tbuckley/cabot-search huggingface dataset:
Screening for Social Determinants of Health—Reply
Authors: Arvin Garg, Renee Boynton-Jarrett, Paul H. Dworkin
Journal: JAMA (2016)

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Pharmacokinetic-pharmacodynamic models for topotecan-induced neutropenia
Authors: E. Chatelut, W. J. Loos, F. Léger, P. Canal, R. Bugat, J. Verweij, A. Sparreboom
Journal: Journal of Clinical Oncology (2004)

2054 Background: A semi-physiological pharmacokinetic-pharmacodynamic model derived from Friberg et al [J Clin Oncol, 2002, 20:4713] was applied to describe topotecan-induced neutropenia, to quantify the inter-individual pharmacodynamic variability, and to study effect of covariates on the model Methods: The modeling was performed using the NONMEM program. The analysis was based on retrospective data from patients treated with topotecan given either orally (118 patients) or intravenously (71 patients). The drug was given in various schedules, either in combination with cisplatin or as single agent. The model mimics the maturation chain of neutrophils. Topotecan concentration-time profiles affected the proliferation of neutrophils precursors (sensitive cells) through an inhibitory linear model; topotecan is assumed to induce cell loss by a function, Edrug, proportional to the topotecan concentration in the central compartment: Edrug=Slope.Conc. The topotecan plasma concentrations versus time profile was generated for each patient by modeling the data according to a two-compartment pharmacockinetic model and first-order absorption for oral administration Results: The model described the time-course of neutrophils values well. Topotecan-induced neutropenic effects exhibited large inter-patient variability, with a coefficient of variation of 76% for the Slope values. Two significant covariates were observed: the route of topotecan administration and combined treatment with cisplatin. The oral route was associated with a 50% lower value (on average) for Slope, corresponding to a lower toxicity. Combination with cisplatin increased the neutropenic effects compared with topotecan alone. The extent of the increase of Slope values was dependent of the sequence; a factor 2 if cisplatin was given after the last administration of topotecan, and a factor 3.4 if given on day 1 just before topotecan Conclusions: This model can be used to better describe both the length and intensity of the neutropenia rather than considering only nadir values No significant financial relationships to disclose.
Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses
Authors: Khang D. Nguyen, Eunice E. Lee, Yangbo Yue, Jiri Stork, Lumir Pock, Jeffrey P. North, Travis Vandergriff, Clay Cockerell, Gregory A. Hosler, Diana V. Pastrana, Christopher B. Buck, Richard C. Wang
Journal: Journal of the American Academy of Dermatology (2016)
Dispelling the nice or naughty myth: retrospective observational study of Santa Claus
Authors: John J Park, Ben G T Coumbe, Esther H G Park, George Tse, S V Subramanian, Jarvis T Chen
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To determine which factors influence whether Santa Claus will visit children in hospital on Christmas Day. <b>Design</b>&nbsp;Retrospective observational study. <b>Setting</b>&nbsp;Paediatric wards in England, Northern Ireland, Scotland, and Wales. <b>Participants</b>&nbsp;186 members of staff who worked on the paediatric wards (n=186) during Christmas 2015. <b>Main outcome measures</b>&nbsp;Presence or absence of Santa Claus on the paediatric ward during Christmas 2015. This was correlated with rates of absenteeism from primary school, conviction rates in young people (aged 10-17 years), distance from hospital to North Pole (closest city or town to the hospital in kilometres, as the reindeer flies), and contextual socioeconomic deprivation (index of multiple deprivation). <b>Results</b>&nbsp;Santa Claus visited most of the paediatric wards in all four countries: 89% in England, 100% in Northern Ireland, 93% in Scotland, and 92% in Wales. The odds of him not visiting, however, were significantly higher for paediatric wards in areas of higher socioeconomic deprivation in England (odds ratio 1.31 (95% confidence interval 1.04 to 1.71) in England, 1.23 (1.00 to 1.54) in the UK). In contrast, there was no correlation with school absenteeism, conviction rates, or distance to the North Pole. <b>Conclusion</b>&nbsp;The results of this study dispel the traditional belief that Santa Claus rewards children based on how nice or naughty they have been in the previous year. Santa Claus is less likely to visit children in hospitals in the most deprived areas. Potential solutions include a review of Santa’s contract or employment of local Santas in poorly represented regions.
