tbuckley/cabot-search huggingface dataset:
Abstract 3332: Targeting cancer stem cells in ovarian cancer
Authors: Sham S. Kakar, Mariusz Z. Ratajczak
Journal: Cancer Research (2016)

Abstract Ovarian cancer is a disease commonly complicated by the presence of ascites in the abdominal cavity which represents a major clinical problem. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed mainly due to the presence of cancer stem cells (CSCs) present in ascites which are chemo-resistant and responsible for recurrence of cancer. In our preliminary studies, we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors with WFA resulted in a 70% to 80% reduction in tumor growth, complete inhibition of metastasis, and a significant elimination of the cells expressing CSCs markers - CD44, CD24, CD34, CD117, ALDH1 and Oct4 and down regulation of Notch1 and its downstream signaling genes (Hes1 and Hey1) reported to play crucial role for self-renewal and maintenance of CSCs. In addition, WFA also resulted in a significant inhibition of securin expression an “oncogene” important in ovarian tumorigenesis. In contrast, treatment of mice with CIS alone had the opposite effects, causing an increase in cells expressing CSC markers and Notch1 signaling pathway. However, combining of WFA with CIS showed enhanced effects on suppression of securin as well as elimination of CSCs. This may explain the development of platinum-resistance and recurrence of cancer in patients treated with first line chemotherapy. Based on this information, we hypothesize that a combination of WFA with CIS should target ovarian cancer cells as well as cancer stem cells by reducing securin and CSCs thereby reducing CIS resistance and recurrence of ovarian cancer. In our study, we used cells from ascites from patients with recurrent ovarian cancer and determine the effect of WFA alone and in combination with CIS on tumorigenic functions of ascites cells and CSCs from ascites in vitro and in vivo, and defined the molecular mechanisms associated with self-renewal, maintenance and recurrence of cancer in relation to expression of securin. Because the two agents act synergistically, this combination may minimize side effects as well as induction of cisplatin resistance and recurrence of cancer. In addition, this study will justify the initiation of phase I/phase II clinical trials to assess potential toxicity and efficacy of WFA/CIS combination in advanced/recurrent ovarian cancer patients. Citation Format: Sham S. Kakar, Mariusz Z. Ratajczak. Targeting cancer stem cells 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 3332.
Abstract LB-345: Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration
Authors: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo
Journal: Cancer Research (2016)

Abstract During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their cell-cell junctions, apical-basal polarity, and reorganize their actin cytoskeleton. These changes, among others, increase the motility of individual cells and promote a highly invasive phenotype. The actin cytoskeleton is also key in cell migration and invasion, as the polymerization of actin at the leading edge provides the necessary driving force for translocation and protrusions. Therefore, the actin cytoskeleton is a potential target for inhibiting tumour progression. In this study we characterized a novel tri-cyclic synthetic triterpenoid derivative, TBE-31, in its ability to associate with actin and inhibit cell migration. Using a pull-down approach, we demonstrate that TBE-31 binds directly to actin. Furthermore, TBE-31 inhibited branched and linear actin polymerization in vitro, and stress fibre formation in cultured cells. Actin cytoskeleton reorganization and stress fiber formation was also inhibited in TGFβ-dependent EMT of non-small cell lung cancer cells. We next used SwissDock software to investigate the potential molecular interaction between TBE-31 and actin. Swissdock predicted that TBE-31 would have a high affinity for binding to the same cleft as Cytochalasin D, a bona-fide actin polymerization inhibitor. As triterpenoids associate with cysteine residues in target proteins, we generated cysteine to alanine mutants of actin and verified TBE-31 binding using pull-down assays. We identified that cysteine 374 is important for TBE-31 interaction with actin. Finally, we observed that TBE-31 inhibited fibroblast and non-small cell lung tumour cell migration with an IC50 of 1.0 and 2.5 μM, respectively. Taken together, our results suggest that TBE-31 targets actin polymerization to alter cell morphology and inhibit cell migration. Citation Format: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo. Acetylenic tricyclic bis-(cyano enone) interacts with cysteine residues of actin and inhibits non-small cell lung cancer cell migration. [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 LB-345.
Diagnostic potential of mucins in pancreatic juice for pancreatic cancer.
Authors: Asish Patel, Sukhwinder Kaur, Lynette Smith, Chandrakanth Are, Surinder Batra
Journal: Journal of Clinical Oncology (2016)

