tbuckley/cabot-search huggingface dataset:
7. Lentiviral Vector-Mediated CFTR Gene Transfer to CF Pig Airways Corrects the Anion Transport Defect In Vivo
Authors: Ashley L. Cooney, Mahmoud H. Abou Alaiwa, David A. Stoltz, Michael J. Welsh, Patrick L. Sinn, Paul B. McCray
Journal: Molecular Therapy (2015)

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations and is caused by mutations in CFTR. Complementation of CFTR rescues the anion transport defect in vitro, making this monogenetic disease a candidate for CF gene therapy. Lentiviral vector-mediated CFTR gene transfer has long been discussed as a promising strategy for gene therapy. Lentiviral vectors can efficiently transduce non-dividing cells and persistently express a therapeutic transgene. We previously demonstrated that the non-primate lentiviral vector derived from feline immunodeficiency virus (FIV) and pseudotyped with a GP64 envelope confers gene transfer to porcine airway epithelia both in well-differentiated primary cultures in vitro and in wild-type pig lungs in vivo. The CF pig model recapitulates many features of human disease and provides a new platform for preclinical gene therapy studies. Here, we show that lentiviral-mediated delivery of CFTR to nasal and lung epithelia corrects the anion channel defect in the CF pig model. We delivered GP64-FIV-pigCFTR to the nose and lung of 2-week old gut-corrected CF pigs using a MADgic atomizer. Two weeks post-transduction, we harvested sinus, trachea, and bronchus tissue to assay for gene correction. In freshly excised trachea and bronchus tissue explants, we observed a short-circuit current response to forskolin and IBMX (F&I) and inhibition by GlyH-101, consistent with CFTR function. Compared to non-transduced animals, cultured ethmoid sinus epithelia also showed evidence of correction by short-circuit current measurements. Loss of CFTR results in reduced bicarbonate transport and a lower ASL pH. A reduction in ASL pH impairs bacterial killing. Following gene transfer, we observed an increase in nasal and tracheal pH and rescue of bacterial killing. Together, these exciting results demonstrate the first evidence of functional in vivo correction of CFTR by a lentivirus in the CF pig model. These findings support the utility of a lentivirus for CF gene therapy.
European Perspectives
Journal: Circulation (2011)

de Zeeuw recalls, "He was doing some early work on the use of one of the first ACE [angiotensinconverting enzyme] inhibitors [captopril], when he discovered by chance that this drug was doing something to the kidney, and increased proteinuria.Years later I tested another ACE inhibitor with Paul de Jong, MD, PhD, and discovered by chance that this one lowered the protein in the urine.This gave me a focus, and although Ab Donker had advised me about the importance of being broadly based, I decided I wanted to be focused."The approach paid off, and gave Professor de Zeeuw the area of research that he continues to investigate.He says, "Luckily for me, the topic stayed viable, and it was f103
Morbidity and mortality after closure of protective loop ileostomy.
Authors: G. Cipe, B. Erkek, A. Kuzu, E. Gecim
Journal: Journal of Clinical Oncology (2011)

