tbuckley/cabot-search huggingface dataset:
Abstract IA13: Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome
Authors: Mara H. Sherman, Ronald M. Evans
Journal: Cancer Research (2016)

Abstract Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment. Citation Format: Mara H. Sherman, Ronald M. Evans.{Authors}. Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA13.
Foot orthoses reduce sports injury but shock absorbing insoles do not, study finds
Authors: Susan Mayor
Journal: BMJ (2016)

Foot orthoses that closely fit the contour of the sole protect against injuries or stress fractures from physical activity, but shock absorbing insoles do not reduce exercise related musculoskeletal problems, a review of randomised trials has found.1

Injuries are common in people who exercise regularly, particularly in endurance sports involving repetitive movements, such as long distance running. The most common injuries include medial tibial stress syndrome, Achilles tendinopathy, plantar fasciitis, and patellofemoral pain.

To prevent these injuries people often …
Are There Two Distinct Mechanistic Pathways That Explain the Varying Clinical Presentations, Laboratory Findings, and Outcomes of Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura (TTP)?.
Authors: Benjamin Kim, Kenneth R. Carson, Kathryn McCaffrey, Denise Finley, Anaadriana Zakarija, Nicholas Bandarenko, Dilip K. Pandey, Dennis W. Raisch, Hau C. Kwaan, Paul R. Yarnold, Charles L. Bennett
Journal: Blood (2004)
Abstract 3374: Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP6 induction
Authors: Geun Taek Lee, Seok Joo Kwon, Isaac Yi Kim
Journal: Cancer Research (2015)

Abstract Prostate cancer (CaP) is the second leading cause of cancer death in American men. Traditional androgen ablation is a first-line therapy in relapsed or metastatic prostate cancer cases, but it is eventually rendered ineffective by the development of castration-resistant prostate cancer (CRPC). Once CRPC develops, treament options include taxol-based chemotherapy and second-line hormonal agents, but these have limited effectiveness. In the present study, we have investigated the role of Bone Morphogenetic Protein-6 (BMP6) in the development of castration resistant prostate cancer (CRPC) in the context of bone metastases. We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model. In these patients, we found that the median time to PSA progression was significantly shorter when bone metastases were present (14 months [95% CI, 10.2-17.8 months] vs. 57 months [95% CI, 19.4-94.6 months]). These results suggest that bone-tumor interactions may accelerate castration resistance. Mechanistically, gene expression analysis using quantitative polymerase chain reaction (Q-PCR) arrays showed a dramatic induction of BMP6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP6 by CaP cells; BMP6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP6 expression via PKC/NF-κB pathway in CaP cell lines. Taken together, these observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP6 loop. We have herein demonstrated that the bone-CaP interaction promotes resistance to androgen deprivation. At the cellular and molecular level, this castration-resistance is mediated by bone stroma-derived WNT5A that leads to the induction of BMP6; BMP6, in turn, permits CaP cells to proliferate in the absence of androgens by interacting with β-catenin. Targeting WNT5A/BMP6/β-catenin may be a viable therapeutic option in men with CaP skeletal metastases and CRPC. Citation Format: Geun Taek Lee, Seok Joo Kwon, Isaac Yi Kim. Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP6 induction. [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 3374. doi:10.1158/1538-7445.AM2015-3374
Adoptive Immunotherapy with Tregs and Tcons Ensures Low TRM and a Low Incidence of Post Transplant Leukaemia Relapse After HLA Haploidentical Transplants for Acute Leukemia
Authors: Mauro Di Ianni, Franca Falzetti, Alessandra Carotti, Adelmo Terenzi, Loredana Ruggeri, Pierini Antonio, Vincenza de Fazio, Valentina Zoi, Maria Speranza Massei, Yair Reisner, Andrea Velardi, Franco Aversa, Massimo Fabrizio Martelli
Journal: Blood (2011)
Phase I trial of angiotensin-(1–7): An endogenous anti-angiogenic hormone
Authors: W. J. Petty, A. A. Miller, T. P. McCoy, P. E. Gallagher, E. A. Tallant, F. M. Torti
Journal: Journal of Clinical Oncology (2008)