222 Background: Pancreatic juice remains an underutilized resource for diagnosing pancreatic cancer. Mucins are high molecular weight glycoproteins differentially upregulated in pancreatic cancer, and we hypothesize that their profile in pancreatic juice may have diagnostic potential. Methods: Pancreatic juice was obtained during endoscopy from non-healthy non-pancreatic control (NHPC, n = 57), chronic pancreatitis (CP, n = 23), and pancreatic cancer (PC, n = 23) patients. Sandwich ELISA was used to detect MUC1, MUC4, MUC5AC, CA125, and CA19-9. Kruskal-Wallis test and Wilcoxon rank sum test for group and pairwise comparison was done with p &lt; 0.05 as significant. Logistic regression with ROC curve modeling of log transformed data was done for each biomarker individually and in combination to determine odds ratio (OR), sensitivity (SN), and specificity (SP) for PC. Results: PC vs NHPC: MUC5AC had the best individual performance for diagnosing PC with an OR = 2.78 (95% CI = 1.51-5.13), AUC = 0.81, and optimal SN/SP of 0.83 and 0.67, respectively. CA125 was increased in PC with an OR = 2.31 (95% CI = 1.4-4.0), AUC = 0.73, and optimal SN/SP of 0.88 and 0.67. CA19-9 was increased in PC with an OR = 1.5 (95% CI = 1.2-1.8), AUC = 0.76, and optimal SN/SP of 0.73 and 0.70. A combination of MUC1, MUC5AC, CA125, and CA19-9 outperformed all individual markers and had the largest AUC (0.89) with optimal SN/SP of 0.84 and 0.79. PC vs CP: MUC1 concentration in PC was significantly less than CP with an OR = 0.21 (95%CI = 0.088-0.49), AUC = 0.82, and optimal SN/SP of 0.87 and 0.78. PC vs NHPC+CP: MUC1 was decreased significantly in PC with an OR = 0.65 (95% CI = 0.44-0.96), AUC = 0.69, and optimal SN/SP of 0.87 and 0.63. CA125 was increased in PC with an OR = 1.64 (95%CI = 1.1-2.4), AUC = 0.66, and optimal SN/SP of 0.67 and 0.64. CA19-9 was increased in PC with an OR = 1.32 (95%CI = 1.1-1.6), AUC = 0.68, and optimal SN/SP of 0.63 and 0.67. A combination of MUC1, MUC5AC, CA125, and CA19-9 had an AUC = 0.86 with optimal SN/SP of 0.87 and 0.77 for PC. Conclusions: MUC1, MUC5AC, CA125, and CA19-9 combination provides a significantly improved diagnostic panel compared to any individual marker in pancreatic juice for detecting malignancy.
Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes
Authors: Jon White, Daniel I. Swerdlow, David Preiss, Zammy Fairhurst-Hunter, Brendan J. Keating, Folkert W. Asselbergs, Naveed Sattar, Steve E. Humphries, Aroon D. Hingorani, Michael V. Holmes
Journal: JAMA Cardiology (2016)

Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins.To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant.Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015.Coronary artery disease and diabetes.Genetic instruments composed of 130 single-nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation.Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes.
Abstract 1797: Loss of FoxO1 expression is associated with decreased IGF-1R levels and alters IGFBP-1 induction in tamoxifen-resistant breast cancer cells
Authors: Ali Vaziri-Gohar, Kevin D. Houston
Journal: Cancer Research (2016)

