tbuckley/cabot-search huggingface dataset:
Abstract 2522: Molecular and cellular mechanisms underlying the therapeutic efficacy of the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011, in a preclinical model of myeloproliferative neoplasia
Authors: Maria Pinzon-Ortiz, Tyler Longmire, Xianhui Rong, Giordano Caponigro, Gary Vanasse, Benjamin H. Lee, Z. Alexander Cao
Journal: Cancer Research (2015)

Abstract The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. The genetic aberration of JAK2V617F and the associated activation of STAT in myeloproliferative neoplasia (MPN) is one example of the involvement of this pathway in human cancer. We have previously shown the combination benefits of combining ruxolitinib (Jak1,2 inhibitor), with LGH447 (PIM inhibitor) and LEE011 (CDK4/6 inhibitor) in a Ba/F3-JAK2V617F-driven MPN model. Here, we set to explore the molecular and cellular mechanisms underlying this combination benefit in the JAK2V617F UKE-1 model of MPN. The triple combination of ruxolitinib, LGH447 and LEE011 resulted in sustained tumor regression in the UKE-1 model. Ruxolitinib, LGH447 and LEE011 inhibited pSTAT5, pBAD and pRb respectively. The monotherapies and the combination of ruxolitinib + LGH447 did not affect G1-S cycle. In contrast, the combination of ruxolitinib+LEE011, LGH447+LEE011 and the triple combination resulted in significant inhibition of G1-S progression. Consequently, after 72 hours of treatment, the percentage of cells in S phase decreased from 67% under DMSO to 15.8% under ruxolitinib+LEE011, and to 1.6% under the triple combination. Furthermore, monotherapies of LGH447 or LEE011 did not affect cell viability. Ruxolitinib monotherapy and ruxolitinib+LGH447 combination reduced viable cell% by 47% and 86%, respectively. The triple combination reduced it by 91%. Our data suggest that the triple combination efficacy is the result of both cell killing and cell cycle blockade. The inhibition of JAK-PIM pathway significantly reduced cell viability. And the inclusion of CDK4/6 inhibition by LEE011 lead to more potent cell killing and cell growth arrest. Taken together, the triple combination achieves sustained tumor regression in preclinical models of MPN. Citation Format: Maria Pinzon-Ortiz, Tyler Longmire, Xianhui Rong, Giordano Caponigro, Gary Vanasse, Benjamin H. Lee, Z. Alexander Cao. Molecular and cellular mechanisms underlying the therapeutic efficacy of the combination of JAK inhibitor, ruxolitinib, PIM inhibitor, LGH447, and CDK4/6 inhibitor, LEE011, in a preclinical model of myeloproliferative neoplasia. [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 2522. doi:10.1158/1538-7445.AM2015-2522
Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson Disease and Motor Fluctuations
Authors: Andrew J. Lees, Joaquim Ferreira, Olivier Rascol, Werner Poewe, José-Francisco Rocha, Michelle McCrory, Patricio Soares-da-Silva
Journal: JAMA Neurology (2016)

