tbuckley/cabot-search huggingface dataset:
192. Regulated Atrial Natriuretic Peptide Expression with a Novel Spatiotemporal AAV Vector Cassette for Treating Congestive Heart Failure
Authors: Matthew L. Hillestad, Soulmaz Boroumand, Atta Behfar, Andre Terzic
Journal: Molecular Therapy (2015)

Patients suffering from congestive heart failure (CHF) are vulnerable to a fluid overloaded state, contributing to significant morbidity and the mortality of ~287,000 patients per year in the US. This vulnerability is in part mediated by a dysregulation of atrial natriuretic peptide (ANP) – a molecule acting on kidneys to induce diuresis. Multiple preclinical studies show that injecting pre-synthesized ANPs can induce diuresis, however pre-synthesized ANPs degrade rapidly making their impact only transient. Sustained ANP-mediated diuresis may provide a novel approach to curb fluid retention. To this end, we hypothesize that the use of AAV9 vectors will mediate delivery of a more biologically active version of ANP (aka mANP) in the context of a cardiomyocyte-specific, tetracycline-regulated expression cassette. Methodology – For temporal regulation we inserted a Tet-On 3G System into an AAV cassette (AAV-Tet). For cardiac restricted expression we also introduced a cardiomyocyte specific regulatory element. Preliminary Data – Doxycycline specifically induces expression in vitro of all tested genes, i.e. mANP, EGFP, and firefly luciferase (Luc). Regulation is tight, showing Luc expression increases of ~2000-fold over baseline. Using murine models we are currently accessing the pharmacokinetics of the AAV9-Tet vectors. Finally, diuretic potentials will be assessed in murine models of CHF. Conclusion – The spatiotemporally regulated mANP AAV vectors being developed herein could represent a new paradigm for treatment in CHF.
Phase I Dose-Escalation Trial of SB1518, a Novel JAK2/FLT3 Inhibitor, in Acute and Chronic Myeloid Diseases, Including Primary or Post-Essential Thrombocythemia/ Polycythemia Vera Myelofibrosis.
Authors: Srdan Verstovsek, Olatoyosi Odenike, Bart Scott, Zeev Estrov, Jorge Cortes, Deborah A. Thomas, Jeanette Wood, Kantharaj Ethirajulu, Ann Lowe, Huan J. Zhu, Hagop Kantarjian, H. Joachim Deeg
Journal: Blood (2009)
Next-Generation Sequencing Technology Reveals a Characteristic Pattern of Molecular Mutations in 75% of Chronic Myelomonocytic Leukemia (CMML) by Detecting Frequent Alterations in TET2, RUNX1, CBL, and RAS.
Authors: Alexander Kohlmann, Vera Grossmann, Claudia Haferlach, Beray Kazak, Sonja Schindela, Hans-Ulrich Klein, Tamara Weiss, Frank Dicker, Susanne Schnittger, Martin Dugas, Wolfgang Kern, Torsten Haferlach
Journal: Blood (2009)
Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness
Authors: B. Hilvering, S. J. H. Vijverberg, J. Jansen, L. Houben, R. C. Schweizer, S. Go, L. Xue, I. D. Pavord, J.‐W. J. Lammers, L. Koenderman
Journal: Allergy (2016)

