tbuckley/cabot-search huggingface dataset:
Is There Cross-Cultural Evidence for an Association Between Intersectionality and Bioethical Decision Making? Not Yet, but Awaiting Advances in Mental Mapping
Authors: Darryl R. J. Macer
Journal: The American Journal of Bioethics (2019)

One of the most interesting questions before a thinking being is whether we can comprehend the ideas and thoughts of other beings. To better understand this question, we need to know how we make de...
Feasibility of human umbilical cord blood plasma for ex vivo expansion, maturation and activation of human umbilical cord blood derived T lymphocytes
Authors: Min Hyung Jung, Yong Man Kim, Yong Il Ji, Ha Young Song, Hyun Ok Yang, Chi Heum Cho, Jong Hyeok Kim, Young Tak Kim, Joo Hyun Nam, Jung Eun Mok
Journal: Cancer Research (2005)

6025  Several different approaches have been used to expand and activate human umbilical cord blood (UCB) T cells ex vivo for infusion into patients with various cancers and infectious diseases. This study was designed to establish a more effective and safe culture system for the ex vivo expansion, maturation and activation of human UCB T cells by investigating the use of autologous or homologous cord blood plasma (ACBP, HCBP), instead of fetal bovine serum (FBS). We collected 36 UCB samples at the time of delivery from uncomplicated normal full-term pregnancies. Fresh umbilical mononuclear cells were isolated by Ficoll-Hypaque density centrifugation. The nonadherent mononuclear cell fractions of each of the 12 samples were cultured with anti-CD3 antibody, IL-2 and individually with ACBP, HCBP or FBS. On day 8, the cellular proliferation rate, cell surface markers and cytotoxicity were assessed. There was no significant difference in proliferation rate among each supplemented medium (P >0.05). The CD3+ was expressed on over 95% of the cells cultured in all three media, compared to the precultured cells. The CD4+/CD8+ ratio of expanded T cells in FBS-supplemented medium appeared to remain greater than one on day 8, but did not in ACBP or HCBP. In ACBP-contained medium, the expression of CD3+CD8+, CD3+CD25+ and CD3+CD45RO+ cells was significantly increased, whereas CD3+CD4+ decreased (P   0.05) among three media, but a significant difference was shown in ACBP-supplemented medium at 40:1 ratio (P
Novel applications of MVA to improve outcomes in immunooncology
Authors: C. Heery, C. Pico-Navarro, T. Adams, L. Bauman, J. Medina, M. Hinterberger, A. Heiseke, H. Lauterbach, H. Hochrein
Journal: Annals of Oncology (2019)

Background: Our understanding of the interaction between the host immune system and cancer has evolved rapidly over the previous 10 years due to the clinical success induced by checkpoint inhibition. Previous immunologic work can now be realized in combination strategies. Modified Vaccinia Ankara (MVA) offers significant opportunities due to its natural induction of innate and adaptive immunity, large payload, and excellent safety profile. Methods: MVA vectors were administered subcutaneously (SC), intravenously (IV) or intratumorally (IT) into tumor-bearing mice. Cytokine secretion profile in serum was assessed by Luminex analysis. NK and T cell infiltration and activation in various organs and cytolytic activity against target cells were determined by flow cytometry-based assays. PD-1 immune checkpoint blockade (ICB), low dose cyclophosphamide, tumor-targeting Abs or 15 Gy radiotherapy were administered along with IV MVA. Results: Recombinant MVA (rMVA) in which tumor antigens and costimulatory molecules are encoded can be customized for maximal effect by route of administration. rMVA administered intravenously (IV) causes superior induction of antigen specific T cells, cytokines and NK cells than previously seen with subcutaneous or intramuscular routes. Encoding CD40L in addition amplifies the effects and efficacy improves in relevant models. This is dependent on T cells and NK cells, indicating a potential solution to one tumor-resistance mechanism, MHC loss and/or mutation. Furthermore, the combination of rMVA with tumor targeting antibodies, checkpoint inhibition, radiotherapy or chemotherapy often showed additional synergistic therapeutic effects. Administration of MVA alone intratumorally (IT) causes innate immune activation through toll like receptors (TLRs) as well as the cGAS / STING pathway. Recombinant antigen encoding rMVA improves systemic and local antigen-specific T cell responses. These effects can be bolstered by encoding certain costimulatory molecules. Conclusions: IV and IT recombinant MVA may offer off the shelf solutions to resolve many of the host – tumor immunity interactions that result in lack of efficacy of checkpoint inhibition alone in most patients. Bavarian Nordic plans to initiate clinical trials with existing agents in 2019 applied IV and IT and will create novel constructs to maximize clinical effect, planned to initiate in 2020 and beyond. Legal entity responsible for the study: Bavarian Nordic, Inc. Funding: Bavarian Nordic, Inc. Disclosure: C. Heery: Employee and shareholder: Bavarian Nordic, Inc. C. Pico-Navarro, T. Adams, L. Bauman, J. Medina, M. Hinterberger, A. Heiseke, H. Lauterbach, H. Hochrein: Employee of Bavarian Nordic.
EZH2 Inhibition in Ewing Sarcoma Upregulates GD2 Expression for Targeting with Gene-Modified T Cells
Authors: Sareetha Kailayangiri, Bianca Altvater, Stefanie Lesch, Sebastian Balbach, Claudia Göttlich, Johanna Kühnemundt, Jan-Henrik Mikesch, Sonja Schelhaas, Silke Jamitzky, Jutta Meltzer, Nicole Farwick, Lea Greune, Maike Fluegge, Kornelius Kerl, Holger N. Lode, Nikolai Siebert, Ingo Müller, Heike Walles, Wolfgang Hartmann, Claudia Rossig
Journal: Molecular Therapy (2019)

Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression. Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.
<i>LINC00261</i> Is an Epigenetically Regulated Tumor Suppressor Essential for Activation of the DNA Damage Response
Authors: Shandy Shahabi, Vishaly Kumaran, Jonathan Castillo, Zhengmin Cong, Gopika Nandagopal, Daniel J. Mullen, Alexander Alvarado, Michele Ramos Correa, Autumn Saizan, Riya Goel, Amrita Bhat, Sean K. Lynch, Beiyun Zhou, Zea Borok, Crystal N. Marconett
Journal: Cancer Research (2019)

Lung cancer is the leading cause of cancer-related death in the United States. Long noncoding RNAs (lncRNA) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression with that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in the primary human tumors, and interrogated for lncRNAs whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing G2-M cell-cycle arrest, while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development. SIGNIFICANCE: These findings identify LINC00261 as a tumor suppressor that blocks cellular proliferation by activating the DNA damage response and suggest that epigenetic therapy to inhibit DNA methylation may enhance treatment of LUAD. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3050/F1.large.jpg.See related commentary by Davalos and Esteller, p. 3028.
Effect of Novartis Access on availability and price of non-communicable disease medicines in Kenya: a cluster-randomised controlled trial
Authors: Peter C Rockers, Richard O Laing, Paul G Ashigbie, Monica A Onyango, Carol K Mukiira, Veronika J Wirtz
Journal: The Lancet Global Health (2019)

