tbuckley/cabot-search huggingface dataset:
Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival
Authors: Anna Theiler, Thomas Bärnthaler, Wolfgang Platzer, Georg Richtig, Miriam Peinhaupt, Sonja Rittchen, Julia Kargl, Trond Ulven, Leigh M. Marsh, Gunther Marsche, Rufina Schuligoi, Eva M. Sturm, Akos Heinemann
Journal: Journal of Allergy and Clinical Immunology (2019)

BackgroundLung eosinophilia is a hallmark of asthma, and eosinophils are believed to play a crucial role in the pathogenesis of allergic inflammatory diseases. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are produced in high amounts in the gastrointestinal tract by commensal bacteria and can be absorbed into the bloodstream. Although there is recent evidence that SCFAs are beneficial in allergic asthma models, the effect on eosinophils has remained elusive.ObjectiveThe role of SCFAs was investigated in human eosinophil function and a mouse model of allergic asthma.MethodsEosinophils were purified from self-reported allergic or healthy donors. Migration, adhesion to the endothelium, and eosinophil survival were studied in vitro. Ca2+ flux, apoptosis, mitochondrial membrane potential, and expression of surface markers were determined by using flow cytometry and in part by using real-time PCR. Allergic airway inflammation was assessed in vivo in an ovalbumin-induced asthma model by using invasive spirometry.ResultsFor the first time, we observed that SCFAs were able to attenuate human eosinophils at several functional levels, including (1) adhesion to the endothelium, (2) migration, and (3) survival. These effects were independent from GPR41 and GPR43 but were accompanied by histone acetylation and mimicked by trichostatin A, a pan–histone deacetylase inhibitor. In vivo butyrate ameliorated allergen-induced airway and lung eosinophilia, reduced type 2 cytokine levels in bronchial fluid, and improved airway hyperresponsiveness in mice.ConclusionThese in vitro and in vivo findings highlight the importance of SCFAs, especially butyrate as a promising therapeutic agent in allergic inflammatory diseases.Graphical abstract
Progesterone for Threatened Abortion
Authors: Michael F. Greene
Journal: New England Journal of Medicine (2019)

Threatened abortion is defined as bleeding through the vagina, with a closed cervix, that occurs before the gestational age at which a fetus would be viable ex utero. Beyond this simple definition, some investigators have used additional criteria, such as confirmation that the source of the bleeding is from within the uterus and not from the cervix or vagina or requiring that the bleeding be more than mere "spotting." It is not surprising, then, that estimates of the incidence of threatened abortion vary considerably, with an incidence of approximately 25% being a reasonable contemporary estimate.1 For similar reasons, the estimate . . .
Abstract P2-06-25: A phenotypic screening and machine learning platform efficiently identifies triple negative breast cancer-selective and readily druggable targets
Authors: P Gautam, A Jaiswal, T Aittokallio, A-A Hassan, K Wennerberg
Journal: Cancer Research (2019)

