Recent literature suggests that blood pressure variability (BPV) predicts outcome beyond blood pressure level (BPL) and that antihypertensive drug classes differentially influence BPV. We compared calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockade for effects on changes in self-measured home BPL and BPV and for their prognostic significance in newly treated hypertensive patients.
We enrolled 2484 patients randomly allocated to first-line treatment with a calcium channel blocker (n=833), an angiotensin-converting enzyme inhibitor (n=821), or angiotensin receptor blockade (n=830). Home blood pressures in the morning and evening were measured for 5 days off treatment before randomization and for 5 days after 2 to 4 weeks of randomized drug treatment. We assessed BPL and BPV changes as estimated by variability independent of the mean and compared cardiovascular outcomes. Home BPL response in each group was significant (P≤0.0001) but small in the angiotensin-converting enzyme inhibitor group (systolic/diastolic: 4.6/2.8 mm Hg) compared with the groups treated with a calcium channel blocker (systolic/diastolic: 8.3/3.9 mm Hg) and angiotensin receptor blockade (systolic/diastolic: 8.2/4.5 mm Hg). In multivariable adjusted analyses, changes in home variability independent of the mean did not differ among the 3 drug classes (P≥0.054). Evening variability independent of the mean before treatment significantly predicted hard cardiovascular events independent of the corresponding home BPL (P≤0.022), whereas BPV did not predict any cardiovascular outcome based on the morning measurement (P≥0.056). Home BPV captured after monotherapy had no predictive power for cardiovascular outcome (P≥0.22).
Self-measured home evening BPV estimated by variability independent of the mean had prognostic significance, whereas antihypertensive drug classes had no significant impact on BPV changes. Home BPL should remain the primary focus for risk stratification and treatment.
URL: View Source Unique identifier: C000000137.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

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Monolayer cultures of immortalised cell lines are a popular screening tool for novel anti-cancer therapeutics, but these methods can be a poor surrogate for disease states, and there is a need for drug screening platforms which are more predictive of clinical outcome. In this study, we describe a phenotypic antibody screen using three-dimensional cultures of primary cells, and image-based multi-parametric profiling in PC-3 cells, to identify anti-cancer biologics against new therapeutic targets.
ScFv Antibodies and designed ankyrin repeat proteins (DARPins) were isolated using phage display selections against primary non-small cell lung carcinoma cells. The selected molecules were screened for anti-proliferative and pro-apoptotic activity against primary cells grown in three-dimensional culture, and in an ultra-high content screen on a 3-D cultured cell line using multi-parametric profiling to detect treatment-induced phenotypic changes. The targets of molecules of interest were identified using a cell-surface membrane protein array. An anti-CUB domain containing protein 1 (CDCP1) antibody was tested for tumour growth inhibition in a patient-derived xenograft model, generated from a stage-IV non-small cell lung carcinoma, with and without cisplatin.
Two primary non-small cell lung carcinoma cell models were established for antibody isolation and primary screening in anti-proliferative and apoptosis assays. These assays identified multiple antibodies demonstrating activity in specific culture formats. A subset of the DARPins was profiled in an ultra-high content multi-parametric screen, where 300 morphological features were measured per sample. Machine learning was used to select features to classify treatment responses, then antibodies were characterised based on the phenotypes that they induced. This method co-classified several DARPins that targeted CDCP1 into two sets with different phenotypes. Finally, an anti-CDCP1 antibody significantly enhanced the efficacy of cisplatin in a patient-derived NSCLC xenograft model.
Phenotypic profiling using complex 3-D cell cultures steers hit selection towards more relevant in vivo phenotypes, and may shed light on subtle mechanistic variations in drug candidates, enabling data-driven decisions for oncology target validation. CDCP1 was identified as a potential target for cisplatin combination therapy.

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Use of estrogen or estrogen / progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.

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Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198 nucleotide sequence into the HN-L intergenic region resulting in reduced viral gene expression and viral replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, other viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene and still retain the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus.
The avian paramyxovirus type 1, Newcastle disease virus (NDV) has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step towards moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide, without impacting viral production in cell culture. The selective tumor replication of this recombinant NDV, bothin vitroandin vivo, along with efficient tumor cell killing makes it an attractive oncolytic virus candidate that may provide clinical benefit to patients.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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Here, we describe an approach to identify novel selective estrogen receptor downregulator (SERD) compounds with improved properties such as oral bioavailability and the potential of increased efficacy compared to currently marketed drug treatments. Previously, methodologies such as Western blotting and transient cell reporter assays have been used to identify and characterize SERD compounds, but such approaches can be limited due to low throughput and sensitivity, respectively. We have used an endogenous cell-imaging strategy that has both the throughput and sensitivity to support a large-scale hit-to-lead program to identify novel compounds. A screening cascade with a suite of assays has been developed to characterize compounds that modulate estrogen receptor α (ERα)-mediated signaling or downregulate ERα levels in cells. Initially, from a focused high-throughput screening, novel ERα binders were identified that could be modified chemically into ERα downregulators. Following this, cellular assays helped determine the mechanism of action of compounds to distinguish between on-target and off-target compounds and differentiate SERDs, selective estrogen receptor modulator (SERM) compounds, and agonist ERα ligands. Data are shown to exemplify the characterization of ERα-mediated signaling inhibitors using a selection of literature compounds and illustrate how this cascade has been used to drive the chemical design of novel SERD compounds.
© 2015 Society for Laboratory Automation and Screening.

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