e14111 Background: A diverting loop ileostomy is often created to protect distal colorectal, colo-anal and ileoanal anastomoses. Ileostomy closure is associated with morbidity and mortality. The aim of this study was to determine the morbidity and mortality of ileostomy closure. Methods: Two hundred fifty-five patients with a diverting loop ileostomy, created between October 1999 and May 2010, were analyzed retrospectively. Results: One hundred thirty-nine male and 116 female patients with a median age of 54 (range 17- 79) years underwent ileostomy closure. Forty-seven patients (18.4%) developed complications: 16 (6.3%) intestinal obstruction (2 required re-laparotomy), 11 (4.3%) wound infection, 6 (2.3%) pulmonary complication, 5 (1.9%) anastomotic leak (2 subsequently died), 3 (1.2%) ileus, 2 (0.8%) myocardial infarction (1 subsequently died), 2 (0.8%) hematoma, 1 (0.4%) urinary retention, and 1 (0.4%) transient ischemic attack. The median length of the hospital stay was 6 (range 2-14) days. Conclusions: Closure of loop ileostomy is a simple procedure with low morbidity and a small but real risk of mortality. Fortunately, most complications are minor; nevertheless, preventions to reduce the complications should be considered. Classification of morbidity and mortality according to primary pathology. Primary pathology N Morbidity N (%) Mortality N (%) Colorectal cancer 136 23 (16.9) 1 (0.7) Ulcerative colitis 45 8 (17.8) 1 (2.2) Familial adenomatous polyposis 32 6 (18.8) 0 (0) Crohn’s disease 14 3 (21.4) 0 (0) Diverticular disease 8 3 (37.5) 1 (8) Bowel ischemia 4 1 (25) 0 (0) Ileus 3 0 (0) 0 (0) Bladder cancer 3 1 (33.3) 0 (0) Distal pancreatic cancer 1 0 (0) 0 (0) Other (benign conditions)* 9 2 (22.2) 0 (0) Total benign 115 23 (20) 2 (1.7) Total malign 140 24 (17.1) 1 (0.7) Total 255 47 (18.4) 3 (1.2) * Two rectovajinal fistula, two sigmoid volvulus, two perforation due to gunshot injury and blunt trauma, one enterocutaneous fistula, one entero-behcet disease and one strangulated hernia.
A Phase 1 Trial of SNS-032, a Potent and Specific CDK 2, 7 and 9 Inhibitor, in Chronic Lymphocytic Leukemia and Multiple Myeloma
Authors: William G. Wierda, R. Chen, William Plunkett, Steven Coutre, Ashraf Z. Badros, Leslie Popplewell, David Siegel, Rajni Sinha, Donald Harvey, Judith Fox, Kristi Mahadocon, Peggy Kegley, Mary G. Bolton
Journal: Blood (2008)
Distribution of therapeutic response in asthma control
Authors: T.F. Reiss, J.M. Edelman, J.F. Heyse
Journal: European Respiratory Journal (2003)

From the authors: 

We are in agreement with G.L. Braunstein's comment that it is important to discuss end­points that are of clinical relevance to patients and to describe not just average values but results accounting for the entire population. His letter also provides us with an opportunity to rechallenge some of the commonly held assumptions about the clinical interpretation of asthma data and re­emphasise the clinical advantages of our approach to describing the response of patients to asthma therapy. We particularly wish to focus on the methodological issues that he has raised.

The best definition available of asthma control is from theconsensus guidelines; unfortunately, this description is neither population­based nor validated. Difficulties have been encountered in efforts to identify and accurately validate the important clinical measures of asthma control, and it remains …
Immunoglobulin Heavy/Light Chain Ratio and Suppression of the Myeloma Non-Involved Heavy/Light Chain Pair Isotype Correlate with Poor Survival in Multiple Myeloma at Diagnosis and after Autologous Stem Cell Transplant
Authors: José Luís García de Veas Silva, Nuno Barbosa, Rafael Rios Tamayo, Carmen Bermudo Guitarte, Tiago M Pais, Teresa Rodríguez Ruiz
Journal: Blood (2016)
Abstract 1440: Mitochondrial superoxide dismutase (Sod2) modulates ovarian clear cell carcinoma transcoelomic metastatic pathway
Authors: L.P.Madhubhani P. Hemachandra, Usawadee Dier, Nadine Hempel
Journal: Cancer Research (2015)

Abstract Ovarian clear cell carcinoma (OCCC) is a highly aggressive histological subtype that represents approximately 10% of all ovarian cancer cases and displays high expression of mitochondrial superoxide dismutase (Sod2), a major mitochondrial antioxidant enzyme. In the female body ovarian cancer cells metastasize via the transcoelomic route, where cells detach from the primary tumor into the intraperitoneal (IP) cavity and survive as unattached single cells or spheroid aggregates until they get carried via ascites fluid to the omental wall and surrounding organs for metastatic colonization. Ovarian cancer spheroids evade anoikis and display strong resistant to most anti-proliferative cancer drugs. This may contribute to the high recurrence rate and chemoresistance of ovarian cancer. The present study suggests that Sod2 is critically important for the key events of this transcoelomic metastatic route of OCCC. Levels of Sod2 are further increased in OCCC cell lines when these are cultured as anchorage-independent spheroid aggregates, suggesting that Sod2 may play a major role in spheroid stability and survival. When Sod2 levels are reduced using RNA interference, spheroid morphology of ES-2 OCCC cell line is compromised, suggesting a potential correlation between anoikis resistant and Sod2 levels in OCCC. Sod2 knockdown compromises mitochondrial metabolism, as a consequence of reduced superoxide scavenging, and enhances spheroid sensitivity to cisplatin. In addition, Sod2 is necessary for spheroid attachment and outgrowth on extracellular matrix components, representing the invasion of spheroids into the omental wall. Further, tumor cell metastasis is attenuated with reduced Sod2 levels when ES-2 spheroids are placed on the vasculature of the Chorioallantoic membrane (CAM). Scavenging H2O2 by exogenous addition of catalase inhibits the migration of OCCC and our data suggest that high levels of Sod2 in OCCC shift the intracellular redox balance to drive H2O2-dependent pro-metastatic signaling. These results indicate that Sod2 plays a major role in OCCC tumor metastasis, by regulating survival and chemoresistance of tumor spheroids in the IP cavity and by supporting attachment and migration at secondary metastatic sites. Inhibition of Sod2 can be a potential therapeutic target against OCCC transcoelomic metastasis. Citation Format: L.P.Madhubhani P. Hemachandra, Usawadee Dier, Nadine Hempel. Mitochondrial superoxide dismutase (Sod2) modulates ovarian clear cell carcinoma transcoelomic metastatic pathway. [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 1440. doi:10.1158/1538-7445.AM2015-1440
Abstract 1435: Role of PRKD2 in HSP90- and hypoxia-mediated epithelial-to-mesenchymal transition
Authors: Ninel Azoitei, Alexander Becher, Kristina Diepold, Susanne Bobrovich, Cornelia Brunner, Gabriela Chiosis, Stefan Fröhling, van Lint Johan, Claudia Scholl, Thomas Seufferlein
Journal: Cancer Research (2015)