Catechol O-methyltransferase (COMT) inhibitors are an established treatment for end-of-dose motor fluctuations associated with levodopa therapy in patients with Parkinson disease (PD). Current COMT inhibitors carry a high risk for toxic effects to hepatic cells or show moderate improvement. Opicapone was designed to be effective without the adverse effects.To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with PD experiencing end-of-dose motor fluctuations.This phase 3 international, multicenter outpatient study evaluated a 25- and a 50-mg/d dosage of opicapone in a randomized, double-blind, 14- to 15-week, placebo-controlled clinical trial, followed by a 1-year open-label phase during which all patients received active treatment with opicapone. Patients with PD who experienced signs of end-of-dose deterioration and had a mean total awake off-time (state of akinesia or decreased mobility) of at least 1.5 hours, not including morning akinesia, were enrolled. Data were collected from March 18, 2011, through June 25, 2013. Data from the evaluable population were analyzed from July 31, 2013, to July 31, 2014.The primary efficacy outcome of the double-blind phase was the change from baseline in absolute off-time vs placebo based on patient diaries. The open-label phase focused on maintenance of treatment effect in off-time.A total of 427 patients (258 men [60.4%] and 169 women [39.6%]; mean [SD] age, 63.1 [8.8] years) were randomized to a 25-mg/d (n = 129) or a 50-mg/d (n = 154) dosage of opicapone or to placebo (n = 144). Of these, 376 patients completed the double-blind phase and entered the open-label phase, of whom 286 completed 1 year of open-label treatment. At the end of the double-blind phase, the least squares mean change (SE) in off-time was -64.5 (14.4) minutes for the placebo group, -101.7 (14.9) minutes for the 25-mg/d opicapone group, and -118.8 (13.8) minutes for the 50-mg/d opicapone group. The adjusted treatment difference vs placebo was significant for the 50-mg/d opicapone group (treatment effect, -54.3 [95% CI, -96.2 to -12.4] minutes; P = .008), but not for the 25-mg/d opicapone group (treatment effect, -37.2 [95% CI, -80.8 to 6.4] minutes; P = .11). The off-time reduction was sustained throughout the open-label phase (-126.3 minutes at 1-year open-label end point). The most common adverse events in the opicapone vs placebo groups were dyskinesia, constipation, and dry mouth. Fifty-one patients (11.9%) discontinued from the study during the double-blind phase.Treatment with a 50-mg once-daily dose of opicapone was associated with a significant reduction in mean daily off-time in levodopa-treated patients with PD and motor fluctuations, and this effect is maintained for at least 1 year. Opicapone was safe and well tolerated.clinicaltrials.gov Identifier: NCT01227655.
Double Autologous Transplant Versus Tandem Autologus - Non Myeloablative Allogeneic Transplant for Newly Diagnosed Multiple Myeloma.
Authors: B. Bruno, M. Rotta, F. Patriarca, N. Mordini, B. Allione, F. CarnevaleSchianca, L. Giaccone, P. Omedè, R. Sorasio, M. Giarin, P. Falco, M.T. Ambrosini, S. Bringhen, D. Mattei, M. Massaia, A. Palumbo, M. Aglietta, A. Levis, A. Gallamini, R. Fanin, R. Storb, G. Ciccone, M. Boccadoro
Journal: Blood (2005)
Clinical features and short-term outcomes of cancer patients with suspected and unsuspected pulmonary embolism: the EPIPHANY study
Authors: Carme Font, Alberto Carmona-Bayonas, Carmen Beato, Òscar Reig, Antonia Sáez, Paula Jiménez-Fonseca, Juana M. Plasencia, David Calvo-Temprano, Marcelo Sanchez, Mariana Benegas, Mercedes Biosca, Diego Varona, Maria Angeles Vicente, Laura Faez, Maria del Pilar Solís, Irma de la Haba, Maite Antonio, Olga Madridano, Eduardo Castañon, María Jose Martinez, Pablo Marchena, Avinash Ramchandani, Angel Dominguez, Alejandro Puerta, David Martinez de la Haza, Jesus Pueyo, Susana Hernandez, Angela Fernandez-Plaza, Lourdes Martinez-Encarnacion, Mar Martin, Gema Marin, Francisco Ayala, Vicente Vicente, Remedios Otero
Journal: European Respiratory Journal (2016)

The study aimed to identify predictors of overall 30-day mortality in cancer patients with pulmonary embolism including suspected pulmonary embolism (SPE) and unsuspected pulmonary embolism (UPE) events. Secondary outcomes included 30- and 90-day major bleeding and venous thromboembolism (VTE) recurrence. The study cohort included 1033 consecutive patients with pulmonary embolism from the multicentre observational ambispective EPIPHANY study (March 2006–October 2014). A subgroup of 497 patients prospectively assessed for the study were subclassified into three work-up scenarios (SPE, truly asymptomatic UPE and UPE with symptoms) to assess outcomes. The overall 30-day mortality rate was 14%. The following variables were associated with the overall 30-day mortality on multivariate analysis: VTE history, upper gastrointestinal cancers, metastatic disease, cancer progression, performance status, arterial hypotension &lt;100 mmHg, heart rate &gt;110 beats·min −1 , basal oxygen saturation &lt;90% and SPE ( versus overall UPE). The overall 30-day mortality was significantly lower in patients with truly asymptomatic UPE events (3%) compared with those with UPE-S (20%) and SPE (21%) (p&lt;0.0001). Thirty- and 90-day VTE recurrence and major bleeding rates were similar in all the groups. In conclusion, variables associated with the severity of cancer and pulmonary embolism were associated with short-term mortality. Our findings may help to develop pulmonary embolism risk-assessment models in this setting.
A Phase I Study of a Novel Human Monoclonal Antibody (mAb216) with Chemotherapy for the Treatment of Patients with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia.
Authors: Michaela Liedtke, Clare Twist, Marcia Bieber, Neelima Bhat, Nelson N.H. Teng, Steven Coutre
Journal: Blood (2007)
Re: Phillip J. Gray, Chun Chieh Lin, Matthew R. Cooperberg, Ahmedin Jemal, Jason A. Efstathiou. Temporal Trends and the Impact of Race, Insurance, and Socioeconomic Status in the Management of Localized Prostate Cancer. Eur Urol 2017;71:729–37
Authors: Philipp Gild, Nicolas von Landenberg, Alexander P. Cole
Journal: European Urology (2016)
Fucosylated Antigen-Specific Cytotoxic T Lymphocytes Demonstrate Enhanced Killing of Leukemia Targets
Authors: Gheath Alatrash, Mao Zhang, Na Qiao, Pariya Sukhumalchandra, Madhushree Zope, Anne V. Philips, Alexander Perakis, Lisa St. John, Maria R. Khouri, Victor Gall, Karen C. Dwyer, Jodie Polan, Jeffrey J. Molldrem, Elizabeth J. Shpall, Elizabeth A. Mittendorf
Journal: Blood (2015)
Comorbidities and Subgroups of Patients Surviving Severe Acute Hypercapnic Respiratory Failure in the Intensive Care Unit
Authors: Dan Adler, Jean-Louis Pépin, Elise Dupuis-Lozeron, Katerina Espa-Cervena, Roselyne Merlet-Violet, Hajo Muller, Jean-Paul Janssens, Laurent Brochard
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