Abstract Breast cancer is one of the leading causes of cancer-related deaths in the world. The majority of breast cancers express estrogen receptor alpha (ERα) and tamoxifen, a selective estrogen receptor modulator, is commonly prescribed as adjuvant therapy for ERα-positive breast cancer patients. The development of chemoresistance is a common occurrence in treated patients, however, the molecular mechanisms associated with acquired tamoxifen resistance are not well defined. Previous work from our lab identified a novel mechanism of tamoxifen action that involved the accumulation of extracellular Insulin-like growth factor binding protein-1 (IGFBP-1) and modulates IGF-1-dependent signaling transduction. Tamoxifen-induced IGFBP-1 induction in this model was mediated by G protein-coupled estrogen receptor (GPER)-dependent CREB activation as shown by phosphorylation on serine 133. To determine IGFBP-1 induction is altered during the development of chemoresistance, this mechanism of action was studied in tamoxifen resistant MCF-7 (TamR) cells. Whereas CREB was constitutively phosphorylated in TamR cells, IGFBP-1 levels were not elevated when compared to parental cells and IGFBP-1 was not induced by tamoxifen treatment in TamR cells. These data suggest that another transcription factor(s) are also necessary for the induction of IGFBP-1 in breast cancer cells. FoxO1 is a known regulator of IGFBP-1 transcription and we tested whether FoxO1 contributes to tamoxifen-induced IGFBP-1 transcription. Our results indicate that FoxO1 expression levels were significantly reduced in TamR cells compared with parental cells. Furthermore, FoxO1 knockdown experiments demonstrated this transcription factor mediates tamoxifen-induced IGFBP-1 induction in MCF-7 cells. Consistent with previously published observations, IGF-1R expression was reduced in TamR cells compared to parental MCF-7 cells. To determine if loss of IGF-1R expression in involved in the loss of FoxO1 expression in TamR cells, IGF-1R was exogenously expressed and FoxO1 expression was measured. IGF-1R expression increases FoxO1 levels and partially restores tamoxifen-induced IGFBP-1 induction in TamR cells. These results suggest that FoxO1-mediated IGFBP-1 accumulation is altered during the development of tamoxifen resistance and is associated with decreased IGF-1R expression. Citation Format: Ali Vaziri-Gohar, Kevin D. Houston. Loss of FoxO1 expression is associated with decreased IGF-1R levels and alters IGFBP-1 induction in tamoxifen-resistant breast cancer cells. [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 1797.
Impact of a targeted isolation strategy at intensive-care-unit-admission on intensive-care-unit-acquired infection related to multidrug-resistant bacteria: a prospective uncontrolled before–after study
Authors: G. Ledoux, S. Six, R. Lawson, J. Labreuche, C. Blazejewski, F. Wallet, A. Duhamel, S. Nseir
Journal: Clinical Microbiology and Infection (2016)
Rhesus sensitization and abortion. (Letter to the editor)
Authors: Normington Ea, Jennison Rf
Journal: BMJ (1969)

