Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570's formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.Peer reviewe

Strain variations in InGaAsP/InGaP superlattices studied by scanning probe microscopy

Strain-compensated InGaAsP/InGaP superlattices are studied in cross section by atomic force microscopy and scanning tunneling microscopy. Undulations in the morphology of the {110} cross-sectional faces are observed, and are attributed to elastic relaxation of this surface due to underlying strain arising from thickness and compositional variations of the superlattice layers. Finite element computations are used to extract a quantitative measure of the strain variation. © 1998 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71059/2/APPLAB-72-14-1727-1.pd

MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods

[EN] In patients with multiple myeloma, obtaining posttreatment minimal residual disease (MRD) negativity is associated with longer progression-free survival and overall survival. Here, we compared the diagnostic performance of a single 10-color tube with that of a EuroFlow 8-color 2-tube panel for MRD testing. Bone marrow samples from 41 multiple myeloma patients were tested in parallel using the 2 approaches. Compared with the sum of the cells from the EuroFlow two 8-color tubes, the Memorial Sloan Kettering Cancer Center (MSKCC) single 10-color tube had a slight reduction in total cell number with a mean ratio of 0.85 (range, 0.57-1.46; P < .05), likely attributable to permeabilization of the cells. Percent of plasma cells showed a high degree of concordance (r2 = 0.97) as did normal plasma cells (r2 = 0.96), consistent with no selective plasma cell loss. Importantly, concordant measurement of residual disease burden was seen with abnormal plasma cells (r2 = 0.97). The overall concordance between the 2 tests was 98%. In 1 case, there was a discrepancy near the limit of detection of both tests in favor of the slightly greater theoretical sensitivity of the EuroFlow 8-color 2-tube panel (analytical sensitivity limit of MSKCC single 10-color tube: 6 cells in 1 million with at least 3 million cell acquisitions; EuroFlow 8-color 2-tube panel: 2 cells in 1 million with the recommended 10 million cell acquisitions)

Institutional conditions for integrated mobility services (IMS): Towards a framework for analysis

The present text is a theoretical framework that has been developed with the aim to generate knowledge of and policy recommendations for the promotion of integrated mobility services (IMS), with specific regard to institutional dimensions. Integrated mobility services are services where the passenger’s transport needs are met by a service that not only integrates a range of mobility services, both public and private, but also provides one-stop access to all services through a common interface. These types of services are currently being developed in several cities globally, and the purpose of the project is to understand and explain how institutions can enable, but also impede, their realization. Institutions are defined as a relatively stable collection of rules and practices, embedded in structures that enable action. In the project a broad theoretical approach, developed by an interdisciplinary research team, will be applied. As such, the framework includes factors at the macro, meso and micro levels, thus including extensive societal trends as well as individual\u27s needs and behaviour. The macro level includes broader social and political factors, including both formal rules and more informal social norms and perceptions. The division between formal and informal variables recur on the meso and micro levels respectively. The meso level – which includes both public and private actors at regional and local levels – consists of both formal institutional factors such as taxation and regulations, and informal factors such as organizational culture and inherited networks between regional actors. Each actor enters the collaborative processes that signify IMS with their own ideals, interests and expectations, and it is in these processes of negotiation that the framework takes it point of departure. It is also in this context that business models will be developed, another central aspect of the realisation of IMS. Finally, the framework also includes the micro level, where an individual perspective is placed at centre stage. Individuals are affected by various formal incentives and push factors, as well as more informal aspects such as self-image and social status. Through the application of the framework in a number of case studies, empirical findings will help illuminate which institutional factors enable or constrain the development of IMS. The findings will provide the empirical and analytical foundation for suggestions on how formal and informal rules and practices can be modified to enable new IMS to contribute to sustainable mobility

Management planning for woodland owners : why and how

Management planning—the words conjure up visions of gray suits, corporate boardrooms, and Ivy League business schools. Planning for the woodland owner need not be so intimidating. A plan, simply put, is a guide that tells what you have, what you want to do, and how to do it.Published September 1983. A more recent revision exists. Facts and recommendations in this publication may no longer be valid. Please look for up-to-date information in the OSU Extension Catalog: http://extension.oregonstate.edu/catalo

Management planning for woodland owners : an example

This publication demonstrates one way of organizing and preparing a forest management plan for your property. By no means should you consider this the best or only way for you to plan; conditions vary—and so should your approach to planning.Published August 1983. Facts and recommendations in this publication may no longer be valid. Please look for up-to-date information in the OSU Extension Catalog: http://extension.oregonstate.edu/catalo

Demonstration of integrated microscale optics in surface-electrode ion traps

In ion trap quantum information processing, efficient fluorescence collection is critical for fast, high-fidelity qubit detection and ion-photon entanglement. The expected size of future many-ion processors require scalable light collection systems. We report on the development and testing of a microfabricated surface-electrode ion trap with an integrated high numerical aperture (NA) micromirror for fluorescence collection. When coupled to a low NA lens, the optical system is inherently scalable to large arrays of mirrors in a single device. We demonstrate stable trapping and transport of 40Ca+ ions over a 0.63 NA micromirror and observe a factor of 1.9 enhancement in photon collection compared to the planar region of the trap.Comment: 15 pages, 8 figure

Growing and harvesting Douglas-fir poles.pdf

Published November 1983. Reprinted November 1994. Facts and recommendations in this publication may no longer be valid. Please look for up-to-date information in the OSU Extension Catalog: http://extension.oregonstate.edu/catalo

Management planning for woodland owners : why and how

Discusses the benefits of having a management plan for your property. Describes how to prepare a management plan, including describing the property, setting goals, identifying resources, making recommendations, and keeping records. Includes additional sources for information.Published September 1983. Revised 2013. Revised May 2014. Facts and recommendations in this publication may no longer be valid. Please look for up-to-date information in the OSU Extension Catalog: http://extension.oregonstate.edu/catalo