Outpatient Treatment with Clofarabine in a Phase II Study of Older Adult Patients with Previously Untreated Acute Myelogenous Leukemia (AML).
Authors: David F. Claxton, Thomas J Myers, Harry P Erba, Stefan Faderl, M. Arellano, Roger M Lyons, Tibor J. Kovacsovics, Janice Gabrilove, Clay R Warnock, Hagop M. Kantarjian
Journal: Blood (2009)
Old Age Affects Survival but Not Response in Philadelphia Positive (Ph+) Chronic Myeloid Leukemia (CML) Patients Treated with Imatinib (IM): A Study of the GIMEMA CML WORKING PARTY.
Authors: Gabriele Gugliotta, Fausto Castagnetti, Francesca Palandri, Massimo Breccia, Marilina Amabile, Simona Soverini, Nicoletta Testoni, Giulia Marzocchi, Carmen Baldazzi, Mario Annunziata, Emilio Usala, Simona Sica, Mario Tiribelli, Monica Bocchia, Antonella Gozzini, Sabina Russo, Fausto Palmieri, Vittorio Meneghini, Anna D'Emilio, Giuliana Alimena, Giovanni Martinelli, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, Gianantonio Rosti
Journal: Blood (2009)
ZAP-70 Status Does Not Predict Outcome after Nonmyeloablative Allogeneic Stem-Cell Transplantation (NST) in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) That Fails To Respond to Conventional Chemoimmunotherapy.
Authors: Issa F. Khouri, Rima M. Saliba, Joan Admirand, Susan O’Brien, Ming-S. Lee, Barry I. Samuels, Sergio Giralt, Marcos de Lima, Michael J. Keating, Richard E. Champlin, Carlos Bueso-Ramos
Journal: Blood (2006)
A Phase 1 Pharmacokinetics (PK) Study of Hydroxyurea (HU) 1,000 mg Coated Breakable Tablets and 500 mg Capsules in Pediatric and Adult Patients with Sickle Cell Disease (SCD).
Authors: Mariane De Montalembert, Dora Bachir, Anne Hulin, Linda Gimeno, Agnes Mogenet, Jean-Louis Bresson, Isabelle Macquin-Mavier, Alain Astier, Frederic Galacteros
Journal: Blood (2005)
PTH-101 Mild enteropathy (Marsh 1 and 2) coeliac disease: a comparison with more severe disease using a population-based cohort
Authors: N R Lewis, R F A Logan, D S Sanders, J West
Journal: Gut (2010)

<h3>Introduction</h3> In a population-based screening study, adults with undetected coeliac disease had an increased risk of mild anaemia and osteoporosis though they did not regard themselves as being unwell in comparison to serological negative controls.1 While a recent randomised trial reported some benefits from gluten withdrawal in adults with mild enteropathy coeliac disease,2 the benefits and possible harm of early detection of mild enteropathy disease is not clear and only limited data exist on the occurrence and clinical features at diagnosis of this group. We compared the presenting features of coeliacs presenting with mild (Marsh 1, 2) vs severe (Marsh 3) enteropathy disease. <h3>Methods</h3> Consecutive incident cases of coeliac disease diagnosed between January 2000–December 2006 at Nottingham University Hospital and Royal Hallamshire Hospital were compared at diagnosis using χ<sup>2</sup> tests and following 12 months gluten-free diet (GFD) using paired t-tests. <h3>Results</h3> Of 724 coeliacs diagnosed during the study period, 51(7%) had mild enteropathy. Mean (SD) haemoglobin (13.9 (1.6) g/dl), ferritin (67.7 (53.2) μg/l), folate (11.0 (5.9) μg/l), B12 (415 (204.9) ng/l), albumin (40.9 (3.1) g/l) and cholesterol (4.6 (1.0) mmol/l) in coeliacs with mild enteropathy were within normal laboratory range and significantly higher than those with severe enteropathy disease. These measures did not change on exposure to a GFD in mild enteropathy disease while the expected beneficial improvements that were observed in severe enteropathy disease. Coeliacs with severe enteropathy had a 10-fold increased risk (OR 10.2, 95% CI 4.4 to 23.4) of presenting with iron deficiency anaemia (IDA) in comparison to those with mild enteropathy whereas there was no difference in odds of presenting with classic (such as weight loss) or non-classic features (such as irritable bowel like symptoms) between mild and severe enteropathy coeliac disease. There was no difference in age at diagnosis of coeliac disease or gender proportion between mild and severe enteropathy groups. Proportion of coeliacs that were EMA positive was lower in mild enteropathy (71% vs 92% in severe enteropathy, p&lt;0.05) disease with median tTG (iu) also lower in mild enteropathy (18.5 (IQR 6–300) vs 210.5 (IQR 43–300) in severe enteropathy, p&lt;0.05). <h3>Conclusion</h3> Coeliacs with mild enteropathy have few biochemical deficiencies at diagnosis of coeliac disease and show no important biochemical improvements following GFD treatment in comparison to those with severe enteropathy. Aside from the presence of IDA neither demographic nor presenting symptoms differed between the two groups.
