tbuckley/cabot-search huggingface dataset:
Abstract 3665: Reconstructing the itraconazole scaffold towards improved specificity for hedeghog signaling inhibition
Authors: Albert M. DeBerardinis, M. Kyle Hadden
Journal: Cancer Research (2015)

Abstract Inappropriate regulation of the hedgehog (Hh) signaling pathway contributes to the development and progression of a number of human cancers; most notably, basal cell carcinoma (BCC) and medulloblastoma (MB). Clinical validation of small molecule mediated silencing of the Hh pathway was recently demonstrated by the FDA approval of vismodegib for the treatment of locally advanced BCC, representing a first-in-class inhibitor of the Hh signaling pathway. Vismodegib antagonizes Hh signaling by directly binding smoothened (SMO), a critical regulator of the pathway and target of numerous small molecule preclinical and clinical drug candidates. Vismodegib treatments in MB patients revealed novel SMO mutants that demonstrated resistance to vismodegib therapy, which underscores the need for continued development of novel Hh pathway inhibitors. Recently, itraconazole (ITZ) was identified as an inhibitor of Hh signaling in vitro and in vivo. Characterization indicated ITZ, a clinically used antifungal agent, maintains Hh inhibition against vismodegib-resistant SMO mutants. Ongoing structure-activity analysis for the ITZ scaffold is currently being investigated to identify analogues with improved potency and reduced non-specific toxicity. Results from these studies to identify candidates with improved pharmacological profiles and selectivity for Hh signaling modulation will be described herein. Citation Format: Albert M. DeBerardinis, M. Kyle Hadden. Reconstructing the itraconazole scaffold towards improved specificity for hedeghog signaling inhibition. [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 3665. doi:10.1158/1538-7445.AM2015-3665
The Pharmacokinetic Properties, Safety and Tolerability of a New Nonacog Alfa (Innonafactor) in Patients with Hemophilia B
Authors: Vladimir Yu. Zorenko, Georgy Mishin, Tatiana Severova, Alexandr Shuster, Dmitry Kudlay, Sergey Lukyanov, Anton Borozinets, Eugene Nikitin, Ekaterina Klykova
Journal: Blood (2015)
Molecular Mechanisms Involved in Homing and Migration of Plasma Cells in Response to CXCR4 Stimulation and Downstream Activation of the PI3K Pathway.
Authors: Irene M. Ghobrial, Joanna M. Ghobrial, Patricia Bramati, Terry Kimlinger, Michael M. Timm, Ashock Kumar, Karen E. Hedin, Thomas E. Witzig
Journal: Blood (2004)
Letter to the editor: New metrics to monitor progress towards global HIV targets: using the estimated number of undiagnosed HIV-infected individuals as denominator
Authors: André Sasse
Journal: Eurosurveillance (2016)

Preview this article: Letter to the editor: New metrics to monitor progress towards global HIV targets: using the estimated number of undiagnosed HIV-infected individuals as denominator, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/21/50/eurosurv-21-30424-5-1.gif
Back to the Basics: Cnidarians Start to Fire
Authors: Thomas C.G. Bosch, Alexander Klimovich, Tomislav Domazet-Lošo, Stefan Gründer, Thomas W. Holstein, Gáspár Jékely, David J. Miller, Andrea P. Murillo-Rincon, Fabian Rentzsch, Gemma S. Richards, Katja Schröder, Ulrich Technau, Rafael Yuste
Journal: Trends in Neurosciences (2016)
Higher Than Expected Incidence of Chronic Myeloid Leukemia in Solid Organ Transplant Recipients.
Authors: Asha R. Dhanarajan, Jack W Hsu, John R. Wingard, Myron N Chang, Consuela Soldevila-Pico, Shehzad Rehman, Maher Baz, Maxim Norkin
Journal: Blood (2012)
550. Developing an Optimal Insulin Augmentation Therapy to Improve AAV Gene Transfer to Skeletal Muscle and Liver in Mice
Authors: Sean Carrig, Mitchell J. Wopat, Ashley T. Martino
Journal: Molecular Therapy (2016)

