tbuckley/cabot-search huggingface dataset:
Abstract 3215: GITRL-Fc can significantly reduce tumor growth by stimulating innate and adaptive immunity
Authors: Hyun-Bae Jie, Minu K. Srivastava, Erin Mayes, Rui Yun, Fumiko Axelrod, Jorge Monteon, Austin Gurney, Angie In-Kyung Park.
Journal: Cancer Research (2016)

Abstract Although the interaction between GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor) and GITRL (its ligand) is important for the development of immune responses, the cellular mechanisms underlying anti-tumor immunity including both innate and adaptive immunity is not fully understood. We generated a novel single-gene linkerless GITRL trimer fused to an immunoglobulin Fc domain (GITRL-Fc), and investigated its effect on controlling tumor growth and immune responses in preclinical tumor models. Treatment with GITRL-Fc significantly reduced tumor growth in several preclinical tumor models by inducing Th1 biased anti-tumor immunity and reducing Treg-mediated immune suppression. Immune cell depletion studies showed that anti-tumor immunity induced by GITRL-Fc depended on CD8+ T cells as well as NK cells. Furthermore, the combination of GITRL-Fc with PD-1 blockade significantly reduced the tumor growth in the Renca murine kidney adenocarcinoma tumor model. Taken together, these results suggest that GITRL-Fc can improve cancer treatment as a single agent or in combination therapy by enhancing innate and adaptive cellular immunity. Citation Format: Hyun-Bae Jie, Minu K. Srivastava, Erin Mayes, Rui Yun, Fumiko Axelrod, Jorge Monteon, Austin Gurney, Angie In-Kyung Park. GITRL-Fc can significantly reduce tumor growth by stimulating innate and adaptive immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3215.
Fish oil omega 3 fatty acids improve heart muscle recovery after MI, trial shows
Authors: Susan Mayor
Journal: BMJ (2016)

Taking high dose omega 3 fatty acids from fish oil improves heart muscle function and reduces cardiac scarring after a myocardial infarction (MI), a randomised trial has shown.1

Previous studies have shown benefits from omega 3 fatty acids, but their effects on patients receiving the latest evidence based therapy after an MI have been less clear.

The new study randomly allocated 358 patients with acute MI attending three hospitals in …
Posttransplantation cyclophosphamide and sirolimus for prevention of GVHD after HLA-matched PBSC transplantation
Authors: Raffaella Greco, Francesca Lorentino, Mara Morelli, Fabio Giglio, Daniele Mannina, Andrea Assanelli, Sara Mastaglio, Serena Dalto, Tommaso Perini, Lorenzo Lazzari, Simona Piemontese, Consuelo Corti, Magda Marcatti, Massimo Bernardi, Maria Teresa Lupo Stanghellini, Fabio Ciceri, Jacopo Peccatori
Journal: Blood (2016)
Is Acute Erythroid Leukemia a Transitional Stage from MDS to AML?: A Study by Fluorescence in Situ Hybridization and Cytogenetics
Authors: Sang Mee Hwang, Sang-ho Lee, Seong_Ho Kang, Seonyang Park, Sung-Soo Yoon, Byoung Kook Kim, Hyun Kyung Kim, Han Ik Cho, Dong Soon Lee
Journal: Blood (2008)
Abstract 3084: The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation, apoptosis, cell stress, and tumor growth
Authors: Dario R. Roque, Weiya Z. Wysham, Chunxiao Zhou, Ken W. Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump
Journal: Cancer Research (2016)

