tbuckley/cabot-search huggingface dataset:
Racial and Ethnic Disparities in Survival of Children with ESRD
Authors: Elaine Ku, Charles E. McCulloch, Barbara A. Grimes, Kirsten L. Johansen
Journal: Journal of the American Society of Nephrology (2016)

Observational studies have reported that black and Hispanic adults receiving maintenance dialysis survive longer than non-Hispanic white counterparts. Whether there are racial disparities in survival of children with ESRD is not clear. We compared mortality risk among non-Hispanic black, Hispanic, and non-Hispanic white children who started RRT between 1995 and 2011 and were followed through 2012. We examined all-cause mortality using adjusted Cox models. Of 12,123 children included for analysis, 1600 died during the median follow-up of 7.1 years. Approximately 25% of children were non-Hispanic black, and 26% of children were of Hispanic ethnicity. Non-Hispanic black children had a 36% higher risk of death (95% confidence interval [95% CI], 1.21 to 1.52) and Hispanic children had a 34% lower risk of death (95% CI, 0.57 to 0.77) than non-Hispanic white children. Adjustment for transplant as a time-dependent covariate abolished the higher risk of death in non-Hispanic black children (hazard ratio, 0.99; 95% CI, 0.88 to 1.12) but did not attenuate the finding of a lower risk of death in Hispanic children (hazard ratio, 0.59; 95% CI, 0.51 to 0.68). In conclusion, Hispanic children had lower mortality than non-Hispanic white children. Non-Hispanic black children had higher mortality than non-Hispanic white children, which was related to differences in access to transplantation by race. Parity in access to transplantation in children and improvements in strategies to prolong graft survival could substantially reduce disparities in mortality risk of non-Hispanic black children treated with RRT.
Sildenafil Therapy in Patients with Thalassemia and an Elevated Tricuspid Regurgitant Jet Velocity (TRV) On Doppler Echocardiography At Risk for Pulmonary Hypertension: Report From the Thalassemia Clinical Research Network
Authors: Claudia R. Morris, Hae-Young Kim, John C Wood, Felicia Trachtenberg, Elizabeth S Klings, John B. Porter, Nancy Sweeters, Nancy F Olivieri, Janet L. Kwiatkowski, Sylvia Titi Singer, Ali T Taher, Ellis J. Neufeld, Alexis A. Thompson, Vandana Sachdev, Sandra K Larkin, Jung H Suh, Frans A Kuypers, Elliott Vichinsky
Journal: Blood (2012)
622. Oncolytic Adenoviruses Loaded With Active Drugs as a Novel Drug Delivery System for Cancer Therapy
Authors: Mariangela Garofalo, Barbara Iovine, Lukasz Kuryk, Cristian Capasso, Mari Hirvinen, Andrea Vitale, Maria Assunta Bevilacqua, Vincenzo Cerullo
Journal: Molecular Therapy (2015)

L-carnosine (β-Ala-His) is a naturally occurring histidine dipeptide, normally found in brain, kidney and in large amounts in muscle. L-carnosine has biological functions, including antioxidant activity, ability to chelate metal ions, as well as anti-inflammatory and anti-senescence properties. Recent studies have demonstrated that 50-100 mM of L-carnosine decreases cell proliferation in a colon cancer cell line HCT116, bearing a mutation in codon 13 of the RAS proto-oncogene. In addition, pre-treatment with L-carnosine decreases the intracellular concentration of Adenosine Triphosphate (ATP) and Reactive Oxygen Species (ROS) and inhibits the cell cycle progression in the G1 phase. The proto-oncogene KRAS is mutated in a wide array of human cancers and is important both in tumour progression and resistance to anticancer drugs. To overcome treatment limitations due to the high intracellular concentration required we have hypothesized that L-carnosine can be conjugated on the capsid of oncolytic viruses. Oncolytic viruses are viruses that are able to replicate specifically in and destroy tumor cells and this property is either inherent or genetically-engineered. The association of viruses with specific drugs, would increase the efficacy of the treatment of human neoplasia due to the synergistic action of virus and drug. First we have developed a strategy to conjugate peptides on viral capsid, based on electrostatic interaction. Then, using different cancer cell lines we found that oncolytic virus coated with L-carnosine with a tail of positively charged polylysine was able to enhance a positive anticancer synergistic effect. Finally, in order to investigate the molecular mechanisms underlying the effect of tumor reduction by oncolytic virus coated with modified L-carnosine, we have used three different approaches. First, we have examined, in samples with virus alone, or in combination with L-carnosine, the oncolytic replication by evaluating the E1A expression, second the apoptotic mechanism by expression of specific genes and at end the autophagy regulation via the amount of LC3-II. In conclusion, we have developed a model to use oncolytic adenovirus as a scaffold to deliver active drugs. Once validated the proposed model could be used as a novel drug delivery system for cancer therapy.
380. Use of Somatotransgenic Bioimaging as a Platform for Studying NFkB Pathway in a Tissue-Specific Manner in Two Mouse Models of Inflammation: Rheumatoid Arthritis and Contact Dermatitis
Authors: Dany P.B. Perocheau, Suzanne M.K. Buckley, Juliette M.K.M. Delhove, Rajvinder Karda, Tristan R. McKay, Simon N. Waddington
Journal: Molecular Therapy (2015)

