tbuckley/cabot-search huggingface dataset:
Comparison of Accessorized Pre-Filled Syringe with Autoinjector for Benralizumab Pharmacokinetic Exposure in Healthy Volunteers Following Administration of a Single Subcutaneous Dose: AMES Trial Results
Authors: Ubaldo Martin, Rainard Fuhr, Pablo Forte, Peter Barker, Milton Axley, Li Yan, Magnus Aurivillius
Journal: Journal of Allergy and Clinical Immunology (2019)
Reply
Authors: Càndid Villanueva, Isabel Graupera, Edilmar Alvarado
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. We thank Dr. Sauerbruch for the interest in our study. We agree that a relevant issue in the study was the improved survival observed in chronic hemodynamic responders versus nonresponders. However, the assertion of our colleague, suggesting that nonresponders might not get any benefit from medication (given the inefficacy to reduce hepatic venous pressure gradient [HVPG]) and that drugs may even worsen outcomes in such cases, is debatable. β‐blockers have beneficial effects beyond the capacity to decrease portal pressure and experts recommend to add endoscopic variceal ligation (EVL; if not performed) in nonresponders to β‐blockers instead of switching to EVL.1 Combined therapy with β‐blockers ± nitrates plus EVL is currently recommended after acute bleeding, with drugs being the cornerstone because meta‐analysis of RCTs comparing combined therapy with monotherapy have shown an improvement in survival with the addition of drugs to EVL, whereas the addition of EVL to β‐blockers has no effect on mortality.2 Our study further suggests that intensifying drug therapy may achieve hemodynamic response in previous nonresponders and that this can improve prognosis. The suggestion of our colleague is based in the fact that, in contrast to our study, in the HVPG‐guided arm of their study comparing transjugular intrahepatic portosystemic shunt with HVPG‐guided therapy, hemodynamic nonresponders (switched to EVL alone) had similar survival than responders.3 However, such apparent difference in the prognosis of nonresponders versus responders between the two studies may reflect a different baseline risk. Among survivors to variceal hemorrhage, those who only have bleeding have better survival than those with other decompensation of cirrhosis in addition to bleeding.4 In the German study, 92% of patients had Child class A/B (in the HVPG‐guided arm, 49% were class A, 45% without ascites).3 Thus, a high proportion had bleeding without other decompensation. In our study, 131 patients (77%) had other decompensation in addition to bleeding, and death risk was higher in these patients than in those who only had bleeding: 44% versus 8% (P < 0.001 by log‐rank). In a post‐hoc analysis, we have observed, among patients who had only bleeding, a similar risk of death in chronic hemodynamic responders versus nonresponders (hazard ratio [HR] = 1.01; 95% confidence interval [CI] = 0.06‐16.2; P = 0.99). Conversely, among patients who had other decompensation in addition to bleeding, we observed a trend toward lower risk of death in responders versus nonresponders (HR = 0.59; 95% CI = 0.32‐1.01; P = 0.09). These data suggest that death risk is concentrated in patients with other decompensation of cirrhosis in addition to bleeding, and that a survival advantage should be investigated in studies focusing this population.
Abstract 9967: Altered TGF-β Signalling and Myofibroblast-like Cell Differentiation Contribute to Myxomatous Mitral Valve Disease
Authors: Alex Sahagian, Candice Dilworth, Elizabeth Robertson, Yaxin Lu, Murat Kekic, Sanaz Maleki, Bob Bao, Niek Beijerink, Brett Hambly
Journal: Circulation (2015)