Abstract 4082: PDLIM2 : A cytoskeleton to nuclear courier protein for the IGF-1, Wnt and TGF beta signalling pathways in Epithelial to Mesenchymal Transition
Authors: Milan Bustamante Garrido, Orla T. Cox, Ciara O'Flanagan, Deirdre A. Buckley, Patrick A. Kiely, Rosemary O'Connor
Journal: Cancer Research (2015)

Abstract PDLIM2 is a PDZ-LIM domain protein that regulates the stability and activity of transcription factor families (including NFκB, STATs and beta catenin). PDLIM2 expression is repressed in certain cancers but it is also highly expressed in Triple Negative Basal Breast cancers that are characterized by poor survival. Suppression of PDLIM2 reverses the EMT phenotype, inhibits polarized cell migration, and disrupts formation of polarized epithelial acini in 3D cell cultures. PDLIM2 shuttles from the cytoskeleton to the nucleus, but what mediates this nuclear translocation or activity in transcription factor regulation is unknown. The aim of this study was to identify the mechanisms governing PDLIM2 subcellular localization and nuclear translocation. We found that IGF-1or TGF-β promotes PDLIM2 accumulation in the nucleus. Similarly, WNT3a stimulation enhances PDLIM2 accumulation in the nucleus while inhibition of WNT activity results in PDLIM2 stabilization in the cytoplasm. Cytoplasmic to nuclear translocation is associated with reduced phosphorylation on several serine residues in PDLIM2. The de-phosphorylation and subsequent nuclear translocation of PDLIM2 can be prevented by inhibiting the protein phosphatase PP1. In contrast, PDLIM2 phosphorylation can be enhanced by activation of protein kinase C, which is dependent on the presence of the focal adhesion scaffolding protein RACK1 in a complex with PDLIM2. Overall, the data indicate that PDLIM2 cytoplasmic to nuclear translocation in response to IGF-1, WNT or TGF beta signalling is mediated by serine phosphorylation and de-phosphorylation by cytoskeleton-associated kinases and phosphatases. Thus PDLIM2 acts as a “cytoskeleton to nucleus” courier protein for these signalling pathways to promote cancer cell migration and EMT. Citation Format: Milan Bustamante Garrido, Orla T. Cox, Ciara O'Flanagan, Deirdre A. Buckley, Patrick A. Kiely, Rosemary O'Connor. PDLIM2 : A cytoskeleton to nuclear courier protein for the IGF-1, Wnt and TGF beta signalling pathways in Epithelial to Mesenchymal Transition. [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 4082. doi:10.1158/1538-7445.AM2015-4082
Immunogenetic Analysis Reveals the Association of INF-γ (+874 A/T) Hypersecretor Genotype in AA and a Low Frequency of KIR-2DL3/C1 Mismatch in Responders to Immunosuppression.