Abstract Objectives: Obesity and diabetes are associated with increased risk and worse outcomes in endometrial cancer (EC). Anti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 (NovaTarg Therapeutics) is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and 3. We sought to compare the effects of NT-1044 on cell proliferation in human EC cell lines and on tumor growth in an endometrioid EC mouse model. Methods: Cell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by flow cytometry. Reactive oxygen species (ROS) were measured using a DCFH-DA assay. Western immunoblotting was performed to evaluate the effects of NT-1044 on the downstream targets of the AMPK/mTOR pathway and proteins related to cell cycle and cellular stress. For in vivo studies, we utilized the LKB1f/f/p53f/f mouse model of endometrioid endometrial cancer. Mice were treated with placebo or NT-1044 (200 mg/kg/day, oral gavage) following tumor onset for 4 weeks. Results: NT-1044 significantly inhibited proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 uM for ECC-1; 87 uM for Ishikawa). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose dependent-fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 inhibited endometrial tumor weight in the LKB1f/f/p53f/f mice by 56% (p = 0.031). Conclusions: NT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis, cellular stress and inhibition of the AMPK/mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes. Citation Format: Dario R. Roque, Weiya Z. Wysham, Chunxiao Zhou, Ken W. Batchelor, Wendy R. Brewster, Victoria L. Bae-Jump. The effects of NT-1044, a novel AMPK activator, on endometrial cancer cell proliferation, apoptosis, cell stress, and tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3084.
Autophagy: A Druggable Process
Authors: Etienne Morel, Maryam Mehrpour, Joëlle Botti, Nicolas Dupont, Ahmed Hamaï, Anna Chiara Nascimbeni, Patrice Codogno
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Macroautophagy (hereafter called autophagy) is a vacuolar, lysosomal pathway for catabolism of intracellular material that is conserved among eukaryotic cells. Autophagy plays a crucial role in tissue homeostasis, adaptation to stress situations, immune responses, and the regulation of the inflammatory response. Blockade or uncontrolled activation of autophagy is associated with cancer, diabetes, obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. During the past decade, researchers have made major progress in understanding the three levels of regulation of autophagy in mammalian cells: signaling, autophagosome formation, and autophagosome maturation and lysosomal degradation. As we discuss in this review, each of these levels is potentially druggable, and, depending on the indication, may be able to stimulate or inhibit autophagy. We also summarize the different modulators of autophagy and their potential and limitations in the treatment of life-threatening diseases.
Abstract 585: Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy
Authors: Olivier Nolan-Stevaux, Flordeliza Fajardo, Lily Liu, Suzanne Coberly, Patricia McElroy, Aaron Nazarian, Franziska Bott, Elisabeth Nahrwold, Tobias Raum, Roman Kischel, Ralf Lutterbuese, Patrick Hoffmann, Peter Kufer
Journal: Cancer Research (2016)

Abstract BiTE® therapeutics are single chain antibody constructs harboring two binding moieties: one directed at a tumor associated antigen and one directed at the CD3e protein, which trigger T cell dependent cellular cytotoxicity (TDCC) against targeted cancer cells. Here, we evaluated the suitability of ENPP3 as a potential BiTE® target. The ENPP3 mRNA is highly differentially expressed in clear cell Renal Cell Carcinoma (ccRCC) and the ENPP3 protein is detected with high uniformity and intensity in ccRCC tumor samples by immunohistochemistry. We demonstrated the surface expression of this protein in Renal Cancer cell lines and confirmed that the ENPP3 protein was highly restricted to the luminal side of normal epithelial layers in which it was detected (proximal renal tubules, bronchial epithelium, salivary glands). We developed highly potent anti-ENPP3 BiTE® molecules and demonstrated the in vitro TDCC activity of these molecules. Two anti-ENPP3 BiTE® molecules further demonstrated tumor formation inhibition activity in a human T cell / human target cell admixture mouse xenograft model. Citation Format: Olivier Nolan-Stevaux, Flordeliza Fajardo, Lily Liu, Suzanne Coberly, Patricia McElroy, Aaron Nazarian, Franziska Bott, Elisabeth Nahrwold, Tobias Raum, Roman Kischel, Ralf Lutterbuese, Patrick Hoffmann, Peter Kufer. Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 585.
Complex systems approach for sports injuries: moving from risk factor identification to injury pattern recognition—narrative review and new concept
Authors: N F N Bittencourt, W H Meeuwisse, L D Mendonça, A Nettel-Aguirre, J M Ocarino, S T Fonseca
Journal: British Journal of Sports Medicine (2016)