Upregulated Transforming Growth Factor-beta (TGF-β) signaling has been implicated in the pathogenesis of myxomatous mitral valve disease (MMVD) in both humans and canines. Moreover, it has been postulated that the phenotypic transformation of valve interstitial cells (VICs) in the mitral valve into alpha-smooth muscle actin (α-SMA)-positive myofibroblast-like cells contribute to elevated levels of proteolytic enzymes such as matrix metalloproteinases (MMPs), which subsequently induce pathological remodeling of the extracellular matrix (ECM) in the mitral valve. We hypothesized that, in MMVD, upregulation of TGF-β signaling would induce the transformation of VICs into myofibroblast-like cells, which subsequently express increased levels of MMPs. Computational immunohistochemistry was used to quantify protein expression in mitral valve leaflet tissue from canines affected by MMVD (n=4) and from control canines (n=5). TGF-β and α-SMA expression was significantly increased (p&lt;0.001) in MMVD tissue compared to control tissue. Moreover, a significant positive correlation was found between TGF-β expression and α-SMA expression (p&lt;0.05) across the entire cohort. There were also significant increases in MMP-2 and MMP-9 expression (p&lt;0.05) in MMVD tissue compared to control tissue. No change in MMP-3 expression was detected. These findings are consistent with abnormal TGF-β signaling inducing the differentiation of VICs into α-SMA-positive myofibroblast-like cells. Moreover, the increases in expression of MMP-2 and MMP-9 in MMVD indicate the likely role of these myofibroblast-like cells in mediating pathological remodeling of the ECM throughout the disease process. The paradoxical finding of no change in MMP-3 expression may represent a compensatory mechanism that attempts to limit further degenerative damage to the mitral valve. In conclusion, MMVD is characterized by TGF-β-induced differentiation of VICs into myofibroblast-like cells, which subsequently facilitate ECM degradation via the increased expression of MMPs. This supports the rationale for the use of angiotensin II receptor blockers, capable of attenuating TGF-β signaling, in the treatment of MMVD.
Rammya Mathew: Three questions I ask before using a guideline
Authors: Rammya Mathew
Journal: BMJ (2019)

Scenes of vehement nodding are all too familiar when someone proclaims that “clinical guidelines are just guiding principles, not a set of rules to be slavishly followed.” But equally familiar is the sense of unease that sits high in one’s stomach when choosing to actively ignore them. The worry that ensues, about our decision making being called into question, has probably plagued most of us at some point.

So, although the limitations of guidelines may be widely acknowledged, when it comes to making tough choices in medicine …
Development of a liquid-biopsy-based technique for the supplementary diagnosis of highly advanced lymph node metastasis in patients with locally advanced gastric cancer.
Authors: Takashi Oshima, Yohei Miyagi, Naohide Oue, Munetaka Masuda, Yayoi Kimura
Journal: Journal of Clinical Oncology (2019)

56 Background: The outcomes of patients with locally advanced gastric cancer who have highly advanced lymph node metastasis such as N3 remain poor despite radical resection. If the preoperative diagnoses of such patients improve, further improvement in treatment outcomes is expected to be obtained by means of personalized therapies such as preoperative chemotherapy; however, the accuracy of diagnosis remains unsatisfactory. Therefore, exploratory proteome analysis using sera was performed with the aim of developing a supplementary liquid-biopsy-based technique to diagnose highly advanced lymph node metastasis in patients with locally advanced gastric cancer. We report the results obtained thus far. Methods: The subjects were 24 patients with pT4a gastric cancer (12 with pN0 disease and 12 with pN3 disease). Proteins that had significantly different (P&lt;0.001) expression levels in the preoperative serum on exploratory proteome analysis by liquid chromatography and mass spectrometry were identified. These proteins were verified by Enzyme-Linked ImmunoSorbent Assay (ELISA) using a different cohort (20 patients with pN0 disease and 13 with pN3 disease) from that described above. Results: In the exploratory proteome analysis, 2,357 kinds of proteins were identified and examined. Six these proteins were identified as candidate predictive markers of highly advanced lymph node metastasis. These proteins were verified using existing and newly developed ELISA kits, and reproducibility was verified for one protein (Protein V) (P = 0.003). Conclusions: The possibility of the supplementary diagnosis of highly advanced lymph node metastasis by liquid biopsy was suggested in patients with locally advanced gastric cancer. Further evaluations by prospective studies are now in progress, with the ultimate goal of clinical application.
MC1R gene variants and nonmelanoma skin cancer: a pooled analysis from the M-SKIP project
Authors: E Tagliabue, M C Fargnoli, S Gandini, P Maisonneuve, M Kayser, J Han, R Kumar, N Gruis, W Branicki, T Dwyer, L Blizzard, P Helsing, P Autier, J Garcia-Borron, P Kanetsky, Landi, J Little, J Newton-Bishop, F Sera, S Raimondi
Journal: British Journal of Dermatology (2014)
Immune regulation by glucocorticoids can be linked to cell type–dependent transcriptional responses
Authors: Luis M. Franco, Manasi Gadkari, Katherine N. Howe, Jing Sun, Lela Kardava, Parag Kumar, Sangeeta Kumari, Zonghui Hu, Iain D.C. Fraser, Susan Moir, John S. Tsang, Ronald N. Germain
Journal: The Journal of Experimental Medicine (2019)

Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.
Monogenic causes of chronic kidney disease in adults
Authors: Dervla M. Connaughton, Claire Kennedy, Shirlee Shril, Nina Mann, Susan L. Murray, Patrick A. Williams, Eoin Conlon, Makiko Nakayama, Amelie T. van der Ven, Hadas Ityel, Franziska Kause, Caroline M. Kolvenbach, Rufeng Dai, Asaf Vivante, Daniela A. Braun, Ronen Schneider, Thomas M. Kitzler, Brona Moloney, Conor P. Moran, John S. Smyth, Alan Kennedy, Katherine Benson, Caragh Stapleton, Mark Denton, Colm Magee, Conall M. O’Seaghdha, William D. Plant, Matthew D. Griffin, Atif Awan, Clodagh Sweeney, Shrikant M. Mane, Richard P. Lifton, Brenda Griffin, Sean Leavey, Liam Casserly, Declan G. de Freitas, John Holian, Anthony Dorman, Brendan Doyle, Peter J. Lavin, Mark A. Little, Peter J. Conlon, Friedhelm Hildebrandt
Journal: Kidney International (2019)
The Zygosity of JAK2V617F Determines the Disease Entities of Myeloproliferative Neoplasms By Modulating Erythropoiesis but Not Megakaryopoiesis
Authors: Hiraku Takei, Yoko Edahiro, Lihua Li, Yoshihisa Mizukami, Misa Imai, Soji Morishita, Akimichi Ohsaka, Marito Araki, Norio Komatsu
Journal: Blood (2018)
Whole-exome sequencing in unresectable pancreatic cancer patients with long-term survival.
Authors: Kentaro Sudo, Sana Yokoi, Osamu Ohara, Kazuyoshi Nakamura, Akiko Tsujimoto, Emiri Kita, Yoshinori Hasegawa, Manabu Nakayama, Hiroshi Ishii, Tadamichi Denda, Taketo Yamaguchi
Journal: Journal of Clinical Oncology (2019)

260 Background: Advances in technology of genomic sequencing have revealed the mutational landscape of pancreatic cancer. However, little is known with regard to molecular mechanisms underlying clinical diversity in “unresectable” advanced pancreatic cancer. Methods: We performed whole-exome sequencing using frozen cancer tissues prospectively obtained by EUS-FNA from primary tumors before chemotherapy in patients with metastatic or locally advanced pancreatic cancer (n = 35). All patients had pathological confirmation (adenocarcinoma, n = 34; carcinoma, n = 1). Somatic alterations in the cancer genome were compared with clinical outcomes. Results: Seventeen patients had metastatic disease and 18 had locally advanced disease. Thirty-four patients received chemotherapy with or without radiotherapy and one patient was treated with supportive care alone because of rapidly progressive disease. With a median follow-up time of 60.6 months (range 41.9–94.0) for censored cases, the median survival for all patients was 10.8 months. Nine patients survived more than 2 years ( &gt; 6 years, n = 2; &gt; 3 years, n = 3; &gt; 2 years, n = 4), while 11 patients died within 4 months. We show mutational landscape of unresectable advanced pancreatic cancer and identified somatic mutations in known cancer related genes including KRAS (89%), TP53 (71%), SMAD4 (20%), CDKN2A (17%) and ARID1A (14%). We found that ARID1A mutation was mutually exclusive with TP53 mutation except for one tumor and had a significant correlation with survival outcomes. Among 9 patients who survived more than 2 years, 5 patients (56%) had ARID1A somatic mutation, whereas none (0%) had mutations in the remaining 26 patients who died within 2 years ( P = 0.0004). The median overall survival was 47.7 months for 5 patients with ARID1A-mutated tumors and 8.9 months for 30 patients with ARID1A wild-type tumors ( P = 0.0101). Conclusions: This is the first study to perform whole-exome sequencing in unresectable pancreatic cancer patients including very long-term survivors. We found that ARID1A mutations were associated with longer survival.
Germline GAB2 Mutations in Childhood Acute Lymphoblastic Leukemia
Authors: Adam J de Smith, Geneviève Lavoie, Kyle M Walsh, Sumeet Aujla, Erica Evans, Helen M Hansen, Ivan Smirnov, Alice Y Kang, Martin Zenker, John J Ceremsak, Elliot Stieglitz, Roberta McKean-Cowdin, Catherine Metayer, Philippe P Roux, Joseph L Wiemels
Journal: Blood (2018)
Circular RNA Control of Vascular Smooth Muscle Cell Functions
Authors: Andreas W. Heumüller, Stefanie Dimmeler
Journal: Circulation Research (2019)

