tbuckley/cabot-search huggingface dataset:
Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies
Authors: Paul Monagle, Anthonie W A Lensing, Kirstin Thelen, Ida Martinelli, Christoph Male, Amparo Santamaría, Elena Samochatova, Riten Kumar, Susanne Holzhauer, Paola Saracco, Paolo Simioni, Jeremy Robertson, Gernot Grangl, Jacqueline Halton, Phillip Connor, Guy Young, Angelo C Molinari, Ulrike Nowak-Göttl, Gili Kenet, Stefanie Kapsa, Stefan Willmann, Akos F Pap, Michael Becka, Teresa Twomey, Jan Beyer-Westendorf, Martin H Prins, Dagmar Kubitza, Paul Monagle, Jeremy Robertson, Gernot Grangl, Christoph Male, Werner Streif, Jorge Carniero, Sandra Logetto, Leonardo Brandao, Jacqueline Halton, Pascal Amedro, Damien Bonnet, Jan Beyer-Westendorf, Sven Dietrich, Susanne Holzhauer, Ulrike Nowak-Göttl, Krisztian Kallay, Gili Kenet, Shoshana Revel-Vilk, Hannah Tamary, Paola Giordano, Maria Abbattista, Andrea Artoni, Angelo C Molinari, Paola Saracco, Paolo Simioni, Daniela Tormene, Hiroshi Ono, Maroeska WM Te Loo, Heleen Van Ommen, Margreet A Veening, Monique H Suiker, Marjolein Peters, Elena Samochatova, Anastasia Shamardina, Nizhny Novgorod, Lyudmila Zubarovskaya, Maria A Dasi, Maria Elorza, Amparo Santamaria, Manuel Sánchez-Luna, Manuela Albisetti, Sebastian Grunt, Kaan Kavakli, Tina Biss, Philip Connor, Mike Williams, Suchitra Acharya, Rumi Bhat, Susan Kearney, Riten Kumar, Kavita Patel, Madvi Rajpukar, Jeffrey H Schwartz, Terry Vik, Tung Wynn, Donald L Yee, Guy Young
Journal: The Lancet Haematology (2019)
Abstract 18630: Targeting Inhibitor of Protein Phosphatase 2A (I2PP2A) Mediates Plasma Membrane Beta-Adrenergic Receptor Resensitization
Authors: Elizabeth E Martelli, Neelakantan T Vasudevan, Maradumane L Mohan, Manveen K Gupta, Sathyamangla V Naga Prasad
Journal: Circulation (2013)

βAR downregulation and desensitization are hallmarks of heart failure. Agonist occupied βARs undergo desensitization through phosphorylation by G-protein coupled receptor kinases leading to βAR internalization. Phosphorylated βAR becomes resensitized following dephosphorylation by PP2A in the endosome, a paradigm in receptor resensitization. Our recent studies have suggested that resensitization of βARs can occur on the plasma membrane through the inhibition of PP2A activity by I2PP2A. To test whether I2PP2A regulates βAR and cardiac function we generated transgenic mice with cardiac specific over expression of I2PP2A. Assessment of age dependent cardiac function of these mice showed that transgenic mice have cardiac hypertrophic response followed by dilated cardiomyopathy. These observations are further supported by immunohistochemistry. Since we have observed cardiac dysfunction and βAR desensitization in transgenic mice, we tested whether targeting I2PP2A in cells would allow for plasma membrane resensitization. We generated a stable HEK (Human Embryonic Kidney) cell line expressing short hairpin RNA targeting I2PP2A (shRNA-I2PP2A). Confocal microscopy studies show that cells expressing shRNA-I2PP2A resulted in significant loss of receptor phosphorylation despite the presence of the agonist. Furthermore, radioligand binding and confocal imaging showed marked inhibition of receptor internalization upon depletion of I2PP2A with significant PP2A activation. Consistently, we also observed preservation of βAR function despite the presence of agonist as measured by cAMP generation and adenylyl cyclase activity. Together these studies suggest that targeting I2PP2A may lead to plasma membrane receptor resensitization demonstrating that modulating PP2A function can potentially change desensitization and resensitization dynamics of the receptors on the plasma membrane.
The Amount of Evidence Needed to Support ERBB2 as a Biomarker for Resistance to EGFR Inhibitors in Metastatic Colorectal Cancer
Authors: Andrea Sartore-Bianchi, Silvia Marsoni, Salvatore Siena
Journal: JAMA Oncology (2019)

