tbuckley/cabot-search huggingface dataset:
Abstract 5131: Efficient delivery of siRNA targeted CCDC88A mRNA to pancreatic cancer tumor inhibits the invasiveness and metastasis
Authors: Keisuke Taniuchi, Toshio Yawata, Tetsuya Ueba, Toshiji Saibara
Journal: Cancer Research (2017)

Abstract Introduction: We identified CCDC88A messenger RNA (mRNA) that accumulates in lamellipodia by binding to an RNA-binding protein IGF2BP3 with a next generation sequencer. The objectives of this study are as follows: (1) To identify CCDC88A specific small interfering RNAs (siRNAs) as RNA interference agents that have an inhibitory effect on the invasion and metastasis of pancreatic cancer cells in a mouse model of the invasion and metastasis of pancreatic cancer; and (2) To develop a nucleic-acid delivery system to efficiently transport the siRNAs to PDAC tissue. Methods: After intravenous injection of CCDC88A-specific siRNAs supplemented with folic acids that can bind to the folic acid receptor—which are highly expressed on pancreatic cancer cells—and polyethylene glycol-chitosan oligosaccharide nanoparticles to a mouse model of invasion and metastasis in which a human pancreatic cell line was transplanted to induce tumor formation in the mouse pancreas, accumulation of the siRNAs in the pancreatic cancer tissue was determined by using an in vivo imaging system. After CCDC88A-specific siRNA accumulation in the pancreatic cancer tissue was identified, invasion to the retroperitoneum as well as metastasis to the lung or liver from the human primary pancreatic tumor was compared between the mice in which CCDC88A-specific siRNA accumulation was identified and those receiving a scrambled control siRNA. Results: CCDC88A-specific siRNAs could be delivered to the pancreatic cancer cells of cancer-bearing nude mice by supplementation with folic acids and chitosan oligosaccharide nanoparticles. Supplementation with folic acids and chitosan oligosaccharide nanoparticles caused no hemolysis and had no effect on liver, kidney, or pancreatic function. Invasion to the retroperitoneum and metastasis to the lung or liver from the primary pancreatic cancer were suppressed in cancer-bearing nude mice by administration of those siRNAs, which target CCDC88A mRNA accumulated in lamellipodia of pancreatic cancer cells. Conclusions: This study suggests the potential to develop a siRNA drug to inhibit the invasion and metastasis of pancreatic cancer. Citation Format: Keisuke Taniuchi, Toshio Yawata, Tetsuya Ueba, Toshiji Saibara. Efficient delivery of siRNA targeted CCDC88A mRNA to pancreatic cancer tumor inhibits the invasiveness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5131. doi:10.1158/1538-7445.AM2017-5131
Abstract 4383: Novel fusion transcripts in colorectal cancer patients revealed by next-generation RNA sequencing
Authors: Yuri Choi, Chae Hwa Kwon, Hye Ji Park, Yeo-Jin Won, Do Youn Park
Journal: Cancer Research (2017)

Abstract Although colorectal cancer (CRC) is the third most common type of cancer in the world, there is an insufficient research on molecular targets for prevention and therapies of CRC. Gene fusions are associated with tumorigenesis and tumor activation, and could be a standard to distinguish tumor heterogeneity for personalized therapy. In the present study, we performed next-generation RNA sequencing (150 tumor and 50 matched normal tissues) in order to discover novel fusion transcripts in CRC. A total 25 transcript candidates were detected by GFP, deFuse, and FusionMap algorithms. Among the candidates, 6 fusion transcripts were selected (B4GALT1-BAG1, GTF3A-CDK8, NAGLU-IKZF3, RNF121-FOLR2, STRN-ALK, and TAF4-NDRG3) after analyzing expression and function of the acceptor genes. All of them were validated by sanger-sequencing and were not found in another cohort. Overexpression of these fusion genes, except B4GALT1-BAG1, increased proliferation of CRC cells. In addition, overexpression of NAGLU-IKZF3 enhanced migration of CRC cells. These results reveal novel fusion transcripts and their tumorigenic effects in CRC. Ultimately, it could illuminate a genomic-driven strategy to develop personalized medicine. Key words: fusion transcript, colorectal cancer, RNA-seq Citation Format: Yuri Choi, Chae Hwa Kwon, Hye Ji Park, Yeo-Jin Won, Do Youn Park. Novel fusion transcripts in colorectal cancer patients revealed by next-generation RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4383. doi:10.1158/1538-7445.AM2017-4383
Genetic Causes of Functional Adrenocortical Adenomas
Authors: Maria-Christina Zennaro, Sheerazed Boulkroun, Fabio Fernandes-Rosa
Journal: Endocrine Reviews (2017)

Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormones in humans, are produced in the adrenal cortex, which is composed of three concentric zone with specific functional characteristics.Adrenocortical adenomas (ACA) may lead to the autonomous secretion of aldosterone responsible for primary aldosteronism, the most frequent form of secondary arterial hypertension.In the case of cortisol production, ACA lead to overt or subclinical Cushing syndrome.Genetic analysis driven by next generation sequencing technology has enabled the discovery, during the last seven years, of the genetic causes of a large subset of ACA.In particular, somatic mutations in genes regulating intracellular ionic homeostasis and membrane potential have been identified in aldosterone producing adenoma.These mutations all promote increased intracellular calcium concentrations, with activation of calcium signaling, the main trigger for aldosterone production.In cortisol producing adenomas, recurrent somatic mutations in PRKACA (coding for the cAMP-dependent protein kinase catalytic subunit alpha) affect cyclic AMP-dependent protein kinase A signaling, leading to activation of cortisol biosynthesis.In addition to these specific pathways, the Wnt/β-catenin pathway appears to play an important role in adrenal tumorigenesis, as βcatenin mutations have been identified in both aldosterone as well as cortisol producing adenomas.This, together with different intermediate states of aldosterone and cortisol cosecretion, raises the possibility that the two conditions share a certain degree of genetic susceptibility.Alternatively, different hits may be responsible for the diseases, with one hit leading to adrenocortical cell proliferation and nodule formation, with the second one specifying the hormonal secretory pattern.
Abstract CT078: Impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia
Authors: Jae H. Park, Isabelle Rivere, Xiuyan Wang, Brigitte Senechal, Kevin Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Daniel Li, Renier Brentjens, Michel Sadelain
Journal: Cancer Research (2017)

Abstract Objectives: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL with a focus on impact of pre-treatment disease burden and post-CAR T cell allogeneic transplant on long-term clinical outcome. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion. We grouped patients into 2 cohorts based on disease burden upon T cell infusion: minimal residual disease (MRD) with &amp;lt;5% blasts in bone marrow and morphologic disease (≥5% blasts). Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p=0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 - 36.2) (p=0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p=0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p=0.0326 and p=0.0001, respectively). Conclusion: Despite comparable initial CR rates between the two cohorts, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Citation Format: Jae H. Park, Isabelle Rivere, Xiuyan Wang, Brigitte Senechal, Kevin Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Daniel Li, Renier Brentjens, Michel Sadelain. Impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT078. doi:10.1158/1538-7445.AM2017-CT078
Early outcomes in MDR-TB and XDR-TB patients treated with delamanid under compassionate use
Authors: Jeffrey Hafkin, Norbert Hittel, Alexandra Martin, Rajesh Gupta
Journal: European Respiratory Journal (2017)

