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Prostate cancer is the second leading cause of cancer death in men in the United States. The androgen receptor (AR) plays critical roles in both early disease and advanced prostate cancer. Current therapeutic approaches targeting the androgen/AR axis are initially effective, but castration resistant prostate cancer (CRPC) inevitably develops. CRPC is tightly linked with increased AR activity via gene overexpression, amplification, and gain-of-function mutations. To address these mechanisms of AR-dependent prostate tumor growth, we have developed a novel therapeutic agent, ARV-110, a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-110 robustly degrades AR in various prostate cancer cell lines with a half-maximal degradation concentration (DC50) of ~1 nM. Whole cell lysate proteomics and ubiquitin proteomics demonstrated high selectivity for AR in VCaP cells. ARV-110 potently downregulates androgen responsive genes, inhibits proliferation and induces apoptosis in AR dependent prostate cancer cells. In vivo, ARV-110 is orally bioavailable and robustly degrades AR with a >90% observed maximum degradation (Dmax) at efficacious doses. ARV-110 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including enzalutamide-resistant VCaP and enzalutamide-insensitive patient-derived xenograft models. These preclinical data supported the clinical development of ARV-110 for the treatment of men with metastatic CRPC. The discovery, chemical structure and initial clinical data of ARV-110 will be presented Citation Format: Lawrence B. Snyder, Taavi K. Neklesa, Xin Chen, Hanqing Dong, Caterina Ferraro, Deborah A. Gordon, Jennifer Macaluso, Jennifer Pizzano, Jing Wang, Ryan R. Willard, Nicholas Vitale, Ron Peck, Marcia Dougan Moore, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 43.

259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often relatively short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC degrader, ARV-110, that promotes ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, and DMPK, toxicology and preclinical efficacy studies. Results: ARV-110 robustly degrades AR in all cell lines tested, with an observed half-maximal degradation concentration (DC50) of ~1 nM. ARV-110 treatment leads to highly selective AR degradation, as demonstrated by proteomic studies. In VCaP cells, PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces apoptosis at low nanomolar concentrations. Further, ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader, ARV-110, that demonstrates efficacy in multiple prostate cancer models. ARV-110 has completed IND-enabling studies and FIH studies are planned for 1Q2019.

The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, ARV-110 demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. In summary, we report preclinical data on ARV-110, an orally bioavailable androgen receptor PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer. Citation Format: Taavi Neklesa, Lawrence B. Snyder, Ryan R. Willard, Nicholas Vitale, Kanak Raina, Jennifer Pizzano, Deborah Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Zheng Liu, Caterina Ferraro, Gan Wang, Jing Wang, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. ARV-110: An androgen receptor PROTAC degrader for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5236.

The Transportation Science and Logistics (TSL) Section Dissertation Prize Competition is the oldest and most prestigious competition for doctoral dissertations in the transportation science and logistics area. The 2004 TSL dissertation prize committee consisted of Professor Ravi Ahuja (University of Florida), Professor Amy Cohn (Michigan University), Professor Randy Hall (University of Southern California), Professor Mark Hickman (Arizona University), and Professor Patrick Jaillet (Massachusetts Institute of Technology). Eligible doctoral dissertations were those completed and submitted between June 1, 2003, and May 31, 2004, in the general area of transportation science and logistics. To be considered, a dissertation had to be nominated by the thesis supervisor. This year we received 16 nominations. In addition to the large number of submissions, the quality of the theses was outstanding. I would like to extend my sincere thanks to the committee members for the time, effort, and professionalism they devoted to the difficult task of judging these entries. The awards were announced at the 2004 INFORMS Meeting in Denver. It is important to remember that submissions to the TSL Dissertation Prize Competition are already distinguished by the fact that they have been nominated for the award. Each makes a unique and valuable contribution to transportation science and logistics, and all entrants and their advisors deserve warmest congratulations.

The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Our lead oral AR PROTAC degrades approximately 98% of total AR in all cell lines tested, with 50% degradation concentration (DC50) < 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo. Citation Format: Taavi K. Neklesa, Lawrence B. Snyder, Mark Bookbinder, Xin Chen, Andrew P. Crew, Craig M. Crews, Hanqing Dong, Deborah Gordon, Jennifer Macaluso, Kanak Raina, AnnMarie Rossi, Ian Taylor, Nicholas Vitale, Jing Wang, Ryan R. Willard, Kurt Zimmermann. An oral Androgen Receptor PROTAC degrader for prostate cancer [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 5637. doi:10.1158/1538-7445.AM2017-5637

273 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Methods: Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Results: Our lead oral AR PROTAC degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentration (DC50) < 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. Conclusions: In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo.