Somatotransgenic bioimaging is a technology for in vivo imaging using lentiviral mediated delivery of a luciferase construct into neonatal mice. This luciferase marker, under the control of transcription factor binding elements or surrogate promoters, can be activated during physiological and pathological processes and can be quantified as photonic readout by whole-body bioluminescence imaging technology. The technique permits lifelong expression with immune tolerance to the transgenic proteins. In this study, we show the utility of somatotransgenic bioimaging using NFkB signaling as a model of inflammation in mouse models of rheumatoid arthritis and contact dermatitis. An NFkB transcription factor response element was inserted upstream of a mouse minimal promoter and the genes encoding firefly luciferase and green fluorescent protein. The cassette was inserted into a lentivirus vector. VSV-G-pseudotyped lentivirus vector was injected subcutaneously into CD1 outbread neonatal (P0) mice either in the footpad or in the abdominal skin to generate paw or skin specific light emitting transgenic mice. Canonical NFkB signaling (through TLR4) was first validated using ultrapure LPS in both the paw and skin of somatic transgenic mice. Following intraperitoneal LPS injection we observed upregulation of luciferase activity in the paw or the skin which returned to background levels within a few days. As a model of inflammatory mediated rheumatoid arthritis, we injected zymosan, which activates NFkB via TLR2 into the mouse paw fat pad. Induction of contact dermatitis was achieved by applying topically oxazolone, which plays an indirect activator role in the NFkB pathway. Luciferase expression was then monitored by whole body bioluminescence. Stimulation with Zymosan of the paw biosensor mice induced a prolonged upregulation of luciferase expression, specifically into the mouse paw which peaked at day 3 post injection and gradually returned to background level after twenty days. Similarly, after topical application of oxazolone onto the skin biosensor mice, we observed a specific, localised and increased luciferase activity which peaked at day 2 and returned to baseline by day 5. We have therefore shown that targeted gene expression can be achieved in two mouse models of inflammation. This also allowed us to quantify NFkB-mediated response to pro-inflammatory stimuli in a disease- and tissue-specific manner. Applied to collagen-induced arthritis, this technique could improve quantitation of disease severity compared to subjective scoring.
Abstract LB-229: Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy
Authors: Mikayel Mkrtichyan, Rajeev Shrimali, Shamim Ahmad, Rasha Abu Eid, Zuzana Berrong, Anu Wallecha, Robert Petit, Samir N. Khleif
Journal: Cancer Research (2015)