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) remain significant global health challenges, with an annual incidence of approximately 480 000 and 46 000 cases, respectively [1]. Treatment outcomes in MDR-TB patients remain poor overall (52% success) and outcomes in XDR-TB patients are even more dismal (28% success) [1–3]. To improve these outcomes, new drugs are needed [4]. Delamanid, a nitroimidazooxazole agent that has been included in the guidelines for MDR-TB treatment by the World Health Organization (WHO), has been shown to improve two-month sputum culture conversion (SCC) and long-term treatment outcomes, when added to an optimised background regimen (OBR) in MDR-TB patients [5–7]. As part of a global access initiative, Otsuka Pharmaceutical Co., Ltd. in coordination with the European Respiratory Society (ERS)/WHO TB Consilium, and Médecins Sans Frontières/Partners in Health (MSF-PIH) established its first Compassionate Use (CU) programme in February 2014 to provide patients with very limited treatment options access to delamanid. We present here early safety and efficacy outcomes of patients enrolled in this effort. Early data from the CU programme show delamanid may be effective in MDR/XDR-TB with few treatment options <http://ow.ly/tA6Y30cs2Yg> We would like to thank Clotilde Picard and Lusine Breitscheidel (Otsuka Novel Products GmbH, Munich, Germany) for their assistance with data collection, as well as Zuzanna Huebschmann (Otsuka Novel Products GmbH) for her critical review of the manuscript.
A novel technique for biliary polypectomy
Authors: Lionel D’Souza, Andrew Korman, Petros Benias, David Carr-Locke
Journal: Endoscopy (2017)

We present a case of a 37-year-old man with known ulcerative colitis and primary sclerosing cholangitis. He had been diagnosed at the age of 17 years, but was lost to follow-up for about 15 years. He returned to an outpatient gastroenterologist and was found to have abnormal liver enzyme levels. As part of the work-up he had magnetic resonance cholangiopancreatography (MRCP) that showed a filling defect, measuring 10 mm × 7 mm, in the common hepatic duct. He underwent an endoscopic retrograde cholangiopancreatography (ERCP) with cholangioscopy which revealed a smooth benign-appearing polyp in the common hepatic duct that was causing obstruction of the right intrahepatic system. Biopsy of the mass was performed with a miniature biopsy forceps, and showed denuded fibrous tissue with acute and chronic inflammation without any evidence of carcinoma.
Abstract 346: Fatty acid synthase is a risk factor for bleomycin-induced lung fibrosis in mice
Authors: Mi-Yeon Jung
Journal: Cancer Research (2017)

Abstract Pulmonary fibrosis is a significant complication in cancer patients treated with radiation or various chemotherapeutic agents. One such reagent, bleomycin, is used to treat a variety of cancers including, but not limited to, lymphoma, ovarian cancer, and melanoma. Its efficacy, however, is impacted by the incidence of significant pulmonary fibrosis, which often becomes dose limiting. In studies investigating the role(s) of metabolism in the profibrotic actions of transforming growth factor beta, we previously determined that increased fatty acid synthase (FASN) expression was observed in the fibrotic areas of lungs from idiopathic pulmonary fibrosis (IPF) patients compared to healthy controls. In that FASN levels are significantly increased in numerous human tumors including breast, prostate, colorectal, and ovarian, we wished to integrate these findings by examining whether inhibiting FASN activity could reduce pulmonary fibrosis. To that end, the cerulenin-derived FASN inhibitor C75 was tested in a murine treatment model of bleomycin-induced lung fibrosis. Following addition of C75, there was significant diminution in a number of profibrotic targets including collagen 1α1, fibronectin, connective tissue growth factor, and total lung collagen as assessed by hydroxyproline content. Not only was there a C75 dose-dependent decrease in the aforementioned targets, but lung function as assessed by peripheral blood oxygenation (on room air) was also stabilized/improved. Thus, FASN inhibition might reflect a possible target to maintain normal lung physiology in the context of cancer chemotherapy. This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences. Citation Format: Mi-Yeon Jung. Fatty acid synthase is a risk factor for bleomycin-induced lung fibrosis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 346. doi:10.1158/1538-7445.AM2017-346
Charles Douglas Forbes
Authors: Stuart Forbes, Donald Forbes, William Jackson
Journal: BMJ (2017)

Charles Douglas Forbes was born in Glasgow, attended the High School of Glasgow, and subsequently studied medicine at Glasgow University, starting in 1955 at the tender age of 16. His mother was a general practitioner in the Gorbals in Glasgow. After qualifying, Charles worked at the Rotten Row and Stobhill Hospitals in Glasgow. At Stobhill, he also met his wife to be, Janette Robertson, then ward sister in the maternity unit.