C ircular RNAs (circRNA) are generated by an alternative RNA splicing process called backsplicing, in which a splice donor is spliced to an upstream acceptor thereby resulting in the formation of an RNA loop that is stably expressed.CircRNAs initially have been described in the 90s, but only recently computational analysis suggested that circRNAs are more prevalent than initially thought.Several studies have reported on regulatory activities in different biological processes, including the control of angiogenesis, smooth muscle cell functions, and cardiac injury responses. 1,2Evidence so far indicates that circRNAs predominantly act as noncoding RNAs but may also encode for peptides/proteins.Towards their mechanism of action, first studies suggested that they may act as microRNA (miRNA, miR) sponges preventing the biological activity of these small noncoding RNAs.However, circRNAs have also been shown to control transcription, bind to proteins and other RNAs thereby interfering with multiple effector pathways.
Dermoscopy for the diagnosis of eyelid margin tumours
Authors: E. Cinotti, A. La Rocca, B. Labeille, D. Grivet, V. Lambert, M. Kaspi, N. Nami, F. Cambazard, M. Fimiani, G. Thuret, P. Gain, L. Tognetti, P. Rubegni, J.L. Perrot
Journal: British Journal of Dermatology (2019)
Diet and risk of glioma: combined analysis of 3 large prospective studies in the UK and USA
Authors: Ai Seon Kuan, Jane Green, Cari M Kitahara, Amy Berrington De González, Tim Key, Gillian K. Reeves, Sarah Floud, Angela Balkwill, Kathryn Bradbury, Linda M Liao, Neal D Freedman, Valerie Beral, Siân Sweetland
Journal: Neuro-Oncology (2019)

Abstract Background Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimize possible differential dietary recall between those with and without glioma, we present findings from 3 large prospective studies. Methods Participants included 692 176 from the UK Million Women Study, 470 780 from the US National Institutes of Health–AARP study, and 99 148 from the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse variances of the relative risks. Separate analyses by &lt;5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis. Results The 1 262 104 participants (mean age, 60.6 y [SD 5.5] at baseline) were followed for 15.4 million person-years (mean 12.2 y/participant), during which 2313 incident gliomas occurred, at mean age 68.2 (SD 6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fiber and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex. Conclusions The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern.
Abstract P111: Racial Disparity and Outcomes Among Parturients Undergoing Cesarean Section With Epidural Anesthesia
Authors: Ya-Ching Hsieh, John Doucette, Erin Thanik, Pradeep Balasubramaniam
Journal: Circulation (2018)