No methodical assessment of the lung, cardiac, and sleep function of patients surviving an acute hypercapnic respiratory failure episode requiring admission to the intensive care unit (ICU) has been reported in the literature.To prospectively investigate the prevalence and impact of comorbidities in patients treated by mechanical ventilator support (invasive or noninvasive) for acute hypercapnic respiratory failure in the ICU.Seventy-eight consecutive patients admitted for an episode of acute hypercapnic respiratory failure underwent an assessment of lung, cardiac, and sleep function by pulmonary function tests, transthoracic echocardiography, and polysomnography 3 months after ICU discharge.Sixty-seven percent (52 of 78) of patients exhibited chronic obstructive pulmonary disease (COPD), although only 19 had been previously diagnosed. Patients without COPD were primarily obese. Prevalence of severe obstructive sleep apnea was 51% (95% confidence interval, 34-69) in patients with COPD and 81% (95% confidence interval, 54-96) in patients without COPD. Previously undiagnosed cardiac dysfunction with preserved ejection fraction was highly prevalent (44%), as was hypertension (67%). More than half of the population demonstrated at least three major comorbidities known to precipitate acute hypercapnic respiratory failure. Multimorbidity was associated with longer time to hospital discharge. Hospital readmission or death occurred in 46% of patients over an average of 3.5 months after discharge.Severe hypercapnic respiratory failure requiring ICU admission resulted primarily from COPD or obesity. Major comorbidities are highly prevalent in both cases and most often ignored. Surviving acute hypercapnic respiratory failure should be an opportunity to systematically evaluate lung, heart, and sleep functions to improve poor outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02111876).
454. The Surface Marker Expression Changes in Monolayer Cultured Human Chondrocytes by TGF-β1
Authors: Hyun Joo Yoon
Journal: Molecular Therapy (2016)

Due to avascular environment, damaged or defective cartilage cannot be recovered voluntarily without intervention of a medical treatment. Among the treatments, autologous or allogenic chondrocyte transplantation is considered as one of promising methods. However, because the cell number that can be driven from a patient or a donor is limited, isolated chondrocytes should be in vitro cultured for amplification before being applied to a patient. This strategy was hindered again with dedifferentiation of monolayer cultured chondrocytes. Dedifferentiated chondrocytes change the phenotype and ECM profiles toward fibroblast-like ones, eventually resulting in insufficient recovery of cartilage. Previously, we showed that chondrocytes supplemented with TGF-β1 could be redifferentiated similar to articular chondrocytes. In this study, we investigated surface markers expressed on dedifferentiated chondrocytes utilizing flow cytometry analyses. The investigated markers include integrins and adhesion molecules like CD44, CD49a, CD49c, CD54, CD106, CD166, tetraspnins like CD9 and CD151, receptors like CD14 and CD105, and ectoenzyme, CD10. When compared to their expression pattern on chondrocytes cultured in TGF-β1 supplemented media, several markers showed differences in their expression levels, for example, such as up -regulation of CD49a and down-regulation of CD105 with TGF-β1 supplemented culture. The result seems supporting our previous study that showed chondrocyte redifferentiation by TGF-β1 and we speculate that the surface marker analysis would be applicable as a testing method to determine the potency and the comparability of chondrocytes originated from different donors and/ or from different manufacturing batches.
Abstract 1677: Annexin A2 antibody inhibits the progression of triple-negative and herceptin-resistant breast cancer by blocking epidermal growth factor receptor functions
Authors: Pankaj Chaudhary, Lee Daniel Gibbs, Jamboor K. Vishwanatha
Journal: Cancer Research (2015)