The identification of inflammatory asthma phenotypes, using sputum analysis, has proven its value in diagnosis and disease monitoring. However due to technical limitations of sputum analysis, there is a strong need for fast and noninvasive diagnostics. This study included the activation state of eosinophils and neutrophils in peripheral blood to phenotype and monitor asthma.To (i) construct a multivariable model using the activation state of blood granulocytes, (ii) compare its diagnostic value with sputum eosinophilia as gold standard and (iii) validate the model in an independent patient cohort.Clinical parameters, activation of blood granulocytes and sputum characteristics were assessed in 115 adult patients with asthma (training cohort/Utrecht) and 34 patients (validation cohort/Oxford).The combination of blood eosinophil count, fractional exhaled nitric oxide, Asthma Control Questionnaire, medication use, nasal polyposis, aspirin sensitivity and neutrophil/eosinophil responsiveness upon stimulation with formyl-methionyl-leucyl phenylalanine was found to identify sputum eosinophilia with 90.5% sensitivity and 91.5% specificity in the training cohort and with 77% sensitivity and 71% specificity in the validation cohort (relatively high percentage on oral corticosteroids [OCS]).The proposed prediction model identifies eosinophilic asthma without the need for sputum induction. The model forms a noninvasive and externally validated test to assess eosinophilic asthma in patients not on OCS.
A Comparative Retrospective Survey of Reinduction Chemotherapy Regimens for Acute Myeloid Leukemia (AML) in First Relapse: A Single-Institution Experience
Authors: Andrew Brunner, Hossein Sadrzadeh, Lillian Werner, Karen K. Ballen, Yi-Bin A. Chen, Philip C. Amrein, Eyal C. Attar, Steven L. McAfee, Thomas R. Spitzer, Donna Neuberg, Amir T Fathi
Journal: Blood (2011)
TM6SF2 rs58542926 impacts lipid processing in liver and small intestine
Authors: Elizabeth A. O'Hare, Rongze Yang, Laura M. Yerges‐Armstrong, Urmila Sreenivasan, Rebecca McFarland, Carmen C. Leitch, Meredith H. Wilson, Shilpa Narina, Alexis Gorden, Kathy A. Ryan, Alan R. Shuldiner, Steve A. Farber, G. Craig Wood, Christopher D. Still, Glenn S. Gerhard, Janet D. Robishaw, Carole Sztalryd, Norann A. Zaghloul
Journal: Hepatology (2016)

The transmembrane 6 superfamily member 2 ( TM6SF2 ) loss‐of‐function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride‐rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride‐rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high‐fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco‐2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. Conclusions : These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride‐rich lipoproteins. (H epatology 2017;65:1526‐1542).
Early palliative care, depression, and survival in metastatic NSCLC.
Authors: W. F. Pirl, J. A. Greer, E. R. Gallagher, V. A. Jackson, I. T. Lennes, J. S. Temel
Journal: Journal of Clinical Oncology (2011)

6024 Background: We observed that early palliative care (EPC) for metastatic non-small cell lung cancer (NSCLC) improves survival. Because depression is associated with worse survival in this population, we hypothesized that the survival benefit may be the result of treating depression. As a secondary analysis of our randomized trial of EPC, we examined the effect of EPC on depression and its relationship with survival. Methods: 151 patients with metastatic NSCLC were enrolled within 8 weeks of diagnosis in a randomized trial of EPC (n=76) versus standard care (n=75). Depression was assessed at baseline and week 12 with the Patient Health Questionnaire-9 (PHQ-9), scored diagnostically using DSM-IV criteria for major depression syndrome (MDS) and with less stringent criteria of PHQ-9 scores ≥ 10 for probable depression (PD). Depressed patients with ≥ 50% reduction in PHQ-9 scores at 12 weeks were considered responders. Differences in rates were tested with Chi square. Survival was calculated from time of enrollment and differences were tested with Cox proportional hazards models. Results: Over a quarter (41/151) had PD at baseline, but only 21 met diagnostic criteria for MDS. Depression rates were balanced between trial arms. Among those with depression, EPC was associated with greater rates of response at 12 weeks (PD 37.5% vs. 9.5%, p=.05; MDS 42.9% vs. 0%, p=.04). However, EPC was not significantly associated with increased survival among those with depression (compared to standard care, EPC median survival was 33 days shorter for PD and 10 days longer for MDS). Among those without depression, the difference in median survival between arms was twice that of the sample as a whole. Controlling for ECOG performance status, sex, age, smoking, and marital status, depression was only associated with survival in the EPC arm (PD HR=1.78, p=.05; MDS HR=3.27, p=.006). Conclusions: EPC for metastatic NSCLC improved survival only in patients without depression. Although EPC improves depression in patients with metastatic NSCLC, it is not associated with longer survival among those with depressive syndromes. These findings result in an association of depression with survival only in the EPC arm. Depression appears to moderate the observed survival benefit from EPC.
10. Human Mesenchymal Stem Cell (hMSC) Delivery System Induces Favorable Post-Infarct Cardiac Remodeling with an Increase in Coronary Artery Blood Flow
Authors: Young Sook Lee, Wan Seok Joo, Hyun Soo Kim, Sung Wan Kim
Journal: Molecular Therapy (2015)

