tbuckley/cabot-search huggingface dataset:
Abstract 2927: Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer
Authors: Shigeru Kawabata, Chun-Te Chiang, Regan M. Memmott, Takefumi Komiya, Joell J. Gills, Phillip A. Dennis
Journal: Cancer Research (2014)

Abstract Non-small-cell lung cancer (NSCLC) accounts for 80-85% of lung cancers and almost half of patients with newly diagnosed NSCLC have metastatic disease. Platinum-based chemotherapy regimens given as first-line treatment for advanced NSCLC patients with metastasis are standard but have modest response rates. Pemetrexed is well tolerated and inhibits several folate-dependent enzymes including thymidylate synthase, TS. Increased expression of TS confers resistance to pemetrexed in vitro and is a predictive factor for poor response to pemetrexed. Rapamycin is a mTOR inhibitor and suppresses protein synthesis. Here, we show that rapamycin decreases endogenous expression of TS in NSCLC cells. The combination of rapamycin and pemetrexed synergistically inhibits NSCLC cell proliferation and enhances the inhibition of 4E-binding protein 1 (4E-BP1) activation that is regulated by mTOR. Although pemetrexed as a single agent upregulated expression of TS, pretreatment with rapamycin suppressed pemetrexed-upregulated TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited the growth of NSCLC xenografts, which correlated with decreased mTOR activity and inhibition of pemetrexed-induced upregulated expression of TS. Based on these preclinical data, we have conducted a Phase I/II clinical trial combining rapamycin and pemetrexed in subjects with relapsed NSCLC. This regimen was well tolerated, and resulted in a 22% partial response rate that is above what is expected for response to single agent pemetrexed (9%). In biomarker analyses, pretreatment with rapamycin decreased the expression of TS in peripheral blood mononuclear cells, which correlated with increased progression free survival. Collectively, these studies identify rapamycin and pemetrexed as an effective combination in NSCLC, and suggest that rapamycin enhances the efficacy of pemetrexed by suppressing TS expression. Citation Format: Shigeru Kawabata, Chun-Te Chiang, Regan M. Memmott, Takefumi Komiya, Joell J. Gills, Phillip A. Dennis. Rapamycin decreases expression of thymidylate synthase and enhances the response to pemetrexed in preclinical studies and a Phase I/II clinical study of subjects with non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2927. doi:10.1158/1538-7445.AM2014-2927
Abstract 4444: The role of small GTPase Rab7 in the secretion of extracellular microvesicles by head and neck squamous cells carcinoma
Authors: Fernanda S. Giudice, Bruna R. Rodrigues, Marcos V. S. Dias, Antuani R. Baptistella, Tonielli Cristina S. Lacerda, Luiz P. Kowalski, Vilma R. Martins
Journal: Cancer Research (2014)

Abstract Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor that shows its highest incidence in the upper aerodigestive tract and is considered one of the six most common malignancies worldwide. Among the processes involved in the poor prognosis of HNSCC, local invasion and subsequent metastasis are the most important events. Recent evidences have shown that metastasis can be the result of extracellular microvesicles (MVEs) being released from the tumor cells to the blood or lymphatic system. The molecular mechanisms involved in MVEs biogenesis and secretion are, however, poorly understood. Herein, we have performed a screen targeting for the components of MVEs biogenesis in three HNSCC cell lines (SCC-9, Cal27 and FaDu) through western blotting. MVEs were quantified using Nanoparticle Tracking Analysis (NTA - NanoSight®) and the lysosomal compartment was followed in the cell lines through immunofluorescence. Comparing the three cell lines, FaDu cells presented higher expression of proteins responsible for MVEs formation (p&amp;lt;0.05), such as Flotilin-1, Tsg101, VPS36 and also Rab7, a small GTPase that directs vesicles to lysosomes. However, FaDu cells secreted less MVEs than SCC-9 and Cal27. Immunofluorescence experiments showed the presence of numerous perinuclear clusters positive to LAMP-1 (lysosome marker) in FaDu cells, while SCC-9 and Cal27 showed LAMP1-positive organelles dispersed throughout their cytoplasms. Taken together, the results highlight a role for Rab7 protein in the negative regulation of MVEs secretion by HNSCC cell lines, which may provide important information related to tumor progression, treatment response, and especially the development of metastasis. Supported by São Paulo Research Foundation (FAPESP) Citation Format: Fernanda S. Giudice, Bruna R. Rodrigues, Marcos V. S. Dias, Antuani R. Baptistella, Tonielli Cristina S. Lacerda, Luiz P. Kowalski, Vilma R. Martins. The role of small GTPase Rab7 in the secretion of extracellular microvesicles by head and neck squamous cells carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4444. doi:10.1158/1538-7445.AM2014-4444
Feedback Control in Ehrlich Ascites Cells
Authors: Edward Bresnick, George H. Hitchings
Journal: Cancer Research (1961)