Abstract Short Description: Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting this role is still unknown. Methods: Triple-negative (MDA-MB-231) and Herceptin-resistant (JIMT-1) breast cancer cell lines were grown in complete DMEM and DMEM/F12 medium respectively, in a humidified incubator at 37°C with 5% CO2. The membrane function of AnxA2 was blocked by incubating cells with anti-AnxA2 antibodies. Western blotting, immunoprecipitation, immunofluorescence, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic, and wound-healing assays were performed in this study Results: We demonstrate that in triple-negative and Herceptin-resistant breast cancer cells a large amount of AnxA2 is specifically translocated to the outer membrane domain. In addition, AnxA2 interacts with extracellular domain of epidermal growth factor receptor (EGFR) at the cell surface and has an important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalization by blocking its homodimerization. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR-dependent PI3K-AKT and Raf-MEK-ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and migration. Conclusions: These studies indicate that association of AnxA2 with EGFR in the membrane domain might play a positive regulatory role in keeping EGFR signaling events in an activated state in triple negative and Herceptin-resistant breast cancer thus making AnxA2 an important therapeutic target. Citation Format: Pankaj Chaudhary, Lee Daniel Gibbs, Jamboor K. Vishwanatha. Annexin A2 antibody inhibits the progression of triple-negative and herceptin-resistant breast cancer by blocking epidermal growth factor receptor functions. [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 1677. doi:10.1158/1538-7445.AM2015-1677
626. Directing Skeletal Myogenic Progenitor Cell Lineage Specification with CRISPR/Cas9 Transcriptional Activators
Authors: Jennifer B. Kwon, Charles A. Gersbach
Journal: Molecular Therapy (2016)

Induced pluripotent stem cells (iPSCs) are a promising source for autologous cell-based therapies, disease modeling, and drug discovery in pathologies of muscular disease and wasting. The field of regenerative medicine has made significant strides in the successful reprogramming of iPSCs into various specialized cell types, including skeletal muscle cells. Genetic reprogramming of iPSCs into skeletal muscle progenitors and myocytes has been previously demonstrated by cDNA expression of exogenous myogenic transcription factors, including Pax7 and MyoD, to achieve varying levels of conversion toward the myogenic lineage. Recent advances in genome engineering technologies have established the CRISPR/Cas9 system as a programmable transcriptional regulator capable of targeted activation or repression of endogenous genes. The nuclease-deactivated dCas9 protein can be fused to a variety of transcriptional activation domains, such as the histone acetyltransferase p300 and the transactivation domain VP64, to potently activate genes in their natural chromosomal context. In contrast to ectopic expression of transgenes, activation of endogenous genes can facilitate chromatin remodeling and can also capture the full complexity of transcript isoforms, mRNA localization and stability, and other effects of non-coding regulatory elements. Here, we use VP64dCas9VP64 and dCas9-p300 constructs for targeted activation of the endogenous myogenic transcription factor Pax7 in human iPSCs to direct differentiation into skeletal muscle progenitors. We hypothesize that Pax7 activation will be sufficient to induce the myogenic program, as it plays a key role in myogenesis through regulation of muscle regeneration and the function of muscle progenitor cells. Lentiviral transduction of the dCas9 transcriptional activators under a constitutive promoter along with gRNAs targeted to the Pax7 promoter resulted in increased Pax7 transcript levels as assessed by qRT-PCR at 4 days after transduction. Additionally, widespread expression of Pax7 protein was detected by immunofluorescence staining by 13 days post transduction, indicating a high efficiency of endogenous gene activation by dCas9 effector constructs. Current efforts aim to achieve transient induction of high levels of Pax7 to examine progressive differentiation into mature myotubes expressing downstream myogenic markers. Future experiments will focus on assessing the in vivo skeletal muscle regenerative potential of Pax7+ human iPSC-derived myogenic progenitor cells by examining engraftment and self-renewal in injured muscle tissues of immunodeficient mice. These studies aim to introduce a novel method for the ex vivo derivation and expansion of myogenic precursor cells from patient-derived iPSCs, which will create new opportunities for disease modeling and cell therapies in disorders of skeletal muscle regeneration including muscular dystrophies, sarcopenia, and cachexia.
IMPS-07T CELL RECEPTOR VARIABLE β CHAIN (TCR Vβ) USAGE TO PREDICT AND GENERATE TUMOR SPECIFIC T LYMPHOCYTES AGAINST INVASIVE GLIOMAS
Authors: Catherine Flores, Christina Pham, Jeffrey Drake, Tyler Wildes, Daune Mitchell
Journal: Neuro-Oncology (2015)

