tbuckley/cabot-search huggingface dataset:
Abstract 18515: Forward Flow Ejection Fraction as a Major Determinant of Outcome in Organic Mitral Regurgitation
Authors: Marlène Dupuis, Marie-Annick Clavel, Haïfa Mahjoub, Kim O’Connor, Mario Sénéchal, Philippe Pibarot
Journal: Circulation (2015)

Introduction: The optimal timing of mitral valve (MV) surgery in patients with organic mitral regurgitation (OMR) is controversial. The objective of this study was to determine independent predictors of cardiac events in patients with OMR and no triggers for mitral valve surgery. Hypothesis: We hypothesized that forward LV ejection fraction (LVEF) calculated by the Dumesnil’s method (i.e. stroke volume measured in LV outflow tract divided by left ventricular end diastolic volume) is superior to the LVEF measured by the biplane Simpson’s method. Methods: Two hundred seventy eight patients with OMR (i.e. severity grade ≥1/4) and Doppler echocardiography exam at least 6 months before MV surgery or death were included. Clinical and echocardiographic data of 278 patients with OMR were analyzed retrospectively. The study end-point was the composite of death or need for mitral valve surgery. Results: During a mean follow-up of 5.4 ± 3.2 years, there were 147 (53%) events: 96 (35%) mitral surgeries and 66 (24%) deaths. There was no difference in the Simpson LVEF (65 ± 6% vs 65 ± 4%; p=0.86) and global longitudinal strain (-21.18 ± 3.26 % vs -21.26 ± 2.44 %; p=0.86) between patients who had an event versus those who were event-free during follow-up. However, LVEF calculated by Dumesnil’s method at baseline was lower in the event-group (47 ± 15%vs 59 ± 15%; p&lt;0.0001) compared to the non-event group. After adjustment for age, sex, Charlson’s probability, coronary artery disease, ACE inhibitors, β-blockers, diuretics, AF and MR grade, forward LVEF by Dumesnil’s method remained an independent predictor of the occurrence of cardiac events (adjusted hazard ratio: 1.09, 95% interval confidence: 1.02-1.17; p=0.01). Conclusion: This study shows that the forward LVEF calculated by the Dumesnil’s method is superior to the standard LVEF or to longitudinal strain to predict outcomes in OMR. These results could help to improve risk stratification of patients with OMR and thereby individualized the treatment’s strategy. Further prospective studies are needed to confirm these findings.
94. A Scalable Recombinant HSV-Based Manufacturing System for Production of Highly Potent Adeno-Associated Type 9 Vectors
Authors: Nathalie Clement
Journal: Molecular Therapy (2016)

Introduction: Adeno-associated virus vectors (AAV) have been utilized as a gene delivery tool to treat a multitude of diseases. As the potential uses for these vectors expand, the need for improved manufacturing methods becomes essential for large-scale implementation. Recombinant Herpes Simplex Virus (rHSV)-based method delivering AAV capsid and transgenes for recombinant AAV (rAAV) production has been shown to be a robust and scalable method for producing multiple rAAV serotypes for pre-clinical and clinical studies. Here we will present the first scalable production and purification method for rAAV serotype 9 utilizing the rHSV system. Methods: Recombinant rAAV9-GFP stocks were produced by transfection or rHSV co-infection on HEK 293. Vector genome titers were assessed by quantitative PCR, digital droplet PCR and dot blot. Infectivity was assessed by an infectious center assay, flow cytometry, and green cell transduction assay (GCA). Coomassie SDS-PAGE, or western blot analyses were performed to evaluate identity and purity of rAAV samples and electron microscopy to assess full versus empty ratio for each method. Results: rAAV vectors produced by the HSV method showed a 7 and 10 fold increase in total vector genomes and transducing units per CellStack®, respectively. Increased infectivity was observed in rHSV-made vectors as demonstrated by an increasing in transducing unit titers by GCA and infectious center assay. Flow cytometry of C12 cells infected with equal vector genome amounts of both transfection and rHSV made rAAV showed a 30% increase in GFP expressing cells. Coomassie staining and western blot analysis showed a 20-32% reduction in total capsid proteins in rAAV made by rHSV co-infection. Electron microscopy confirmed this reduction in total capsid protein was due to a decrease in empty particles in HSV-made rAAV samples. Overall, this method produced greater than 1×1014 rAAV9 vector genomes per liter equivalent of 293 cells of a final, purified product. Conclusions: Our data demonstrated the significant improvement in rAAV9 manufacturing by utilization of the rHSV based manufacturing methods. An improvement in both vector titer and infectivity was observed in rHSV made rAAV vectors compared to transfection-based production. Importantly, this scalable purification method is readily suitable for pre-clinical GLP studies and GMP manufacturing in our laboratory. Further improvements will be presented specifically evaluating rHSV production in a suspension-adapted HEK 293 cell system in view of a large scale manufacturing protocol of rAAV9 vectors for clinical studies.
Genome-Wide Aberrant Splicing in Patients with Acute Myeloid Leukemia (AML) Indetifies Potential Novel Targets
Authors: Sophia Adamia, Michal Bar-Natan, Benjamin Haibe-Kains, Hervé Avet-Loiseau, Laurence Lode, Samuel Pevzner, Sigitas Verselis, Edward Fox, Ilene Galinsky, John Quackenbush, Richard M. Stone, James D Griffin
Journal: Blood (2011)
Clinical and Radiographic Course of Bone Disease in Relapsed Multiple Myeloma in the Era of Novel Agents: Occurrence, Definition and Impact of Resclerosis Documented by Whole-Body Low-Dose Multidetector Computed Tomography
Authors: Katharina Oehrlein, Marius Horger, Anja Schmidt, Manola Zago, Maximilian Schulze, Lothar Kanz, Katja C Weisel
Journal: Blood (2012)
Abstract LB-026: Pin1 negatively regulated Grb7 protein stability via the ubiquitin-proteasome cascade requires the peptidyl-prolyl cis/trans isomerase activity of Pin1
Authors: Yu-Ling Tai, Tang-Long Shen
Journal: Cancer Research (2015)