14591 Background: Angiotensin-(1–7), or Ang-(1–7), is a seven amino-acid peptide hormone in the renin-angiotensin system that inhibits proliferation of vascular endothelial cells. Ang-(1–7) exerts biologic effects by binding to a G protein-coupled receptor called mas. In A549 human lung cancer cells, Ang-(1–7) treatment reduces levels of two angiogenic ligands, VEGF and placental growth factor (PlGF). Murine xenograft studies found that treatment with Ang-(1–7) decreases microvessel density and significantly reduces tumor growth. Methods: Patients with advanced solid tumors refractory to standard therapy were treated with Ang-(1–7) by subcutaneous injection once daily for five days on a 21 day cycle. Doses of Ang-(1–7) were escalated in cohorts of 3 patients. Toxicities were assessed on a weekly basis during the first cycle and every three weeks with subsequent cycles. Patients were treated until disease progression or unacceptable toxicity. Patients were monitored for response or progression with CT scans every two cycles. Plasma levels of Ang-(1–7) as well as VEGF and PlGF were measured prior to treatment, 1, 2, 3, 4, and 6 hours after treatment on days 1 and 5 of the first cycle. Results: Fifteen patients have been treated to date (of 21 planned). The maximum tolerated dose (MTD) of Ang-(1–7) has not yet been established. One dose limiting toxicty occured which was a grade 3 deep venous thrombosis possibly related to Ang-(1–7). No other treatment related toxicities > grade 2 have been observed. Plasma drug levels of Ang-(1–7) increased more than 100-fold in all patients treated. No drug accumulation has been observed with pre-treatment levels on day 5 at baseline levels in all patients. Significant (p < .05) decreases in plasma levels of angiogenic ligands have occured in three patients. No partial radiographic responses have have been observed. Three patients have had stabilization of disease for more than three months. One of these patients with metastatic prostate cancer an showed transient reductions in PSA after treatment. Conclusions: Ang-(1–7), an agonist for the mas receptor, is a first-in-class compound for the treatment of cancer. This hormone provides a previously unrecognized link between cardiovascular physiology and cancer angiogenesis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Patent Filed
miRNAs signature in microdissected tissues and primary cultured cells of malignant mesotelioma.
Authors: P. G. Betta, F. Olivieri, R. Lazzarini, A. Ceka, L. Graciotti, L. Babini, M. R. Rippo, A. Procopio, F. Grosso, R. Libener
Journal: Journal of Clinical Oncology (2011)

e21031 Background: Patients diagnosed for malignant mesothelioma (MM) have poor prognosis and show poor response to conventional chemotherapy. As a consequence, there is a compelling need to identify new targets for the management of MM patients. A growing body of evidence suggests that miRNAs play crucial roles in tumorigenesis of many cancer types. However, their role in MM progression, diagnosis and prognosis is not clear and exhaustive. Methods: miRNA profiling was analyzed in a total of 7 MM compared to 2 normal mesothelium (NM) micro-dissected paraffine embedded tissue specimens and, furthermore, in 6 human cultured primary cell lines (3 MM and 3 NM). The differently expressed miRNAs in tissues and cultured cells were validated by real time PCR. Independent samples T-test was used to determine statistical significance between samples. P <0.05 was considered significant. Results: The miRNA analysis shows that 5 miRNAs are strongly de-regulated in MM compared to NM samples: 2 of them are hypo-expressed whereas the other 3 are hyper-expressed. For the identification of MM de-regulated miRNAs- targets we used a custom made Fortran program (SID1.0). Conclusions: The differentially expressed miRNAs that have been identified could be useful for diagnosis and prognosis of MM. Furthermore, the validation of their potential protein targets should suggest new molecular mechanisms of MM progression and therefore new therapeutic strategies.
Abstract 4006: MiRNA profiling in esophageal precancerous for malignancy progression risk assessment
Authors: Josef Srovnal, Ondrej Slaby, Jiri Ehrmann, Jan Gregar, Lenka Radova, Katerina Staffova, Marian Hajduch
Journal: Cancer Research (2015)