Authors: Bianca Serio, Giridharan Ramsingh, Ramon Tiu, Antonio M. Risitano, Mikkael A. Sekeres, Jaroslaw M.D. Maciejewski
Journal: Blood (2007)
Abstract 3219: A patient-centric repository of PDX models for translational oncology research
Authors: Tin O. Khor, Ido Ben Zvi, Amanda Katz, David Vasquez-Dunddel, Ido Sloma, Daniel Ciznadija, David Sidransky, Keren Paz
Journal: Cancer Research (2015)

Abstract Patient-derived xenograft (PDX) models maintain the complex intra-tumoral biology and heterogeneity of an intact malignancy, as well as the interplay with stromal components and other cells fluxing into the tumor environment. This intrinsic cross-talk between different elements of the tumor makes PDX models a superior tool for translational drug discovery research and personalized oncology studies. Champions PDX models were originally developed for personalizing cancer treatments through the different Champions clinical programs. These models accurately reflect the population of patients enrolling in clinical trials. We describe herein our extensive TumorBank of PDX models, a valuable resource for translational oncology research to predetermine target populations for intervention with novel therapeutics in specific cancer subtypes. Tumor tissue from over 950 patients with a variety of primary and metastatic solid malignancies, across all ages and ethnicities and encompassing both treatment-naïve and heavily-pretreated individuals, has been implanted into immunodeficient mice with successful engraftment observed in ∼72% of cases. Comprehensive and translational-relevant clinical annotations have been maintained for these PDX models, including patient demographics, disease stage, anatomic location, tumor grade and histology, and treatment history. Importantly, whole exome and RNA sequencing, tissue histopathology, and protein immunohistochemistry have all been applied to 297 of these models. Finally, 70 of the models were screened against the corresponding patient's treatment used in the clinic, demonstrating a sensitivity of 98%, specificity of 76%, positive predictive value of 89% and negative predictive value of 96%. This wealth of information can be accessed through the Champions TumorGraft Database. The combination of extensive molecular and clinical annotation, together with opportunities for unlimited prospective preclinical testing, makes Champions TumorBank a pioneering resource for pharmaceutical companies seeking to identify target populations for therapeutic intervention. Citation Format: Tin O. Khor, Ido Ben Zvi, Amanda Katz, David Vasquez-Dunddel, Ido Sloma, Daniel Ciznadija, David Sidransky, Keren Paz. A patient-centric repository of PDX models for translational oncology research. [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 3219. doi:10.1158/1538-7445.AM2015-3219
Abstract 4751: Simple modifications in Ion Torrent Variant Caller (TVC) parameters improve somatic variant detection from circulating tumor cells and cell free DNA to 1% allele frequency
Authors: Colin Davidson, Yongming Sun, Christopher Davies, Chaitali Parikh, Warren Tom, Fiona Hyland, Charles Scafe, Dalia Dhingra
Journal: Cancer Research (2015)

Abstract By increasing quality-associated parameters and lowering sensitivity thresholds, a significant improvement in low frequency allele detection was achieved. The approach described was optimized using a dilution series of synthetic spike-ins (the AcroMetrix® Oncology Hotspot Control), and a titrated range of tumor cell lines in a normal background. The optimized variant calling approach was then applied to the analysis of somatic variants in circulating tumor cell (CTC) samples and associated cell-free DNA (cfDNA) using next-generation sequencing (NGS). Libraries were produced using the Ion AmpliSeq™ Cancer Hotspot Panel v2 for coverage of 50 cancer-associated genes and 2,800 COSMIC mutations. Using the above samples, the improved somatic variant detection workflow demonstrated analytical sensitivity down to 1% allele ratio in the observed sequence reads. Citation Format: Colin Davidson, Yongming Sun, Christopher Davies, Chaitali Parikh, Warren Tom, Fiona Hyland, Charles Scafe, Dalia Dhingra. Simple modifications in Ion Torrent Variant Caller (TVC) parameters improve somatic variant detection from circulating tumor cells and cell free DNA to 1% allele frequency. [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 4751. doi:10.1158/1538-7445.AM2015-4751
Abstract 473: Functional polarization of macrophage triggered by tumor-conditioned medium
Authors: Weina Zhang
Journal: Cancer Research (2015)

