tbuckley/cabot-search huggingface dataset:
Abstract 2094: Hsp70 inhibitors overcome tamoxifen resistance, in cell culture model
Authors: John Koren, Yoshinari Miyata, Janine Kiray, Jianping Guo, Jason Gestwicki, Jin Q. Cheng, Chad Dickey
Journal: Cancer Research (2011)

Abstract A prevalent problem in the use of chemotherapies for the treatment of human cancers is the potential for the development of resistance. While the exact nature of the mechanisms involved in resistance development vary based on cancer type as well as the nature of the therapeutics; some oncogenic factors have been established to have roles in the desensitization to common treatments. Previous data from our lab demonstrated Hsp70 inhibitors can reduce Akt levels. a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance. We have, Uusing these Hsp70 ATPase-inhibiting compounds and ain a cell culture model of tamoxifen resistant breast cancer, we have identified compounds which can re-sensitize resistant cells. These compounds inhibit cytosolic and mitochondrial members of the 70-kDA heat-shock protein family. These compounds also reduce Akt levels, a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance, as well as Thus, in addition to reducing Akt levels and possibly other oncogenic chaperone clients, these drugs may also interrupt mitochondrial function leading to reduced viability in the presence of tamoxifen. With these mechanisms in mind, we now have data that Ttamoxifen resistant MCF7 cells regained sensitivity to tamoxifen after brief treatments with Hsp70-family inhibitors. The resistant cells were grown in media containing tamoxifen. This media was replaced with media containing an Hsp70 inhibitor compound for four hours. After the four hours, the Hsp70 inhibitor media was removed and tamoxifen-containing media was reapplied to the cells. Multiple viability and cytotoxicity assays confirm the drop in viability and increased cytotoxicity following these treatments. These studies demonstrate that Hsp70 family members are potentially valuable targets for new cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2094. doi:10.1158/1538-7445.AM2011-2094
Abstract 4539: Anti-leukemic activity of mitochondria-targeted asymmetrical 2,2′-binaphthoquinones
Authors: Rebecca M. Ricklis, Milena Vuica-Ross, Robert A. Brodsky, Edward Sausville, Chi V. Dang, Judith E. Karp, Ashkan Emadi
Journal: Cancer Research (2010)

Abstract Introduction: Binaphthoquinones are unique molecules consisting of two linked naphthoquinone units. By definition biquinones cause more effective oxidative stress than their monoquinone counterparts. Previously, we regiospecifically synthesized a series of asymmetrical binaphthoquinones, which possess HIV integrase inhibitory activity. Potent activity against HIV-uninfected CEM-T4 cells prompted us to investigate other cytotoxic mechanisms. A genome-wide yeast screen uncovered that mitochondria-related genes are required for sensitivity and resistance to these agents. Since mitochondria membrane permeabilization occurs early in the apoptotic program and is located downstream of most identified chemotherapy resistance mechanisms in hematological malignancies, we hypothesized that binaphthoquinones would be able to interfere with mitochondria function in leukemia cells and induce apoptosis by abrogating or bypassing other mechanisms of drug resistance. Materials and Methods: Seventeen of our biquinones were incubated with four leukemia cell lines (MV411, MOLM14, HL-60, U937) grown under standard conditions. A standard MTT cell proliferation assay was used to identify IC50 values. Two of the most potent compounds, biquinones #7 and #10 (BiQ7 &amp; BiQ10), were assayed against MV411 cells and analyzed by flow cytometry for loss of mitochondria membrane potential (via rhodamine 123 staining), as well as a variety of apoptosis markers, such as phosphatidylserine, activated caspases, and sub-2n DNA increases by using Annexin V-PE (with 7AAD), a fluorescent caspase inhibitor reagent, and propidium iodide (PI), respectively. Results: The IC50 values for both compounds were less than 5 μM against all cell lines. A loss of mitochondria membrane potential was observed in 98-100% of the treated cells (control 5%). Loss of plasma membrane phosphatidylserine asymmetry was observed in 94-95% of the treated cells (control 18%). The cells showed increases in staining for activated caspases 3 &amp; 7 (control 10%; BiQ7 98%; and BiQ10 96%). Finally, the cell cycle analyses showed increases in sub-2n DNA in the treated cells compared to the control (control 12%; BiQ7 34%; and BiQ10 54%). These assays were subsequently repeated to obtain triplicate results. Conclusion: Our study shows that this new class of compounds possesses promising in vitro anti-leukemic effects by targeting mitochondria membrane potential. In vivo experiments in a xenograft model and ex vivo experiments on primary human cells are in progress. The cytotoxicities of binaphthoquinones could vary widely as a result of the array of structural configurations available. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4539.
NC-03 * POLYMORPHISMS IN THE COMT, BDNF AND DTNBP1 GENES AND COGNITIVE FUNCTIONS IN PATIENTS WITH BRAIN TUMORS
Authors: D. Correa, J. Satagopan, R. Baser, K. Cheung, L. DeAngelis, I. Orlow
Journal: Neuro-Oncology (2014)