Abstract Identifying effective oncogenic targets is challenged by the complexity of genetic alterations in cancer and their poorly understood relation to cell function and survival. This, combined with the fact that the majority of the proteome is predicted to be undruggable, may explain why genomic approaches have had only moderate success in identifying and translating oncogenic drug targets. There is a need for methods that rapidly and accurately identify “pharmacologically effective” targets without the requirement for priori knowledge of complex signaling networks. We developed an approach that uses machine learning to relate results from unbiased phenotypic screening of kinase inhibitors to their biochemical activity data. This process, which we call idTRAX (Identification of Drug TaRgets and Anti-targets by Cellular and Molecular Cross-referencing), identifies targets that are pharmacologically responsive and readily druggable. Additionally, the identified targets are not typically overcome by the robustness of signaling networks, because only targets that effectively induce a phenotype upon pharmacological engagement are selected. We applied this methodology to triple negative breast cancer, which still lacks targeted therapy. We screened 19 breast cancer cell lines with ˜500 small-molecule kinase inhibitors with annotated kinase activity data and identified cell-line specific kinase targets, i.e. kinases whose inhibition causes cell line-specific cytotoxicity or cytostaticity. We were able to identify various unique cell line selective kinase addictions along with well-known driver kinase addictions, for example, dependence on FGFR2 in the MFM-223 cell line and AKT kinases in MFM-223, CAL-148, and others. We also found that triple negative breast cancer cell lines exhibit heterogeneous target patterns, indicating the need of personalized medicine approach to tackle them. We further compared candidate targets identified by idTRAX with those reported from RNAi- and CRISPR-based screens. Strikingly, the correlation between targets identified by the pharmacological approach and those identified by knockdown/knockout-based screens was low [average rank correlation (ρ) = 0.0273- 0.1074], suggesting that gene-silencing approaches may not be the most efficient at identifying targets for small-molecule drug discovery or repurposing. Our approach provides a platform for rapidly identifying sample-specific drug targets and potentially guiding personalised therapy regimens. Citation Format: Gautam P, Jaiswal A, Aittokallio T, Hassan A-A, Wennerberg K. A phenotypic screening and machine learning platform efficiently identifies triple negative breast cancer-selective and readily druggable targets [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-25.
Causal Link between n-3 Polyunsaturated Fatty Acid Deficiency and Motivation Deficits
Authors: Fabien Ducrocq, Roman Walle, Andrea Contini, Asma Oummadi, Baptiste Caraballo, Suzanne van der Veldt, Marie-Lou Boyer, Frank Aby, Tarson Tolentino-Cortez, Jean-Christophe Helbling, Lucy Martine, Stéphane Grégoire, Stéphanie Cabaret, Sylvie Vancassel, Sophie Layé, Jing Xuan Kang, Xavier Fioramonti, Olivier Berdeaux, Gabriel Barreda-Gómez, Elodie Masson, Guillaume Ferreira, David W.L. Ma, Clementine Bosch-Bouju, Véronique De Smedt-Peyrusse, Pierre Trifilieff
Journal: Cell Metabolism (2020)
How to use the Lupus Low Disease Activity State (LLDAS) in clinical trials
Authors: Ioannis Parodis, Mandana Nikpour
Journal: Annals of the Rheumatic Diseases (2019)

Recently, two different studies1 2 applied the criteria of the Lupus Low Disease Activity State (LLDAS)3 to the data sets of the BLISS-524 and BLISS-765 phase III trials of belimumab. The studies reported similar LLDAS attainment frequencies at key time points; however, not identical. We herein discuss possible explanations in order to guide future usage of the LLDAS.

In the study by Parodis et al ,1 LLDAS at week 52 was achieved by 10.0% of the patients in BLISS-52 and 7.1% in BLISS-76, with a greater percentage within patients who received belimumab 10 mg/kg compared with patients who received placebo in BLISS-52 (11.9% vs 6.2%; p=0.030), but not in BLISS-76 (8.3% vs 6.4%; p=0.473). In the study by Oon et al ,2 LLDAS at week 52 was attained by 12.5% and 14.4% in the belimumab 10 mg/kg arm versus 5.8% and 7.8% in the placebo arm in BLISS-52 (p=0.02) and BLISS-76 (p=0.04), respectively.

The small-scale differences …
Effect of experience and commercialisation on survival in Himalayan mountaineering: retrospective cohort study
Authors: Martin Burtscher
Journal: BMJ (2012)

The paper

Westhoff JL, Koepsell TD, Littell CT. Effect of experience and commercialisation on survival in Himalayan mountaineering: retrospective cohort study. BMJ 2012;344:e3782, doi:10.1136/bmj.e3782

Abstract

Objectives —To determine whether previous Himalayan experience is associated with a decreased risk of climbing death, and whether mountaineers participating in commercial expeditions differ in their risk of death relative to those participating in traditional climbs.

Design —Retrospective cohort study.

Setting —Expeditions in the Nepalese Himalayan peaks, from 1 January 1970 to the spring climbing season in 2010.

Participants—23 995 non-porters venturing above base camp on 39 038 climbs, 23 295 on 8000 m peaks.

Outcome —Death.