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Stage II or III colorectal cancer which expressed VEGF would be candidate for postoperative molecular targeting adjuvant therapy for VEGF in combination with chemotherapy using oral fluoropyrimidines
Authors: Yutaka Ogata, Keiko Matono, Teruo Sasatomi, Nobuya Ishibashi, Tomoaki Mizobe, Kazuo Shirouzu
Journal: Cancer Research (2005)

2162  Background: The aim of this study was to clarify any relationship between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. Patients and Methods: The data on 379 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy including mesenteric lymph nodes, were reviewed. Of these, 228 received postoperative administration of oral fluoropyrimidines (Chemotherapy Group), while other 151 patients underwent surgery alone (Surgery-alone Group). Immunostainig for VEGF was performed using surgical specimens from all 379 patients. Results: The positive ratio of VEGF expression was 47 % over all patients. The disease-free survival rate and overall survival rate in the Chemotherapy Group were significantly higher than those in the Surgery-alone Group. However, no significant difference in disease-free survival rate was found between the two groups for those with tumor positive for VEGF, tumor which involved mesenteric lymph nodes or nodes belonging to the internal iliac artery, or with tumor with lymphatic permeation or venous invasion. The positive ratio of VEGF expression was higher in those at stage III, and in those with severe lymphatic permeation. Conclusion: Postoperative adjuvant chemotherapy using oral fluoropyrimidines could not reduce the risk to recurrence for patients with a tumor positive for VEGF. Thus, combined use of molecular targeting therapy for VEGF with postoperative adjuvant chemotherapy using oral fluoropyrimidines would be ideal in tumors positive for VEGF in stage II or III colorectal cancer.
Decoy-insensitive TRAIL variants kill tumour cells more efficiently without damaging non-transformed cells
Authors: Eva Szegezdi, Devalingam Mahalingam, Almer van der Sloot, Wim Quax, Maccon Keane, Afshin Samali
Journal: Cancer Research (2007)

5170  Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF death ligand family. It is best known for its ability to induce apoptosis selectively in cancer cells but not in untransformed cells. TRAIL is recognized by four distinct membrane-bound receptors: DR4, DR5, DcR1 and DcR2. Of the four receptors, only DR4 and DR5 contain a death domain, which is required for induction of apoptosis. DcR1 and DcR2 do not have a functional death domain and thus they are thought to act as decoy receptors. Currently the role of the decoy receptors in TRAIL-resistance of tumour cells is controversial, but their ubiquitous expression on the surface of almost all somatic cells may limit the in vivo efficiency of TRAIL.  We previously described the successful design of DR5-selective TRAIL variants using a computational design strategy. We found that double mutation at positions D269H/E195R resulted in enhanced affinity for DR5, and an 8-12 fold reduced affinity for DR4. This mutant showed no binding to recombinant DcR1 and a 2-10 fold lower binding to recombinant DcR2, compared to wild-type TRAIL. Analysis of biological functionality confirmed the DR5-specific, receptor-agonistic action of the D269H/E195R variant. Furthermore, when compared to wild-type TRAIL, D269H/E195R displayed a 3-5 fold increased cytotoxic potential in DR5-responsive cancer cells. We found that soluble recombinant DcR1 and DcR2 could completely block the pro-apoptotic activity of wild-type TRAIL. On the contrary, only high concentration of soluble recombinant DcR2, but not DcR1 could reduce the pro-apoptotic activity pf D269H/E195R. Using neutralizing antibodies to DcR1 and DcR2, we found that inhibition of TRAIL-binding to either DcR1 or DcR2 increases TRAIL-mediated cell death by up to 42%. Inhibition of both decoy receptors resulted in a cumulative effect with a up to XX% increase in TRAIL-mediated cell death. At the same time, neutralization of the decoy receptors failed to further increase cell death induced by D269H/E195R, suggesting the greater cytotoxic potential of D269H/E195R over wild type TRAIL is due to its decreased binding to the decoy receptors. Importantly, D269H/E195R induced apoptosis only in tumour cells, but not in primary human keratinocytes or endothelial cells, two cell types shown to be sensitive to certain forms of recombinant TRAIL.  Overall, these results suggest that decoy receptors can greatly reduce the death-inducing potential of TRAIL. Selective activation of the DR5 receptor and elimination of the binding to the decoy receptors can thus provide higher anti-tumour potential without leading to toxicity in non-transformed cells.
Abstract 16279: Impact of Left Atrial Appendage (LAA) Morphology on Intraprocedural Outcomes for Watchman Device Implantation
Authors: Tawseef Dar, Bharath Yarlagadda, Gurjit Singh, Seth M Sheldon, Senthil Thambidorai, Dhanunjaya Lakkireddy, Y. Madhu Reddy
Journal: Circulation (2018)