BACKGROUND: Cognitive dysfunction is prevalen among brain tumor patients treated with radiotherapy (RT) and chemotherapy (CT). However, little is known about genetic risk factors that may moderate their vulnerability for developing cognitive impairment. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in three genes, Catechol-O-Methyl-Transferase (COMT), Brain-Derived-Neurotrophic-Factor (BDNF), and dystrobrevin binding protein 1 (DTNBP1), and cognitive functions in brain tumor survivors. METHODS: One hundred and fifty brain tumor patients participated in the study: ninety had been treated with RT ± CT, fifty-seven had CT alone, and three had no therapy. All Patients completed a battery of neuropsychological tests of attention, executive functions and memory, and provided a blood sample. Genotyping of SNPs in the BDNF (n = 9), COMT (n = 17) and DTNBP1 (n = 7) genes was performed. RESULTS: Linear regressions with stepwise backward elimination of SNPs based on change in AIC criterion, adjusting for age, education, and treatment type indicated a significant (p< 0.05) association between the COMT SNP rs4680 (Val158Met) and cognitive function, with lower working memory scores in homozygotes (G/G) and higher executive function and delayed recall scores in heterozygotes (A/G). Five additional SNPs in the COMT gene were significantly associated with lower scores in attention and executive functions. There were significant associations among five SNPs in the BDNF gene and lower performance in executive function, learning and delayed recall. Four SNPs in the DTNBP1 gene were associated with attention and memory scores. CONCLUSION: The findings suggest that in brain tumor patients, cognitive outcome may be differentially affected by polymorphisms in genes previously associated with executive and memory functions in healthy individuals and other clinical populations. Further work is underway to quantify the variation in cognitive outcomes explained by these polymorphisms.
Abstract 1408: Activation status and function of the canonical Wnt pathway in murine mammary tumor cells reexpressing Glypican-3 (GPC3)
Authors: María A. Lago Huvelle, Silvina A. Romero, Lilian Castillo, Elisa Bal de Kier Joffé, María G. Peters
Journal: Cancer Research (2012)

Abstract GPC3 is a proteoglycan downregulated in breast cancer cells. We previously demonstrated that GPC3 reexpression inhibits in vivo metastatic potential of LM3 murine mammary adenocarcinoma cells. This event was associated in vitro with a lower motility and an increased aggregation, as well as with an enhanced senescence and apoptosis. We have previous evidence indicating that the canonical Wnt pathway is inhibited in LM3-GPC3 cells. The aim of this work was to validate the inhibition of canonical Wnt signaling in GPC3 reexpressing cells and to investigate whether differences in cell behavior are due to the regulation of GPC3 on this pathway. By means of western blots (WB) we established that LM3-GPC3 cells have 5-10 folds less phosphorylated GSK3B. Using cytoplasmic protein extracts and WB we also determined that GPC3 reexpressing cells present lower levels of cytoplasmic B-Catenin. This was further studied by immunofluorescence (IF), where it was found that while LM3-vector cells show positive signal for B-catenin mainly in nucleus and cytoplasm, this staining is restricted to the membrane and cytoplasm in LM3-GPC3 cells. In addition, a gene reporter assay employing OT/OF plasmids confirmed the canonical Wnt pathway inhibition induced by GPC3. To determine whether cell properties modulated by GPC3 are mediated by the canonical Wnt pathway, we treated cells with its activator LiCl (or NaCl as control). LiCl treatment increases 10-fold the phosphorylation of GSK3B, as compared to LM3-GPC3 cells treated with NaCl, and induces an enhance of about 50% of the canonical Wnt transcriptional activity (gene reporter assay). We confirm that although LiCl partially reverted senescence induced by GPC3 reexpression (Senescent X-Gal positive cells: LM3-GPC3+NaCl= 85% vs. LM3-GPC3+LiCl= 65%, p&amp;lt;0.05), it had no effects on apoptosis. We established by wound healing assays that LM3-GPC3 cells +LiCl recover their ability to migrate (Coverage of the wound: LM3-GPC3+NaCl= 15% vs LM3-GPC3+LiCl= 75%, p&amp;lt;0.05). Finally, LiCl treatment reduced LM3-GPC3 homotypic cell aggregation, reaching similar levels to LM3-vector clones (p&amp;lt;0.05). In summary, we confirm by a new methodological approach that GPC3 inhibits the canonical Wnt signaling. Our results suggest that GPC3 would be modulating senescence, migration and cell aggregation of mammary tumor cells through this pathway inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1408. doi:1538-7445.AM2012-1408
Transnasal endoscopy to facilitate nasobiliary tube placement: a simple and safe technique to avoid injury to the endoscopist
Authors: T. Baron
Journal: Endoscopy (2010)

