tbuckley/cabot-search huggingface dataset:
Abstract A2-30: A new fluorescence-based andrographolide exhibits anticancer activity
Authors: Ya-Hsin Hsu, Yu-Ling Hsu, Sheng-Hung Liu, Hsin-Chia Liao, Po-Xuan Lee, Chao-Hsiung Lin, Lee-Chiang Lo, Shu-ling Fu
Journal: Cancer Research (2015)

Abstract Andrographolide is a lactone diterpenoid compound isolated from the medicinal plant Andrographis paniculata. The anticancer activity of andrographolide has been previously demonstrated both in vitro and in vivo. We recently synthesized an andrographolide derivative, ANDRO-FL, in which a fluorescent chemical structure was covalently conjugated to andrographolide. We found that ANDRO-FL exhibited potent anticancer activity: ANDRO-FL reduced the viability of various types of cancer cells; ANDRO-FL suppressed the migration activity of melanoma cells; ANDRO-FL treatment induced the cleavage of heat shock 90 protein (Hsp90) as well as the downregulation of Hsp90 client oncoproteins such as v-Src and Bcr-abl. Notably, in all aforementioned experiments, ANDRO-FL showed stronger inhibitory effects than andrographolide. The kinetics and distribution of ANDRO-FL in cancer cells were further examined using fluorescence microscopy. The fluorescent signals could be detected within the cells in five minutes after ANDRO-FL treatment and the intensity increased as incubation time increased. Furthermore, the fluorescent signal could be detected in nucleus, cytoplasm, mitochondria, and lysosome. In vitro binding assays demonstrated that ANDRO-FL could covalently bind to several known target proteins of andrographolide, including NF-kB, GST and hnRNP K. In summary, our data indicate that ANDRO-FL is a promising anticancer compound. Moreover, with comparable anticancer profile to andrographolide, Andro-FL can serve an effective tool to further explore the molecular targets underlying the anticancer mechanism of andrographolide. The in vivo anticancer activity of ANDRO-FL is currently under investigation. Citation Format: Ya-Hsin Hsu, Yu-Ling Hsu, Sheng-Hung Liu, Hsin-Chia Liao, Po-Xuan Lee, Chao-Hsiung Lin, Lee-Chiang Lo, Shu-ling Fu. A new fluorescence-based andrographolide exhibits anticancer activity. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-30.
Acute Otitis Media in Children
Authors: J. G. Tilles, J. O. Klein, R. L. Jao, J. E. Haslam, M. Feingold, S. S. Gellis, M. Finland
Journal: New England Journal of Medicine (1967)

IT has generally been assumed that viruses are involved in the pathogenesis of otitis media either as primary agents or as antecedents of bacterial infections, but neither of these possibilities has been well documented. This report presents the results of attempts to isolate viruses and mycoplasmas from middle-ear fluids obtained by needle aspiration in 90 children with acute otitis media, and results of serologic studies using 18 viral antigens and a Mycoplasma pneumoniae antigen in 73 of these children. The results of bacteriologic studies of the middle-ear fluids, throat and nasopharynx and a discussion of the clinical findings have been . . .
Meta-analyses of 22 randomized trials assessing the influence of chemotherapy in advanced/recurrent gastric cancer.
Authors: H. Bleiberg, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