We would disagree with the comment in your leading article (October 11 p. 61 therapeutic and spontaneous abortion) that because of the scarcity of Rh-immunoglobulin and the very small risk entailed in therapeutic and spontaneous abortion   is certainly no indication to give Rh-immunoglobulin....  The importance of abortion in relation to rhesus iso-immunization was emphasized by Clarke because of the possibility of an Rh-negative woman immunized by an Rh-positive  abortus having her future pregnancies affected by hemolytic disease.  Therapeutic abortion carries a higher risk of transplacental feto-maternal hemorrhage than spontaneous abortion (Matthews).  Krebs demonstrated that the risk of transplacental hemorrhage is increased if therapeutic abortion is carried out late in pregnancy.  In our own series of 110 cases of therapeutic abortions in which maternal blood was taken before and after abortion for fetal cell count the incidence of transplacental hemorrhage was much higher in the cases terminated by abdominal  hysterotomy or Utus paste as opposed to vaginal evacuation (Table).  Since induction of abortion with Utus paste and abdominal hysterotomy was carried out in cases past 12 weeks gestation the Table shows that the important factor with regard to the incidence of transplacental hemorrhage in cases of  therapeutic abortion is the gestation age of the fetus and not the route by which termination is effected as was also shown by Matthews.  There is a national shortage of anti-D immunoglobulin and while the risk may be small we cannot agree that there is no indication to give immunoglobulin in cases of therapeutic and spontaneous abortion.  If rhesus sensitization is to be considered a preventable disease Rh-negative women having a termination of pregnancy should be afforded protection as soon as sufficient anti-D immunoglobulin is available.  This is particularly true in primigravidae where the postoperative fetal cell count is high and the termination is carried out late in pregnancy.  There is no reason to condemn Rh-negative women to affected infants in a later marriage because they had a therapeutic abortion earlier.  Fetal Cells in Maternal Blood following Terapeutic Abortion: Method of termination -- Dilatation and evacuation -- 77 cases 22.7% positive; Method of termination -- Utus paste -- 11 cases 45% positive; Method of termination -- Hysterotomy  -- 12 cases 41.5% positive.(FULL TEXT)
Abstract 1355: A novel derivative of benzoxazole enhances radiosensitivity of human colon cancer cells through p53-mediated G2/M arrest and mitochondrial apoptotic pathway
Authors: Hwani Ryu, Bitna Seo, Jooyoung Kim, In-Sung Jung, Jie-Young Song, Jiyeon Ahn
Journal: Cancer Research (2016)

Abstract The tumor suppressor p53 plays a critical role in cell cycle regulation and apoptotic cell death, and its activation can sensitize cancer cells to radio- or chemotherapy. To identify small molecules that induce apoptotic cell death via increasing p53 transcriptional activity, we designed and synthesized 44 benzoxazole derivative small molecule compounds. Using a cell-based screening with p53-responsive luciferase reporter assay system of benzoxazole derivatives, we found AU14022, which significantly increased p53 transcriptional activity in a concentration dependent manner. Treatment of AU14022 increased p53 protein expression, its phosphorylation on serine 15 and its target p21 gene/protein expression and induced apoptotic cell death measured by FACS analysis using Annexin V/PI double staining in wild-type p53 HCT116 human colon cancer cells but not in p53 knockout HCT116 cells. Furthermore, treatment of HCT116 cells with AU14022 exhibited mitochondrial dysfunction including bcl-2 family modulation and cytochrome c release. Combination treatment of AU14022 and ionizing radiation (IR) synergistically induced apoptotic cell death, compared to IR or AU14022 alone. Further investigation demonstrated that cell cycles are significantly arrested at G2/M phase, and marked inductions of p21 protein expression and phosphorylation of Chk1 protein and a decrease of cyclin B1 protein expression were observed by treatment of AU14022 alone and combination treatment with AU14022 and IR. Our findings indicate that AU14022 induced apoptosis through p53-mediated cell cycle arrest with mitochondrial dysfunction, leading to enhanced radiosensitivity of colon cancer cells. These results provide a basis for the further investigations required for its assessment as a promising anticancer agent. Citation Format: Hwani Ryu, Bitna Seo, Jooyoung Kim, In-Sung Jung, Jie-Young Song, Jiyeon Ahn. A novel derivative of benzoxazole enhances radiosensitivity of human colon cancer cells through p53-mediated G2/M arrest and mitochondrial apoptotic pathway. [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 1355.
Occupational Asbestos Exposure and Incidence of Colon and Rectal Cancers in French Men: The Asbestos-Related Diseases Cohort (ARDCo-Nut)
Authors: Christophe Paris, Isabelle Thaon, Fabrice Hérin, Benedicte Clin, Aude Lacourt, Amandine Luc, Gaelle Coureau, Patrick Brochard, Soizick Chamming’s, Antoine Gislard, Pilar Galan, Serge Hercberg, Pascal Wild, Jean-Claude Pairon, Pascal Andujar
Journal: Environmental Health Perspectives (2016)