Endoscopic nasobiliary tube placement was described 30 years ago [1]. The placement technique has not changed: after positioning the nasobiliary tube within the biliary tree, the duodenoscope is withdrawn, leaving the tube exiting the mouth; a transfer tube is passed transnasally; and finally, the endoscopist (or designee) passes his or her fingers into the patient’s mouth to retrieve the transfer tube from the oropharynx to allow the nasobiliary tube to be transferred from mouth to nose. Placing one’s fingers into the patient’s mouth can be dangerous, since the uncooperative patient has a tendency to bite the doctor (or designee). Use of a bite block or mouthpiece offers some protection [2]. A new technique is described that avoids this risk during nasobiliary tube transfer.
Lung Cancer after Employment in Shipyards during World War II
Authors: William J. Blot, J. Malcolm Harrington, Ann Toledo, Robert Hoover, Clark W. Heath, Joseph F. Fraumeni
Journal: New England Journal of Medicine (1978)

A case-control study, undertaken to identify reasons for the exceptionally high rate of lung cancer among male residents of coastal Georgia, revealed a significantly increased risk associated with employment in area shipyards during World War II. The summary relative-risk estimate, adjusted for smoking, other occupations, age, race and county of residence was 1.6 (95 per cent confidence limits = 1.1 to 2.3). A synergistic relation was found between shipyard employment and cigarette smoking. These findings suggest that asbestos and possible other shipyard exposures during wartime employment account for part of the excess mortality from lung cancer in certain coastal areas of the United States.
Endoscopic closure of a post-traumatic pancreatic fistula with interventional radiology techniques
Authors: T. Miłek, P. Ciostek
Journal: Endoscopy (2010)

A patient aged 54 years sustained predominantly abdominal, multiorgan trauma in a road traffic accident. A computed tomography (CT) scan showed rupture of the right hepatic lobe with a large amount of blood in the abdominal cavity. The patient underwent an emergency operation. Postoperatively there was leakage of the pancreatic contents (200 – 300 mL/24 h) and symptoms of acute pancreatitis. A follow-up CT scan revealed damaged pancreatic tissue at the border between the corpus and the tail ([Fig. 1]). The pancreatic fistula was treated conservatively with total parenteral nutrition, octreotide, and antibiotics. Due to pus formation and transverse colon necrosis, four debridement procedures were carried out; the abscesses were drained and the transverse colon resected with formation of a descending colostomy [1] [2]. After the inflammation was controlled and the pancreatic fistula was closed, enteral nutrition was initiated [3]. Octreotide withdrawal caused reappearance of the pancreatic fistula. After several laparotomy attempts, surgical closure of the fistula was deemed technically difficult. Therefore, a decision was made to close the fistula using an endoscopic approach. For this purpose, the large communication between the damaged pancreatic duct and the peritoneum was reduced by endoscopic retrograde cholangiopancreatography (ERCP) ([Fig. 2]) [4] [5]. With the use of interventional radiology techniques, a vascular coil was implanted into Wirsung’s duct, just proximal to the site of the damage. The coil was additionally sealed with a tissue adhesive ([Fig. 3]). Following this procedure, the pancreatic fistula, which had been persistent for several weeks, closed. The peripheral part of the pancreas did not cause any therapeutic difficulties. Placement of a vascular coil at the end of a torn Wirsung’s duct causes increased pressure in this part of the duct and free flow of pancreatic juice into the duodenum is possible after sphincterotomy.
Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis
Authors: Lars W Andersen, Tobias Kurth, Maureen Chase, Katherine M Berg, Michael N Cocchi, Clifton Callaway, Michael W Donnino
Journal: BMJ (2016)