Both carbamyl phosphate-aspartate transcarbamylase and dihydroorotase were found to be present in cell-free preparations from Ehrlich ascites tumor. Both enzymes were inhibited by various pyrimidines and derivatives thereof. Uridine-5′-phosphate was the most potent inhibitor of carbamyl phosphate-aspartate transcarbamylase, whereas fluoroorotic acid, orotic acid, and orotidine were most effective against dihydroorotase. These data demonstrate feedback control by preformed pyrimidine derivatives upon at least two of the steps which are involved in the biosynthesis of pyrimidines. Since pyrimidine analogs exhibit similar inhibitory effects, the results support the view that these antimetabolites may inhibit the biosynthesis of pyrimidines, in addition to their competitions with the products.
Phenotypes of alveolar macrophages in normal human lung and their polarization with disease
Authors: Erica Bazzan, Mariaenrica Tinè, Claudia Radu, Graziella Turato, Elena Mutti, Paolo Simioni, Riccardo Cazzuffi, Simonetta Baraldo, Marina Saetta, Manuel G. Cosio
Journal: European Respiratory Journal (2014)

BACKGROUND Macrophages are crucial components of innate immunity. During inflammatory responses monocytes are recruited into tissues, skewed first toward unpolarized macrophages (M0) and then polarized toward proinflammatory M1 or antiinflammtory M2 functional phenotype. However the different macrophages polarization (M0, M1, M2) in normal human lungs and their plasticity with the disease is not understood.  AIM To investigate the phenotype of alveolar macrophages (AM) in normal human lung tissue and their change with disease.  METHODS M1 (iNOS + ), M2 (CD206 + ) and M0 (iNOS - /CD206 - ) AM were studied by immunohistochemical and immunofluoresence techniques in human lung sequential slides of 17 nonsmokers (11 with tumor and 6 donors without tumor) 13 smokers without COPD and 23 COPD (11 severe and 12 mild/moderate). Positive AM were counted and expressed as percentage of total AM.  RESULTS Baseline AM population in normal donor lungs comprised 57%(31-68) of M0, 31%(24-60) of M1 and 7%(4-16) of M2. However, in nonsmokers with lung cancer M2 increased to 43%(2-65), but not the M1. In smokers M2 [68%(40-86)] was higher than in nonsmokers [43%(2-65)] but did not increase further with COPD severity [61%(36-94) in mild/moderate COPD and 78%(53-98) in severe COPD]. M1 is minimally present in nonsmokers [24%(3-38)] and increases gradually and significantly with worsening COPD [68%(40-93) in mild/moderate COPD and 84%(36-99) in severe COPD].  CONCLUSION The baseline (normal) AM polarization is mainly M0 with a small percentage of proinflammatory M1, which increases along with worsening COPD. M2 increase is probably partially related to the presence of cancer.
Antenatal screening is important
Authors: J N Weber, G P Taylor
Journal: BMJ (1996)

EDITOR,—In their editorial A Pagliuca and colleagues revive the debate on whether British blood donors should be screened for human T cell leukaemia/lymphoma virus type I (HTLV-I).1 Five European Union countries with rates of HTLV infection among blood donors similar to that in Britain now screen blood donors routinely, and Portugal will start to do so this year, so we agree that Britain will need to follow suit.

Antenatal screening may, however, be an even more urgent …
Abstract 18475: Natural Killer Cell Deficient E4BP4 Knockout Mice Develop Spontaneous, Age-related Pulmonary Hypertension
Authors: Stephen D Moore, Salema Jafri, Mark Southwood, Hugh J Brady, Francesco Colucci, Nicholas W Morrell, Mark L Ormiston
Journal: Circulation (2014)

BACKGROUND: There is a well-established link between pulmonary arterial hypertension (PAH) and immune dysfunction, including the impairment of circulating Natural Killer (NK) cells in PAH patients. While decidual NK cells are now recognized to play a role in vascular remodeling during pregnancy, little is known of the ability of peripheral NK cells to influence other vascular beds. We aimed to test the importance of NK deficiency to the pathogenesis of PAH using mice bearing a homozygous knockout of the E4BP4 transcription factor. E4BP4-/- mice possess normal T and B cell numbers, but are grossly deficient in circulating NK cells. METHODS: Cardiopulmonary hemodynamics were assessed in naive E4BP4-/- mice and wild type (WT) littermate controls by right and left heart catheterization at 3 and 9 months, as well as by echocardiography at 3, 6 and 9 months. For the Sugen-hypoxia model, 3-month-old mice were exposed to 21 days of hypoxia (10% O2) combined with 20mg/kg/week SU5416 prior to cardiopulmonary phenot...
Abstract 1692: Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer
Authors: Edmund C. Jenkins, Kelly S. Levano, Eric H. Jung, Matthew Levy, Paraic A. Kenny
Journal: Cancer Research (2015)