[Background] Myocardial infarction (MI) caused by coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. We are at a crucial juncture where novel therapeutic approaches for reversing adverse cardiac remodeling are solely needed. The beneficial effects of multipotent mesenchymal stem cells (MSCs) are primarily mediated via combined paracrine, endocrine, and homing actions. Human MSCs are one of the best candidates for inducing favorable cardiac remodeling after MI. Recently, we constructed porous PLGA/PEI1.8k biodegradable microspheres (PPP) for the delivery of hMSCs using electrostatic attraction and structural entrapment. These MSC–loaded PPP particles showed increased in vivo engraftment rates and maintained better stemness characteristics of hMSCs in comparison with hMSCs–alone in rats 2 wks after intramyocardial injections. [Aim] We hypothesized that human MSCs delivered with a biocompatible porous scaffold would produce cardio-protective effects on post-infarct cardiac remodeling. [Results] hMSCs–alone and PPP loaded with 3 different amounts of hMSC (High, Medium, and Low) demonstrated improved systolic function and preserved cardiac geometry compared with ischemia-reperfusion (I-R) group in rats 1 wk after post-infarct intramyocardial administration. The functional improvement of hMSC–loaded PPP groups was sustained 4 wks after MI and comparable between groups. However, the hMSCs–alone group didn't maintain functional improvement. The functional improvement of hMSC–loaded PPP groups was supported by reduced infarct size, ameliorated cardiac fibrosis, protection from cardiomyocyte loss, and decreased apoptotic activity. Also, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the cardio-protective effects of hMSC–loaded PPP. Interestingly, hMSC–loaded PPP groups enhanced blood flow of infarct-related coronary artery. [Conclusion] These results suggest that an hMSC–loaded PPP delivery system would provide amplification and decrease costs of hMSC therapy, especially in ex vivo preparation.
295. Intrathecal Delivery of rAAV9-ABCD1 by Osmotic Pump in a Mouse Model of Adrenomyeloneuropathy
Authors: Yi Gong, Rene Kok, Dakai Mu, Guangping Gao, Florian Eichler
Journal: Molecular Therapy (2016)

Adrenomyeloneuropathy (AMN) is a debilitating neurological disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. The Abcd1-/- mouse develops a phenotype similar to AMN, manifesting spinal cord axon degeneration as well as peripheral neuropathy due to affected dorsal root ganglion neurons (DRGs). We previously reported successful transduction of central nervous system cells in vitro and in vivo using recombinant adeno-associated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene. Unfortunately, intravenous delivery in young mice was associated with cardiac toxicity due to transgene overexpression. We therefore set out to optimize delivery to the spinal cord while minimizing systemic leakage using an intrathecal osmotic pump. Self complementary AAV9 GFP(scAAV9GFP) and rAAV9 encoding ABCD1 (rAAV9-ABCD1) were delivered to Abcd1-/- mice intrathecally (IT) either by bolus over a 2min duration or by osmotic pump over 24h duration with PBS injection as sham control. Two weeks after injection, mice were sacrificed and perfused with 4% PFA. Tissues were then collected, sectioned and stained for immunofluorescence analysis. scAAV9-GFP delivered IT by osmotic pump led to widespread expression across CNS-relevant cell types and DRGs in a dose-dependent manner. Spinal cord and DRG had higher expression compared with brain, but GFP expression was also detected in peripheral organs (liver, heart and adrenal gland), with highest expression seen at 3X1011GC. A similar distribution pattern of ABCD1 protein was detected after rAAV9-ABCD1 intrathecal pump delivery. In general, higher doses (2X1011GC and 1X1011GC) led to more expression in CNS and peripheral organs compared with a lower dose (0.5X1011GC). However, widespread expression of ABCD1 across CNS was even detected after direct intrathecal bolus injection of 0.5X1011GC. Importantly, the same dose delivered by pump led to higher expression in brain and spinal cord far from the injection site and comparatively less leakage to peripheral organs compared with bolus injection. Preliminary experiments delivering rAAV9-ABCD1 at 0.5X1011GC by intracerebroventricular approach suggest behavioral improvement in the Abcd1-/- mouse despite localized expression in brain. We therefore anticipate even better performance at this dose using the outlined intrathecal pump delivery. We conclude that rAAV9-mediated ABCD1 gene transfer via intrathecal osmotic pump leads to more uniform and widespread gene delivery to CNS with reduced leakage into the systemic circulation compared with intrathecal bolus injection.
Azacitidine-Containing Induction Regimens Followed by Azacitidine Maintenance Therapy in High Risk Acute Myeloid Leukemia: First Results of the Randomized Phase-II AMLSG 12-09 Study (ClinicalTrials.gov No. NCT01180322)
Authors: Richard F Schlenk, Wolfgang Herr, Gerald Wulf, Helmut R Salih, Jürgen Krauter, Hans Guenter Derigs, Andrea Kündgen, Mark Ringhoffer, Uwe M. Martens, Bernd Hertenstein, Martin Griesshammer, Michael Girschikofsky, Helga Bernhard, Jens Kersten, Maria von Lilienfeld-Toal, Elisabeth Koller, Elisabeth Lange, Jörg Westermann, Daniela Späth, Gudrun Göhring, Veronica Teleanu, Axel Benner, Konstanze Döhner, Arnold Ganser, Hartmut Döhner
Journal: Blood (2012)
Prolonged clinical benefit with the maintenance hormone therapy in patients with metastatic breast cancer.
Authors: S. Lim, S. Lee, B. Park, S. I. Kim, S. Park, J. Kim, H. J. Choi, J. H. Sohn
Journal: Journal of Clinical Oncology (2011)