<b>Objectives</b>&nbsp;To evaluate whether patients who experience cardiac arrest in hospital receive epinephrine (adrenaline) within the two minutes after the first defibrillation (contrary to American Heart Association guidelines) and to evaluate the association between early administration of epinephrine and outcomes in this population. <b>Design</b>&nbsp;Prospective observational cohort study. <b>Setting</b>&nbsp;Analysis of data from the Get With The Guidelines-Resuscitation registry, which includes data from more than 300 hospitals in the United States. <b>Participants</b>&nbsp;Adults in hospital who experienced cardiac arrest with an initial shockable rhythm, including patients who had a first defibrillation within two minutes of the cardiac arrest and who remained in a shockable rhythm after defibrillation. <b>Intervention</b>&nbsp;Epinephrine given within two minutes after the first defibrillation. <b>Main outcome measures</b>&nbsp;Survival to hospital discharge. Secondary outcomes included return of spontaneous circulation and survival to hospital discharge with a good functional outcome. A propensity score was calculated for the receipt of epinephrine within two minutes after the first defibrillation, based on multiple characteristics of patients, events, and hospitals. Patients who received epinephrine at either zero, one, or two minutes after the first defibrillation were then matched on the propensity score with patients who were "at risk" of receiving epinephrine within the same minute but who did not receive it. <b>Results</b>&nbsp;2978<b></b>patients were matched on the propensity score, and the groups were well balanced. 1510 (51%) patients received epinephrine within two minutes after the first defibrillation, which is contrary to current American Heart Association guidelines. Epinephrine given within the first two minutes after the first defibrillation was associated with decreased odds of survival in the propensity score matched analysis (odds ratio 0.70, 95% confidence interval 0.59 to 0.82; P&lt;0.001). Early epinephrine administration was also associated with a decreased odds of return of spontaneous circulation (0.71, 0.60 to 0.83; P&lt;0.001) and good functional outcome (0.69, 0.58 to 0.83; P&lt;0.001). <b>Conclusion</b>&nbsp;Half of patients with a persistent shockable rhythm received epinephrine within two minutes after the first defibrillation, contrary to current American Heart Association guidelines. The receipt of epinephrine within two minutes after the first defibrillation was associated with decreased odds of survival to hospital discharge as well as decreased odds of return of spontaneous circulation and survival to hospital discharge with a good functional outcome.
Phase I Study of Adozelesin Administered by 24-Hour Continuous Intravenous Infusion
Authors: G. F. Fleming, M. J. Ratain, S. M. O'Brien, R. L. Schilsky, P. C. Hoffman, J. M. Richards, N. J. Vogelzang, D. A. Kasunic, R. H. Earhart
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Phase I Study of Adozelesin Administered by 24-Hour Continuous Intravenous Infusion Get access Gini F. Fleming, Gini F. Fleming * Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, Unversity of ChicagoIII. * Gini F. Fleming. M.D., Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., MC 2115. Chicago. IL 60637-1470 Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark J. Ratain, Mark J. Ratain Committee on Clinical Pharmacology, Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago. Search for other works by this author on: Oxford Academic PubMed Google Scholar Sheila M. O'Brien, Sheila M. O'Brien Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, Unversity of ChicagoIII. Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard L. Schilsky, Richard L. Schilsky Committee on Clinical Pharmacology, Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago. Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip C. Hoffman, Philip C. Hoffman Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, Unversity of ChicagoIII. Search for other works by this author on: Oxford Academic PubMed Google Scholar Jon M. Richards, Jon M. Richards Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, Unversity of ChicagoIII. Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. Vogelzang, Nicholas J. Vogelzang Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, Unversity of ChicagoIII. Search for other works by this author on: Oxford Academic PubMed Google Scholar Dorothy A. Kasunic, Dorothy A. Kasunic The Upjohn Co.,Kalamazoo, Mich. Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert H. Earhart Robert H. Earhart The Upjohn Co.,Kalamazoo, Mich. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 5, 2 March 1994, Pages 368–372, https://doi.org/10.1093/jnci/86.5.368 Published: 02 March 1994 Article history Received: 09 September 1993 Revision received: 02 December 1993 Accepted: 09 December 1993 Published: 02 March 1994
PWE-159 The Costs Of Irritable Bowel Syndrome (ibs) In An Increasingly Cost Aware Nhs
Authors: P Wilson, A Poullis, J Wilkins, M Rance
Journal: Gut (2014)