INTRODUCTION: Adoptive cellular therapy has been demonstrated to be a highly efficacious immunotherapy against solid tumors. In this study, we predict T cell populations with high affinity to glioma and generate a T cell population highly enriched for tumor-reactive T cells. OBJECTIVES: Major barriers to therapeutic development against brain tumors are that brain tumors are highly heterogeneous and tumor antigens are largely uncharacterized. The primary objective of this study was to predict and generate a polyclonal population of T lymphocytes that is highly enriched for tumor-specific T cells and overcomes these limitations. METHODS: We spectratyped the TCR Vβ repertoire of glioma infiltrating CD3+ cells in order to identify T cell populations with high affinity to tumor. Based on the identified TCR Vβ family expression, we isolated and reliably expanded these T cells from splenocytes of mice previously immunized with tumor RNA-pulsed dendritic cells. These cells were adoptively transferred into intracranial glioma bearing mice followed by dendritic cell vaccine. RESULTS: In vitro functionality assays demonstrated that T cells with TCR Vβ families predicted to have high affinity to tumors were responsible for anti-tumor immunity. Adoptive cellular therapy using T cells expressing TCR Vβ 5.1, 5.2, TCR Vβ 6, and TCR Vβ 8.1, 8.2 against intracranial tumor led to cures in 60% of treated mice. We further identify that the in vivo expansion of T cells expressing the TCR Vβ 6 family is specifically associated with long term survival. Failure of the persistence of these T cells is directly associated with tumor escape. CONCLUSION: Our methods allow us to generate highly tumor-reactive polyclonal T cell populations without the need for identifying tumor antigens. We are currently employing these analyses in clinical trials of adoptive cellular therapy targeting pediatric and adult gliomas under development at our center (FDA IND BB-14058).
332. Correction of the Sickle Cell Anemia Mutation in Human Induced Pluripotent Stem Cells
Authors: R. Geoffrey Sargent, Shingo Suzuki, Luke Gruenert, Fei Xie, Lin Ye, Yuet W. Kan, Dieter C. Gruenert
Journal: Molecular Therapy (2016)

The prevalence of sickle cell anemia (SCA) in the US is approximately 70,000 to 100,000 individuals, affecting mostly the African American and Hispanic communities. While improvements in the treatment of SCA has increased both the lifespan and the quality of life of SCA patients, only hematopoietic stem cell transplants offer a lasting cure. Induced pluripotent stem cells (iPSCs) have significantly advanced the potential of developing a personalized, cell and genetic therapy for diseases like SCA by generating patient-specific stem cells in which the underlying disease-causing mutations could be corrected. Differentiation of the corrected cells into engraftable progenitors underlies their utility for autologous replacement or repair of diseased tissues. In these studies, homology directed repair (HDR) was achieved using sequence-specific TALENs in conjunction with HBB targeting vectors to generate seamless, footprint-free gene correction of the HBs exon 1 SCA A-to-T transversion mutation in sickle cell iPSCs (SC-iPSCs). These studies were supported by NIH Program Project Grant (PPG) DK088760.
NHS health checks may have prevented 8400 heart attacks and strokes over five years
Authors: Susan Mayor
Journal: BMJ (2016)

The NHS Health Check programme has prevented an estimated 4600-8400 myocardial infarctions, strokes, or deaths due to these causes over the past five years by increasing statin use and improving diagnosis and treatment of diabetes, hypertension, and chronic kidney disease, an observational study has found.1

The programme, which started in 2009, offers a free health check to all adults aged 40-74 to help identify those at highest risk of cardiovascular disease and new comorbidities and to offer treatment, support, and advice on behavioural change. But researchers and politicians have questioned its evidence base.2 3 4 …