We previously reported a novel finding that showed an insulin augmentation therapy can improve rAAV transduction of skeletal muscle and liver in cultured cells and mice. The insulin augmentation therapy in this earlier report was given just prior to AAV administration and was sustained for 28 days. The use of a long-term insulin augmentation was to determine if mice showed early signs of insulin resistance due to prolonged hyperinsulinemia. From the initial study we concluded that long-term insulin augmentation therapy improved AAV gene transfer to skeletal muscle and liver but that the mice showed a lack of elevated insulin activity and an increase in cortisol over time which are signs of insulin resistance. Additionally, our initial findings also suggested that an acute insulin augmentation therapy during the window of AAV administration would be sufficient without the concern for developing insulin resistance. The purpose of this new study was to investigate if an acute insulin augmentation therapy during the window of AAV delivery was sufficient to improve AAV transduction of skeletal muscle and liver. Additionally, we wanted to determine if an insulin augmentation therapy given after AAV infection would also enhance AAV gene transfer. Another aspect of this follow up study was to determine if an insulin augmentation therapy protocol would improve AAV transduction of lung tissue in mice. Finally, we wanted to investigate if fasting mice (which promotes reduced insulin activity) would result in sub-optimal AAV gene transfer. Our results showed an acute insulin augmentation therapy (4 hr treatment) given 30 minutes prior to intramuscular (IM) injection of AAV1-CMV-sc-hFIX or liver-directed delivery (via splenic capsule injection) of AAV8-CMV-sc-hFIX significantly improved (up to 5 Fold) sustained transduction for the length of the study (56 days). The acute therapy showed a minor (but significant) 1.7 Fold increase in AAV1-CMV-EGFP transduction in lung. In-vitro AAV2-CMV-LacZ transduction of HuH7 (human liver) and differentiated C2C12 (mice myofibers) also showed improvement with an acute insulin treatment. A 2hr treatment (5 ug/ml) resulted in a 2.7 fold increase while 8hr, 24hr & 72hr treatments had a 3.5 fold increase and giving insulin 24 hrs after AAV infection had no impact of AAV transduction. Finally, prolonged fasting will reduce insulin levels which could impact AAV gene transfer. Fasting mice for 12 hrs prior to and 4 hrs after IM delivery of AAV1-CMV-sc-hFIX or at weekly intervals after administration timed around blood collection did not have an impact on AAV transduction of skeletal muscle.
343. Repair of the Sickle-Cell Disease Mutation in Human Stem Cells Using CRISPR/Cas9 and Single-Stranded Oligodeoxynucleotides
Authors: Jorge Mansilla-Soto, Yan Leifman, Michel Sadelain
Journal: Molecular Therapy (2015)

Sickle cell disease is a hereditary anemia caused by a homozygous point mutation in the β-globin gene resulting in a glutamic acid to valine change at position 6 in the globin β-chain. Association of the mutated β-chain with α-chain results in the formation of hemoglobin S, which polymerizes intracellularly thus causing erythrocyte sickling. One promising therapy relies on the transplantation of autologous hematopoietic stem cells transduced with a lentiviral vector encoding a wild-type or mutant β-globin gene. However, one of the main concerns associated with the use of recombinant retroviruses to deliver therapeutic genes in stem cells is the risk of insertional mutagenesis following semi-random retroviral DNA integration. Alternatively, gene repair by homology-directed repair (HDR) is recognized as a potentially less genotoxic approach to repair mutations. Although HDR is intrinsically inefficient in human cells, enzymes that create specific DNA double-strand breaks can efficiently increase HDR frequency. Our long-term goal is to develop an efficient HDR approach to repair the sickle cell anemia mutation in stem cells. We have previously evaluated meganucleases and TALEN-based approaches to edit the β-globin gene in a human induced pluripotent stem (iPS) cell line carrying a homozygous sickle cell mutation. Here, we investigate the use of CRISPR/Cas9 system in combination with single-stranded oligodeoxynucleotides (ssODNs) to repair the sickle mutation in the above mentioned sickle iPS line (sciPS). Based on gene alignment analysis with the highly homologous Δ-globin gene, we have designed two β-globin-gene-specific CRISPR guide RNAs (gRNAs). Using these gRNAs, along with Cas9 and ssODNs, we show repair of the sickle cell mutation in sciPS cells. In the short term, we expect to translate these genome editing technologies to repair the sickle mutation in patient-specific cells, such as CD34+ hematopoietic cells, an approach that holds promise for future autologous stem cell therapies.
Survivorship in Children and Young Adults With Congenital Heart Disease in Sweden
Authors: Zacharias Mandalenakis, Annika Rosengren, Kristofer Skoglund, Georgios Lappas, Peter Eriksson, Mikael Dellborg
Journal: JAMA Internal Medicine (2016)