Abstract Background: Barrett's esophagus (BE) is a metaplastic disease with risk to develop esophageal adenocarcinoma (EAC). Current screening method for BE patients (endoscopy and biopsy) is discomfort, expensive and relatively risky for patients. Moreover, the procedure is complicated by subjective histopathology examination and only 2% of BE patients annually progress to adenocarcinoma. The aim of our study was to identify miRNA profiles in order to predict cancer progression in high-risk BE patients. Methods and patients: FFPE samples were obtained from 113 patients (35 EAC, 21 low-grade dysplasia of esophagus, 33 BE and 24 healthy control). There were 74 males and 39 females; mean age was 55.9 years, range 15 - 94 years. Total RNA was purified from FFPE biopsy samples using proteinase K treatment followed by RNeasy kit (Qiagen). Microarray analysis was performed using the GeneChip miRNA 3.0 Array (Affymetrix). The data were analyzed using “R” software and the Bioconductor package. Results: In total, 113 GeneChip miRNA 3.0 Arrays were performed in 113 patients. Expression profiles of 1733 human miRNAs were analyzed. In supervised clustering analysis we found 8 differentially expressed miRNAs (p&amp;lt;0.001 or logFC 2) in BE patients compared to EAC patients and 10 differentially expressed miRNAs (p&amp;lt;0.001 or logFC 2) in LGD patients compared to EAC patients. One of the dominant findings was decreased expression of miR-223 in EAC and LGD samples, which is known to function as a tumor suppressor blocking E2F1. Using LOOCV classifier with 13 miRNAs signature we were able to correctly classify 86 from 113 samples (AUC = 0.840). Prediction model fails mostly in LGD prediction (18/21), probably due to incorrect pathological classification. Conclusion: We have identified miRNA profiles and signature allowing for better diagnostics of cancer progression in BE and LGD patients, which, however, will require further validation. Acknowledgment: This work was financially supported by IGA UP LF 2014_019, NPU LO1304, CZ.1.05/2.1.00/01.0030 and CZ.1.07/2.3.00/30.0004. Citation Format: Josef Srovnal, Ondrej Slaby, Jiri Ehrmann, Jan Gregar, Lenka Radova, Katerina Staffova, Marian Hajduch. MiRNA profiling in esophageal precancerous for malignancy progression risk assessment. [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 4006. doi:10.1158/1538-7445.AM2015-4006
Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients
Authors: D Rossille, I Azzaoui, A L Feldman, M J Maurer, G Labouré, M Parrens, C Pangault, T M Habermann, S M Ansell, B K Link, K Tarte, T E Witzig, T Lamy, S L Slager, M Roussel, N Milpied, J R Cerhan, T Fest
Journal: Leukemia (2016)
Abstract 4050: Association of long term NK cell culture and TIMP3 over-expression with NK cell reduced susceptibility to leukemia and epithelial cancer cell induced damage
Authors: Giuseppe Sconocchia, Roberto Arriga, Sara Caratelli, Giulia Lanzilli, Andrea Coppola, Giulio C. Spagnoli, Adriano Venditti, Sergio Amadori, Davide Lauro, Maria I. Del Principe, Luca Maurillo, Francesco Buccisano, Barbara Capuani, Xinhui Wang, Soldano Ferrone
Journal: Cancer Research (2015)

Abstract Allogeneic leukemia and cancer epithelial (CE) cells have been recently shown to induce,in vitro, NK cell abnormalities (NKCA). The latter include NK cell depletion and apoptosis as well as natural cytotoxic receptor (NCR) CD16 down-regulation. The potential negative impact of leukemia and CE cell induced NKCAs on the in vivo anti-tumor activity of NK cells and the limited information about strategies to protect NK cells from NKCAs have prompted us to characterize NKCAs and to develop strategies to counteract them. NKCA induction by leukemia and CE cells is influenced neither by interleukin-2 (IL-2) treatment nor by HLA class I antigen expression, but is abrogated by a long term culture of peripheral blood mononuclear cells (PBMCs) at 37 ºC. Following a 10 day culture of PBMCs, NK cells become resistant to cancer cell induced NKCA but maintain their cytotoxic activity. Actinomycin D restores the susceptibility of long term NK (LTNK) cells to NKCAs suggesting that the generation of resistance to NKCAs requires RNA transcription. TAPI-0, a functional analogue of the tissue inhibitor of metalloproteinases (TIMP) 3, inhibits cancer cell induced NKCAs indicating a role for a restricted number of metalloproteinases (MMPs) in the generation of this phenomenon. This conclusion is supported by the reduced susceptibility to cancer cell induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. Finally, subcutaneous infusion of IL-2 stimulated LTNK cells inhibited subcutaneous growth of the monoblastic leukemia cells, ML-2 in CB17scid mice while short term, IL-2 stimulated NK cells did not suggesting that LTNK cells have significant anti-leukemia capacity in vivo. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy for the treatment of myeloid leukemias with haploidentical or allogeneic NK cells. Citation Format: Giuseppe Sconocchia, Roberto Arriga, Sara Caratelli, Giulia Lanzilli, Andrea Coppola, Giulio C. Spagnoli, Adriano Venditti, Sergio Amadori, Davide Lauro, Maria I. Del Principe, Luca Maurillo, Francesco Buccisano, Barbara Capuani, Xinhui Wang, Soldano Ferrone. Association of long term NK cell culture and TIMP3 over-expression with NK cell reduced susceptibility to leukemia and epithelial cancer cell induced damage. [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 4050. doi:10.1158/1538-7445.AM2015-4050
Clinical utility of a HER-2/<i>neu</i> assay in monitoring and predicting response to therapies in patients with metastatic breast cance
Authors: C. D. Cheli, R. P. Thiel, D. Luftner
Journal: Journal of Clinical Oncology (2004)