4109 Background: Advanced or recurrent stomach cancer remains an incurable disease and little progress has been obtained in prolonging survival. Multiple drugs and combinations of chemotherapy (CT) have been investigated with limited benefit on overall survival. The GASTRIC project initiated an individual-patient-data (IPD) based meta-analysis to quantify the benefit of various CTs. Methods: Randomized clinical trials (RCT) closed to patient accrual before 2004 were searched based on predefined criteria. The primary endpoint was overall survival (OS), the secondary progression-free-survival (PFS). The log-rank test, stratified by trial, was used to compare treatment arms; Peto heterogeneity tests were used. “Experimental” arms were defined as containing more drugs and/or a newer agent. We subsequently restricted analyses to trials that compared a CT with the same plus an additional compound. Eventually, we investigated comparisons of regimens including FUs, anthracyclines, platinums, taxanes, or irinotecan. Results: Fifty RCTs (N = 7,746) were identified, IPD (N = 4,245) was available from 22 studies. In the comparison of experimental with the control arms, highly significant differences were observed. Addition of a compound also showed a significant improvement in OS and PFS. There was no specific regimen which showed statistically significant differences on OS while platinums- and irinotecan-based regimens showed the statistically significant PFS improvements vs comparative arms. Conclusions: This IPD meta-analysis showed that OS and PFS have been modestly but significantly improved by the addition of experimental CT agents to preexisting control or standard regimens, but no specific regimen was identified as clearly superior. No. of trials Events/N HR (95% CI) P value Heterogeniety P Experimental Control OS 22 2,204/2,477 1,562/1,737 0.87 (0.81, 0.93) < 0.001 0.10 PFS 20 2,250/2,404 1,572/1,669 0.79 (0.68, 0.84) < 0.001 0.01 CT + additional CT OS 13 936/1,060 745/850 0.89 (0.81, 0.98) 0.02 0.72 PFS 13 946/1,022 751/815 0.74 (0.66, 0.81) < 0.001 0.11
The variability and reproducibility of whole genome sequencing technology for detecting resistance to anti-tuberculous drugs
Authors: Jody Phelan, Denise M. O’Sullivan, Diana Machado, Jorge Ramos, Alexandra S. Whale, Justin O’Grady, Keertan Dheda, Susana Campino, Ruth McNerney, Miguel Viveiros, Jim F. Huggett, Taane G. Clark
Journal: Genome Medicine (2016)

The emergence of resistance to anti-tuberculosis drugs is a serious and growing threat to public health. Next-generation sequencing is rapidly gaining traction as a diagnostic tool for investigating drug resistance in Mycobacterium tuberculosis to aid treatment decisions. However, there are few little data regarding the precision of such sequencing for assigning resistance profiles. We investigated two sequencing platforms (Illumina MiSeq, Ion Torrent PGM™) and two rapid analytic pipelines (TBProfiler, Mykrobe predictor) using a well characterised reference strain (H37Rv) and clinical isolates from patients with tuberculosis resistant to up to 13 drugs. Results were compared to phenotypic drug susceptibility testing. To assess analytical robustness individual DNA samples were subjected to repeated sequencing. The MiSeq and Ion PGM systems accurately predicted drug-resistance profiles and there was high reproducibility between biological and technical sample replicates. Estimated variant error rates were low (MiSeq 1 per 77 kbp, Ion PGM 1 per 41 kbp) and genomic coverage high (MiSeq 51-fold, Ion PGM 53-fold). MiSeq provided superior coverage in GC-rich regions, which translated into incremental detection of putative genotypic drug-specific resistance, including for resistance to para-aminosalicylic acid and pyrazinamide. The TBProfiler bioinformatics pipeline was concordant with reported phenotypic susceptibility for all drugs tested except pyrazinamide and para-aminosalicylic acid, with an overall concordance of 95.3%. When using the Mykrobe predictor concordance with phenotypic testing was 73.6%. We have demonstrated high comparative reproducibility of two sequencing platforms, and high predictive ability of the TBProfiler mutation library and analytical pipeline, when profiling resistance to first- and second-line anti-tuberculosis drugs. However, platform-specific variability in coverage of some genome regions may have implications for predicting resistance to specific drugs. These findings may have implications for future clinical practice and thus deserve further scrutiny, set within larger studies and using updated mutation libraries.
199. Genetic Engineering of Hematopoietic Stem Cells to Generate Invariant Natural Killer T Cells
Authors: Drake J. Smith
Journal: Molecular Therapy (2016)

Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (0.01-1% in mouse and human blood). Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells. When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy.
Canine cancer immunotherapy studies: linking mouse and human
Authors: Jiwon S. Park, Sita S. Withers, Jaime F. Modiano, Michael S. Kent, Mingyi Chen, Jesus I. Luna, William T. N. Culp, Ellen E. Sparger, Robert B. Rebhun, Arta M. Monjazeb, William J. Murphy, Robert J. Canter
Journal: Journal for ImmunoTherapy of Cancer (2016)