Abstract The protein kinase D (PRKD) family of serine/threonine kinases belongs to the calcium/calmodulin-dependent protein kinase superfamily and comprises three isoforms, PRKD1, PRKD2 and PRKD3. We have recently identified PRKD2 as a novel client of HSP90 chaperone in several cancer cell lines. Depletion of PRKD2 protein following pharmacologic inhibition of HSP90 was associated with tumor cell death in vitro and in vivo. Furthermore, abrogation of PRKD2 in cancer cells prevented hypoxia-induced accumulation and promoter activity of HIF-1a, an oxygen sensor also shown to be regulated by HSP90. Since, both HSP90 and hypoxia/HIF-1a regulate epithelial-to-mesenchymal transition (EMT), we sought to investigate the role played by PRKD2 in this process. Here we report that ectopic expression of PRKD2 was associated with a change in morphology, from epithelial polarized to a spindle-like phenotype, in lung and pancreatic cancer cells. This observation was associated with impaired E-cadherin and augmented vimentin protein levels. Pharmacologic inhibition of HSP90 was associated not only with PRKD2 degradation but also with decreased vimentin expression. However, the higher remaining PRKD2 levels after HSP90 inhibition of tumor cells expressing ectopic PRKD2 partially restored the vimentin expression suggesting a contribution of kinase to the chaperone-supported EMT. Incubation of cancer cells under low oxygen atmosphere showed decreased epithelial marker proteins and elevated vimentin levels, which was further enhanced by overexpressing PRKD2 suggesting that PRKD2 is involved in hypoxia-triggered EMT process. The fact that PRKD2 is able to interact with hypoxia-stabilized HIF-1a, which regulates EMT by controlling expression of Twist, a basic helix-loop-helix transcription factor reported to repress E-cadherin, suggests that PRKD2 may influence crucial EMT molecules via HIF-1a. Altogether, these findings 1) suggest PRKD2 as a crucial modulator of HSP90- and hypoxia-mediated EMT process, 2) suggest PRKD2 ablation through HSP90 inhibition as a potential therapeutic strategy in cancer with immediate implementation since several chaperone inhibitors are in clinical trials and 3) promote the intensification of designing specific PRKD2 inhibitors and their implementation in targeted therapy in human cancer. Citation Format: Ninel Azoitei, Alexander Becher, Kristina Diepold, Susanne Bobrovich, Cornelia Brunner, Gabriela Chiosis, Stefan Fröhling, van Lint Johan, Claudia Scholl, Thomas Seufferlein. Role of PRKD2 in HSP90- and hypoxia-mediated epithelial-to-mesenchymal transition. [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 1435. doi:10.1158/1538-7445.AM2015-1435
Busulfan, Melphalan and Etoposide Followed by Autologous Stem Cell Transplantation on Patients with Non-Hodgkin's Lymphoma: Multicenter Study From Consortium for Improving Survival of Lymphoma (CISL) in Korea
Authors: Kyoung Ha Kim, Won Seog Kim, Sung-Kyu Park, Mark Hong Lee, Sang Kyun Sohn, Cheolwon Suh, Hye Jin Kang, Chul Won Choi, Ho Sup Lee, Sung Hwa Bae, Jinny Park, Eunkyung Park, Jae-Yong Kwak, Han Jo Kim, Se-Hyung Kim, Jong-Ho Won
Journal: Blood (2011)
Assessment of Tumor Growth (g) and Regression (d) Rate Constants in Patients with Multiple Myeloma (MM) Shows That the Superiority of Bortezomib with Liposomal Doxorubicin (PLD+B) Over Bortezomib Alone (B) Is a Result of Reduced Growth of Refractory Tumor Cells and Not of Higher Regression Rates, and Provides An Earlier Efficacy Endpoint That Allows for Comparison Across Trials
Authors: Elisabet E. Manasanch, Julia Wilkerson, Liang Xiu, Sen Zhuang, Susan Bates, Wilfred Stein, Antonio T Fojo
Journal: Blood (2011)
Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant.
Authors: Anas Younes, Tee-Chuan Ong, Vincent Ribrag, Andreas Engert, Dina Ben-Yehuda, Robin McCabe, Angela Shen, Christophe Le Corre, Samit Hirawat, Anna Sureda
Journal: Blood (2009)
Abstract B68: Role of CD44 in pancreatic cancer cell plasticity
Authors: James W. Freeman, Shujie Zhao, Chen Chen, Anand Karnad
Journal: Cancer Research (2016)