Introduction: Left atrial appendage (LAA) is a very heterogeneous structure and has traditionally been classified into 4 different morphologies: the cauliflower/broccoli, cactus, windsock and chick...
Validation of the chemotherapy-induced neuropathy assessment scale.
Authors: Sheeba K. Thomas, Tito R. Mendoza, Elisabeth G. Vichaya, Xin Shelley Wang, Mary H Sailors, Loretta A. Williams, Patrick M. Dougherty, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2012)

9140 Background: Many of the assessment tools used to assess peripheral neuropathy in clinical trials focus on painful neuropathy. However, some chemotherapy agents cause both painful and non-painful peripheral neuropathy. The Chemotherapy-Induced Neuropathy Assessment Scale (CINAS) was designed to evaluate the multi-dimensional nature of chemotherapy-induced neuropathy, including non-painful sensory and motor deficits. This study evaluated the psychometric properties of the CINAS in patients with multiple myeloma (MM) receiving induction chemotherapy and/or autologous hematopoietic stem cell transplantation. Methods: We collected demographic and clinical data and administered 2 items measuring pain and numbness/tingling at its worst (0-10 scale), and the CINAS. A total CINAS score was computed by summing all 11 CINAS items. For reliability and validity analyses, we used the highest total CINAS score for each patient. Validity was assessed by factor analysis and by correlating CINAS subscales with the pain and numbness/tingling items. Cronbach alpha reliability coefficients were computed. To test sensitivity, we compared change in total CINAS score during induction from baseline to last total CINAS score in a subset of patients (N=20) receiving bortezomib or thalidomide. We hypothesized that such patients would develop neuropathy. Results: Ninety patients were enrolled. Participants were primarily white (90%) and male (63%). Factor analysis revealed 3 underlying constructs for the CINAS - sensory, motor functioning, and allodynia - explaining 74% of the common variance. Cronbach alphas were 0.84, 0.85, and 0.83 for the sensory, motor functioning, and allodynia subscales, respectively, while subscale correlations with the numbness/tingling item were 0.74, 0.56, and 0.52, respectively. Pain was only modestly correlated with these subscales (0.21, 0.36, 0.29). Total CINAS scores of patients receiving bortezomib or thalidomide induction worsened significantly (from 3.4 to 11.9, effect size=0.55, p&lt;.02). Conclusions: The CINAS demonstrated validity, reliability and sensitivity in patients with MM during and after chemotherapy and can be used to assess the multidimensional aspects of chemotherapy-induced neuropathy.
MUC1 deficiency promotes nasal epithelial barrier dysfunction in subjects with allergic rhinitis
Authors: Li-Bo Zhou, Yao-Ming Zheng, Wen-Jing Liao, Li-Juan Song, Xuan Meng, Xin Gong, Gui Chen, Wei-Xing Liu, Ying-Qi Wang, De-Min Han, Nan-Shan Zhong, Wen-Ju Lu, Ping-Chang Yang, Xiao-Wen Zhang
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 11415: Enhancing Direct Cardiac Reprogramming Efficiency Using Small Molecules
Authors: Tamer M Mohamed, Nicole Stone, Emily Berry, Haixia Wang, Sheng Ding, Deepak Srivastava
Journal: Circulation (2015)

