Epithelial Ovarian Cancer Experimental Models

Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase, and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge and many approaches used to study other solid tumors (lung, colon, and breast, for example) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment. This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients, and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis, and chemoresistance. As these new approaches more accurately recapitulate the complex tumor microenvironment, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge

Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99099/1/bjh12382.pd

Characterization of BTBD1 and BTBD2, two similar BTB-domain-containing Kelch-like proteins that interact with Topoisomerase I

BACKGROUND: Two-hybrid screening for proteins that interact with the core domain of human topoisomerase I identified two novel proteins, BTBD1 and BTBD2, which share 80% amino acid identities. RESULTS: The interactions were confirmed by co-precipitation assays demonstrating the physical interaction of BTBD1 and BTBD2 with 100 kDa topoisomerase I from HeLa cells. Deletion mapping using two-hybrid and GST-pulldown assays demonstrated that less than the C-terminal half of BTBD1 is sufficient for binding topoisomerase I. The topoisomerase I sequences sufficient to bind BTBD2 were mapped to residues 215 to 329. BTBD2 with an epitope tag localized to cytoplasmic bodies. Using truncated versions that direct BTBD2 and TOP1 to the same cellular compartment, either the nucleus or the cytoplasm, co-localization was demonstrated in co-transfected Hela cells. The supercoil relaxation and DNA cleavage activities of topoisomerase I in vitro were affected little or none by co-incubation with BTBD2. Northern analysis revealed only a single sized mRNA for each BTBD1 and BTBD2 in all human tissues tested. Characterization of BTBD2 mRNA revealed a 255 nucleotide 90% GC-rich region predicted to encode the N-terminus. BTBD1 and BTBD2 are widely if not ubiquitously expressed in human tissues, and have two paralogs as well as putative orthologs in C. elegans and D. melanogaster. CONCLUSIONS: BTBD1 and BTBD2 belong to a small family of uncharacterized proteins that appear to be specific to animals. Epitope-tagged BTBD2 localized to cytoplasmic bodies. The characterization of BTBD1 and BTBD2 and their interaction with TOP1 is underway

Small molecules and targeted therapies in distant metastatic disease

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders

Augmented Two-Channel Arrhythmia Detection: An Efficient Diagnostic Method for Implantable Devices

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75624/1/j.1540-8159.1996.tb03164.x.pd

Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial

Background:This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer.Methods:Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more.Results:In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%).Conclusion:Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted

TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer

Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation

Carvedilol and cardiac biomarkers in dialysis patients: Secondary analysis of a randomized controlled trial

Published online: December 04, 2017Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman’s rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.Matthew A. Roberts, Darsy Darssan, Sunil V. Badve, Robert P. Carroll, Magid A. Fahim, Brian A. Haluska, Carmel M. Hawley, Nicole M. Isbel, Mark R. Marshall, Elaine M. Pascoe, Eugenie Pedagogos, Helen L. Pilmore, Paul Snelling, Tony Stanton, Ken-Soon Tan, Andrew M. Tonkin, Liza A. Vergara, Francesco L. Ierin

Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: An interventional cohort study

Background: Nightly extended hours hemodialysis may improve left ventricular hypertrophy and function and endothelial function but presents problems of sustainability and increased cost. The effect of alternate nightly home hemodialysis (NHD) on cardiovascular structure and function is not known