Abstract Combinational anti-cancer immune therapies that target multiple tumor-mediated suppressive mechanisms or enhance effector immunity are emerging as promising strategies for cancer treatment. Recently, we demonstrated that the combination of Listeria monocytogenes (Lm-LLO)-based immunotherapy (ADXS11-001) and anti-PD-1 antibody results in improved anti-tumor therapeutic and immune efficacy. Interestingly, regardless of the presence of an antigen or treatment with anti-PD-1 antibody, treatment with the Lm-LLO alone significantly inhibited the suppressive arm of the immune system, including regulatory T cells and myeloid-derived suppressor cells. We therefore hypothesized that combination of ADXS11-001 with agonistic antibodies against co-stimulatory molecules will lead to further improvement of immune and therapeutic efficacy as a result of the combined down-regulation of the suppressive arm and the enhancement of the effector arm. Here we demonstrate that combining Lm-LLO-based immunotherapy with anti-OX40 or anti-GITR antibodies lead to significant inhibition of tumor growth and prolonged survival of animals. The complete regression of established TC-1 tumors occurs in 40% and 60% of animals treated with ADXS11-001 in combination with anti-OX40 and anti-GITR antibodies, respectively. We show that this therapeutic potency enhancement is due to a significant increase in antigen-specific immune responses along with ADXS11-001-mediated inhibition of suppressor cells. Thus, we believe that simultaneous stimulation of T cells while inhibiting the suppressor cells, specifically using Lm-LLO-based immunotherapy combination with agonistic anti-co-stimulatory molecule antibody is a feasible and translatable approach that can lead to overall enhancement of the efficacy of an anti-tumor immunotherapy. Citation Format: Mikayel Mkrtichyan, Rajeev Shrimali, Shamim Ahmad, Rasha Abu Eid, Zuzana Berrong, Anu Wallecha, Robert Petit, Samir N. Khleif. Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy. [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-229. doi:10.1158/1538-7445.AM2015-LB-229
Monoclonal Antibody Against ROR1 in Chronic Lymphocytic Leukemia Cells Induced Apoptosis Via PI3-Kinase/AKT/CREB Pathway
Authors: Amir Hossein Daneshmanesh, Mohammad Hojjat-Farsangi, Asa Sandin, Abdul Salam Khan, Ali Moshfegh, Mahmood Jeddi-Tehrani, Anders Österborg, Håkan Mellstedt
Journal: Blood (2012)
Abstract 3309: Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells
Authors: Chunrong Li, Shyhmin Huang, Fang Ma, Eric A. Armstrong, David Francis, Lauryn Werner, Paul M. Harari
Journal: Cancer Research (2015)

Abstract ALK (anaplastic lymphoma kinase), EGFR (epidermal growth factor receptor) and c-MET are molecular drivers for a subset of non-small cell lung cancers (NSCLC). Approximately 4-7% of NSCLCs carry the EML4-ALK chromosomal rearrangement. We identified overexpression of EGFR and c-MET in EML4-ALK-positive NSCLC cell lines H3122 and H2228. ALK, EGFR, and c-MET may function cooperatively to modulate tumor growth, stress response, and survival in EML4-ALK-positive cells and co-inhibition may favorably impact tumor control. We therefore investigated the effects of co-inhibition of ALK and EGFR or c-MET on cell survival and response to radiation in EML4-ALK-positive NSCLC cells. Compared with ALK-negative cell lines (H226, A549 and H520), the ALK-positive cell lines (H3122, H2228) were highly sensitive to the ALK inhibitors crizotinb, ceritinib and alectinib, although with differing sensitivity to radiation. Crizotinib, ceritinib and alectinib sensitized H3122 and H2228 to radiation, as evaluated by clonogenic assay. However, knockdown of ALK by siRNA in H3122 and H2228, or overexpression of EML4-ALK in NIH-3T3 cells, had only moderate effects on radiosensitivity. Simultaneous knockdown of ALK and MET, or ALK and EGFR, increased radiosensitivity as assessed by clonogenic survival in H3122 and H2228 cells, while also increasing inhibitory effects on cell growth and proliferation. These results were confirmed in cells treated with the combination of ceritinib and su11274 (c-MET inhibitor) or with ceritinib and erlotinib (EGFR inhibitor). We further assessed the impact of drug alone or in combination with radiation on cell cycle, cell survival and DNA damage repair pathways. To further evaluate ALK function in the cellular response to radiation in NSCLC, we are developing EML4-ALK stable expression cell lines. Evaluation of drug-radiation interactions in xenograft model systems are also under consideration. These data indicate that co-inhibition of ALK and EGFR or c-MET can enhance growth inhibitory effects in ALK-positive cells and augment radiosensitivity in-vitro, suggesting the potential value for ALK inhibitors combined with EGFR/c-MET-targeting for therapeutic benefit in ALK-positive NSCLC patients with or without radiation. Citation Format: Chunrong Li, Shyhmin Huang, Fang Ma, Eric A. Armstrong, David Francis, Lauryn Werner, Paul M. Harari. Co-inhibition of ALK and EGFR and/or c-MET on cell growth and response to radiation in ALK-positive NSCLC cells. [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 3309. doi:10.1158/1538-7445.AM2015-3309
Stem Cell Transplant without Growth Factor In Multiple Myeloma: Engraftment Kinetics, Bacteremia, and Hospitalization.
Authors: Morie Abraham Gertz, Dennis Gastineau, Martha Lacy, Angela Dispenzieri, Suzanne R. Hayman, Shaji Kumar, David Dingli, Nelson Leung, Robert Wolf, William J Hogan, Francis Buadi
Journal: Blood (2010)
390. Impact of rAAV9-ABCD1 Upon Behavioral Outcome in a Mouse Model of X-ALD
Authors: YI Gong, Dakai Mu, Jiaqian Ren, Ann Moser, Casey A. Maguire, Florian S. Eichler
Journal: Molecular Therapy (2015)