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.
Genetic Susceptibility Loci and Risk of Infant Leukemia by Subtype and MLL status: A Children's Oncology Group Report
Authors: Julie A. Ross, Amy M. Linabery, Crystal Blommer, Erica Langer, Logan G. Spector, Joanne M. Hilden, Nyla A. Heerema, Richard L. Tower, Stella M. Davies
Journal: Blood (2011)
645. T-Cell Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC
Authors: Arpad Szoor, Zhuyong Mei, Adrian Gee, Andras Heczey, Stephen Gottschalk
Journal: Molecular Therapy (2016)

Background: The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites and to deliver 'toxic payloads'. We have recently shown that cells can be genetically engineered to secrete bispecific T-cell engagers (ENG), which activate T cells in an antigen-dependent fashion. The goal of this project was now to determine if it is feasible to genetically modify MSCs to secrete ENG molecules that are specific for the HCC-associated tumor antigen Glypican-3 (GPC3), and to evaluate their ability to redirect T cells to HCC. Methods: Bone-marrow derived MSCs were genetically modified with lentiviral vectors encoding GPC3-ENG or an irrelevant ENG (EGFRvIII-ENG) and GFP. We performed coculture assays with GPC3-ENG-secreting MSCs (GPC3-ENG.MSCs, +/- freshly isolated T cells, and GPC3+ (HUH7 and G401) or GPC3- (A549) tumor cells. MSCs expressing an irrelevant ENG (EGFRvIII-ENG) served as control. We used standard immunological techniques for measuring cytokine production, proliferation, and cytolytic activity of T cells. Results: Transduction of MSCs resulted in a median transduction efficiency of 95% (range 90-97%) as judged by GFP expression. GPC3-ENG. MSCs activated T cells only in the presence of GPC3+ targets as judged by IFNγ production, and their ability to T-cell proliferation and killing of GPC3+ targets. EGFRvIII-ENG.MSCs did not activate T cells, confirming specificity. However, GPC3-ENG.MSCs did not induce IL2 secretion by T cells indicating lack of costimulation. To evaluate if provision of costimulation could overcome this obstacle, ENG.MSCs were further genetically modified to express CD80, 41BBL, or both. GPC3-ENG.MSCs expressing CD80 and 41BBL induced robust IL2 production in the presence of GPC3+ tumor cells in contrast to GPC3-ENG.MSCs expressing only CD80 or 41BBL. Conclusions: We have successfully generated MSCs that secrete GPC3-ENG and express costimulatory molecules on their cell surface. These MSCs induced potent anti-HCC T-cell responses in vitro, warranting further exploration of our MSC-based cell therapy approach for HCC.
Circulating Megakaryocyte-Derived Cells Detected by Flow Cytometry As Marker of Aggressive Neoplasms of Megakaryocytic Lineage in Acute Megakaryoblastic Leukemia and Allied Malignancies Presenting As Primary Myelofibrosis
Authors: Serena Marotta, Giovanna Giagnuolo, Giulia Scalia, Maddalena Raia, Santina Basile, Giuseppe Ciancia, Guido Pettinato, Fabrizio Pane, Gennaro de Rosa, Luigi Del Vecchio, Antonio M. Risitano
Journal: Blood (2012)
P108 Lung cancer resection outcomes in the first year: a 5 year review
Authors: J Ibrahim, A Mukhopadhyay, V Lostarakos, A Mahmood, S Khan, N Maddekar, I Hussain, A Lea, C Satur, Q Abid, S Ghosh, M Haris
Journal: Thorax (2016)