Injury prediction is one of the most challenging issues in sports and a key component for injury prevention. Sports injuries aetiology investigations have assumed a reductionist view in which a phenomenon has been simplified into units and analysed as the sum of its basic parts and causality has been seen in a linear and unidirectional way. This reductionist approach relies on correlation and regression analyses and, despite the vast effort to predict sports injuries, it has been limited in its ability to successfully identify predictive factors. The majority of human health conditions are complex. In this sense, the multifactorial complex nature of sports injuries arises not from the linear interaction between isolated and predictive factors, but from the complex interaction among a web of determinants. Thus, the aim of this conceptual paper was to propose a complex system model for sports injuries and to demonstrate how the implementation of complex system thinking may allow us to better address the complex nature of the sports injuries aetiology. According to this model, we should identify features that are hallmarks of complex systems, such as the pattern of relationships (interactions) among determinants, the regularities (profiles) that simultaneously characterise and constrain the phenomenon and the emerging pattern that arises from the complex web of determinants. In sports practice, this emerging pattern may be related to injury occurrence or adaptation. This novel view of preventive intervention relies on the identification of regularities or risk profile, moving from risk factors to risk pattern recognition.
Abstract 2227: Positive correlation between the gamma-H2AX and PD-L1 expressions in lung squamous cell carcinoma
Authors: Atsushi Osoegawa, Takafumi Hashimoto, Yohei Takumi, Miyuki Abe, Hitomi Hiraishi, Shuji Suehiro, Michiyo Miyawaki, Kenji Sugio
Journal: Cancer Research (2016)

Abstract Lung cancer is a leading cause of cancer death worldwide. Recently, molecular targeting therapy has been developed and it has shown promising results against advanced lung cancer. Among them, lung squamous cell carcinoma has fewer treatment options because it is not driven by oncogenic mutations, but by alterations in tumor suppressor genes and subsequent chromosomal instability. Programmed death-ligand 1 (PD-L1) is one of the immune checkpoint molecules that is expressed on the surface of tumor cells, where it inhibits activities of cytotoxic T cells. Recent studies revealed that the PD-1/PD-L1 blockade could improve the overall survival in lung squamous cell carcinoma, potentially because it carries high mutation burdens and neoantigens which could be targeted by cytotoxic T cells. We hypothesized that DNA damage could accumulate in tumors with high mutation burdens, thereby inducing the PD-L1 expression on tumor cells, sensitizing them to anti-PD-1 therapy. An immunohistochemical analysis of 41 consecutive lung squamous cell carcinoma cases, which received surgery at our institution between April 2013 and March 2014, revealed that a high PD-L1 expression was observed in 15 patients (37%) that was associated related with a poor recurrence-free survival (p = 0.028). The PD-L1 expression level was also positively associated with the γH2AX expression (a direct marker for DNA damage) (p = 0.02). The γH2AX expression in tumor cell nuclei was confirmed by immunofluorescent staining. It forms foci in tumor cell nuclei, indicating the incidence of DNA double strand breaks. Our findings demonstrate for the first time that the nuclear γH2AX expression in lung squamous cell carcinoma is positively associated with the PD-L1 expression. Further studies are warranted to investigate whether γH2AX could be a biomarker for PD-1 targeting therapy and whether combination therapy with PD-1 targeting therapy and a DNA-damaging agent has synergistic effects. Citation Format: Atsushi Osoegawa, Takafumi Hashimoto, Yohei Takumi, Miyuki Abe, Hitomi Hiraishi, Shuji Suehiro, Michiyo Miyawaki, Kenji Sugio. Positive correlation between the gamma-H2AX and PD-L1 expressions in lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2227.
Abstract 2859: Chloroquine and vitamin D3 modulate proliferation in early stage breast cancer models
Authors: Virginia A. Espina, Solomon Yeon, Joshua N. VanHouten, John Wysolmerski, Lance A. Liotta
Journal: Cancer Research (2016)