X-linked adrenoleukodystrophy(X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette (ABC) transporter. 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 (ABCD1). Here we report first results of long term experiments to evaluate the therapeutic effect of AAV9-ABCD1 in a mouse model of X-ALD that develops motor and sensory symptoms around 18 months of age. rAAV9 encoding ABCD1 (rAAV9-ABCD1) was delivered to Abcd1-/- mouse CNS by stereotactic intraventricular (ICV) injection at young (4 months) and old (12 months) age, while intravenous (IV) injection was tested at only old age (12 months). Mouse body weight was monitored every month, while mouse behavior including hind limb reflex extension (scoring system 0-4, paralysis to normal), mechanical sensitivity (von Frey testing) and motor function (rotarod testing) were recorded starting from 15 months of age. No changes in body weight occurred regardless of delivery route or age injected, suggesting no obvious toxicity of the rAAV9-ABCD1 vector. ICV injection at both young and old age showed significant improvement upon mouse hind limb reflex extension after 15 months of age. Scores of hind limb reflex extension in untreated Abcd1-/- mice dropped to 1.75 at 18 months of age (wild type mice: 3.5), whereas Abcd1–/– mice treated via ICV at an old age retained scores around 3.25 (p<0.05). ABCD1-/- mice treated via ICV at a young age had an average score of 3.5 at 15 months (compared to untreated Abcd1-/- mice: 2.4; p<0.05). IV injection at old age showed mild but not significant improvement. Mechanical sensitivity also improved after both ICV injection at young age and IV injection at old age but not ICV injection in old Abcd1-/- mice. Analysis of rotarod data is pending. We conclude that rAAV9-mediated ABCD1 gene transfer is safe and efficacious at improving behavior of a known X-ALD mouse model including mouse hind limb reflex extension and mechanical sensitivity. However timing and delivery route are crucial determinants of efficacy and need to be independently assessed.
The ESVEM trial. Electrophysiologic Study Versus Electrocardiographic Monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. The ESVEM Investigators.
Journal: Circulation (1989)

ESVEM (Electrophysiologic Study Versus Electrocardiographic Monitoring) is an ongoing multicenter trial supported by the National Heart, Lung, and Blood Institute that began enrollment of patients on October 1, 1985. We describe here the methodology of the trial and data regarding enrollment of patients in the trial. The purpose of the trial is to determine whether electrophysiologic study or electrocardiographic Holter monitoring more accurately predicts antiarrhythmic drug efficacy in patients with aborted sudden death or sustained ventricular tachyarrhythmias. Consenting patients with inducible, sustained ventricular tachyarrhythmias and at least 480 premature ventricular contractions during 48 hours are randomized to undergo antiarrhythmic drug selection either by electrophysiologic study or by Holter monitoring. Up to six drugs (mexiletine, pirmenol, procainamide, propafenone, quinidine, and sotalol) are assessed in random order until one is predicted effective. An efficacy prediction is achieved in the electrophysiology limb if ventricular tachyarrhythmias are no longer inducible and in the Holter limb if ventricular ectopy is largely suppressed. Patients in whom a drug is predicted effective are followed while they are taking that drug to detect one of the three primary endpoints: arrhythmia recurrence, sudden death, or unmonitored syncope. In the first 37 months, 967 patients satisfied inclusion and exclusion criteria to undergo baseline studies. Two hundred eighty-six were eligible for and consented to randomization. In total, approximately 500 patients will be randomized and 285 subjects will be followed while receiving drugs that are predicted effective in this trial. Approximately 70 patients are expected to attain a primary end-point during a mean follow-up ot 3 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract 1566: Association of a serum HPV16 IgG signature and risk of oropharyngeal cancer
Authors: Karen S. Anderson, Hilde Langseth, Garrick Wallstrom, Marshall Posner, Julia N. Cheng, Rizwan Alam, Diego Chowell, Jon Mork
Journal: Cancer Research (2015)