Chaotic routers are randomizing, nonminimal adaptive packet routers designed for use in the communication networks of parallel computers. Chaotic routers combine the flexibility found in adaptive routing with a design simple enough to be competitive with the most streamlined oblivious routers. We review chaotic routing and compare it with other contemporary network routing approaches, including state-of-the-art oblivious and adaptive routers. A detailed head-to-head comparison between oblivious, minimal adaptive, and chaotic routing is then presented, exploring the performance of comparable VLSI implementations through analysis and simulation. The results indicate that chaotic routers provide very effective and efficient high-performance message routing.

The Chaos router, a randomizing, nonminimal adaptive packet router is introduced. Adaptive routers allow messages to dynamically select paths, depending on network traffic, and bypass congested nodes. This flexibility contrasts with oblivious packet routers where the path of a packet is statically determined at the source node. A key advancement of the Chaos router over previous nonminimal routers is the use of randomization to eliminate the need for livelock protection. This simplifies adaptive routing to be of approximately the same complexity along the critical decision path as an oblivious router. The primary cost is that the Chaos router is probabilistically livelock free rather than being deterministically livelock free, but evidence is presented implying that these are equivalent in practice. The principal advantage is excellent performance for nonuniform traffic patterns. The Chaos router is described, it is shown to be deadlock free and probabilistically livelock free, and performance results are presented for a variety of work loads. >

We have designed and demonstrated a standoff Raman system for detecting high explosive materials at distances up to 50 meters in ambient light conditions. In the system, light is collected using an 8-in. Schmidt–Cassegrain telescope fiber-coupled to an f/1.8 spectrograph with a gated intensified charge-coupled device (ICCD) detector. A frequency-doubled Nd: YAG (532 nm) pulsed (10 Hz) laser is used as the excitation source for measuring remote spectra of samples containing up to 8% explosive materials. The explosives RDX, TNT, and PETN as well as nitrate- and chlorate-containing materials were used to evaluate the performance of the system with samples placed at distances of 27 and 50 meters. Laser power studies were performed to determine the effects of laser heating and photodegradation on the samples. Raman signal levels were found to increase linearly with increasing laser energy up to ∼3 × 106 W/cm2 for all samples except TNT, which showed some evidence of photo- or thermal degradation at higher laser power densities. Detector gate width studies showed that Raman spectra could be acquired in high levels of ambient light using a 10 microsecond gate width.

Contracts F30602-97-l-0150 and F306O2-97-l-0270 were a joint effort but funded using different contract vehicles at the request of DARPA, the sponsoring agency. This report documents the design and development of CILK, a language for multi-threaded parallel programming based on ANSI C. CILK is designed for genera-purpose parallel programming, but it is especially effective for exploiting dynamic, highly asynchronous parallelism, which can be difficult to write in data-parallel or message-passing style. Three world-class chess programs were written in CILK by the CILK group at MIT. CILK provides an effective platform for programming dense and sparse numerical algorithms, such as matrix factorization and N-body simulations. Unlike many other multithreaded programming systems, CILK is algorithmic, in that the runtime system employs a scheduler that allows the performance of programs to be estimated accurately based on abstract complexity measures. CILK is available for download at http:/supertech. lcs . mit. edu/cilk/

This report documents the task of migrating MATLAB programs to ZPL so that the computations can run on parallel platforms and achieve significant performance improvements. It entails three tasks: Upgrade ZPL to support sparse representations, provide an interface to a parallel scientific library, and provide a mechanism by which programmers can know when their MATLAB programs have limited parallelism. The project achieved all three goals. The prototype was fully implemented and made available over the Internet. In benchmark tests ZPL programs were shown to perform as well as or better than programs written by experts using C and message passing. ZPL programs are fully portable running well on any UNIX platform. Additionally, the language is convenient, automatically producing all concurrency, all communication and very aggressive scalar optimizations. This research produced two dozen technical papers and four PhD dissertations.

Generally, routers used in state-of-the-art parallel computers are a form of oblivious router known as demonstration order routers. Examples include the iPSC/2, nCUBE, DELTA, Paragon, Dash, J-Machine, etc. In networks based on these routers all packets between source S and destination D take a single path, oblivious to network congestion and faults. This can lead to poor performance under high loads when congestion can be significant, and to system failure in large or unmaintainable systems where faults are likely. For these two reasons - performance and dependability - adaptive routing techniques have long been advocated. Adaptive routers can be divided into two broad classes, minimal adaptive, in which packets always take a shortest path to their destinations, and nonminimal adaptive, in which packet routes are not restricted to shortest paths. Though there have been many proposals for both types, it is generally true that nonminimal adaptive routers are superior minimal adaptive routers 10, 13. This is consistent with one's intuition follows: Although minimal adaptive router can bypass congestion by sending packets along alternate paths, they discover the congestion too late. That is, when there are no alternate forward paths to choose from, the packet's forward progress is stalled, and is now contributing to the congestion. This affect motivates nonminimal adaptive routing in which a packet can back up or deroute, and go around congestion when there are no forward paths.