Abstract Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein in cooperation with numerous tyrosine kinases to regulate various cellular signaling and functions. Although the regulatory mechanisms on the activation of Grb7 have been documented, the molecular mechanism governing Grb7 stability and its functional consequence is still not clearly understood. Here, we observed a novel negative regulatory mechanism of Grb7 by peptidyl-prolyl cis/trans isomerases Pin1 at the post-translational level. The Grb7 phosphorylation on the Ser194-Pro motif facilitated its binding to the WW domain of Pin1 and subsequently ubiquitination on Grb7, which, in turn, enhanced the process of proteosome-dependent proteolysis. Moreover, the interaction between Grb7 and Pin1 is dependent on the phosphorylation that is mediated by c-Jun N-terminal kinases MAPK. Both the phosphorylated Ser/Thr-Pro motif binding module and the peptidyl-prolyl cis/trans isomerase activity of Pin1 is essentail for Pin1-mediated Grb7 ubiquitin-proteasome proteolysis. By contrast, inhibition of Pin by lentiviral-mediated gene silencing resulted in accumulation of Grb7 protein as well as prolonged Grb7 protein stability. A stable Grb7S194A mutant that cannot be bound to and modulated by Pin1 utilize its potential to influence cell cycle progression. Our finding revealed that the Pin1/Grb7 complex formation enables negatively regulating Grb7-mediated cell proliferation due to the influence of Grb7 protein stability. Note: This abstract was not presented at the meeting. Citation Format: Yu-Ling Tai, Tang-Long Shen. Pin1 negatively regulated Grb7 protein stability via the ubiquitin-proteasome cascade requires the peptidyl-prolyl cis/trans isomerase activity of Pin1. [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 LB-026. doi:10.1158/1538-7445.AM2015-LB-026
Abstract 4051: Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma
Authors: Douglas M. Marvel, Dmitry Gabrilovich
Journal: Cancer Research (2015)