The relationships between asbestos exposure and colorectal cancer remain controversial.We examined the association between asbestos exposure and colorectal cancer incidence.Volunteer retired workers previously exposed to asbestos were invited to participate in the French ARDCo screening program between 2003 and 2005. Additional data on risk factors for colorectal cancer were collected from the ARDCo-Nut subsample of 3,769 participants in 2011. Cases of colon and rectal cancer were ascertained each year through 2014 based on eligibility for free medical care following a cancer diagnosis. Survival regression based on the Cox model was used to estimate the relative risk of colon and rectal cancer separately, in relation to the time since first exposure (TSFE) and cumulative exposure index (CEI) to asbestos, and with adjustment for smoking in the overall cohort and for smoking, and certain risk factors for these cancers in the ARDCo-Nut subsample.Mean follow-up was 10.2 years among 14,515 men, including 181 colon cancer and 62 rectal cancer cases (41 and 17, respectively, in the ARDCo-Nut subsample). In the overall cohort, after adjusting for smoking, colon cancer was significantly associated with cumulative exposure (HR = 1.14; 95% CI: 1.04, 1.26 for a 1-unit increase in ln-CEI) and ≥ 20-40 years since first exposure (HR = 4.67; 95% CI: 1.92, 11.46 vs. 0-20 years TSFE), and inversely associated with 60 years TSFE (HR = 0.26; 95% CI: 0.10, 0.70). Although rectal cancer was also associated with TSFE 20-40 years (HR = 4.57; 95% CI: 1.14, 18.27), it was not associated with ln-CEI, but these findings must be interpreted cautiously due to the small number of cases.Our findings provide support for an association between occupational exposure to asbestos and colon cancer incidence in men. Citation: Paris C, Thaon I, Hérin F, Clin B, Lacourt A, Luc A, Coureau G, Brochard P, Chamming's S, Gislard A, Galan P, Hercberg S, Wild P, Pairon JC, Andujar P. 2017. Occupational asbestos exposure and incidence of colon and rectal cancers in French men: the Asbestos-Related Diseases Cohort (ARDCo-Nut). Environ Health Perspect 125:409-415; http://dx.doi.org/10.1289/EHP153.
Abstract 4127: Blockade of TGFβ signaling enhances anticancer effect of chemotherapeutics in gynecologic cancers
Authors: Haiyan Zhu, Junhua Yang, Xiang Gu, Luzhe Sun
Journal: Cancer Research (2016)

Abstract Chemoresistance is a significant clinical challenge in the management of gynecologic malignancies. Previous studies have showed that TGF-β signaling pathway can mediate chemotherapy resistance. However, the underlying mechanisms of how TGF-β pathway is activated and causes chemoresistance are not well understood. Here, we found that ovarian cancer patients displayed an increased RNA transcripts of genes associated with TGF-β signaling after chemotherapy. In vitro, treatment with four commonly used drugs for gynecologic malignancies, including cisplatin, doxorubicin, paclitaxel and camptothecin, activated TGFβ signaling by stimulating phosphorylation of Smad2 and Smad3, two intracellular mediators of TGFβ signaling pathway in ovarian and cervical cancer cell lines. Furthermore, cisplatin and doxorubicin can induced epithelial-mesenchymal transition (EMT) and promote migration. Blockade of TGFβ signaling abrogated chemotherapeutics-stimulated Smad phosphorylation, epithelial-mesenchymal transition, and migration. These observations suggest that chemotherapy-mediated activation of TGFβ signaling may be a mechanism of chemoresistance, and that TGFβ pathway inhibitor may prevent the development of chemoresistant. We are currently testing the anti-tumor efficacy of the combination therapy with a novel pan-TGFβ inhibitor and cisplatin in a mouse xenograft model of ovarian cancer and whether the treatment with TGFβ inhibitor can alleviate symptoms of nephrotoxicity, which is known to be caused by cisplatin. Our studies may reveal new strategies for the treatment of gynecologic malignancies. Citation Format: Haiyan Zhu, Junhua Yang, Xiang Gu, Luzhe Sun. Blockade of TGFβ signaling enhances anticancer effect of chemotherapeutics in gynecologic cancers. [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 4127.