The ability to directly trans-differentiate fibroblasts into cardiomyocytes through overexpression of three core transcription factors, Gata4, Mef2C &amp;TBX5 (GMT), has been demonstrated by our group and others. Direct cardiac reprogramming has great potential to treat heart failure. However, clinical application remains limited due to inefficiencies in the reprogramming process and immaturity of the differentiated cardiomyocytes. In the current work, using a chemical approach we aim to increase the efficiency and the maturation of these directly reprogrammed cardiomyocytes. We have optimized a high-throughput screening method in 384-well plates using an alpha-MHC-GFP reporter to detect cardiac reprogramming in mouse cardiac fibroblasts. We screened 5500 compounds and identified 20 hits which have increased the reprogramming efficiency by 2-6 fold compared to controls. Among these top hits, 4 TGF-β inhibitors (DS 1-4) and 4 WNT inhibitors (DS 5-8) enhanced direct cardiac reprogramming. Further in depth investigations showed that the combination of the TGF-β inhibitor DS1 and the WNT inhibitor DS5 increased reprogramming efficiency 7 fold when added to the GMT-overexpressing fibroblasts on the first day of reprogramming. This combination of small molecules also enhanced the maturation of the reprogrammed cells, as we observed beating cells after only 1 week of reprogramming compared to 6–8 weeks without the small molecules. Activation of canonical WNT signaling or TGF-β signaling significantly abrogates the improvement in cardiac reprogramming by DS1 and DS5. These results indicate the specificity of the action of these inhibitors through the canonical WNT and TGF-β pathways. In a translational effort, we injected DS1, 2 and 5 intraperitoneally in mice for 2 weeks in combination with GMT following myocardial infarction (MI) and found a significant improvement in cardiac function as represented by an ejection fraction of 39.11% ±1.2% in the GMT + compounds group vs. 28.44% ± 3.98% in the GMT only group (p&lt;0.05), 6 weeks after MI compared to an ejection fraction of 22.72% in the control untreated group. In conclusion, small molecules, especially the TGF-β inhibitors and WNT inhibitors, greatly enhanced direct reprogramming in vitro and in vivo.
Treatment patterns among cancer patients with anemia who do not respond to erythropoietin-stimulating agents.
Authors: Allicia C Girvan, Yiu-Keung Lau, Lee Bowman, Gerhardt Pohl, Pamela Landsman-Blumberg, Nianwen Shi, Helen Varker
Journal: Journal of Clinical Oncology (2013)

e20525 Background: While broadly utilized for treatment of anemia in cancer patients, treatment with Erythropoetin Stimulating Agents (ESAs) is contraindicated in patients who fail to respond within 6-8 weeks. This study examined rates of ESA response and rates of continued ESA use following non-response in five cancer cohorts treated by community-practice oncologists. Methods: Patients with breast, head and neck, cervical, non-small cell lung cancer, or multiple myeloma initiating ESAs on or before 7/1/2011 were identified from EMRs in the ACORN Data Warehouse (ACORN, Memphis TN). The study included those with at least 6-8 weeks of ESA use and documented hemoglobin (Hb) values ≤28 days before start of ESA (“baseline”) and anytime during day 43-70 of ESA treatment. Per ASCO/ASH guidelines, patients were noted as responders if Hb increased ≥1g/dL between baseline and the Hb value closest to day 56 in the 43-70 day window, and non-responders if Hb increased &lt;1g/dL. Non-responders were further classified as continuing or discontinuing therapy based on record of ESA treatment following determination of non-response. Results: A total of 2,197 patients were studied. ESA response rate was 45%. For non-responders, 83% continued ESAs after determination of non-response. Hb increase at end of therapy among non-responders remained lower than for patients who demonstrated initial response. Additionally, non-responders received nominally longer treatment, with a mean exposure of 169 days. Conclusions: Among cancer patients, a majority of ESA non-responders remained on ESA treatment beyond the recommended response window as defined by ASCO/ASH guidelines. Moreover, non-responders remained on treatment longer than those who demonstrated an initial response. [Table: see text]
Multifunctional nanoparticles for genetic engineering and bioimaging of natural killer (NK) cell therapeutics
Authors: Kwang-Soo Kim, Jun-Hyeok Han, Jung-Hoon Park, Hyung-Keun Kim, Seung Hee Choi, Gyeong Ryeong Kim, Haengseok Song, Hee Jung An, Dong Keun Han, Wooram Park, Kyung-Soon Park
Journal: Biomaterials (2019)
Clinicopathological features of gastric cancer with CpG island methylator phenotype and its association to Epstein-Barr virus
Authors: Masanobu Kusano, Minoru Toyota, Hiromu Suzuki, Kimishige Akino, Hiroaki Mita, Fumio Itoh, Kohzoh Imai, Takashi Tokino
Journal: Cancer Research (2005)