Abstract The presence of peroxynitrite (PNT) in tumor tissue, as measured by its surrogate tissue marker, nitrotyrosine (NT), is correlated with poor clinical prognosis and poor response to immunotherapy. The production of PNT at the tissue can be attributed to multiple sources. For example, many tumors are characterized by extensive infiltration by immature myeloid cells with robust immuno-suppresive activity. These myeloid derived suppressor cells (MDSC) are known to produce high level of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the reaction of these two species is a major source of PNT at the tumor site. In addition to MDSC, iNOS expression in tumor cells themselves can act as a major source of PNT. Here we show that B16 melanoma cells are protected from CTL mediated lysis via iNOS expression. This effect is independent of effects on the T cells themselves as ability to lyse iNOS expressing and non-expressing cells was assessed in the same culture. Previously it was shown that peroxynitrite treated cells bound certain exogenous MHC class I peptides with lower affinity than their non-treated counterparts. Using a system of endogenous iNOS expression, our data supports the existence of a similar phenomenon for endogenously processed and presented peptide antigens, suggesting that the repertoire of surface bound immunogenic peptides is different in tumors when compared to the presentation of those same antigens in the tumor draining lymph node, where PNT is less prevalent. As a result, immune responses generated in the lymph node are against antigens which are not relevant and will fail to control tumor growth. Additionally, our data suggests that pharmaceutical intervention to reduce intratumoral PNT levels may buoy concurrent immunotherapy. Citation Format: Douglas M. Marvel, Dmitry Gabrilovich. Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma. [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 4051. doi:10.1158/1538-7445.AM2015-4051
Abstract 4224: CD133 knockdown sensitizes melanoma to kinase inhibitors
Authors: Maryam AbdusSamad, Anirudh Gaur, Hengbo Zhou, John L. Zapas, Cynthia M. Simbulan-Rosenthal, Edward C. McCarron, Dean S. Rosenthal
Journal: Cancer Research (2015)

Abstract Melanoma is an aggressive and lethal form of cancer, responsible for 9,710 deaths in the US every year, as indicated by the Surveillance Epidemiology and End Results (SEER) program. Although early stages are surgically treatable, the advanced or metastatic stages are the most fatal, presumably due to resistance to chemotherapy, radiation or other therapies. Refractoriness of metastatic melanoma is due to self-renewal properties of a subpopulation of resistant cells, which may be the same as what have been termed “melanoma initiating cells” (MIC), many of which have been associated with the expression CD133. CD133 (PROM-1) is a 5-transmembrane-glycoprotein that is a cell surface marker for different cancers including late-stage cutaneous melanoma. By magnetic activated cell sorting, we isolated a CD133-positive population derived from a patient harboring a difficult-to-treat NRASQ61R/BRAFWT profile. The MIC were transfected with CD133-specific small-interfering RNA (siRNAs) to deplete CD133 protein levels in cells. Our results show that knocking down CD133 in NRASQ61R/BRAFWT mutant melanoma renders cells more sensitive to clinically employed-MEK/BRAF inhibitors. Thus, specific gene knockdown or small molecule targeting, along with the multikinase inhibitors, may be a high potency therapeutic of late-stage and recurrent melanoma. Analyses of patient-derived melanomas harboring different mutation signatures are currently in progress to determine if CD133 and MIC play broader roles in melanoma chemoresistance. Citation Format: Maryam AbdusSamad, Anirudh Gaur, Hengbo Zhou, John L. Zapas, Cynthia M. Simbulan-Rosenthal, Edward C. McCarron, Dean S. Rosenthal. CD133 knockdown sensitizes melanoma to kinase inhibitors. [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 4224. doi:10.1158/1538-7445.AM2015-4224
Abstract IA14: Single-cell sequencing in cancer genomics
Authors: J. Christopher Love
Journal: Cancer Research (2015)

Abstract Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple hurdles. This talk will present a collaborative research program that has generated an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of &amp;gt;99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis, and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. The talk will also present some technical considerations for enabling single-cell sequencing of tumor cells, including a description of statistical methods to quantitatively assess the amplification bias resulting from whole-genome amplification of single-cell genomic DNA. This study establishes a foundation for CTC genomics in the clinic, and initial applications to patient monitoring will be described. Citation Format: J. Christopher Love. Single-cell sequencing in cancer genomics. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA14.
The relationship between the development of rash and clinical and health-related quality of life outcomes by <i>KRAS</i> mutation status in patients with colorectal cancer treated with cetuximab in NCIC CTG CO.17.
Authors: C. J. O'Callaghan, D. Tu, C. S. Karapetis, H. Au, M. J. Moore, N. C. Tebbutt, M. G. Trudeau, T. J. Price, D. Yip, D. J. Jonker
Journal: Journal of Clinical Oncology (2011)