Results —After controlling for use of standard route, peak, age, season, sex, summit success, and year of expedition, increased Himalayan experience was not associated with a change in the odds of death (odds ratio 1.00, 95% confidence interval 0.96 to 1.05, P=0.904). Participation in a commercial climb was associated with a 37% lower odds of death relative to a traditional venture, although not significantly (0.63, 0.37 to 1.09, P=0.100). Choice of peak was clearly associated with altered odds of death (omnibus P<0.001); year of expedition was associated with a significant trend toward reduced odds of death (0.98, 0.96 to 0.99, P=0.011).

Conclusions —No net survival benefit is associated with increased Himalayan experience or participation in a traditional (versus commercial) venture. The incremental decrease in risk associated with calendar year suggests that cumulative, collective knowledge and general innovation are more important than individual experience in improving the odds of survival.

Increasing numbers of climbers are attracted by the Himalayan mountains, and their climbing activities are associated with an extremely high risk of death.123 It is important to provide accurate data on the risk of death from climbing, and any other risks. Such information is particularly relevant with the …
Abstract P3-03-07: Withdrawn
Authors: JR Benson, S Gnanakumar, D Dumitru, E Provenzano
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Benson JR, Gnanakumar S, Dumitru D, Provenzano E. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-07.
AFM26 - Targeting B Cell Maturation Antigen (BCMA) for NK Cell-Mediated Immunotherapy of Multiple Myeloma
Authors: Thorsten Gantke, Uwe Reusch, Christian Kellner, Katja Klausz, Torsten Haneke, Stefan Knackmuss, Thomas Müller, Kristina Ellwanger, Ivica Fucek, Ute Schniegler-Mattox, Joachim Koch, Anne Kerber, Matthias Peipp, Martin Treder
Journal: Blood (2017)
Uptake of Drug-Eluting Bioresorbable Vascular Scaffolds in Clinical Practice
Authors: Katherine Hsin-Yu Chau, Kevin F. Kennedy, John C. Messenger, Kirk N. Garratt, Thomas M. Maddox, Robert W. Yeh, Ajay J. Kirtane
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Physicians have been criticized for having an overly enthusiastic response to new device approvals, especially for novel technologies. However, to our knowledge, the rates of new product adoption and patterns of new device usage in clinical practice have not been well described. <h3>Objective</h3> To characterize the patterns of uptake of bioresorbable vascular scaffolds (BVS) within the United States following device approval and to describe changes in response to subsequent releases of data and US Food and Drug Administration (FDA) warnings. <h3>Design, Setting, and Participants</h3> This analysis of the uptake of BVS between January 2016 and June 2017 used CathPCI Registry data; all percutaneous coronary intervention (PCI) procedures with an implant of either a BVS or conventional stent were included. Data analysis was performed in October 2017. <h3>Exposures</h3> Implant of BVS. <h3>Main Outcomes and Measures</h3> The primary outcome was monthly use of BVS in the United States. In addition, the characteristics of patients who received BVS and of hospitals that used BVS were assessed and comparisons of patient characteristics between BVS recipients and patients who were treated contemporaneously with metallic stents were made. <h3>Results</h3> Of 682 951 procedures, 471 064 (69.0%) were done in men, 587 301 (86.0%) were among white people, and the mean (SD) age of those undergoing procedures with BVS vs conventional stents was 62.6 (11.4) years vs 65.7 (11.9) years. Of these, 4265 procedures (0.6%) used BVS overall (after FDA approval of BVS). Procedures with implants of BVS occurred among patients with fewer comorbidities and lower-acuity presentations compared with procedures with implants of conventional stents. The patient characteristics for BVS use were not dissimilar to the inclusion criteria of the ABSORB III FDA approval trial, with notable differences based on trial eligibility (eg, excluding patients with myocardial infarctions). The maximum monthly use of BVS was 1.25% of all PCI procedures that occurred 90 days after FDA approval, but with site-to-site variability. Declines in use were observed coincident with the scientific presentation of adverse event data as well as FDA warnings. <h3>Conclusions and Relevance</h3> Most US physicians and hospitals were selective in their use of BVS, primarily using them in patients similar to those in the device's FDA approval trial. In addition, declines in use were evident in the subsequent month following the release of data that reported negative outcomes. These results illustrate an example of an appropriate physician response to adverse data updates and FDA warnings.
A lower leg injury not to be overlooked
Authors: David Shields, Timothy Patrick Crowley, Paul Vincent Fearon
Journal: BMJ (2012)