<h3>Introduction</h3> The NHS is faced with increasing cost pressures making the efficient use of resources paramount. Both NICE and BSG guidelines state that patients with IBS should be managed in primary care.<sup>1,2</sup> Despite this up to 50% of patients with a diagnosis of IBS are referred to secondary care for investigation.<sup>3</sup> Outpatient visits and endoscopic investigations consume a considerable NHS resource. <h3>Methods</h3> Hospital Episode Statistics (HES) data for 2012–13 for all the Care Commissioning Groups (CCGs) in England were analysed to calculate the financial cost of IBS. IBS symptom codes were included. Organic gastrointestinal (GI) disease codes were excluded from the analysis. Primary Care prescribing analyses and cost (PACT) data 2012–13 were analysed to calculate IBS treatment costs. <h3>Results</h3> In England in 2012/13, there were 1,219,961 patients attending gastroenterology and colorectal surgery outpatient specialties, with a total cost of £365,868,937. Despite this, only a total of 1,982 patients who were coded as IBS with a total estimated cost of £744,812 were recorded. However, if we look at the total costs of patients under 50 years of age with excluded diagnosis as described above, we get a total of 28,849 patients with a cost of £11,002,874. In 2011/12, there were also 323,752 day case and outpatient diagnostic endoscopies with a total cost of £169,676,704 where no further activity was seen either as an inpatient or outpatient for the 12 months following the diagnostic endoscopy. This represents 49% of the total diagnostic endoscopies performed in this group of patients. In Primary Care, treatment with laxatives and antispasmodics totalled over 50 million pounds, with £40,219,270 spent on macrogol and £11,024,948 spent on mebeverine. <h3>Conclusion</h3> Despite being poorly clinically coded it is clear that IBS is a significant costs burden to the NHS. Over half of patients seen for day case and outpatient diagnostic endoscopies have no further clinical activity coded over the subsequent 12 months implying functional symptoms. Better diagnosis and subsequent management of IBS within a Primary Care setting would provide direct savings in the cost of IBS management as well as enabling GI services to target its resources such as colonoscopy services towards other GI conditions more appropriately in areas of greater clinical need. Work funded by Almirall as a “Service to Medicine”. Hospital Episode Statistics Data provided via Harvey Walsh Ltd under commercial reuse licence from the Health and Social Care Information Centre 2014. <h3>References</h3> 1N. I. C. E. IBS in Adults. Clinical Guidelines 61. 2008 2B. S. G. Guidelines on IBS. 2007 3B. S. G. Commissioning Report on IBS. 2009 <h3>Disclosure of Interest</h3> P. Wilson: None Declared, A. Poullis: None Declared, J. Wilkins Employee of: Harvey Walsh Ltd, M. Race Employee of: Almirall
IMPACT OF EICOSAPENTAENOIC ACID PREVENTS ON LATE NEOINTIMAL PROLIFERATION: A SERIAL VOLUMETRIC FREQUENCY DOMAIN-OPTICAL COHERENCE TOMOGRAPHY STUDY
Authors: Ryotaro Yamada, Teruyoshi Kume, Yutaka Goryo, Kenzo Fukuhara, Yoji Neishi, Terumasa Koyama, Ai Kawamura, Kikuko Obase, Tomoko Tamada, Koichiro Imai, Hiroshi Okamoto, Yusuke Kobayashi, Shiro Uemura
Journal: Journal of the American College of Cardiology (2016)