tbuckley/cabot-search huggingface dataset:
G6PC mRNA Therapy Positively Regulates Fasting Blood Glucose and Decreases Liver Abnormalities in a Mouse Model of Glycogen Storage Disease 1a
Authors: Daniel S. Roseman, Tayeba Khan, Fabienne Rajas, Lucy S. Jun, Kirtika H. Asrani, Cleo Isaacs, Jeremiah D. Farelli, Romesh R. Subramanian
Journal: Molecular Therapy (2018)

Glycogen storage disease type Ia (GSD1a) is an inherited metabolic disorder caused by the deficiency of glucose-6-phosphatase (G6Pase). GSD1a is associated with life-threatening hypoglycemia and long-term liver and renal complications. We examined the efficacy of mRNA-encoding human G6Pase in a liver-specific G6Pase−/− mouse model (L-G6PC−/−) that exhibits the same hepatic biomarkers associated with GSD1a patients, such as fasting hypoglycemia, and elevated levels of hepatic glucose-6-phosphate (G6P), glycogen, and triglycerides. We show that a single systemic injection of wild-type or native human G6PC mRNA results in significant improvements in fasting blood glucose levels for up to 7 days post-dose. These changes were associated with significant reductions in liver mass, hepatic G6P, glycogen, and triglycerides. In addition, an engineered protein variant of human G6Pase, designed for increased duration of expression, showed superior efficacy to the wild-type sequence by maintaining improved fasting blood glucose levels and reductions in liver mass for up to 12 days post-dose. Our results demonstrate for the first time the effectiveness of mRNA therapy as a potential treatment in reversing the hepatic abnormalities associated with GSD1a. Glycogen storage disease type Ia (GSD1a) is an inherited metabolic disorder caused by the deficiency of glucose-6-phosphatase (G6Pase). GSD1a is associated with life-threatening hypoglycemia and long-term liver and renal complications. We examined the efficacy of mRNA-encoding human G6Pase in a liver-specific G6Pase−/− mouse model (L-G6PC−/−) that exhibits the same hepatic biomarkers associated with GSD1a patients, such as fasting hypoglycemia, and elevated levels of hepatic glucose-6-phosphate (G6P), glycogen, and triglycerides. We show that a single systemic injection of wild-type or native human G6PC mRNA results in significant improvements in fasting blood glucose levels for up to 7 days post-dose. These changes were associated with significant reductions in liver mass, hepatic G6P, glycogen, and triglycerides. In addition, an engineered protein variant of human G6Pase, designed for increased duration of expression, showed superior efficacy to the wild-type sequence by maintaining improved fasting blood glucose levels and reductions in liver mass for up to 12 days post-dose. Our results demonstrate for the first time the effectiveness of mRNA therapy as a potential treatment in reversing the hepatic abnormalities associated with GSD1a.
Results of the Full Pediatric, Minimal Residual Disease (MRD)-Oriented Trial LAL-RI/2008 for Adolescents and Young Adults (AYA) with Standard Risk (SR), Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL)
Authors: Josep-Maria Ribera, Mireia Morgades, Pau Montesinos, Daniel Martínez-Carballeira, Cristina Gil, Pere Barba, Mar Tormo, Raimundo García-Boyero, Ramon Guàrdia, María Pedreño, Santiago Mercadal, Andrés Novo, Jesús-María Hernández-Rivas, Juan Bergua, José González-Campos, María-Luz Amigo, Marta Cervera, Pilar Martínez-Sánchez, Rodrigo Martino, María Calbacho, Antoni Garcia-Guiñon, Susana Vives, Evarist Feliu, Alberto Orfao
Journal: Blood (2017)
Menopausal Estrogen Therapy and Breast Cancer Mortality
Authors: Martha Hickey, Helen C. McNamara, Gita D. Mishra
Journal: JAMA (2018)

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Abstract 15345: Soluble Isoforms of St2 and Galectin-3 Have Independent and Incremental Prognostic Value in Patients With Hemodialysis
Authors: Hiroaki Sunaga, Masaru Obokata, Hideki Ishida, Kyoko Ito, Tetsuya Ogawa, Yoshitaka Ando, Kazuaki Negishi, Masahiko Kurabayashi
Journal: Circulation (2016)

Introduction: End-stage renal disease is a major clinical and public health problem, and cardiovascular disease accounts for half of the mortality in hemodialysis patients. An existing mortality ri...
Improving the conduct, reporting, and appraisal of animal research
Authors: Merel Ritskes-Hoitinga, Kim Wever
Journal: BMJ (2018)