Abstract Introduction: Human papillomavirus type 16 (HPV16) infection is associated with an increasing fraction of oropharyngeal cancer. The aim of our study was to determine the association of HPV16 antibodies (Abs) and oropharyngeal cancer (OPC) risk in sera obtained prior to clinical diagnosis. Methods: We identified 92 participants with incident oropharyngeal cancers and 460 age-, gender-, region- and year- matched controls from the Janus Serumbank in Norway. Serum samples were collected from cases, on average, 9.2 years before diagnosis (range, -0.6-14.9 years). 11 cases had serum samples from multiple time points. IgG Abs to the HPV16 antigens E1, E4, E5, E6, E7, L1, L2, and the N-terminal and C-terminal fragments of E2 (NE2, CE2) were quantified in blinded fashion using a custom RAPID ELISA assay. Full-length genes were expressed as GST fusion proteins with a mammalian protein expression system, incubated with sera, and bound IgG was measured. The ratio of relative luminescence units (RLU) values for each antigen to control GST protein was determined. Cutoff values were pre-established as 3 SD&amp;gt;median of 247 healthy controls. A logistic regression classifier of a 7-Ab biomarker panel (E1, NE2, CE2, E4, E5, E6, E7) for the predictive diagnosis of OPC was trained on an independent sample set, and applied to these samples. P-values were calculated by Fisher's exact test. Odds ratios (ORs) of cancer and 95% CIs were calculated. Results: HPV16 early antigen seropositivity was present in 13% of patients with OPC and 1% of controls (OR, 17.0; 95% CI, 5.0-74.0, p&amp;lt;0.0001). The probability of seropositivity was inversely associated with the time from serum collection and diagnosis (0-2 years, 84.9; &amp;gt;10 years, 5.4). Abs to CE2 were strongly associated with cases 0-2 years pre-diagnosis (OR, 112.0; 95% CI, 15.0-971.2, p&amp;lt;0.0001). Conclusion: HPV16 Abs to multiple early viral antigens are detectable years prior to diagnosis of oropharyngeal cancer, and the probability of seropositivity increases closer to diagnosis. A model for screening would help identify individuals at risk for whom interventions and surveillance may be evaluated. Citation Format: Karen S. Anderson, Hilde Langseth, Garrick Wallstrom, Marshall Posner, Julia N. Cheng, Rizwan Alam, Diego Chowell, Jon Mork. Association of a serum HPV16 IgG signature and risk of oropharyngeal cancer. [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 1566. doi:10.1158/1538-7445.AM2015-1566
Abstract LB-028: Cell density sensing alters TGF-beta signaling in a cell type-specific manner, independent from Hippo pathway activation
Authors: Flore Nallet-Staub, Xueqian Yin, Cristèle Gilbert, Véronique Marsaud, Saber Ben Mimoun, Delphine Javelaud, Edward B. Leof, Alain Mauviel
Journal: Cancer Research (2015)

Abstract Cell-cell contacts inhibit cell growth and proliferation in part by activating the Hippo pathway that drives the phosphorylation and nuclear exclusion of the transcriptional coactivators YAP and TAZ. Cell density and Hippo signaling have also been reported to block TGF-β responses, based on the ability of phospho-YAP/TAZ to sequester TGF-β-activated SMAD complexes in the cytoplasm. Herein, we provide evidence that epithelial cell polarization interferes with TGF-β signaling well upstream and independent of cytoplasmic YAP/TAZ. Rather, polarized basolateral presentation of TGF-β receptors I and II deprives apically delivered TGF-β of access to its receptors. Basolateral ligand delivery nonetheless remains entirely effective to induce TGF-β responses. These data demonstrate that cell type-specific inhibition of TGF-β signaling by cell density is restricted to polarized epithelial cells and reflects the polarized distribution of TGF-β receptors, which thus impacts SMAD activation irrespective of Hippo pathway activation. Citation Format: Flore Nallet-Staub, Xueqian Yin, Cristèle Gilbert, Véronique Marsaud, Saber Ben Mimoun, Delphine Javelaud, Edward B. Leof, Alain Mauviel. Cell density sensing alters TGF-beta signaling in a cell type-specific manner, independent from Hippo pathway activation. [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-028. doi:10.1158/1538-7445.AM2015-LB-028
Case 40-2016
Authors: Jess L. Kaplan, Sandra P. Rincon, Ann-Christine Duhaime
Journal: New England Journal of Medicine (2016)

A 14-month-old girl presented with a 3-month history of recurrent vomiting, without fever, abdominal pain, or diarrhea. Frontal bossing was present and the fontanelle was full, with mild pulsations. A diagnostic test was performed.