In 1965 he took up a year long secondment to the University of East Africa at the Kenyatta National Hospital, Nairobi, Kenya. His work here included pioneering research into the effects of snake venom on blood coagulation. After his return to Glasgow he was awarded a Fulbright scholarship, and moved to Case Western University School of Medicine, Cleveland, Ohio, USA, with his …
ABC of alcohol. Alcohol in the body.
Authors: J B Saunders, A Paton
Journal: BMJ (1981)

Alcohol (ethanol) is a drug, and health professionals should know something of its physiological and pathological effects and its handling by the body. It is a small, water soluble molecule that is relatively slowly absorbed from the stomach, more rapidly absorbed from the small intestine, and freely distributed throughout the body. Alcoholic drinks are a major source of energy—for example, six pints of beer contain about 500 kcal and half a litre of whisky contains 1650 kcal. The daily energy requirement for a moderately active man is 3000 kcal and for a woman 2200 kcal.
Abstract 5876: Osimertinib (AZD9291), a mutant-selective EGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells
Authors: Xiao-Yu Zhang, Zi-Ning Lei, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Leli Zeng, Megan Xu, Xiu-Qi Wang, Dong-Hua Yang, Zhe-Sheng Chen
Journal: Cancer Research (2017)

Abstract In recent years, tyrosine kinase inhibitors (TKIs) have been shown capable of inhibiting the ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR). In this study, we determine whether osimertinib, a novel selective, irreversible EGFR (epidermal growth factor receptor) TKI inhibitor, could reverse ABC transporter-mediated MDR. The results showed that at non-toxic concentrations, osimertinib significantly sensitized both ABCB1-transfected and drug-selected cell lines to substrate anticancer drugs colchicine, paclitaxel, and vincristine. Osimertinib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant alteration in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 0.3μM osimertinib for 72 h. In addition, ATPase assay showed osimertinib stimulated ABCB1 ATPase activity. Molecular docking and molecular dynamic simulations showed osimertinib has strong and stable interactions at transmembrane domain of human homology ABCB1. Taken together, our findings suggest that osimertinib, a clinically approved third-generation EGFR TKI, can reverse ABCB1-mediated MDR, which supports the combination therapy with osimertinib and ABCB1 substrates may potentially be a novel therapeutic treatment in ABCB1-positive drug resistant cancers. Citation Format: Xiao-Yu Zhang, Zi-Ning Lei, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Leli Zeng, Megan Xu, Xiu-Qi Wang, Dong-Hua Yang, Zhe-Sheng Chen. Osimertinib (AZD9291), a mutant-selective EGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5876. doi:10.1158/1538-7445.AM2017-5876
Abstract 3066: Inhibition of hsp90 by auy922 preferentially kills mutant KRAS colon cancer cells by activating Bim through ER stress
Authors: Chun Yan Wang, Su Tang Guo, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Hamed Yari, Ting La, Fu Xi Lei, Lei Jin, Chen Chen Jiang, Xu Dong Zhang
Journal: Cancer Research (2017)

Abstract Colon cancer is one of the most common and deadly malignancies (1). Despite recent advances in early diagnosis and the development of molecularly targeted therapy, the overall survival of patients with metastatic colon cancers remains disappointing (1). This is often associated with resistance of colon cancer cells to systemic therapies resulting from oncogenic mutations of KRAS that drive activation of multiple downstream signalling pathways important for cell survival and proliferation. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the heat shock protein 90 (HSP90) inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with the comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with activating mutations of KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3 only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. In addition, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and that agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy. Citation Format: Chun Yan Wang, Su Tang Guo, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Yuan Yuan Zhang, Fen Liu, Hamed Yari, Ting La, Fu Xi Lei, Lei Jin, Chen Chen Jiang, Xu Dong Zhang. Inhibition of hsp90 by auy922 preferentially kills mutant KRAS colon cancer cells by activating Bim through ER stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3066. doi:10.1158/1538-7445.AM2017-3066