Abstract The defining feature of premalignant mammary lesions is proliferation of cells within the intraductal niche. Survival in this stressful duct microenvironment requires sophisticated mechanisms to avoid apoptosis caused by hypoxia, nutrient deprivation, metabolic acidosis, and intracellular calcium overload. Two major survival mechanisms of breast ductal carcinoma cells (DCIS) are 1) the upregulation of autophagy and 2) the enhanced export of calcium via plasma membrane calcium-ATPase isoform 2 (PMCA2) efflux pumps. We hypothesize that calcium efflux, through PMCA2, and activation of autophagic catabolism are critical interdependent mechanisms for the survival of pre-invasive human breast neoplastic cells. To assess the proteomic response to autophagy inhibition and/or elevated intracellular calcium, 41 signal transduction proteins/post-translationally modified proteins related to proliferation, autophagy, and calcium pathways were quantified by reverse phase protein microarrays (RPPA) in time course studies of T-47D metastatic ductal breast cancer cell line, and MCF-10A non-tumorigenic breast cell line, both of which express low basal levels of PMCA2, and in human primary DCIS organoid cultures. Cell lines were treated with chloroquine (50μM), or 1,25 dihydroxyvitamin D3 (Calcitriol) (50nM or 100nM), or chloroquine + Calcitriol, and harvested at periodic intervals over 197 hours. Stoichiometric time course studies (24 hours) were evaluated for Calcitriol as a single agent in both T-47D and MCF-10A cell lines. Cell morphology, adhesion, proliferation and autophagic flux in the DCIS organoids were assessed by Immunohistochemistry and RPPA. Calcitriol alone did not increase proliferation based on PCNA expression within DCIS ducts. Chloroquine markedly increased Cleaved PARP (Chi Sq p = 0.004) and CAMKinase II (p = 0.0068). Chloroquine (50μM) plus Calcitriol (100nM) increased E-Cadherin (p = 0.0379) and phosphoPAK1/2 (p = 0.0163), while PMCA2 levels were not significantly different between treatment groups. Autophagy inhibition and calcium efflux may be exploited therapeutically by co-administration of chloroquine and Calcitrol, to inhibit lysosomal catabolism and increase intracellular calcium levels, respectively, switching them from autophagic survival into apoptotic death. Citation Format: Virginia A. Espina, Solomon Yeon, Joshua N. VanHouten, John Wysolmerski, Lance A. Liotta. Chloroquine and vitamin D3 modulate proliferation in early stage breast cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2859.
Abstract 5054: Role and signaling of desmosomal DSP and PKP1 in ovarian cancer
Authors: Yan Xu, Qingchun Cai
Journal: Cancer Research (2016)

Abstract Identification of driver genes/proteins in EOC tumorigenic processes is critical to increase the cure rate for late stage epithelial ovarian cancer (EOC), which has not been in improved over several decades. We have developed a highly aggressive EOC cell line (ID8-P1 or P1) from ID8-P0 (without in vivo passage, or P0) through in vivo passage in C57BL6 mice. Two genes encode important desmosome components, desmoplakin (Dsp) and plakophilin 1 (Pkp1) were found to be significantly over-expressed in P1 vs. P0 cells, as well as human EOC cells. DSP is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. Pkp1 encodes a member of the arm-repeat (armadillo) and plakophilin (PKP) gene families. Our understanding of the functions of desmosomes in cancer is just emerging and the role of desmosomes in EOC is totally unknown. Our data showed the novel functions of DSP in anoikis-resistance and SRC activation using shRNA-mediated DSP-knocked down (KD) stable cell lines. In addition, we found that ID8-P1 cells formed spheroids and P0 cells tended to be single cells when they were cultured in suspension. KD-Dsp dissociated spheroids, suggesting that desmosomes play an important role in spheroid formation, which may be directly related to anoikis-, drug-resistance, and/or the cancer stem cell (CSC) concepts. Moreover, we found that enhanced glycolysis was involved in the increased anoikis-resistance of ID8-P1 cells and an inhibitor of glycolysis, shikonin (SHK) was a potent anoikis-resistance inhibitor and P1 cells gained more drug-resistance, when compared to P0 cells, with the IC50s were 1.7 and 7.4 μM for P0 and P1 cells, respectively. Similarly, the IC50s were 2.4 and 8.1 μM for human EOC PE01 and PE04 cells, respectively. PE01 and PE04 cell lines are identified to represent high-grade serous ovarian cancer (HGSC), which were derived from the same patient before (PE01) and after (PE04) the onset of drug resistance to cis-platinum (CDDP), chlorambucil, and 5-fluorouracil. PP2 (a SRC nhibitor) and SHK were able to dissociate the cell-cells aggregates/spheroids in EOC cells. The previously unknown role of DSP and/or PKP1 in EOC may be related to their signaling activities outside desmosomes. Cells staining of PKP1 protein showed its cytosolic and perinuclear location, providing supporting and proof-of-concept data. Together, our data have suggested the novel links among DSP, PKP1, anoikis-resistance, SRC activation, cell-cell-aggregation, and drug-resistance. These data provide a basis for developing new modalities for EOC treatment. Citation Format: Yan Xu, Qingchun Cai. Role and signaling of desmosomal DSP and PKP1 in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5054.
Nova et Vetera
Authors: S WOOD
Journal: BMJ (1951)