Abstract Approximately 70% of breast cancer cases are Estrogen Receptor (ER) positive. In many cases, these patients are well-served by endocrine therapies such as tamoxifen and aromatase inhibitors, however the emergence of endocrine-resistant disease in up to 40% of these patients is a major clinical concern. This necessitates treatment with more toxic chemotherapies which are often successful at delaying tumor progression, but are not curative. Recent work from our group and others has demonstrated that Amphiregulin, an Epidermal Growth Factor Receptor (EGFR) ligand, is a critical effector of ER signaling in both normal development and breast cancer pathogenesis, and is expressed in both endocrine-sensitive and endocrine-resistant breast cancer. Like other EGFR ligands, Amphiregulin is proteolytically processed at the cell surface to release a soluble EGFR-binding signaling domain and a residual cell-associated stalk. In this project, we are developing antibodies that selectively recognize the residual transmembrane Amphiregulin cleavage product with the goal of developing antibody-drug conjugates with which to selectively target tumor cells with high levels of Amphiregulin shedding. We have generated six humanized antibodies that recognize the cell-associated neo-epitope revealed following the TACE-mediated proteolytic release of Amphiregulin. Using both flow Cytometry and immunofluorescence, we demonstrate that these antibodies selectively recognize cleaved over full-length Amphiregulin in estrogen receptor positive breast cancer cells. Conjugation of these antibodies with a pH-sensitive dye, pHrodo, demonstrates robust and rapid antibody internalization in live cells. Conjugation of these antibodies with monomethyl auristatin E results in the disruption of the microtubule network of breast cancer cells followed by cell death. We propose that these agents may have utility in the treatment of breast and other cancers in which Amphiregulin expression and processing play a prominent role. This study is supported by the Department of Defense Breast Cancer Research Program (W81XWH-14-1-0294). Citation Format: Edmund C. Jenkins, Kelly S. Levano, Eric H. Jung, Matthew Levy, Paraic A. Kenny. Antibody-drug conjugates to target cell surface TACE-cleaved amphiregulin in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2015-1692
Robotic Intracorporeal Orthotopic Neobladder: Urodynamic Outcomes, Urinary Function, and Health-related Quality of Life
Authors: Raj Satkunasivam, Michael Santomauro, Sameer Chopra, Elisabeth Plotner, Jie Cai, Gus Miranda, Salpi Salibian, Monish Aron, David Ginsberg, Siamak Daneshmand, Mihir Desai, Inderbir S. Gill
Journal: European Urology (2015)
Demeclocycline in the prophylaxis of self-induced water intoxication
Authors: R A Nixon, J S Rothman, W Chin
Journal: American Journal of Psychiatry (1982)

Demeclocycline, a competitive inhibitor of antidiuretic hormone at renal tubules, was studied in a patient with the syndrome of psychosis, psychogenic polydipsia, and episodic water intoxication. Under double-blind, placebo-controlled conditions, demeclocycline substantially reduced the severity and frequency of hyponatremic episodes.
Chemically Induced Regressing Experimental Epidermal Tumors in Mice
Authors: J. V. Frei
Journal: Cancer Research (1964)

When tumors are induced by a single application of a carcinogen to the skin of mice, followed by repeated applications of a promoting agent, many of the induced tumors shrink and disappear during the experiment. An analysis of such an experiment has shown that the tumors which appeared earliest regressed less commonly than the ones appearing later. This made it improbable that the continuous application of the promoting agent was the cause of such regressions. Mice bearing many tumors for a long time had fewer regressing tumors than did mice bearing few tumors for a short time. This made it improbable that tumors were made to regress by an immunological mechanism in response to an antigen common to all the tumors. The inherent nature of individual tumors, individual tumor antigens, or the genetic make-up of the experimental animal could have contributed to the regression and disappearance of some of the induced tumors.
The Relationship of Autophagy Defects to Cartilage Damage During Joint Aging in a Mouse Model
Authors: Beatriz Caramés, Merissa Olmer, William B. Kiosses, Martin K. Lotz
Journal: Arthritis & Rheumatology (2015)