A 62 year old woman, previously fit and well, was admitted to the emergency department after a high speed road traffic crash. She was extricated from the overturned car by the emergency services, immobilised, and transferred to the resuscitation room. Full advanced trauma life support assessment was performed; her vital signs were stable; and her only injury was a swollen, deformed, and painful left lower limb. There were no overlying skin wounds, and there was no neurovascular deficit to the left foot. The emergency department staff were concerned she might have had an ankle fracture, and she underwent standard radiographs of her left ankle, one of which is below (see figure⇓).
Brain Lymphoma on 99mTc-TRODAT-1 SPECT
Authors: Chen-Kai Chiu, Shung-Shung Sun, Chia-Hung Kao, Yu-Chin Wu, Te-Chun Hsieh
Journal: Clinical Nuclear Medicine (2019)

Abstract 99m Tc-TRODAT-1, as a tropane-derived compound with highly selective binding to the dopamine transporter, has been extensively used as an in vivo biomarker to evaluate parkinsonism. There have been few reports indicating various etiologies about extrastriatal findings on the 99m Tc-TRODAT-1 SPECT. We herein present an interesting case about the incidental discovery of brain lymphoma with increasing uptake of 99m Tc-TRODAT-1.
Biomarker-Guided Anti-inflammatory Therapies
Authors: Michael Berk, Adam J. Walker, Andrew A. Nierenberg
Journal: JAMA Psychiatry (2019)

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Abstract 2102: Nanochemoprevention: Introducing a novel concept in cancer chemoprevention with a proof of principle for superior activity of green tea polyphenol epigallocatechin-3-gallate encapsulated in PLGA/PVA nanoparticles
Authors: Imtiaz A Siddiqui, Vaqar M Adhami, Bilal Bin Hafeez, Mohammad Asim, Sabih I Khwaja, Dhruba Bharali, Shaker A Mousa, Hasan Mukhtar
Journal: Cancer Research (2008)

Abstract Despite extensive efforts that have been put to prevent cancer through chemoprevention, lack of delivery of desired levels of bioactive agents thus limiting their bioavailability, remains a challenging issue for effective clinical outcome. Thus, there is a strong unmet need in the biomedical technology community to find novel tools for making chemoprevention a success. Because most biological processes including those that are cancer-related occur at nanoscale, nanoparticulate technology has emerged as a potential tool to diagnose and treat cancer. We considered that nanoparticulate technology can prove to be very useful in cancer chemoprevention by allowing for effective and targeted delivery of chemopreventive agents. This delivery system could overcome many biological, biophysical and biomedical barriers that the body stages. Here, for the first time we introduce a concept of ‘nanochemoprevention’. To demonstrate the proof of principle we selected green tea polyphenol epigallocatechin-3-gallate (EGCG) with which we have considerable experience. We encapsulated EGCG in Poly (DL-lactide-co-glycolide acid) (PLGA)/Polyvinyl alcohol (PVA) nanoparticles, hereafter referred to as nano-EGCG, and evaluated it for cytotoxic response against human prostate cancer (PCa) PC3, DU145, 22Rν1 and LNCaP cells. MTT assay showed that treatment of cells with PLGA/PVC nanoparticles alone had negligible effect on cell growth. Interestingly, nano-EGCG, compared to EGCG in PBS, produced remarkably superior effects. For PC3 cells, the IC50 value at 24 hours of nano-EGCG was 3.75 μM compared to 40 μM of EGCG in PBS; 3.75 μM of EGCG in PBS had no effect. These differential effects were persistent at 48 and 72 hours. Similar effects of nano-EGCG were observed in 22Rν1, LNCaP and DU145, other human PCa cells. EGCG in PBS treatment to cells is known to result in induction of apoptosis and inhibition of colony formation which is considered essential for its chemopreventive effects. Next series of experiments were conducted to determine the effect of nano-EGCG on apoptosis and colony formation potential of PC3 cells. Treatment of the cells for 48 hours with nano-EGCG led to significant induction of PARP cleavage in a dose dependent manner and modulation of bax and bcl2 ratio that favored apoptosis. Further, nano-EGCG treatment also led to a dramatic increase in the levels of annexin V, an early marker of apoptosis. We then performed a 2-dimensional colony formation assay to evaluate the effect of nano-EGCG on the cellular growth pattern of PC3 cells and observed a marked decrease in colony number. Validation of these cell culture data to animal model systems could pave way for developing new avenues for cancer chemoprevention.
The Quality and Outcomes of Care Provided to Patients with Cirrhosis by Advanced Practice Providers
Authors: Elliot B. Tapper, Shengchen Hao, Menghan Lin, John N. Mafi, Heather McCurdy, Neehar D. Parikh, Anna S. Lok
Journal: Hepatology (2019)