e11051 Background: The maintenance hormone therapy (MHT) after cytotoxic chemotherapy is widely used by many clinicians in metastatic breast cancer patients with hormone-senstive tumors, although there are insufficient evidences in the literature to support this practice. We evaluated the efficacy of MHT and identify those who benefit most from maintenance hormone therapy. Methods: Metastatic breast cancer patients who had been treated with MHT from 2006 to 2010 in a single institute were retrospectively reviewed. Progression free survival (PFS) was a primary endpoint and predictive factors for PFS were analyzed. Results: A total of 91 patients were reviewed with a median age of 53 (range, 33-70). Aromatase inhibitors were most frequently used drugs (74.2%)for MHT. The median PFS was 12.0 months (range, 1-66). Prolonged PFS was found in patients with less previous palliative chemotherapy (one vs. two vs. more than two, 16.0 vs. 11.0 vs. 6.0 months, respectively; p=0.02), less metastatic sites (one or two vs. more than two, 15.0 vs. 6.0; p=0.04), and minimal residual disease (minimal residual disease vs. Intolerance of chemotherapy, 15.0 vs. 6.0; p=0.05). Multivariate analysis showed that HER2 overexpression status (HR 1. 89, 95% CI 1.06-3.33; p=0.03) and the minimal residual disease (HR 0.44, 95% CI 0.26-0.75; p=0.003) remained as significant variables. Conclusions: Evidence from this study showed that MHT with aromatase inhibitor siginificantly improved PFS and was well tolerated. MHT is a good therapeutic option for patients with metastatic breast cancer who have not progressed on first-line chemotherapy, especially whose hormone receptor positive, HER2-negative and minimal residual disease after cytotoxic chemotherapy.
The Risk of Low Bone Mineral Density with Long-Term G-CSF Therapy for Severe Chronic Neutropenia.
Authors: L. A. DiMeglio, Audrey Anna Bolyard, Tracy M. Marrero, Blanche P Alter, Mary Ann Bonilla, Laurence A. Boxer, Dan Link, Peter E. Newburger, Philip S. Rosenberg, Akiko Shimamura, David C. Dale
Journal: Blood (2010)
Autologous Hematopoietic Cell Transplantation as Consolidation for Younger Patients with Acute Myeloid Leukemia in First Complete Remission: Follow-up of E1900.
Authors: Hugo F. Fernandez, Zhuoxin Sun, Mark R. Litzow, Selina M. Luger, Elisabeth M. Paietta, Gordon W. Dewald, Rhett P. Ketterling, John M Bennett, Jacob M. Rowe, Hillard M. Lazarus, Martin S. Tallman
Journal: Blood (2009)
The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation
Authors: Lin L. Lv, Patrick Ming-Kuen Tang, Chun J. Li, Yong K. You, Jinhong Li, Xiao-Ru Huang, Jun Ni, Min Feng, Bi C. Liu, Hui-Yao Lan
Journal: Kidney International (2016)
Treatment of Adult T-ALL with a Pediatric Asparaginase-Intensive Protocol Results in Survival Benefit When Compared to Other Adult Based Protocols
Authors: Murtadha K. Al-Khabori, Mark Minden, Vikas Gupta, Aaron D. Schimmer, Andre C. Schuh, Karen WL Yee, Wei Xu, Joseph M. Brandwein
Journal: Blood (2008)
Pokémon Go’s health benefits seem short lived
Authors: Jacqui Wise
Journal: BMJ (2016)