Preclinical animal studies aim to establish safety and efficacy before patients are exposed to new treatments.However, the translational success rate from animal studies to humans is quite low, and the non-reproducibility of preclinical studies ranges between 51% and 89%. 1 The inadequate conduct, reporting, and evaluation of animal research underpinning human trials is one reason why big promises of better outcomes for patients so often remain unfulfilled.
Persistent hepatitis C virus–associated cryoglobulinemic vasculitis following virus eradication after direct‐acting antiviral therapy
Authors: Marina Artemova, Dzhamal Abdurakhmanov, Tatiana Ignatova, Nikolay Mukhin
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship TO THE EDITOR: We read with great interest the article by Gragnani et al.,1 which reports that the majority of patients with hepatitis C virus (HCV)‐associated mixed cryoglobulinemia vasculitis (MCV) treated with direct‐acting antivirals (DAAs) achieved a sustained virological response (SVR) and complete clinical and immunological remission. Several recent studies show a dissociation between virological and clinical responses to treatment with different interferon‐free antiviral regimens.2 Here, we report a group of cases that demonstrated persistent mixed cryoglobulinemia (MC) or MCV after DAA treatment. Nine HCV‐positive Caucasian patients (all women; mean age, 59 years [range, 49‐66 years]) were recruited consecutively at the Hepatology Department of the Tareev Clinic for Nephrology, Internal and Occupational Diseases, Moscow, Russia. Four patients had asymptomatic cryoglobulinemia, and five had moderate‐stage MCV. Between January and November 2015, the patients started anti‐HCV treatment with DAAs (five patients on asunaprevir + daclatasvir, four patients on sofosbuvir + daclatasvir for 24 weeks). Therapy was well tolerated, and no severe adverse events occurred. The rate of SVR12 was 100%. The clinical efficacy and virological response were evaluated during a posttherapy follow‐up of at least 20 weeks. We found no correlation between virological response and cryoglobulin production. Three of four patients still exhibited asymptomatic cryoglobulinemia. Five patients had moderate‐stage MCV; therefore, we did not propose addition of rituximab concurrently with DAA treatment. Meanwhile, persistence of MCV was observed in two patients. One patient experienced a reappearance of severe skin purpura with ulceration and a 50% cryocrit level increase compared with the pretreatment level 8 weeks after treatment. The other patient with moderate‐stage MCV also demonstrated no improvement, including skin lesions, high MC serum levels, and a 30‐fold rheumatoid factor increase after 36 weeks of follow‐up. We focused particularly on searching for malignant B cell lymphoproliferative disease as one of the reasons for the persistence of MC and MCV, which was later ruled out. According to the recommendations, rituximab should be considered when treating patients with severe HCV‐associated MCV (i.e., active glomerulonephritis, skin ulcers or refractory peripheral neuropathy).4 However, persistent vasculitis symptoms observed in moderate MCV patients after successful HCV treatment suggest that therapeutic approaches for this subgroup of patients require further improvement to achieve a complete clinical response.
Unproven and Expensive before Proven and Cheap: Extracorporeal Membrane Oxygenation versus Prone Position in Acute Respiratory Distress Syndrome
Authors: Xuehan Li, Damon C. Scales, Brian P. Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

We identified 810 reports that describe extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS), and 61 fulfilled our inclusion criteria. The authors of 26 (43%) reports responded to e-mail requests for confirmation (or clarification). Based on the aggregate (published and e-mailed) information, unambiguous data were available relating to 17 papers. These 17 papers represented 672 patients with ARDS who were cannulated with venovenous ECMO; of these patients, 208 (31%) received a trial of prone positioning before ECMO, and 464 (69%) did not. A key randomized controlled trial was published in 2013 that reported a survival benefit associated with prone positioning (N Engl J Med 2013;368:2159–2168). The proportion of all venovenous ECMO patients in whom prone positioning was used before ECMO was lower in studies published after 2013 (84 of 452 [19%]) than in those published before 2013 (116 of 210 [55%]) (P < 0.05). These data suggest a systematic bias in the reporting of outcomes after ECMO in the literature. The vast majority of reported patients who received ECMO did not first receive therapy that (in contrast to ECMO) is simple, cheap, and of proven benefit; therefore, inferences about the efficacy of ECMO in ARDS are of limited use.
Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry
Authors: M. Worm, W. Francuzik, J.‐M. Renaudin, M. B. Bilo, V. Cardona, K. Scherer Hofmeier, A. Köhli, A. Bauer, G. Christoff, E. Cichocka‐Jarosz, T. Hawranek, J. O.’B. Hourihane, L. Lange, V. Mahler, A. Muraro, N. G. Papadopoulos, C. Pföhler, I. Poziomkowska‐Gęsicka, F. Ruëff, T. Spindler, R. Treudler, M. Fernandez‐Rivas, S. Dölle
Journal: Allergy (2018)