Abstract Purpose: Macrophages are important components of leukocyte infiltrates in various tumor stroma. Macrophages that infiltrate into tumor tissues are called tumor-associated macrophages (TAMs). TAMs show anti-tumorigenesis(M1) or pro-tumorigenesis (M2) functions depending on the cytokine milieu of the tumor microenvironment. TAMs perform some key homeostatic functions that allow tumor maintenance and growth. However, the signals involved in communication between tumor cells and macrophages are poorly defined. The aim of this study is to explore the macrophage polarization treated with the tumor-conditioned medium. Methods: Ana-1 macrophages, human THP-1 monocytes, and bone-marrow-derived macrophages (BMDMs) from C57BL/6J mice were incubated with HCT116-conditioned medium, respectively. Then we detected M1/M2 specific molecular markers by flow cytometry, Western blot and Real-time PCR. Flow cytometry was used to quantitatively assess the change of macrophage populations in macrophages treated with conditioned medium or normal medium. CD68(human) and CD11b(human), F4/80(mouse) and CD11b(mouse) were used as total-macrophage markers, CD206 as a marker of M2 macrophage. Secretory cytokine profile of the polarized macrophages was measured by cytokine array. Then, HCT116 cells were treated with conditioned medium of M2-like macrophage and applied to cell growth and colony formation assay. Results: By Western blot, we found that HCT116-conditioned medium could induce BMDMs and Ana-1 cells to overexpress arginase1(Arg1), but Ana-1 cells to express low inducible nitric oxide synthase(iNOS). Flow cytometry showed high expression level of CD68(human) and CD11b(human), F4/80(mouse) and CD11b(mouse), CD206 in HCT116-conditioned medium induced macrophages. Additionally, mRNA level of Arg1 was higher and M2-related cytokines IL-10,IL13 were also significantly upregulated, while mRNA level of iNOS was lower and M1-related cytokines IL-12,IFN-γwere downregulated in HCT116-conditioned medium induced macrophages. Conditioned medium of M2-like macrophages promoted the HCT116 cell growth and proliferation. Conclusions: HCT116 can secrete the soluble factors into conditioned medium, which would induce TAM polarization. Subsequently, conditioned medium of M2-like macrophages can promote tumor cells growth. Citation Format: Weina Zhang. Functional polarization of macrophage triggered by tumor-conditioned medium. [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 473. doi:10.1158/1538-7445.AM2015-473
A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).
Authors: Michael W. Schuster, J. Mehta, E.K. Waller, R.M. Rifkin, I. Micallef, D. Hurd, S. Parekh, P. Hari, B.S. Skikne, T.C. Shea, D.A. Frei-Lahr, R. Abonour, C.O. Freytes, L. Pineiro, Y.C. Halvorsen, E.J. Anaissie
Journal: Blood (2007)
708. Process Development of Lentiviral Vectors for Large Scale Production Using a HEK293 Producer Cell Line
Authors: Alexandre Audy, Marc-André Robert, Parminder Chahal, Rénald Gilbert, Bruno Gaillet
Journal: Molecular Therapy (2016)

Lentiviral vectors (LVs) are promising vectors for gene therapy. Most often, they are used to deliver a functional copy of a gene to sustainably replace a defective or missing gene. However, processes for LVs must be improved to increase the yield, facilitate the scale up and satisfy Health regulatory agencies. For these reasons, we have developed and optimized a LVs production process in serum-free medium using an inducible HEK293 producer cell line which possesses the capacity to grow in suspension culture. By adding two inducing molecules, (cumate and doxycycline) this cell line produces LVs pseudotyped with the protein G of the vesicular stomatitis virus without the need of any transfection. Our tested LV carried an expression cassette for GFP to facilitate LV quantification. To optimize the process, a design of experiment (DoE) was prepared which included the study of different culture media, high cell density production using six cell boosts commercially available and the addition of sodium butyrate, caffeine and valproic acid. We found that two cell boosts were outperforming the other cell boosts tested. At the present time, two commercial media (Hycell TransFx-H and SFM4TransFx-293 media) were our best candidates to maximize viral titer by achieving high cell density culture. In parallel, a LV carrying the cDNA for a shorter version of dystrophin (mini-dystrophin) was constructed. The truncated version of the dystrophin was produced by transient transfection in 293A cells and its presence was confirmed by western blot. We are planning to evaluate if the optimal conditions for the production of LV-GFP will be also applicable to LV-mini-dystrophin, a LV encoding a much longer transgene than GFP (0.7 kb vs 5.8 kb). This LV could be first evaluated for cell therapy in animal models and later, in patients suffering from Duchenne muscular dystrophy, where the dystrophin gene is defective and the protein is absent.