857   Gastric cancer arises through accumulation of multiple genetic and epigenetic changes. However, it remains unclear whether genetic and epigenetic changes accumulate together or there are distinct differences in genetic and epigenetic pathways. In the current study we classified gastric cancer by methylation profile. Seven genes (p16INK4A, hMLH1, CHFR, HRK, p57KIP2, HLTF, SLC5A8) that have shown to be inactivated by methylation in gastric cancer were selected for analysis. In addition, five genes (PAX-5, SOCS-3, CSPG2, BNIP3, TIG1) that have shown to be methylated in various types of human tumors were also examined. Methylation profiles of 12 genes were determined by COBRA. Methylation was more frequently detected in tumors which were previously characterized as CpG island methylator phenotype-high (CIMP-H) using methylation markers that showed cancer specific methylation in gastric cancer. Gastric cancers with CIMP-H showed simultaneous methylation of multiple genes (average methylated loci: 5.2), whereas gastric cancer in CIMP-low and CIMP-negative showed less frequent methylation (average methylated loci: 2.0 and 0.77). Gastric cancers with CIMP-H showed no p53 mutations, whereas tumors in CIMP-L and CIMP-N showed p53 mutations (17% and 30%). By examining clinicopathological and etiological features of these tumors, we found that gastric cancers involved in Epstein-Barr virus is frequently associated with CIMP-H (67%) CIMP-L (0%), and CIMP-N (4%), indicating the role of Epstein-Barr virus in aberrant methylation in gastric cancer. These results indicated that gastric cancer arises through multiple pathways that involved in distinguished genetic and epigenetic pathways.
Trends in the Use of Cardiac Imaging for Patients With Heart Failure in Canada
Authors: Juarez R. Braga, Howard Leong-Poi, Valeria E. Rac, Peter C. Austin, Heather J. Ross, Douglas S. Lee
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Cardiac imaging is a component of the provision of medical care for patients with heart failure that has experienced a broad expansion in past decades. However, there is a paucity of studies examining the patterns of use of cardiac imaging modalities in real-world clinical practice. <h3>Objectives</h3> To investigate temporal trends in the use and costs of cardiac imaging for the examination of patients with heart failure in Canada and to examine the association between the institution of an accreditation program and the use of echocardiography. <h3>Design, Setting, and Participants</h3> A repeated cross-sectional study based on population-based administrative databases in Ontario, Canada, of individuals with heart failure identified using a validated algorithm based on hospital admissions and ambulatory physician claims was conducted between April 1, 2002, and March 31, 2017. <h3>Main Outcomes and Measures</h3> The incidence and prevalence of heart failure and the age- and sex-adjusted rate of use and costs of cardiac imaging, including resting and stress echocardiography, myocardial perfusion scintigraphy, invasive coronary angiography, computed tomography, magnetic resonance imaging, and positron emission tomography. <h3>Results</h3> A total of 882 355 adults (50.1% women; median age, 76 years [interquartile range, 66-83 years]) with prevalent heart failure were identified. The age- and sex-standardized prevalence of heart failure remained stable during the study (2.4% [95% CI, 2.4%-2.4%] in 2002 and 2.0% [95% CI, 2.0%-2.0%] in 2016). There was an increase in the rate of use of resting echocardiography, from 386 tests (95% CI, 373-398) per 1000 patients with heart failure in 2002 to 533 (95% CI, 519-547) per 1000 patients in 2011. Coinciding with the initiation of an accreditation program for echocardiography in 2012, there was an immediate reduction in the rate of use (−59.5 tests per 1000 patients with heart failure;<i>P</i> &lt; .001), which was followed by a plateau in subsequent years. At the same time, there was a 10.8% relative reduction in the use of myocardial perfusion scintigraphy and an 11.2% relative reduction in the use of invasive coronary angiography from 2011 to 2016 and the incorporation of newer modalities after they became publicly insured health services. <h3>Conclusions and Relevance</h3> These findings suggest that resting echocardiography remains the most used imaging technique for patients with heart failure, exceeding the use of and the cost spent on other modalities. Stabilization in the use of traditional imaging modalities coincided temporally with the emergence of advanced techniques and provincewide quality improvement policy initiatives.
Changing society: changing role of doctors
Authors: Töres Theorell
Journal: BMJ (2000)

Papers p 1437 

The role of the doctor has changed drastically since the 1930s and 1940s, when practitioners struggled with unbelievably large numbers of patients in their districts. Today the numbers of patients are much smaller, but their qualitative demands are much higher. At the same time the high status of the doctor has been diminished. These changing patterns of work and position in society are creating new, and damaging, stresses.

Our own studies in the 1980s at the Swedish National Institute for Psychosocial Factors and Health showed that doctors had longer working hours and more exposure to shiftwork schedules (being on call) but also more stimulating work than men and women in most otheroccupations.1 Doctors also claimed that in relation to most aspects of their work they had reasonable control over their working situation—more than in most other occupations. Since then the situation has changed.

Recent studies of the working population in Sweden show that both female and male doctors report both high demands and little …