<h3>Introduction</h3> Lung cancer survival remains poor despite the use of advanced diagnostic and therapeutic interventions. Surgical resection offers the best chance of cure for those with early stage lung cancer. Those who undergo curative resection for non-small cell lung cancer remain at risk of recurrence. We wished to evaluate thoracotomy outcomes in patients undergoing resection with curative intent. <h3>Methods</h3> Retrospective review of consecutive surgical resections for suspected or confirmed lung cancer over 5-year period between January 2010 and December 2014 in a tertiary thoracic unit. Patients referred from other centres were excluded. Surgical database and post-operative follow up information was reviewed. Futile thoracotomies were defined as inoperable lung cancer at the time of surgery, benign lung lesion, incomplete tumour resection margins and recurrence or death in the first year.<sup>1</sup> <h3>Results</h3> 298 patients underwent surgical resection; mean age 68 years (range 26–91); male 150 (50%). 48 (16%) had histo-cytological confirmation of lung cancer prior to resection. Post-operative histology revealed 248 (83%) primary lung cancer; 31 (10%) benign pathology; 17 (6%) metastatic tumour from other primaries (breast, colorectal, bladder and renal) and 2 lymphomas. Of the 248 primary lung cancers, 88 (35%) had adjuvant chemotherapy and 27 (11%) had adjuvant radiotherapy including cranial irradiation. A total of 40/298 (13%) patients had recurrence in first year of which 20 died within 1 year. Based on previously used definition,<sup>1</sup> the futile thoracotomy rate was 33% (99/298) – see Table 1. If surgical resection of benign lesions is considered diagnostic, the futile thoracotomy rate would be 23% (68/298). <h3>Conclusion</h3> The definition of futile thoracotomy is debatable, but the risk remains high. Prior to surgery every effort should be made to minimise the risk by using combined staging modalities including minimally invasive diagnostic tools and appropriate patient selection. <h3>Reference</h3> Fischer B, Lassen U, Mortensen J, <i>et al</i>. Preoperative staging of lung cancer with combined PET-CT. <i>N Engl J Med</i> 2009;<b>361</b>:32–9.
Liver injury in chemotherapy (CT)-treated breast, colorectal, and lung cancer (CA) patients (Pts) using automated health data.
Authors: L. I. Wang, D. Casso, S. A. Oliveria, K. Wells, S. Hensley Alford, M. Bortolini, Y. Chu, W. Dong, M. Ulcickas Yood
Journal: Journal of Clinical Oncology (2011)

e13566 Background: FDA guidance (2009) recommends that drug development trials use Hy’s Law (a specific pattern of elevated liver enzymes seen in the absence of other known causes of liver dysfunction) as a predictor of potential drug-induced liver injury. In populations with high risk of underlying liver disorders (e.g., hepatitis or CA), modified guidelines may be needed. Published reports of liver dysfunction in CA pts based on Hy’s law are sparse. While liver lab tests (LLT) are generally collected in trials, other causes of liver disorders may not be systematically available. This study quantifies the incidence of potential Hy’s Law (PHL) cases (using LLT only) in CT-treated CA pts and excluding pts with other causes of liver dysfunction. Methods: Newly diagnosed breast CA (BC), colorectal CA (CRC), and lung CA (LC) pts between 2000 & 2007 were identified using Henry Ford Health System tumor registry. Eligible pts received CT and had ≥1 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and total bilirubin (TBL) test results on or after CA diagnosis. A PHL case using LLT only was defined as: ALT or AST>3x upper limit of normal (ULN), TBL>2x ULN, and alkaline phosphatase (ALP)<5x ULN with ≤2 months between 1st and 2nd qualifying LLT. Preliminary analysis excluding other known causes of liver dysfunction (i.e. liver metastases or pre-existing conditions) was performed. Results: Table of percent of PHL cases (with and without known liver dysfunction) in CT-treated pts by CA type and stage is shown. Conclusions: The proportion of CT-treated pts meeting PHL criteria (with and without known liver dysfunction) generally increased by stage across CA types. These data provide context for evaluating liver injury in trials and post-marketing surveillance of anti-cancer therapies. Proportion of potential Hy’s law pts after first chemotherapy exposure. CA type N PHL* (%) PHL excluding known liver dysfunction (%) BC 1,140 2.1 1.8 Stage I 296 1.4 1.4 Stage II 592 1.5 1.0 Stage III 170 2.9 2.9 Stage IV 82 7.3 6.1 CRC 537 6.5 2.8 Stage I 33 0 0 Stage II 129 1.6 1.6 Stage III 238 8.8 3.8 Stage IV 137 8.8 2.9 LC 1,111 2.9 2.6 Stage I 128 1.6 1.6 Stage II 78 1.3 1.3 Stage III 425 2.4 2.1 Stage IV 480 4.0 3.5 * Using lab liver tests only.
Coverage of mucosal recessions at dental implants
Authors: Anton Sculean, Vivianne Chappuis, Raluca Cosgarea
Journal: Periodontology 2000 (2016)