Novartis Access is a Novartis programme that offers a portfolio of non-communicable disease medicines at a wholesale price of US$1 per treatment per month in low-income and middle-income countries. We evaluated the effect of Novartis Access in Kenya, the first country to receive the programme.We did a cluster-randomised controlled trial in eight counties in Kenya. Counties (clusters) were randomly assigned to the intervention or the control group with a covariate-constrained randomisation procedure that maximised balance on a set of demographic and health variables. In intervention counties, public and non-profit health facilities were allowed to purchase Novartis Access medicines from the Mission for Essential Drugs and Supplies (MEDS). Data were collected from all facilities served by MEDS and a sample of households in study counties. Households were eligible if they had at least one adult patient who had been diagnosed and prescribed medicines for one of the non-communicable diseases targeted by the programme: hypertension, heart failure, dyslipidaemia, type 2 diabetes, asthma, or breast cancer. Primary outcomes were availability and price of portfolio medicines at health facilities, irrespective of brand; and availability of medicines at patient households. Impacts were estimated with intention-to-treat analysis. This trial is registered with ClinicalTrials.gov (NCT02773095).On March 8, 2016, we randomly assigned eight clusters to intervention (four clusters; 74 health facilities; 342 patients) or control (four clusters; 63 health facilities; 297 patients). 69 intervention and 58 control health facilities, and 306 intervention and 265 control patients were evaluated after a 15 month intervention period (last visit February 28, 2018). Novartis Access significantly increased the availability of amlodipine (adjusted odds ratio [aOR] 2·84, 95% CI 1·10 to 7·37; p=0·031) and metformin (aOR 4·78, 95% CI 1·44 to 15·86; p=0·011) at health facilities, but did not affect the availability of portfolio medicines overall (adjusted β [aβ] 0·05, 95% CI -0·01 to 0·10; p=0·096) or their price (aβ 0·48, 95% CI -1·12 to 0·72; p=0·500). The programme did not affect medicine availability at patient households (aOR 0·83, 95% CI 0·44 to 1·57; p=0·569).Novartis Access had little effect in its first year in Kenya. Access programmes operate within complex health systems and reducing the wholesale price of medicines might not always or immediately translate to improved patient access. The evidence generated by this study will inform Novartis's efforts to improve their programme going forward. The study also contributes to the public evidence base on strategies for improving access to medicines globally.Sandoz International (a subsidiary of Novartis International).
AB0623 Efficacy of tacrolimus combination therapy during the maintenance phase of systemic lupus erythematosus
Authors: K. Ohtsuka, Y. Miwa, H. Furuya, R. Yanai, M. Sato, R. Takahashi, K. Wakabayashi, T. Odai, N. Yajima, T. Kasama
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Corticosteroid therapy is effective for systemic lupus erythematosus (SLE), but many adverse effects have been observed. Tacrolimus (TAC) is an immunosuppressive agent that is used after organ transplantation. TAC is also used for induction therapy in SLE patients, but no investigations of TAC in maintenance therapy have been reported. <h3>Objectives</h3> This study examined the efficacy of TAC combination therapy during the maintenance phase of SLE. <h3>Methods</h3> Thirty-five patients with SLE (27 females and 8 males) were assessed at baseline and following 6 months of TAC administration (from 1 mg to 5 mg per day) using changes in corticosteroid dose and clinical examination. Proteinuria, serum complement levels (C3c) and anti-double-stranded DNA (dsDNA) titers were assessed. The relapse rate of SLE and adverse effects were assessed. <h3>Results</h3> The mean patient age was 42.0±16.4 years at the initiation of therapy, and the mean disease duration was 76±52 months. Other immunosuppressive drugs (azathioprine, 1 patient; and mizoribine, 9 patients) were combined with corticosteroids, but these agents had been discontinued due to ineffectiveness and/or adverse effects. Corticosteroid doses were reduced from 12.3±8.3 at baseline to 10.4±8.5 mg per day following 6 months of TAC administration (p&lt;0.05). Serum complement levels (C3c) increased significantly from 69.3±29.8 to 75.9±33.9 mg/dL (normal range; 86-160 mg/dL) (p&lt;0.05). However, anti-dsDNA titers were not altered (from 30.2±70.8 to 22.8±50.9). Proteinuria decreased in 10 patients but increased in 3 patients. No significant changes in proteinuria were observed in 22patients. No relapse of SLE was observed in this study. Adverse effects were observed in 2 patients, including the muscle cramp in one patient and an elevation of creatinine kinase and lactic dehydrogenase in one patient. These effects were reversed following the cessation of TAC administration. <h3>Conclusions</h3> TAC combination therapy during the maintenance phase of SLE was found in this study to be beneficial. TAC reduced corticosteroid doses, elevated serum complement level, and decreased proteinuria. No relapse of SLE or major adverse events was observed. <h3>Disclosure of Interest</h3> None Declared
Cost-Effectiveness of Newly Emerging Regimens for Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Autologous Stem Cell Transplantation (ASCT) Compared with the Current Standards of Care in EU5
Authors: John Ashcroft, Callum Shephard, Ashlie Elnoursi, Christopher Pelligra, Sujith Dhanasiri
Journal: Blood (2018)
Combined education and patient-led goal setting intervention reduced chronic low back pain disability and intensity at 12 months: a randomised controlled trial
Authors: Tania Gardner, Kathryn Refshauge, James McAuley, Markus Hübscher, Stephen Goodall, Lorraine Smith
Journal: British Journal of Sports Medicine (2019)