Abstract Two subpopulations of pancreatic adenocarcinoma (PDAC) cells were separated from different cell lines on the basis of CD44 expression level. CD44 high and CD44 low expressing cells were compared for their invasive potential, epithelial/mesenchymal phenotype, in vitro response and in vivo development of resistance to gemcitabine. CD44 high cells showed a mesenchymal phenotype, formed tumor spheres, were more invasive and were less responsive to gemcitabine. In contrast, CD44 low cells had an epithelial phenotype, were weakly invasive, did not grow as tumor spheres and showed greater response to gemcitabine. CD44 high cells showed a predominant expression of CD44 standard isoform with lower levels of various CD44 variant isoforms. Interestingly, gemcitabine treatment of CD44 low cells induced a phenotypic switch, loss of ESRP1 expression with concurrent up regulation in expression of CD44 standard. In an orthotopic mouse model, tumors from CD44 high cells had a selective growth advantage and formed metastases more rapidly. Gemcitabine treatment continuously suppressed tumor growth in animals implanted with CD44 low cells during the 22 weeks of the experiment; whereas, tumors from CD44 high cells initially showed some response to gemcitabine but developed resistance by weeks 10-12. Knockdown of CD44 in CD44 high cells from two different PDAC cell lines, inhibited invasion and increased their response to gemcitabine similar to that seen for CD44 low cells. Collectively this study suggests that a subpopulation of CD44 high expressing PDAC cells with a mesenchymal-like phenotype tends to be highly invasive, more resistant to gemcitabine in vitro and to develop gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response of PDAC. Citation Format: James W. Freeman, Shujie Zhao, Chen Chen, Anand Karnad.{Authors}. Role of CD44 in pancreatic cancer cell plasticity. [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 B68.
Abstract IA11: Pancreatic cancer biology and medicine
Authors: David Tuveson
Journal: Cancer Research (2016)

Abstract Pancreatic cancer remains the most deadly of the common malignancies. To increase our basic understanding of this disease and advance medical approaches, we have recently co-developed with Hans Clevers mouse and human organoid model systems. Our organoid cultures representative of either normal or neoplastic ductal cells facilitate the systematic analysis of neoplastic biochemical cascades, provide a platform to explore therapeutic and diagnostic strategies, and also enable the reconstitution of tumor microenvironment interactions. We have found that Nrf2, a principal regulator of redox metabolism, promotes proliferation in KRAS mutant pancreatic ductal cells in part by regulating the reduced state of the cellular proteome. As a consequence of proteome oxidation, central pathways of homeostasis are impaired, including protein translation. The genes with markedly impaired translation include a number of critical proto-oncogenes. Additionally, diagnostic and therapeutic approaches have revealed new avenues to explore for early detection and disease treatment. Finally, the co-culture of organoids with pancreatic stellate cells promotes the activation of each cell type and results in the production of extracellular matrix. Co-cultures reveal distinct subtypes of stellate cells and provide an opportunity to identify and target novel mediators of the tumor microenvironment. Citation Format: David Tuveson.{Authors}. Pancreatic cancer biology and medicine. [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 IA11.
A Prognostic 51-Gene Signature Linked to Abnormal Metaphase Cytogenetics Identifies Myeloma Patients Who Benefit from Fractionated Melphalan Dosing and Added Bortezomib, Thalidomide and Dexamethasone As Conditioning for Autologous Stem Cell Transplant
Authors: Frits van Rhee, Alan Mitchell, Maurizio Zangari, Jeffery Sawyer, Sarah Waheed, Rashid Z Khan, Christoph Heuck, Sharmilan Thanendrarajan, Carolina Schinke, Yogesh Jethava, Xenofon Papanikolaou, Monica Grazziutti, Nathan Petty, Douglas Steward, Susan Panozzo, Clyde Bailey, Antje Hoering, John Crowley, Faith E Davies, Bart Barlogie, Gareth J Morgan
Journal: Blood (2015)
Abstract 5512: Preclinical evaluation of the recombinant human arginase PEG-BCT-100 leading to arginine deprivation in sarcomas
Authors: Chi Tung Choy, Hio Teng Cheong, Kin Pong U, Chi Hang Wong, Herbert Ho Fung Loong
Journal: Cancer Research (2015)

