clarithromycin after an episode of fever, but this did not ameliorate either the dyspnoea or the cough. On the day he was referred to the ED, his primary physician found him to be hypoxemic, which is what prompted the referral.

The patient’s medical history was significant for hypertension and coronary artery disease with myocardial infarction and coronary stenting 4 years prior to admission. His usual home medications included aspirin, carvedilol, losartan, rosuvastatin, sertraline and zolpidem. He was a former smoker who quit 25 years earlier after accumulating 40 pack-years. He had no occupational or environmental exposures.

On admission, his hypoxaemia was confirmed with an oxygen saturation by pulse oximetry on room air of 76%. The patient was visibly dyspnoeic and had diffuse bilateral crackles on auscultation. His jugular venous pulse was normal. There was no clubbing or oedema. Routine laboratory evaluation was remarkable for a brain natriuretic peptide level of 557 pg/mL (normal <100 pg/mL). There was no blood eosinophilia. Testing of a nasopharyngeal swab specimen for the most common respiratory viral pathogens and Bordetella pertussis by PCR was negative. Frontal chest radiograph (CXR) obtained in the ED demonstrated extensive bilateral airspace opacification (figure 1A), which was new compared with a CXR taken 18 months earlier. There were no pleural effusions. Intravenous furosemide was administered for a presumptive diagnosis of cardiogenic pulmonary oedema. However, the patient’s symptoms and oxygenation failed to improve. Transthoracic echocardiography showed focal left ventricular wall motion abnormalities. However, systolic function …
Abstract 8648: Human Macrophage Regulation via Interaction with Pericardial Adipose Tissue-Derived Mesenchymal Stromal Cells
Authors: Shimrit Adutler-Lieber, Tamar Ben-Mordechai, Nili Naftali-Shani, Elad Asher, Dan Loberman, Ayelet Itzhaki-Alfia, Ehud Raanani, Jonathan Leor
Journal: Circulation (2011)

Background: While mesenchymal stromal cells (MSCs) were found to improve tissue repair, their mechanism of action is not fully understood. We aimed to test the hypothesis that MSCs may act via macrophages and that specifically, human pericardial adipose tissue-derived MSCs can polarize human macrophages into reparative, anti-inflammatory (M2)-like phenotype. Methods and Results: MSCs were isolated and expanded from pericardial adipose tissue of patients undergoing cardiac surgery. Monocytes isolated from human blood using Ficoll and MACS positive selection of CD14+ cells were cultured 5-7 days, washed, and co-cultured with MSCs 1-14 days directly or through a transwell membrane restricting cell contact. Supernatant was collected on different days for cytokine analysis by ELISA. M2 macrophage markers (CD206, CD163 and CD16) and phagocytic ability of fluorescent latex beads were examined using flow cytometry. We found that human MSCs increased the percentage of macrophages expressing alternative macrophage (M2) markers CD206+CD163+ (1.5 fold) and CD16+ (9 fold). MSCs also increased macrophage secretion of anti-inflammatory and reparative cytokines IL-10 (Fig; 9 fold, p&lt;0.001), VEGF (3 fold, p&lt;0.01), IL-13 (2 fold, p&lt;0.05) and IL-4 (2 fold, P&lt;0.05), and decreased IL-1 (2 fold, p&lt;0.01), TNF-α (1.5 fold, p&lt;0.001), IL-12 (1.5 fold, p&lt;0.001), IL-17 (3 fold, p&lt;0.001), IL-23 (16 fold, p&lt;0.01) and IFN-γ (2 fold, p&lt;0.001). In addition, co-culturing induced a star-shaped morphology of macrophages and decreased their phagocytic ability (2 fold). Conclusions: Our findings suggest, for the first time, that human pericardial adipose tissue-derived MSCs can polarize human macrophages towards anti-inflammatory, reparative phenotype. Our findings could be relevant for the mechanism of atherosclerosis and the development of novel immune-modulation therapy for the treatment of MI, atherosclerosis and other inflammatory diseases.
<i>Cdkn2a</i> Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST
Authors: Katherine E. Chaney, Melissa R. Perrino, Leah J. Kershner, Ami V. Patel, Jianqiang Wu, Kwangmin Choi, Tilat A. Rizvi, Eva Dombi, Sara Szabo, David A. Largaespada, Nancy Ratner
Journal: Cancer Research (2020)