Background One model of care that has not been tested for chronic low back pain (LBP) is patient-led goal setting. We aimed to compare the clinical effectiveness and healthcare use of a patient-led goal setting approach (intervention) with simple advice to exercise (control) over 12 months. Methods An assessor-blinded randomised controlled trial. Intervention was education combined with patient-led goal setting compared with a control group receiving a standardised exercise programme. The primary outcomes were back pain disability and pain intensity. Secondary outcomes were quality of life, kinesiophobia, self-efficacy, depression, anxiety and stress. Outcomes and healthcare use were assessed immediately post-treatment (2 months) and after 4 and 12 months. Analysis was by intention to treat. Results Seventy-five patients were randomly assigned to either the intervention (n=37) or the control (n=38) group. Using linear mixed model analyses, adjusted mean changes in primary outcomes of disability and pain intensity were greater in the intervention group than in the control group (disability post-treatment: p&lt;0.05). These differences were clinically meaningful. Mean differences in all secondary measures were greater in the intervention group than in the control group (p&lt;0.05). There was no difference in healthcare use between groups over 12 months. Conclusion A patient-led goal setting intervention was significantly more effective than advice to exercise for improving outcomes in disability, pain intensity, quality of life, self-efficacy and kinesiophobia in chronic LBP. These improvements were maintained at 12 months. Smaller effects were seen in measures of depression, anxiety and stress. Trial registration number ACTRN12614000830695.
Gastric peroral endoscopic myotomy for transthyretin amyloidosis gastroparesis
Authors: Tiago P. Guedes, Ricardo Küttner-Magalhães, Luis Maia, João Sousa, Mónica Garrido, Isabel Pedroto
Journal: Endoscopy (2019)

Hereditary transthyretin amyloidosis is associated with gastrointestinal symptoms which can have a negative impact on quality of life [1], with gastroparesis being a frequent complication of familial amyloidotic polyneuropathy (FAP) [2]. Interventions that target symptoms while liver transplantation is awaited can be of the utmost importance for improvement of nutritional status and optimization of surgical outcomes. Gastric peroral endoscopic myotomy (G-POEM) has been described as safe with high technical and clinical success rates, mainly for postoperative, diabetic, and idiopathic gastroparesis [3].
Expression of Metastatic Tumor Antigen 1 Splice Variant Correlates With Early Recurrence and Aggressive Features of Hepatitis B Virus–Associated Hepatocellular Carcinoma
Authors: Yung‐Tsung Li, Hui‐Lin Wu, Jia‐Horng Kao, Huei‐Ru Cheng, Ming‐Chih Ho, Chih‐Chiang Wang, Pei‐Jer Chen, Ding‐Shinn Chen, Chun‐Jen Liu
Journal: Hepatology (2019)

Overexpression of metastatic tumor antigen 1 (MTA1) was correlated with poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC). The aim of this study was to examine the clinical significance of the expression of MTA1 and its exon 4-excluded form (MTA1dE4), the most abundant spliced variant of MTA1, in patients receiving curative resection for HBV-HCC. We collected 102 patients with HBV-HCC and received curative resection retrospectively and examined the expressions level of total MTA1/MTA1dE4 in their paired nontumor and tumor liver tissues by using RT-qPCR. The association between MTA1/MTA1dE4 expression and various tumor features as well as tumor recurrence was analyzed. During the median follow-up period of 4 years, 25 patients (24.5%) showed early recurrence (within 12 months postresection) and 42 (54.5%) showed late recurrence. In Kaplan-Meier analysis, MTA1dE4 overexpression in tumor, but not MTA1, was associated with early recurrence (P = 0.0365), but not late recurrence. In multivariate analysis, only alpha-fetoprotein (AFP) ≥200 ng/mL (P = 0.006) and large tumor size (P = 0.027) were correlated with early recurrence. In the subgroup of patients with AFP <200 ng/mL, high MTA1dE4, but not total MTA1, expression could help predict early recurrence (P = 0.0195). In vitro, wound healing and invasion assays were performed in HCC cells, and MTA1dE4 was found to exhibit a higher ability in promoting migration and invasion of hepatoma cells than full-length MTA1. Conclusion: MTA1dE4 expression is correlated with more aggressive tumor characteristics and might serve as a more sensitive marker for early recurrence of HBV-HCC, especially for low-AFP patients.
Double-loaded mature dendritic cell (DC) therapy for non-HLA-restricted patients with advanced ovarian cancer: Final results of a clinical phase I study.
Authors: Marianne Imhof, Markus Lipovac, Lukas Angleitner-Boubenizek, Johannes Barta, Ivan Gomez, Astrid Hrdina, Ewa Krupa, Judith Lafleur, Istvan Lang, Katharin Pieta, Heike Rottmann, Martin Imhof
Journal: Journal of Clinical Oncology (2013)

3052 Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8 + and CD4 + T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*10 6 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (&gt;90%), which is proven for both uTAAs in CD8+ as well as CD4+ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.