Abstract Background: Arginine deprivation is a novel approach to limit arginine-dependent tumour growth. The presence of enzymes involved in the de novo synthesis of arginine from citrulline, argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and ornithine transcarbamylase (OTC), can influence the sensitivity of tumour to arginine depletion. We studied the preclinical efficacy of PEG-BCT-100 (also known as rhArg1peg5000), a PEGylated recombinant human arginase 1 on sarcoma cell lines. In this study, ASS, ASL and OTC expression were established in sarcoma cell lines and the sensitivity of each cell line to PEG-BCT-100 treatment was determined in order to establish their suitability as predictive markers to determine responsiveness to PEG-BCT-100 treatment. Methods: Cells from 5 representative soft-tissue sarcoma (STS) cell lines (RD, GCT, HT-1080, SW872, SW982) and 1 osteosarcoma cell line (SJSA-1), either incubated in full culture medium (control), arginine free medium or PEG-BCT-100 (1U/ml) treated medium. They were monitored by live cell imaging for 72 hours. Their corresponding IC50 were determined by cell viability assay. The expression of ASS, ASL and OTC were determined by Western blotting. Results: All sarcoma cell lines were sensitive to PEG-BCT-100 and demonstrated significant cell proliferation inhibition. Their IC50, as determined by cell viability assay were 0.023 U/ml, 0.028 U/ml, 0.023 U/ml, 0.026 U/ml, 0.20 U/ml, 0.053 U/ml, and 0.03 U/ml for GCT, HT-1080, RD, SJSA-1, SW872 and SW982 respectively. Western blot analysis confirmed strong basal protein expression of ASL and low OTC expression in all sarcoma cell lines, suggesting sensitivity to PEG-BCT-100 is not determined by ASL but rather, OTC. On the contrary, low ASS basal protein expression was revealed in all sarcoma cell lines except for RD. A strongly expressed ASS was observed in RD despite of its sensitivity to PEG-BCT-100, implying that ASS might be less important in the response towards PEG-BCT-100. Conclusion: Arginine deprivation by PEG-BCT-100 is effective in suppressing STS cell growth in vitro, suggesting arginine auxotrophism in STSs. Moreover, arginase treatment can be an effective strategy against STS. Low expression of OTC, instead of ASS and ASL, may be a more important predictive biomarker for response to treatment. Further in-vivo and clinical studies are warranted. Citation Format: Chi Tung Choy, Hio Teng Cheong, Kin Pong U, Chi Hang Wong, Herbert Ho Fung Loong. Preclinical evaluation of the recombinant human arginase PEG-BCT-100 leading to arginine deprivation in sarcomas. [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 5512. doi:10.1158/1538-7445.AM2015-5512
Impact of Body Mass Index (BMI) on outcome of metastatic breast cancer (MBC) patients (pts) treated with Eribulin in a real-world population: a multicenter retrospective study
Authors: L. Pizzuti, M. Barba, I. Sperduti, C. Natoli, T. Gamucci, D. Sergi, L. Di Lauro, L. Moscetti, F. Izzo, M. Rinaldi, L. Mentuccia, A. Vaccaro, L. Iezzi, S. Fancelli, A. Grassadonia, A. Michelotti, E. Pescarmona, L. Perracchio, M. Maugeri-Saccà, P. Vici
Journal: Annals of Oncology (2015)