Introduction: In obstetrical health care, racial disparities have been documented in different aspects of maternal care and outcomes. We aimed to examine the effect of race as a factor in affecting outcomes of cesarean section done under epidural analgesia (CS under EA). Methods: We performed a population-based retrospective analysis of the Nationwide Inpatient Sample (NIS) (years 2003-2013) in adult hospitalizations for women undergoing CS with EA to determine outcomes [cost, length of stay (LOS), discharge destination (DD)] and complications (hematoma, surgical site infection, postpartum haemorrhage, blood transfusion, severe anaesthesia complications, amniotic fluid embolism, disseminated intravascular coagulation (DIC), and pulmonary edema) using ICD-9-CM codes. Weighted univariate analysis by chi-square test was performed to analyze the associations between race and outcomes with complications. Multivariate linear regression was used to analyze the cost and LOS. Results: Out of 87,076 women underwent CS with EA, 63% were Caucasians, 13% were African Americans (AA), 20% were Hispanics, 3% were Asians and 1% were Native Americans. The majority of health care coverage for Caucasians and Asians was private insurance, while AA, Hispanics and Native Americans were utilized Medicare and Medicaid. The AA had higher numbers of comorbid conditions including hypertension, obesity, diabetes and renal failure, except for congestive heart failure that was highest in Asians. Though AA had highest DD to home, but cost and LOS were slightly higher in comparison to other races. Though rates of adverse events were very small in the overall cohort, hematoma was highest in Hispanics, anaesthesia complications were highest among Native Americans, and DIC was highest in Asians. (Table) Conclusion: Parturients undergoing CS under EA in minority groups especially AA had higher numbers of comorbidities. Risk stratifications among AA before CS procedure might improve outcome and reduce the cost burden and complications.
Racial Differences in Time to Breast Cancer Surgery and Overall Survival in the US Military Health System
Authors: Yvonne L. Eaglehouse, Matthew W. Georg, Craig D. Shriver, Kangmin Zhu
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Racial disparities in time to surgery (TTS) after a breast cancer diagnosis and whether these differences account for disparities in overall survival have been understudied in the US population. <h3>Objectives</h3> To compare TTS in non-Hispanic black (NHB) and non-Hispanic white (NHW) women with breast cancer and to examine whether racial differences in TTS may explain possible racial disparities in overall survival in a universal health care system. <h3>Design, Setting, and Participants</h3> Retrospective cohort identified from the Department of Defense Central Cancer Registry and Military Health System Data Repository linked databases containing records between January 1, 1998, and December 31, 2008, of 998 NHB women and 3899 NHW women who received a diagnosis of stages I to III breast cancer and underwent breast-conserving surgery (BCS) or mastectomy in the US Military Health System during the study period. Data analyses were conducted from July 5, 2017, to December 29, 2017. <h3>Main Outcomes and Measures</h3> The main outcome was time to breast cancer surgery. Non-Hispanic black and NHW women were compared at the 25th, 50th (median), 75th, and 90th percentiles of TTS by using multivariable quantile regression. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for all-cause death in NHB compared with NHW women after controlling for potential confounders first without and then with TTS. <h3>Results</h3> Among the 4887 NHB and NHW women in the cohort, the mean (SD) age was 50.0 (9.4) years. The median TTS was 21 days (95% CI, 20.6-21.4 days) among NHW women and 22 days (95% CI, 20.6-23.4 days) among NHB women. Non-Hispanic black women had a significantly greater estimated TTS at the 75th (3.6 days; 95% CI, 1.6-5.5 days) and 90th (8.9 days; 95% CI, 5.1-12.6 days) percentiles than NHW women in multivariable models. The estimated differences were similar by surgery type. Non-Hispanic black women had a higher adjusted risk for death (HR, 1.45; 95% CI, 1.06-2.01) compared with NHW women among patients receiving breast-conserving surgery. The risks were similar between races among those receiving mastectomy (HR, 1.06; 95% CI, 0.76-1.48). The HRs remained similar after adding TTS to the Cox proportional hazards regression models. <h3>Conclusions and Relevance</h3> This study's results indicate that time to breast cancer surgery was delayed for NHB compared with NHW women in the Military Health System. However, the racial differences in TTS did not explain the observed racial differences in overall survival among women who received breast-conserving surgery.
Ifosphamide and Carboplatin Based (R-DeVIC) Salvage Therapy in Patients with Relapsed/Refractory PCNSL - a Multicentre Retrospective Analysis
Authors: Hans-Guido Holl, Elisabeth Schorb, Jürgen Finke, Nikolaos Vassiliadis, Benjamin Kasenda, Gerald Illerhaus
Journal: Blood (2018)
Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia
Authors: Mark Bustoros, Romanos Sklavenitis-Pistofidis, Chia-jen Liu, Efstathios Kastritis, Geoffrey Fell, Kalvis Hornburg, Carl-Jannes Neuse, Patrick Henrick, Catherine R. Marinac, Adriana Perilla-Glen, Alexandra Savell, David Liu, Amir Yosef, Bradley Rivotto, Jenny Soiffer, Henry Dumke, Cody J Boehner, Kaitlen Reyes, Kimberly Noonan, Robert J. Soiffer, Steven P Treon, Jorge J. Castillo, Meletios A Dimopoulos, Irene M. Ghobrial
Journal: Blood (2018)
Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy
Authors: Christopher E. Nelson, Yaoying Wu, Matthew P. Gemberling, Matthew L. Oliver, Matthew A. Waller, Joel D. Bohning, Jacqueline N. Robinson-Hamm, Karen Bulaklak, Ruth M. Castellanos Rivera, Joel H. Collier, Aravind Asokan, Charles A. Gersbach
Journal: Nature Medicine (2019)