717 Background: The HER-2/neu oncogene encodes a 185 kd protein (p185). The proteolytic breakdown product of p185 is found in the serum of patients with cancers of epithelial origin. We evaluated the clinical utility of the ADVIA Centaur HER-2/neu assay in monitoring and predicting response to therapies in metastatic breast cancer patients. Methods: HER-2/neu and CA15–3 values were measured in retrospective serum samples obtained from 59 patients with metastatic breast cancer undergoing treatments including immunotherapy, chemotherapy and hormonal manipulation over a 6–12 month period. Serial measurements were analyzed visit-to-visit. Serial changes in HER-2/neu and CA15–3 were correlated with changes in clinical status. For each pair of serial measurements changes of equal or greater than, or less than 15%, and 21% for HER-2/neu and CA15–3, respectively, were considered to indicate progression or lack of progression. Results: The study groups included those who responded to therapy (stable, partial or complete response), or exhibited disease progression. HER-2/neu levels demonstrated concordance of 78.1% (82/105) with clinical course of disease, whereas CA15–3 levels demonstrated concordance of 76.2% (80/105). Concordance increased to 85.7% (90/105) when both markers were used in combination. Furthermore, we stratified patients by baseline levels of HER-2/neu greater than or less than 15ng/mL within therapy type. We found that the odds for obtaining a clinical benefit from Herceptin therapy are 2.6 times higher for those patients with baseline levels above 15ng/mL than for those with levels less than 15ng/mL. In contrast, for all other therapies combined the odds ratio for obtaining a clinical benefit was 0.6. Conclusions: The results indicate that HER-2/neu and CA15–3 maybe useful in identifying disease progression or therapeutic response in different sub-groups of women with metastatic breast cancer. Furthermore, these data suggest that patients with elevated serum HER-2/neu levels benefit from Herceptin treatment in contrast to those patients on other treatment regimens. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer HealthCare Bayer HealthCare Bayer HealthCare Bayer HealthCare
159. Sustained Weight Loss and Altered Lipid Taste Sensitivity Induced by Modulation of Salivary PYY and Excendin-4 in Mice
Authors: Sean M. Crosson, Seth Currlin, Taimoor Khan, Cedric D. Dotson, Sergei Zolotukhin
Journal: Molecular Therapy (2016)

Peptide tyrosine-tyrosine (PYY), known to induce satiation when present in plasma, has recently been described to modulate body weight (BW) and food intake (FI) of diet induced obese (DIO) mice when included in saliva. Similarly, glucagon-like peptide 1 (GLP-1), a GI peptide present in both plasma and saliva, also modulates BW and FI. The purpose of this project was to study the anorexigenic effect of sustained elevation of PYY and Excendin-4 (Ex-4, a GLP-1R agonist) in saliva of mice. Using recombinant Adeno-associated virus serotype 8 (rAAV8) we performed gene transfer of GFP (control), PYY, Ex-4, and PYY-Ex-4 dual vectors to the submandibular salivary glands of C57BL/6 mice fed a high fat diet. We observed a significant (p < 0.05) decrease in BW of mice treated with either Ex-4, or PYY-Ex-4 dual vectors when compared to controls. Notably, mice treated with PYY-Ex-4 dual vector displayed a significant decrease in BW as early as 1-week post vector administration while Ex-4 mice alone did not demonstrate a significant loss until 8 weeks post-injection. PYY mice, while demonstrating a decreasing trend in BW gain with respect to GFP mice, did not show a significant difference in BW during the 12-week experiment. To determine whether the anorexigenic effect of salivary PYY and Ex-4 is modulated through taste perception, we utilized a Davis Rig gustometer to generate brief access taste response curves for a panel of tastants for all groups of treated mice. Notably, the Ex-4 as well as the PYY-Ex-4 dual group displayed a significant increase in sensitivity to intralipid stimulus, suggesting that this taste modality plays a role in BW modulation. This observed weight loss and altered taste perception in PYY and Ex4 treated mice while significant, is complicated by the unintended transduction of hepatocytes. Unintended transduction of the liver may allow for the elevated levels of PYY and Ex4 in the bloodstream in addition to saliva. In order to observe the saliva-specific effect of dual PYY Ex4 vector administration, we have developed viral constructs containing miR122 target sequences, a liver specific micro RNA (miRNA), and miR206, a skeletal muscle specific miRNA, target sequences in the 3' UTR of each construct. These micro RNA target sequences will suppress vector expression in off target tissues such as the skeletal muscle and liver. Additionally, all viral constructs were packaged into AAV5 instead of AAV8 which has the same transduction efficiency of salivary glands but decreased transduction of the murine liver. Using these miRNA constructs, we have observed no detectable expression of GFP in the murine liver.