Mortality in patients with congenital heart disease (CHD) has markedly decreased during recent decades because of advancement in pediatric care. However, there are limited data on survival trends in children and young adults with CHD compared with the general population.To determine survivorship in children and young adults with CHD compared with matched controls.A registry-based, prospective, matched-cohort study was conducted in Sweden. Data from the national patient and cause of death registers were linked to identify individuals with CHD born between January 1, 1970, and December 31, 1993, who were registered at or after birth. Follow-up and comorbidity data were collected until December 31, 2011. Survival analyses were performed with the Cox proportional hazards model; these analyses were performed from January 1, 1970, to December 31, 2011. A total of 21 982 patients with CHD in Sweden were identified. The mean (SD) follow-up time was 27.0 (8.86) years. Children serving as controls (n = 219 816) (10 for each patient), matched for birth year, sex, and county, were randomly selected from the general population.Survivorship in young patients with CHD and controls.Of the 21 982 patients who were born between 1970 and 1993 and were registered with the diagnosis of CHD, 10 650 were female (48.4%). Median age at index registration was 4.22 years (interquartile range, 17.07 years). Survivorship among children younger than 5 years was increased from 96% in those born in 1970-1979 to 98% in those born in 1990-1993. Hazard ratios (HRs) of death in relation to that in control individuals decreased from 225.84 (95% CI, 136.84-372.70) to 33.47 (95% CI, 22.54-49.70). A substantial, but less pronounced, absolute and relative increase in survivorship was found in older patients (HRs ranged from 24.52; 95% CI, 11.72-51.26, at 5-9 years to 4.27; 95% CI, 2.29-7.95, at 18-29 years). According to a hierarchical CHD classification, the group of patients with the most severe complex defects (ie, common arterial trunk, transposition of the great vessels, double inlet ventricle, hypoplastic left heart syndrome, tetralogy of Fallot, and atrioventricular septal defect) had the highest risk for death (HR, 64.07; 95% CI, 53.39-76.89).Despite substantially increasing absolute and relative survivorship in children and young adults with CHD, the mortality risk remains high compared with the risk in matched controls. Further research on reducing the death rate in this vulnerable group is required.
Fludarabine, Mitoxantrone and Dexametasone in the Treatment of Relapsed and Refractory Low-Grade Non-Hodgkin Lymphoma.
Authors: Joanna Sawczuk-Chabin, Ewa Kalinka, Piotr Centkowski, Katarzyna Budziszewska, Bernadeta Ceglarek, Jacek Najda, Maria Blasinska-Morawiec, Kazimierz Sulek, Jerzy Holowiecki, Lech Konopka, Krzysztof Warzocha
Journal: Blood (2005)
ANGI-07MR-PERFUSION DERIVED HEMODYNAMIC PARAMETRIC RESPONSE MAPPING OF BEVACIZUMAB EFFICACY IN RECURRENT GLIOBLASTOMA
Authors: Philipp Kickingereder, Alexander Radbruch, Sina Burth, Antje Wick, Sabine Heiland, Heinz-Peter Schlemmer, Wolfgang Wick, Martin Bendszus, David Bonekamp
Journal: Neuro-Oncology (2015)

BACKGROUND: Bevacizumab has proven beneficial in patients with recurrent glioblastoma (rGB), however its impact on tumor blood flow and oxygenation status remains controversial. Here we examine dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) derived Gaussian-normalized, relative cerebral blood volume and flow (nrCBV, nrCBF) parametric-response-maps (PRMs), for predicting response to bevacizumab in patients with rGB. METHODS: A total of 71 patients diagnosed with rGB underwent conventional-anatomic MRI and DSC-MRI at baseline and at first follow-up after bevacizumab initiation. PRMs were created by a multi-step (non-linear) registration of the patient's post- to pre-treatment scan and voxel-wise subtraction between nrCBV and nrCBF maps. Intratumoral voxels were stratified as increased [PRM(+)] or decreased [PRM(-)] if they exceeded a threshold representing the 95% confidence interval in the normal-appearing brain. Correlation with PFS and OS was performed using Cox-proportional-hazard models. RESULTS: The hazards for progression and death significantly increased with (I) higher baseline nrCBV (HR = 1.86, p < 0.01; HR = 1.52, p < 0.01) and nrCBF values (HR = 1.78, p < 0.01; HR = 1.86, p < 0.01), (II) higher PRM(-) of nrCBV (HR = 1.03, p = 0.01; HR = 1.02, p = 0.03) and nrCBF (HR = 1.04, p < 0.01; HR = 1.03, p < 0.01), but (III) not for higher PRM(+) of nrCBV and nrCBF, and (IV) not for the relative change in mean nrCBV and nrCBF, confirming the superiority of the PRM-approach. The magnitude of PRM(-) for both nrCBV and nrCBF significantly increased for higher baseline values (p < 0.01, respectively). CONCLUSION: Pre-treatment hemodynamic parameters are the principal determinant of BEV-response in rGB and emerge as a potential predictive imaging biomarker for selecting those patients with rGB who may maximally benefit from BEV-treatment. Although the magnitude of PRM(-) is a function of the corresponding pre-treatment parameter, the finding of higher PRM(-) and lack of PRM(+) in BEV non-responders may correspond to a pro-invasive, non-angiogenic evasion.
Dasatinib Dose-Optimization in Chronic Phase Chronic Myeloid Leukemia (CML-CP): Two-Year Data from CA180-034 Show Equivalent Long-Term Efficacy and Improved Safety with 100 Mg Once Daily Dose
Authors: Neil P. Shah, Dong-Wook Kim, Hagop M. Kantarjian, Philippe Rousselot, Pedro Dorlhiac-Llacer, Jorge Milone, Martin C Müller, Yousif Matloub, Alexandre Lambert, Andreas Hochhaus
Journal: Blood (2008)
Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy
Authors: Michael A. Burke, Stuart A. Cook, Jonathan G. Seidman, Christine E. Seidman
Journal: Journal of the American College of Cardiology (2016)

Over the last quarter-century, there has been tremendous progress in genetics research that has defined molecular causes for cardiomyopathies. More than a thousand mutations have been identified in many genes with varying ontologies, therein indicating the diverse molecules and pathways that cause hypertrophic, dilated, restrictive, and arrhythmogenic cardiomyopathies. Translation of this research to the clinic via genetic testing can precisely group affected patients according to molecular etiology, and identify individuals without evidence of disease who are at high risk for developing cardiomyopathy. These advances provide insights into the earliest manifestations of cardiomyopathy and help to define the molecular pathophysiological basis for cardiac remodeling. Although these efforts remain incomplete, new genomic technologies and analytic strategies provide unparalleled opportunities to fully explore the genetic architecture of cardiomyopathies. Such data hold the promise that mutation-specific pathophysiology will uncover novel therapeutic targets, and herald the beginning of precision therapy for cardiomyopathy patients.
Trastuzumab-reactive antibodies (TR-abs) in serum and trastuzumab (Tzb) benefit prediction in patients with HER2-overexpressing breast cancer.
Authors: Paula Raffin Pohlmann, Todd W. Miller, David L Blum, Dipti Pareh, Heping Yan, Cammie R Sutton, Teresa C Dugger, Lupe G Salazar, William Wu, Michelle L. Reyzer, Mary L. Disis, Ray Mernaugh, Carlos L. Arteaga
Journal: Journal of Clinical Oncology (2012)

77 Background: Trastuzumab (Tzb) is a humanized monoclonal antibody (MAb) approved for treatment of HER2-overexpressing breast cancer. Unfortunately not all patients benefit from it and lack of response cannot be predicted. We detected TR-abs in serum of mice and patients treated with Tzb. We hypothesized that TR-abs would associate with response to therapy. Methods: Direct/competition ELISA, dot blot, and mass spectrometry were used to detect and characterize TR-abs in sera from Tzb treated FVB MMTV/HER2 transgenic mice, from hybridoma MAbs stemming from transgenic mice responding favorably to Tzb (992-18 mMAb), and in sera of 22 patients with metastatic breast cancer enrolled in a phase I clinical trial. WST-1 viability assay was used to assess biological activity of 992-18 on SKBR3 or BT474 human breast cancer cell lines. Results: From 12 mice bearing HER2-overexpressing tumors and treated with Tzb, 5 responded to therapy and 7 exhibited progressive disease (PD). All 5 responders had elevated TR-abs, whereas TR-abs were low/undetectable with PD (p=0.002; Mann-Whitney two-tailed). This was confirmed in a second cohort of 16 mice, in which TR-abs were undetectable prior to treatment, but gradually detected with Tzb therapy and tumor regression. TR-MAb 992-18 directly targeted also SKBR3 and BT474 in cell-based ELISAs and immunofluorescence assays. Treatment with 992-18 reduced BT474 and SKBR3 cell viability in comparison to isotype-matched control Ab (p&lt;0.0001). In sera from patients with metastatic breast cancer, higher concentrations of TR-abs were significantly associated with lower risk of disease progression (p=0.023, Cox regression, univariate analysis). Conclusions: Low serum TR-abs are associated with poor response to Tzb in mice and with shorter progression free survival in women with HER2 overexpressing stage IV breast cancer. In addition, TR-abs (e.g. 992-18) produced in response to therapy may be pharmacologically active. Results support prospective evaluation of patients undergoing treatment with therapeutic antibodies to determine if this non-invasive immunoassay detecting anti-therapeutic antibodies would predict benefit to therapy.
Abstract 1879: Prospective study of marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability
Authors: Mingyang Song, Reiko Nishihara, Kana Wu, Zhi Rong Qian, Sun A. Kim, Yasutaka Sukawa, Kosuke Mima, Kentaro Inamura, Atsuhiro Masuda, Juhong Yang, Charles S. Fuchs, Edward L. Giovannucci, Shuji Ogino, Andrew T. Chan
Journal: Cancer Research (2015)

Abstract Background: Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. Methods: We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses’ Health Study and Health Professionals Follow-up Study. We collected updated data on marine ω-3 PUFA intake and documented 1,125 CRC cases during 24-26 years of follow-up. We determined the MSI status of tumors using 10 microsatellite markers, and classified cases into MSI-high tumors in which ≥30% of the microsatellite markers demonstrated instability, and microsatellite stable (MSS) tumors in which &amp;lt;30% of the markers demonstrated instability. Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of microsatellite stable (MSS) tumors and MSI-high tumors in relation to marine ω-3 PUFA intake. Results: There was no statistically significant association between marine ω-3 PUFA intake and overall incidence of CRC. However, a statistically significant difference was detected by MSI status (Pheterogeneity = 0.02): high marine ω-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing ≥0.30g/d to &amp;lt;0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P for linearity = 0.03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P for linearity = 0.28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status. Conclusions: High marine ω-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of ω-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms. Citation Format: Mingyang Song, Reiko Nishihara, Kana Wu, Zhi Rong Qian, Sun A. Kim, Yasutaka Sukawa, Kosuke Mima, Kentaro Inamura, Atsuhiro Masuda, Juhong Yang, Charles S. Fuchs, Edward L. Giovannucci, Shuji Ogino, Andrew T. Chan. Prospective study of marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability. [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 1879. doi:10.1158/1538-7445.AM2015-1879
Evaluation of Microsatellite Instability in Gastric MALT Lymphomas.
Authors: Marina P. Siakantaris, Maria K. Angelopoulou, Konstantinos Lilakos, Yannis Metaxas, Maria Moschoyianni, Maria Gamaletsou, Theodoros P. Vassilakopoulos, Marie-Christine Kyrtsonis, Penelope Korkolopoulou, Panayiotis Panayiotidis, Gerassimos A. Pangalis
Journal: Blood (2006)
Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study
Authors: Michael A Irvine, Wilma A Stolk, Morgan E Smith, Swaminathan Subramanian, Brajendra K Singh, Gary J Weil, Edwin Michael, T Deirdre Hollingsworth
Journal: The Lancet Infectious Diseases (2016)

Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings.We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens.In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low.Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme.Bill & Melinda Gates Foundation.