We present the chaos router, an asynchronous adaptive router, which under certain circumstances can send messages farther from their destinations. The chaos router greatly simplifies the routing logic by removing the livelock protection of previous schemes. Through an effective use of randomness, whose sources include that due to the adaptively processed load, the natural timing differences of selftimed circuitry and explicitly injected randomization, the chaos router avoids long message routes with high probability. In this paper the router is described, it is argued that the chaos router is deadlock free and probabilistically live-lock and starvation free, and simulation results are presented showing that the chaos router performs well.

The design of a protection system for an operating system is seen to involve satisfying the competing properties of richness and integrity. Achieving both requires the interplay of analysis and synthesis. Using a formal model from the literature, three designs are developed whose integrity (with the help of the model) can be shown.

This document gives a succinct description of the facilities available with the Poker Programming Environment. The emphasis is on what is available rather than how to achieve particular results. Although the sections are self-contained, so that they may be referred to independently, there are a few things you should know: 1) Poker uses interactive graphics. The graphics are described in Section 2; the interaction is described in Section 3; 2) The usual programming language notion of a source program as a monolithic piece of symbolic text has been replaced in Poker by a database. The way to create, view, and change the database is described in Section 4; 3) Object programs (the compiled database) are executed or emulated by Poker and snapshots of the execution can be continuously displayed; 4) Poker supports a variety of CHiP architectures; the current one can be displayed or changed using the CHiP parameters facility, Section 7; 5) The back page of this document gives a summary of the command; and 6) Other versions of Poker exist; consult Appendix B for your particular system.

This document gives a succinct description of the facilities available with the Poker Parallel Programming Environment. The emphasis is on what is available rather than how to achieve particular results. Although the sections are self-contained, so that they may be referred to independently, there are a few things you should know: 1) Poker uses interactive graphics. The graphics are described in Section 2; the interaction is described in Section 3; 2) The usual programming language notion of a 'source program' as a monolithic piece of symbolic text has been replaced in Poker by a database. The way to create, view, and change the database is described in Section 4; 3) Object programs (the 'compiled database') are executed or emulated by Poker and snapshots of the execution can be continuously displayed; 4) Poker supports a variety of CHiP architectures; the current one can be displayed or changed using the CHiP Parameters facility; Section 7; 5) The back page of this document gives a summary of the commands; and 6) Other versions of Poker exists; consult Appendix B for your particular system.

Between the conception of a real time signal processor and its functional, VLSI realization there is an enormous amount of effort devoted to designing, revising, optimizing and testing. Since the process is cumulative -- later work builds on previous work -- and since the activity becomes progressively more detailed, more constrained and more exacting, it follows that the global design parameters should be fully explored. Global design decisions, when correct, can have a greater effect on performance than many local optimiza-tions. When the decisions are wrong, they can cause continual difficulty. Accordingly, we propose a design methodology based on the Configurable, Highly Parallel (CHiP) architecture family1 that focuses on exploring global design parameters and is especially well suited to the VLSI implementation of signal processing systems.

The main question under study is how wide the corridor width should be for the switch lattice of the Configurable, Highly Parallel (CHiP) computer. (The CHiP computer family is introduced and its use for parallel algorithm composition is motivated.) It is argued on the basis asymptotic analysis that a constant corridor width is preferred even though such lattices cannot make full use of the processor elements for most complex interconnection patterns, e.g., universal interconnection structures like the cube connected cycles and shuffle exchange, and for certain 'simple' ones, e.g., certain planar graphs. (Author)

Multigauge computers can operate either with their full datapath width or with the datapath split into separate narrower width machines. Such a concept has been previously shown to provide parallelism when the data values are small. This paper reports on the costs of gauge-shiftable computers. Specifically a single chip microprocessor, the 32-bit Quarter Horse machine, is redesigned to be gauge shiftable under software control to two 16-bit microprocessors. A complete accounting of the effects of gauge shifting on computer architecture is thus realized. Care is taken to identify the effects on the design of SIMD and MIMD executions. The general costs of gauge shifting for other implementation strategies are also identified.

This document reports on the research activities of the Northwest Laboratory for Integrated Systems, formerly the UW/NW VLSI Consortium, for the period of April 7, 1987 to November 16, 1987, under the sponsorship of the Defense Advanced Research Projects Agency, under contract number MDA903-85-K- 0072, program code number 5D30. Keywords: Design generators, Architectures, Network, Apex, Netlist, Circuit parallelism, Declarative descriptions, Bezier curves.