The smartphone game Pokemon Go improves physical activity, but the effect is only moderate and no longer observed after six weeks, research published in The BMJ shows.1

Pokemon Go is an augmented reality game in which players walk around to find cartoon characters appearing on their smartphone screen. It was launched in July 2016 and has been downloaded over 500 million times worldwide. …
First Prospective Bone Metastases (BM) Data Base: One-Year experience
Authors: A. Bongiovanni, M. Ricci, F. Foca, R. Vespignani, F. Ciotti, M. Fantini, R.C. Forcignano, E. Campedelli, F. Silvestris, F. Artioli, D. Amadori, T. Ibrahim
Journal: Annals of Oncology (2015)
Outcome and Prognostic Factors in Patients with Hematological Malignancy That Are Admitted to the Intensive Care Unit.
Authors: Christelle Ferra, Maite Misis, Albert Oriol, Pilar Marcos, Natalia Lloveras, Maria-Luisa Bordeje, Juan-Manuel Sancho, Blanca Xicoy, Montserrat Batlle, Alonso Flores, Jose-Tomas Navarro, Javier Grau, Jordi Klamburg, Evarist Feliu, Josep-Maria Ribera
Journal: Blood (2004)
IL-2- and IL-15-Activated Alloreactive NK Cells Infusion Reduces GVHD, Mediates Graft-Versus-Leukemia Effects and Prolongs Survival in Recipients of MHC-Mismatched Hematopoietic Cell Transplantation.
Authors: Guanghua Chen, De Pei Wu, Mingzhen Yang, Ai-ning Sun
Journal: Blood (2007)
Abstract 1629: Prednisone versus dexamethasone acute toxicity and cumulative doses variations in childhood acute lymphoblastic leukemia
Authors: Sophie Marcoux, Aurélie Chapdelaine, Philippe Robaey, Daniel Sinnett, Maja Krajinovic, Caroline Laverdière
Journal: Cancer Research (2015)

Abstract INTRODUCTION Glucocorticoids (GC) are the main components of childhood acute lymphoblastic leukemia (ALL) treatment; in the past decades, there were numerous attempts at finding whether prednisone or dexamethasone is the best drug. EXPERIMENTAL PROCEDURE A retrospective study of patients (n = 119) treated according to Dana-Farber Cancer Institute (DFCI)-ALL treatment protocols 91-01 and 95-01 was done. Medical charts were reviewed and type and doses of glucocorticoids (GC) received were recorded. Bone and psychiatric symptoms, as well as all anthropomorphic data were also recorded. For each patient, a total theoretical dose was calculated according to the initial risk of relapse stratification, treatment protocol indications and assigned arms. Cumulative GC doses actually received were compared to theoretical doses in the form of a dose deviation in% ((theoretical dose - actual dose) / theoretical dose * 100). SUMMARY OF DATA Results indicate that despite an adequate correlation between planned and administered GC doses for most patients, patients treated with dexamethasone were found to have significantly more GC dose deviations than those treated with prednisone (p &amp;lt; 0.001). Findings also indicate that bone toxicity (p = 0.02), but not psychiatric toxicity, is associated with GC dose deviations. CONCLUSIONS Despite representing the current standard in clinical studies, using only different treatment arms or different treatment protocols may lead to significant interpretation caveats if doses actually received are not controlled for. This is of importance especially for drugs likely to induce very severe side-effects requiring dose modification, as it is the case for GC and acute bone toxicity. Citation Format: Sophie Marcoux, Aurélie Chapdelaine, Philippe Robaey, Daniel Sinnett, Maja Krajinovic, Caroline Laverdière. Prednisone versus dexamethasone acute toxicity and cumulative doses variations in childhood acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1629. doi:10.1158/1538-7445.AM2015-1629
FLT3 and KIT Isoforms Activate PI3K/AKT Signaling Which Is Potently Blocked by the Novel Dual PI3K/Mtor Inhibitors NVP-BEZ235 and NVP-BGT226.
Authors: Kerstin M Kampa, Sandra Mueller, Katharina-Henriette Rasp, Lothar Kanz, Michael C Heinrich, Marcus M Schittenhelm
Journal: Blood (2009)