Cirrhosis is morbid and increasingly prevalent, yet the U.S. health care system lacks enough physicians and specialists to adequately manage patients with cirrhosis. Although advanced practice providers (APPs) can expand access to cirrhosis‐related care, their impact on the quality of care remains unknown. We sought to determine the effect on care quality and outcomes for patients managed by APPs using a retrospective analysis of a nationally representative American commercial claims database (Optum), which included 389,257 unique adults with cirrhosis. We evaluated a complication of process measures (i.e., rates of hepatocellular carcinoma [HCC] screening, endoscopic varices screening, and use of rifaximin after hospitalization for hepatic encephalopathy) and outcomes (30‐day readmissions and survival). Compared with patients without APP care, patients with APP care had higher rates of HCC screening (adjusted odds ratio [OR] 1.23, 95% confidence interval 1.19, 1.27), varices screening (OR 1.20 [1.13, 1.27]), use of rifaximin after a discharge for hepatic encephalopathy (OR 2.09 [1.80, 2.43]), and reduced risk of 30‐day readmission (OR 0.68 [0.66, 0.70]). Gastroenterology/hepatology consultation was also associated with improved quality metric performance compared with primary care; however, shared visits between gastroenterologists/hepatologists and APPs were associated with the best performance and lower 30‐day readmissions compared with subspecialty consultation without an APP (OR 0.91 [0.87, 0.95]. Multivariate analysis adjusting for comorbidities, liver disease severity, and other factors including gastroenterology/hepatology consultation showed that patients seen by APPs were more likely to receive consistent HCC and varices screening over time, less likely to experience 30‐day readmissions, and had lower mortality (adjusted hazard ratio 0.57, 95% confidence interval 0.55, 0.60). Conclusion: APPs, particularly when working with gastroenterologists/hepatologists, are associated with improved quality of care and outcomes for patients with cirrhosis.
An 80 year old man with air in the wrong place
Authors: Nicholas A Faure Walker, Rebecca Duerden, Simon Croxson
Journal: BMJ (2011)

An 80 year old man with advanced pulmonary fibrosis secondary to asbestos exposure presented to the emergency department with sudden onset shortness of breath and right sided chest and back pain. He was found to have a large, right sided pneumothorax. The patient was resuscitated and the on-call medical registrar inserted an underwater sealed chest drain. Its position was confirmed with a repeat chest radiograph.

Forty eight hours later, the junior doctor on call was asked to see the patient, who had severe face and chest pain with shortness of breath. He had not been vomiting or retching or undergone any further medical interventions and had not suffered any trauma. On examination, he looked unwell but could talk. The chest drain was in situ, but it was not swinging or bubbling and no leak was identified. His arms, chest, neck, and face were grossly distended, and there were subcutaneous crepitations in his skin. His respiratory rate was 36 breaths/min, oxygen saturation was 98% on 10 L O2/min, pulse was regular at 110 beats/min, and blood pressure was 130/86 mmHg. His skin was easily compressible and …