3588 Background: The NCIC Clinical Trials Group CO.17 trial, conducted with the Australasian Gastrointestinal Trials Group, showed cetuximab monotherapy (CET vs best supportive care - BSC) improved overall (OS) and progression-free survival (PFS) and maintained health-related quality of life (HRQL) in patients (pts) previously treated for advanced colorectal cancer. Correlative analyses showed strong relationships between CET benefits and both rash development and KRAS mutation status. Association between rash and CET benefits is now presented by KRAS mutation status. Methods: Rash was graded weekly by NCI CTC 2.0 criteria. Landmark-type analysis was performed by excluding pts who died within 28 days and then grouping by rash severity (gr 2+ vs gr 0/1) based on worst grade by day 28 (LTA2). Multivariate Cox models were conducted separately for wild-type (WT) and mutated (MUT) KRAS tumors. Results: More rash of severity gr 2+ was observed in WT than MUT pts treated with CET (57.3% vs 44.4%; p=0.08). The median OS, PFS and HRs from LTA2 are presented for WT and MUT groups: (Table). CET benefit in pre-specified HRQL domains was statistically significantly associated with severity of rash only in WT patients at some timepoints, although no consistent trend was evident. Conclusions: Rash severity was positively correlated with PFS and OS and variably associated with HRQL in WT pts who received CET, although only for gr 2+ rash did OS significantly exceed that of BSC ptss. In MUT pts, neither gr 0/1 nor gr 2+ rash was associated with improved PFS, OS or HRQL vs BSC pts. Treatment and grade of rash. LTA2 Median PFS Median OS KRAS WT N Months 95%CI Months 95%CI BSC 105 1.9 1.8-2.0 5.0 4.5-5.7 CET gr 0/1 55 2.2 1.8-3.9 8.0 6.2-10.3 CET gr 2+ 62 5.1 3.6-5.5 9.8 8.0-11.6 HR 95%CI P HR 95%CI P CET gr 0/1 vs BSC 0.57 0.38-0.86 0.008 0.85 0.56-1.31 0.46 CET gr 2+ vs BSC 0.32 0.21-0.49 <0.0001 0.52 0.34-0.80 0.003 KRAS MUT n Months 95%CI Months 95%CI BSC 79 1.7 1.9-3.3 4.6 3.6-5.5 CET gr 0/1 50 1.8 1.7-1.8 4.0 3.3-4.8 CET gr 2+ 31 1.8 1.7-2.0 6.6 5.2-9.6 HR 95%CI p HR 95%CI P CET gr 0/1 vs BSC 0.97 0.65-1.46 0.89 1.47 0.95-2.27 0.08 CET gr 2+ vs BSC 0.82 0.52-1.30 0.39 0.82 0.47-1.41 0.46
Abstract 4463: Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines
Authors: Sonia C. Dolfi, Daniel J. Medina, Shridar Ganesan, Alexei Vazquez, Kim M. Hirshfield
Journal: Cancer Research (2015)

Abstract Metabotropic glutamate receptor 1 (GRM1) has an established oncogenic role in melanoma. Growing evidence supports a similar role in breast cancer. We have previously shown that GRM1 is not only expressed in human breast cancers, but that levels of expression correlate with clinical outcomes with tamoxifen treatment, and that GRM1 knockdown reduces breast cancer cell viability and growth. Others have shown that GRM1 modulating drugs also reduce viability and growth of estrogen receptor (ER) negative breast cancer cell lines. Riluzole, a postulated inhibitor of glutamate release, has been evaluated in pre-clinical studies in melanoma. Early clinical trials have shown promising results for this disease. However, the mechanistic effects of riluzole have not been well-defined. Therefore, we evaluated the functional activity of riluzole in breast cancer. A molecularly diverse set of ER+ and ER- breast cancer cell lines with variable GRM1 expression were evaluated. Cell lines were treated with either riluzole or BAY 36-7620 (non-competitive GRM1 antagonist) or their combination. Treatment with either drug reduces cell number and viability, inhibits cell proliferation, and alters expression of cell cycle and apoptotic pathway genes as determined by gene microarray analysis. Drug treatment produces cell line-dependent effects on markers for proliferation, cell cycle, DNA damage, and apoptosis. Riluzole induces G2/M arrest in all cell lines tested. More specifically, riluzole induces mitotic arrest as demonstrated by changes in histone H3 phosphorylation at serine 10 and cyclin B level. Treatment with BAY 36-7620 induces a modest G2/M arrest and increase in the sub G1 population in a subset of cell lines. However, BAY 36-7620 does not induce mitotic arrest. The combination of riluzole and BAY 36-7620 results in increased cell death and decreased proliferation in all cell lines tested. Our data suggest that either riluzole or BAY 36-7620 induce breast cancer cell death. However, riluzole may modulate the activity of intracellular targets independent of GRM1. As riluzole is an FDA-approved drug, it could be quickly moved into a clinical trial and may provide a novel therapeutic approach in the treatment of breast cancer. Citation Format: Sonia C. Dolfi, Daniel J. Medina, Shridar Ganesan, Alexei Vazquez, Kim M. Hirshfield. Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines. [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 4463. doi:10.1158/1538-7445.AM2015-4463
CFU-GM Assay Can Be Predictive of Umbilical Cord Blood Engraftment.
Authors: Maria Felicitas N. Rodriguez, Alexandra C. Senegaglia, Carmem K. Rebelatto, Daniela V. Pilonetto, Samira Fadel, Mariester Malvezzi, Brent R. Logan, Henrique Ascenço, Luciana Takahashi, Ricardo Pasquini, Noemi F. Pereira
Journal: Blood (2006)
Engineering Social Incentives for Health
Authors: David A. Asch, Roy Rosin
Journal: New England Journal of Medicine (2016)