Abstract Background Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided. Objective To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis. Methods Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis. Results We identified higher age and concomitant mastocytosis ( OR : 3.1, CI : 2.6‐3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise ( OR : 1.5, CI : 1.3‐1.7), male sex ( OR : 1.2, CI : 1.1‐1.3), and psychological burden ( OR : 1.4, CI : 1.2‐1.6) were more often associated with severe reactions. Additionally, intake of beta‐blockers ( OR : 1.9, CI : 1.5‐2.2) and ACE ‐I ( OR : 1.28, CI : 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis. Conclusion Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.
Mutations in <i>CYB561</i> Causing a Novel Orthostatic Hypotension Syndrome
Authors: Maarten P. van den Berg, Rowida Almomani, Italo Biaggioni, Martijn van Faassen, Pim van der Harst, Herman H.W. Silljé, Irene Mateo Leach, Marc H. Hemmelder, Gerjan Navis, Gert Jan Luijckx, Arjan P.M. de Brouwer, Hanka Venselaar, Marcel M. Verbeek, Paul A. van der Zwaag, Jan D.H. Jongbloed, J. Peter van Tintelen, Ron A. Wevers, Ido P. Kema
Journal: Circulation Research (2018)

Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. Objective: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. Methods and Results: As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 ( CYB561 ); a missense variant c.262G&gt;A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G&gt;A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561 (− /− ) mice compared with wild-type mice ( P &lt;0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands ( P &lt;0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l -dihydroxyphenylserine, which can be converted directly to norepinephrine. Conclusions: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
Abstract 17352: Predictors of Ventricular Arrhythmias and Sudden Death in a Quebec Cohort With Brugada Syndrome
Authors: Lena Rivard, Antoine Roux, Isabelle Nault, Jean Champagne, Jean-Francois Roux, Mario Talajic, Rafik Tadros, Julia Cadrin-Tourigny, Azadeh Shohoudi, Blandine Mondesert, Denis Roy, Laurent Macle, Jason Andrade, Katia Dyrda, Marc Dubuc, Peter G Guerra, Peter G Guerra, Jean-Francois Sarrazin, Bernard Thibault, Paul Khairy
Journal: Circulation (2015)

Introduction: Patients with Brugada syndrome (BrS) are at risk for ventricular arrhythmias (VAs) and sudden death. Identification of high-risk individuals beyond those with syncope or resuscitated SCD remains a major challenge. We sought to assess the value of clinical, electrophysiological, and ECG features of depolarization and repolarization in predicting arrhythmic events and SCD in a Quebec population. Methods: Consecutive patients with BrS diagnosed between 2002 and 2013 were recruited from three major university hospitals in the province of Quebec, Canada. Relevant clinical features were recorded at baseline. Qualifying ECGs with the highest type 1 ST-segment elevations were reviewed and analyzed by two electrophysiologists blinded to clinical history, with the following parameters assessed: S duration in V1, aVR sign, QRS duration in V6, R-J interval in V2, maximal Tp-e, duration, Tp-e dispersion, QRS-f, ST elevation and QTc in V2, and presence of an inferolateral ER pattern. Survival analyses considered a left truncation model to account for potential sampling bias, considering that those who died suddenly before recognition of BrS were necessarily excluded. Results: A total of 105 consecutive patients, 79.8% male, were diagnosed with BrS at a median age of 48 years and were followed for 5.0±1.2 years. Ten (9.5%) had a history of SCD, 37 (35.2%) had syncope, and 7 (6.7%) experienced 20 arrhythmic events during follow-up (7 anti-tachycardia pacing; 13 shocks). In multivariate Cox regression analyses adjusted for left truncation and Firth bias correction, a spontaneous type I ECG pattern (HR 10.80; 95% CI 1.03 to 113.87; p=0.0476)], maximal Tp-e duration ≥100ms (HR 29.73; 95% CI 1.33 to 666.37; p= 0.0325) and QRS duration in V6&gt;110 ms (HR 15.27; 95% CI 1.07 to 217.42; p=0.0443) were independently associated with VAs or aborted SCD. Family history of SCD, AF, and inducible VAs during programmed ventricular stimulation were not associated with the primary endpoint. Conclusion: In a cohort of patients with BrS from the province of Quebec, VAs and SCD were independently associated with standard 12-lead ECG features including a spontaneous type 1 pattern, depolarization (QRS in V6 &gt;110 ms), and repolarization (maximal Tp-e duration) criteria.
Targeting Primary Pre-B Cell Acute Lymphoblastic Leukemia and CD19-Negative Relapses Using Trivalent CAR T Cells
Authors: Kristen Fousek, Junji Watanabe, Ann George, Xingyue An, Hebatalla Samaha, Shoba Alaska Navai, Tiara T Byrd, Albert Jang, Hye Na Kim, Sujith Joseph, Matthew Baker, Navin Varadarajan, Meenakshi G. Hegde, Yong-Mi Kim, Nora Heisterkamp, Hisham Abdel-Azim, Nabil Ahmed
Journal: Blood (2017)
Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM)
Authors: Adam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, Simon F Lacey, Eric Lancaster, Dan T. Vogl, Brendan M Weiss, David E Ambrose, Anne Marie Nelson, Fang Chen, Gabriela Plesa, Irina Kulikovskaya, Vanessa Gonzalez, Minnal Gupta, Regina M Young, Karen Dengel, Laura O'keefe, Samantha Le, Celeste Richardson, Randi E. Isaacs, J. Joseph Melenhorst, Bruce L Levine, Carl H June, Michael C. Milone
Journal: Blood (2017)
<i>STAT3/PIAS3</i> Levels Serve as “Early Signature” Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube
Authors: Uksha Saini, Adrian A. Suarez, Shan Naidu, John J. Wallbillich, Kristin Bixel, Ross A. Wanner, Jason Bice, Raleigh D. Kladney, Jenny Lester, Beth Y. Karlan, Paul J. Goodfellow, David E. Cohn, Karuppaiyah Selvendiran
Journal: Cancer Research (2018)