Abstract Facial peri‐implant mucosal recessions represent an increasing complication in implant dentistry and may negatively affect the esthetic outcome and patient satisfaction. The aim of the present paper is to provide a review on the potential causes of facial peri‐implant mucosal recessions and to provide a rationale for treatment along with possible treatment options. The available data indicate that soft tissue augmentation around dental implants is possible, but at present there is no evidence demonstrating that the augmented soft tissues are able to influence the peri‐implant bone levels (e.g. to limit peri‐implant bone loss). Therefore, the rationale to cover or correct peri‐implant mucosal recessions are (i) to optimize the possibility for performing an adequate level of oral hygiene, and (ii) to improve esthetics. At present, there is very limited evidence supporting any specific treatment modality for covering peri‐implant soft tissue recessions. The limited available data indicate that only shallow peri‐implant mucosal recessions (e.g. up to 2 mm) may be treated successfully by means of a coronally advanced flap and subepithelial connective tissue graft or with guided bone regeneration, while no data are available supporting the possibility of covering deep and large peri‐implant mucosal recessions.
Abstract 1526: HOXA5 inhibits cell plasticity and stemness in breast cancer cells by reinforcing epithelial traits
Authors: Wei Wen Teo, Vanessa Merino, Sean Cho, Preethi Korangath, Neil M. Neumann, Andrew J. Ewald, Saraswati Sukumar
Journal: Cancer Research (2015)

Abstract Members of the Retinoic acid receptor (RAR) and HOX gene families are known to be associated with cellular differentiation. Nonetheless, how HOX genes drive differentiation in mammalian cells is poorly understood. HOX genes are transcription factors that orchestrate body segmentation during embryogenesis. But the continued expression of several members in adulthood indicates the necessity of their biological functions in specifying cell fate in adulthood. The mammary gland is an organ that continues to go through multiple cycles of development during life. Here, loss of specific HOX genes could be detrimental to normal development. We have previously shown that expression of HOXA5, a downstream target of the retinoic acid signaling pathway, is often lost in breast cancer. Loss of HOXA5 expression correlates with increasing pathological grades of breast cancer. Expression array analysis of HOXA5-depleted MCF10A (immortalized line of human breast epithelium) revealed its potential role in regulating several traits of the epithelial lineage, including expression of E-cadherin and CD24. Depleting HOXA5 in MCF10A enhanced cell motility, invasiveness and increased stem-cell population (CD24lo/CD44hi). Using an inducible HOXA5-depletion system, differentiation of the stem cells in MCF10A was shown to be mediated by HOXA5. Conversely, ectopic expression of HOXA5 in SUM149 breast cancer cells significantly reduced plasticity and stem cell population, confirmed by in vivo limiting dilution assays in mice. MCF10A-KRAS-HOXA5 depleted cells formed invasive structures in 3D matrigel cultures, and formed larger tumors, implanted orthotopically in mice. MCF10A-KRAS-tumors were histologically dedifferentiated and lost expression of luminal cell markers such as E-cadherin and cytokeratin 18. Collectively, our findings demonstrate the role of HOXA5 in retinoid-induced cell differentiation by regulating cell fate specific surface adhesion molecules. Citation Format: Wei Wen Teo, Vanessa Merino, Sean Cho, Preethi Korangath, Neil M. Neumann, Andrew J. Ewald, Saraswati Sukumar. HOXA5 inhibits cell plasticity and stemness in breast cancer cells by reinforcing epithelial traits. [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 1526. doi:10.1158/1538-7445.AM2015-1526