Interview with Dr. David Asch on the potential uses of social engagement strategies in promoting health. (10:09)Download So much of what determines patients' health occurs out of clinicians' reach. There are many, largely untapped, ways of organizing interactions with friends and relatives who are already part of patients' lives to help engage them in beneficial health-related behavior.
Final Results and Follow-up of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (aka MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
Authors: Jennifer A. Woyach, Farrukh Awan, Ian Flinn, Jesus G. Berdeja, Elizabeth A Wiley, Sharmeen Mansoor, Ying Huang, Gerard Lozanski, Paul A. Foster, John C. Byrd
Journal: Blood (2014)
Tuberculosis in Europe
Authors: Nikesh Parekh, Tamsin Rose, Vanisha Parekh, Michael Hughes
Journal: BMJ (2010)

In the 19th century tuberculosis killed one in four people in Europe and the United States. As living conditions and medical interventions have improved, a drop in mortality occurred over the 20th century,1 but in recent decades these areas have seen a re-emergence of the disease.

The rise of tuberculosis has disproportionately affected the most vulnerable sections of society. Zsuzsanna Jakab, World Health Organization’s regional director for Europe, said that the WHO European Region has “the lowest treatment success rate in the world compared to other WHO regions, and the highest levels of drug resistant TB [tuberculosis] . . . TB hits the poorest and most vulnerable hardest.”2

The European Commission called 2010 “the European year for combating poverty and social exclusion.”3 The European Centre for Disease Prevention and Control published evidence showing a direct relation between wealth inequality and the prevalence of tuberculosis in European countries; and that European countries with a greater Public Wealth Index have a …
Adoptive Transfer of Escalating Doses of Ex Vivo Expanded Autologous Natural Killer (NK) Cells In Patients with Advanced Malignancies Following Bortezomib Treatment to Sensitize to NK-TRAIL Cytotoxicity
Authors: Aleah Smith, Hahn Khuu, Dawn M Betters, Lisa Cook, Catalina Ramos, Sophia Grasmeder, Maria Berg, Rebecca Lopez, Su Su, Vicki Fellowes, David Stroncek, Jeremy Pantin, Sumi Vasu, Theresa Donohue, Keyvan Keyvanfar, Richard Childs
Journal: Blood (2010)
Pacmed Salvage Therapy for Advanced High-Risk Multiple Myeloma (AHRMM)
Authors: Yazan Alsayed, Sarah Waheed, Jackie Szymonifka, Bijay Nair, Saad Usmani, Frits van Rhee, Elias J. Anaissie, Monica Grazziutti, Antje Hoering, Bart Barlogie
Journal: Blood (2010)
A GMCSF/Interleukin-15 Fusokine Leads to the Generation of a Novel Type of CD2/MHCII Immune Regulatory Cell with Potent Immune Suppressive Properties as Demonstrated in the EAE Mouse Model of Multiple Sclerosis.
Authors: Moutih Rafei, Jeremy Hsieh, Meng Yang Li, Simone Zehntner, Kathy Forner, Jacques Galipeau
Journal: Blood (2007)
Atrial Fibrillation and PCI — Do We Still Need Aspirin?
Authors: Sanjit S. Jolly, Madhu K. Natarajan
Journal: New England Journal of Medicine (2016)

The treatment of patients with atrial fibrillation who undergo percutaneous coronary intervention (PCI) is a common clinical dilemma. Approximately 10 to 15% of patients undergoing PCI have a history of atrial fibrillation.1 Patients with atrial fibrillation are at increased risk for stroke, and warfarin has been shown to be superior to dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin for the prevention of stroke.2 However, DAPT has been shown to be markedly superior to aspirin plus warfarin for the prevention of stent thrombosis.3 This has led to the adoption of triple therapy with DAPT plus warfarin in patients with atrial . . .