Abstract The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states. Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739–50. ©2018 AACR.
Effect of Food Allergy on Astma Control in children
Authors: Sukruthi Jois, Betty Andy-Nweye, Alice N. Hackett, Opal J. Kamdar, Kylie N. Jungles, Ruchi S. Gupta, Mary C. Tobin, Mahboobeh Mahdavinia
Journal: Journal of Allergy and Clinical Immunology (2018)
Evaluation of Minimal Residual Disease (MRD) and MRD-Based Treatment Decisions in Ph/BCR-ABL Negative Adult Acute Lymphoblastic Leukemia (ALL): Experience from the German Multicenter Study Group for Adult ALL (GMALL)
Authors: Nicola Goekbuget, Monika Brüggemann, Joachim Beck, Christoph Faul, Christian Koenecke, Heinz A. Horst, Mustafa Kondakci, Doris M. Kraemer, Christoph Lutz, Bernd Spriewald, Michael Starck, Christoph Rollig, Matthias Stelljes, Andreas Viardot, Ralph Wäsch, Knut Wendelin, Hubert Serve, Michael Kneba, Dieter Hoelzer
Journal: Blood (2017)
Exosomes Serve as Nanoparticles to Deliver Anti-miR-214 to Reverse Chemoresistance to Cisplatin in Gastric Cancer
Authors: Xinyi Wang, Haiyang Zhang, Ming Bai, Tao Ning, Shaohua Ge, Ting Deng, Rui Liu, Le Zhang, Guoguang Ying, Yi Ba
Journal: Molecular Therapy (2018)

Chemoresistance is one of the causes of adverse effects in gastric cancer, including a poor response to cisplatin (DDP). Exosomes loaded with microRNA (miRNA), mRNA, and other non-coding RNAs could regulate drug resistance. Exo-anti-214 was extracted and verified. A Cell Counting Kit-8 (CCK-8) cell viability assay, flow cytometry, and transwell and immunofluorescence assays were performed to determine whether exo-anti-214 could sensitize cells to DDP in vitro. A combination of intravenously injected exo-anti-214 and intraperitoneal DDP was utilized in vivo. Additionally, potential targets of miR-214 were screened by mass spectrometry (MS) and confirmed via western blotting (WB). The levels of miR-214 in the human immortalized gastric epithelial cell line ges-1 and the human gastric adenocarcinoma cell lines SGC7901 and SGC7901/DDP gradually increased. Exo-anti-214 could fuse with cells and regulate potential targets, reducing cell viability, suppressing migration, and promoting apoptosis in vitro. Caudally injected exo-anti-214 was applied to reverse chemoresistance and repress tumor growth in vivo due to the downregulation of miR-214 and overexpression of possible target proteins in tumors. Exo-anti-214 could reverse the resistance to DDP in gastric cancer, which might serve as a potential alternative for the treatment of cisplatin-refractory gastric cancer in the future.