A little-known account of a case of recovery from pro- longed drowning is to be found hidden away in a pamphlet on smallpox inoculation published in 1768.' Jane Brown, aged 23, seized with the smallpox, threw herself, while delirious, into the New River at Islington at midday on November 21, 1741.She was first seen, floating face down, by an old man on the opposite side of the river who went round as fast as he could to give the alarm at the Crown alehouse, which was situated at some distance from the river.No one knew how long the woman had been in the water, and when brought ashore she showed not the least
Derivation of gene expression classifiers for the non-invasive detection of bladder cancer in the hematuria and recurrence surveillance populations.
Authors: Karen B. Chapman, Ljubomir Buturovic, Liqun Qiu, Jennifer Kidd, Nadia Sheibani, Damjan Krstajic, Lyssa Friedman, James L. Bailen, Igor Dumbadze, Daniel R. Saltzstein, Matthew T. Olson, Neal D. Shore
Journal: Journal of Clinical Oncology (2016)

11522 Background: The detection of bladder cancer in patients presenting with hematuria or for recurrence surveillance is routinely accomplished with a combination of urine cytology and cystoscopy, each with its inherent limitations. Cystoscopy is an invasive procedure, whereas urine cytology lacks the desired level of sensitivity. This study describes the development of four gene expression classifiers (GECs) optimized for the non-invasive detection of both high-grade and low-grade urothelial carcinoma in patients presenting with hematuria or for bladder cancer recurrence surveillance. Methods: Biomarker identification was carried out via microarray analysis of patient urine samples collected at 9 sites in a training set (n=241) composed of urine samples from patients undergoing cystoscopy for hematuria or recurrence surveillance. Identified mRNA biomarkers (n=171) were transferred to the NanoString nCounter platform and an assay was developed that involves the direct analysis of urine sediment lysates, without mRNA purification. NanoString data collected on 261 patient samples was used to generate four GECs optimized for the detection high-grade and low-grade urothelial carcinoma in hematuria or recurrence surveillance patients. Results: The GEC developed for the detection of high-grade urothelial carcinoma in patients presenting with hematuria (n=123) performed with a cross-validated ROC AUC of 0.96, while the GEC for low-grade performed with an AUC of 0.81. In the recurrence surveillance cohort (n=120) the GEC developed for the detection of high-grade performed with an AUC = 0.86 and low-grade with an AUC = 0.61. Conclusions: These results establish the feasibility of using a urine-based gene expression classifier to detect urothelial carcinoma and also to distinguish between high-grade and low-grade. An ongoing multicenter clinical trial will allow us to validate test performance on a larger independent test set of prospectively collected urine samples.
Single-cell TCRseq: paired recovery of entire T-cell alpha and beta chain transcripts in T-cell receptors from single-cell RNAseq
Authors: David Redmond, Asaf Poran, Olivier Elemento
Journal: Genome Medicine (2016)

Accurate characterization of the repertoire of the T-cell receptor (TCR) alpha and beta chains is critical to understanding adaptive immunity. Such characterization has many applications across such fields as vaccine development and response, clone-tracking in cancer, and immunotherapy. Here we present a new methodology called single-cell TCRseq (scTCRseq) for the identification and assembly of full-length rearranged V(D)J T-cell receptor sequences from paired-end single-cell RNA sequencing reads. The method allows accurate identification of the V(D)J rearrangements for each individual T-cell and has the novel ability to recover paired alpha and beta segments. Source code is available at https://github.com/ElementoLab/scTCRseq .