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST. SIGNIFICANCE: New mouse models recapitulate the stepwise progression of NF1 tumors and will be useful to define effective treatments that halt tumor growth and tumor progression in NF1.
Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency
Authors: Hualong Bai, Nirvana Sadaghianloo, Jolanta Gorecka, Shirley Liu, Shun Ono, Abhay B. Ramachandra, Sophie Bonnet, Nathalie M. Mazure, Serge Declemy, Jay D. Humphrey, Alan Dardik
Journal: Science Translational Medicine (2020)

Radial artery deviation and reimplantation exhibits improved patency rates in both sexes and is associated with improved hemodynamics in a rat model.
Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis
Authors: Matteo Donadon, Guido Torzilli, Nina Cortese, Cristiana Soldani, Luca Di Tommaso, Barbara Franceschini, Roberta Carriero, Marialuisa Barbagallo, Alessandra Rigamonti, Achille Anselmo, Federico Simone Colombo, Giulia Maggi, Ana Lleo, Javier Cibella, Clelia Peano, Paolo Kunderfranco, Massimo Roncalli, Alberto Mantovani, Federica Marchesi
Journal: The Journal of Experimental Medicine (2020)

It has long been known that in vitro polarized macrophages differ in morphology. Stemming from a conventional immunohistology observation, we set out to test the hypothesis that morphology of tumor-associated macrophages (TAMs) in colorectal liver metastasis (CLM) represents a correlate of functional diversity with prognostic significance. Density and morphological metrics of TAMs were measured and correlated with clinicopathological variables. While density of TAMs did not correlate with survival of CLM patients, the cell area identified small (S-TAM) and large (L-TAM) macrophages that were associated with 5-yr disease-free survival rates of 27.8% and 0.2%, respectively (P < 0.0001). RNA sequencing of morphologically distinct macrophages identified LXR/RXR as the most enriched pathway in large macrophages, with up-regulation of genes involved in cholesterol metabolism, scavenger receptors, MERTK, and complement. In single-cell analysis of mononuclear phagocytes from CLM tissues, S-TAM and L-TAM signatures were differentially enriched in individual clusters. These results suggest that morphometric characterization can serve as a simple readout of TAM diversity with strong prognostic significance.
Epidemiology of Chlamydia trachomatis endocervical infection in a previously unscreened population in Rome, Italy, 2000 to 2009
Authors: V Marcone, N Recine, C Gallinelli, R Nicosia, M Lichtner, A M Degener, F Chiarini, E Calzolari, V Vullo
Journal: Eurosurveillance (2012)

As reliable data on Chlamydia trachomatis infection in Italy are lacking and as there is no Italian screening policy, epidemiological analyses are needed to optimise effective strategies for surveillance of the infection in the country. We collected data from 6,969 sexually active women aged 15 to 55 years who underwent testing for endocervical C. trachomatis infection at the Cervico-Vaginal Pathology Unit in the Department of Gynaecology and Obstetrics of Sapienza University in Rome between 2000 and 2009. The mean prevalence of C. trachomatis endocervical infection during this period was 5.2%. Prevalence over time did not show a linear trend. Univariate analysis demonstrated a significant association of infection with multiple lifetime sexual partners, younger age (<40 years), never having been pregnant, smoking, use of oral contraceptives, and human papillomavirus and Trichomonas vaginalis infections. Multivariate stepwise logistic regression showed that T. vaginalis infection, age under 20 years and more than one lifetime sexual partner remained significantly associated with C. trachomatis infection in the final model. Prevalence of C. trachomatis in this study was high, even among women aged 25–39 years (5.1%): our data would suggest that a C. trachomatis screening policy in Italy is warranted, which could lead to a more extensive testing strategy.