Aging is a main risk factor for osteo arthritis (OA), the most prevalent musculoskeletal disorder. Defects in autophagy, an essential cellular homeostasis mechanism, have recently been observed in OA articular cartilage. The objectives of this study were to establish the constitutive level of autophagy activation in normal cartilage and to monitor the temporal relationship between changes in autophagy and aging-related degradation of cartilage in a mouse model.In GFP-LC3-transgenic mice, green fluorescent protein (GFP)-light chain 3 (LC3) is ubiquitously expressed, and the accumulation of GFP puncta, representing autophagosomes, was quantified by confocal microscopy as a measure of autophagy activation. Expression of the autophagy proteins autophagy-related protein 5 (ATG-5) and microtubule-associated protein 1 light chain 3 (LC3) was analyzed by immunohistochemistry. Cartilage cellularity, apoptotic cell death, and cartilage structural damage and changes in synovium and bone were examined by histology and immunohistochemistry.Basal autophagy activation was detected in liver and knee articular cartilage from young (6-month-old) mice, with higher levels in cartilage than in liver in the same animals. In 28-month-old mice, there was a statistically significant reduction in the total number of autophagic vesicles per cell (P < 0.01) and in the total area of vesicles per cell (P < 0.01) in the articular cartilage as compared to that from young 6-month-old mice. With increasing age, the expression of ATG-5 and LC3 decreased, and this was followed by a reduction in cartilage cellularity and an increase in the apoptosis marker poly(ADP-ribose) polymerase p85. Cartilage structural damage progressed in an age-dependent manner subsequent to the autophagy changes.Autophagy is constitutively activated in normal cartilage. This is compromised with aging and precedes cartilage cell death and structural damage.
Abstract 1461: A miR-221 multigene pharmacodynamic signature for assessing miR-221 inhibition
Authors: Adam Pavlicek, Thomas Vincent, Oivin Guicherit, Nelson Chau, Sonya Zabludoff, Neil Gibson, Edmund C. Lee
Journal: Cancer Research (2014)

Abstract miR-221 targets key cancer pathways, inhibits translation of important tumor suppressors, and is overexpressed in hepatocellular carcinoma (HCC). Aberrant miR-221 expression has been linked to HCC progression, while inhibition of miR-221 has been shown to reduce tumor growth. In preclinical models, miR-221 inhibition can be assessed by measuring de-repression of known miR-221 target genes such as p27. However, changes in individual microRNA target genes are often small and model-dependent; and comprehensive assessment of pharmacodynamic (PD) effects following microRNA inhibition is often challenging. Herein, we present a miR-221 multigene PD signature that can assess miR-221 target engagement with a large dynamic window and work across different human HCC models following miR-221 inhibition. In the first stage, we transfected five different human HCC lines with two chemically-modified oligonucleotides that inhibit miR-221 functions (miR-221 anti-miRs) and a microRNA-duplex that mimics miR-221/222 functions (mimic). The resulting global mRNA expression changes were compared to mock treated cells using GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix). Ninety unique human genes with transcripts containing conserved and/or 8-mer target seeds (TargetScan), that significantly went up and down after anti-miR-221s and mimic treatment respectively, were further profiled with qPCR in the second stage. Out of the 90 tested transcripts, 62 of them were significantly up-regulated by anti-miR-221s but not by control oligonucleotides (either mismatch or targeting unrelated microRNAs). From the 62 genes, an optimal multigene signature consisted of 13 unique human genes normalized by 6 reference housekeeping genes was identified. We also devised a “miR-221 signature score” and demonstrated that our multigene signature can separate miR-221 anti-miRs treatment from control oligonucleotides with a high degree of sensitivity and specificity. We further validated this multigene signature by demonstrating that it correctly distinguished miR-221 anti-miRs treatment from controls in three additional HCC cell lines in vitro and one HCC model in vivo. In summary, our miR-221 multigene PD signature analysis provided a comprehensive assessment of miR-221 inhibition, with significantly larger dynamic window compare to individual gene analysis, that may be used to discover, rank order and guide the development of novel miR-221 anti-miRs for the treatment of human cancers. Citation Format: Adam Pavlicek, Thomas Vincent, Oivin Guicherit, Nelson Chau, Sonya Zabludoff, Neil Gibson, Edmund C. Lee. A miR-221 multigene pharmacodynamic signature for assessing miR-221 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1461. doi:10.1158/1538-7445.AM2014-1461
Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms
Authors: Heng-Jie Cheng, Tiankai Li, Che Ping Cheng
Journal: Circulation (2014)

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF. Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF , 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL , 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C). Results: Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (E ES , HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca 2+ ] iT (0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10 -8 M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β 1 -AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB Ser16 /PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β 3 -AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca 2+ ] iT , and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β 1 - and β 3 -AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77). Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β 1 -AR and reverse contrast changes between iNOS and β 3 -AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve.