Decoding the Molecular Universe -- Workshop Report

On August 9-10, 2023, a workshop was convened at the Pacific Northwest National Laboratory (PNNL) in Richland, WA that brought together a group of internationally recognized experts in metabolomics, natural products discovery, chemical ecology, chemical and biological threat assessment, cheminformatics, computational chemistry, cloud computing, artificial intelligence, and novel technology development. These experts were invited to assess the value and feasibility of a grand-scale project to create new technologies that would allow the identification and quantification of all small molecules, or to decode the molecular universe. The Decoding the Molecular Universe project would extend and complement the success of the Human Genome Project by developing new capabilities and technologies to measure small molecules (defined as non-protein, non-polymer molecules less than 1500 Daltons) of any origin and generated in biological systems or produced abiotically. Workshop attendees 1) explored what new understanding of biological and environmental systems could be revealed through the lens of small molecules; 2) characterized the similarities in current needs and technical challenges between each science or mission area for unambiguous and comprehensive determination of the composition and quantities of small molecules of any sample; 3) determined the extent to which technologies or methods currently exist for unambiguously and comprehensively determining the small molecule composition of any sample and in a reasonable time; and 4) identified the attributes of the ideal technology or approach for universal small molecule measurement and identification. The workshop concluded with a discussion of how a project of this scale could be undertaken, possible thrusts for the project, early proof-of-principle applications, and similar efforts upon which the project could be modeled

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Transforming UML 'Collaborating' Statecharts for Verification and Simulation

Due to the increasing complexity of real world problems, it is costly and difficult to validate today's software-intensive systems. The research reported in the paper describes our experiences in developing and applying a set of methodologies for specifying, verifying, and validating system temporal behavior expressed as UML statecharts. The methods combine such techniques/paradigms and technologies as UML, XMI, database, model checking, and simulation. The toolset we are developing accepts XMI input files as an intermediate metadata format. The metadata is then parsed and transformed into databases and related syntax-driven data structures. From the parsed data, we subsequently generate Promela code, which embodies the behavioral semantics and properties of the statechart elements. Compiling and executing Promela automatically invokes SPIN, the underlying temporal logic-based tool for checking the logical consistency of the statecharts' interactions and properties. We validate and demonstrate our methodology by modeling and simulation using both ArgoUML and Rhapsody™, respectively

Abstract 1 MODELING AND SIMULATION OF IEEE 802.11 WIRELESS-LAN AND BLUETOOTH PICONET RANGE INTERFERENCE

The proximity of wireless devices with one another often results in interference in the unlicensed 2.4 GHz ISM bandwidth. Interference has been recognized as a major problem to wireless network performance and improvement. In this paper we report a proposed and investigated Interference Range Model (IRM), a model that allows a user to determine the acceptable range of interference in a given environment. A Java environment for modeling, simulating, and analyzing acceptable/cutoff ranges of interference based on the IRM is discussed. The model was tested on ranges of interferences for Bluetooth devices in a piconet and IEEE 802.11 devices in the wireless LAN setup, which consequently provided a method for determining the signal-to-interference ratio (SIR) for the two protocols. With this approach, it is expected that a model for calculating and calibrating particular threshold values, or SIRs, and the corresponding ranges of interference can be determined for other wireless protocols. 1

Finding Molecular Signature of Prostate Cancer: An Algorithmic Approach

Abstract 123 African American men in America are 65 % more likely to develop prostate cancer and are two to three times more likely to die of the disease than Caucasian men [1]. While research indicates a strong hereditary link in prostate cancer, it has been difficult to pin down the exact genes involved in this disease. Many men develop prostate cancer later in life, and some men may die before prostate cancer even develops, making it difficult to trace the disease through generations of families [2]. Current research efforts in the testing and detecting of various forms of cancer such as breast and prostate cancer have taken new directions [3]. This paper addresses the genetic predispositions or biomarkers that lead or contribute to such diseases, the application of statistical approaches to researching the biomarkers, and a proposed validation process to mitigate the problem using data mining and high-performance computing techniques. Keywords: Prostate Cancer, Hidden-Markov Model, DNA-methylation, CG-islands, CAG-repeat 1

Design and Configuration Rationales for Digital Video Storage and Delivery Systems

. Recent advances in computing technology have brought multimedia information processing to prominence. The ability to digitize, store, retrieve, process, and transport analog information in digital form has changed the dimensions of information handling. Several architectural and network configurations have been proposed for efficient and reliable digital video delivery systems. However, these proposals succeed only in addressing subsets of the whole problem. In this paper, we discuss the characteristics of video services. These include Cable Television, PayPer -View, and Video Repository Centers. We also discuss requirements for "Video On Demand" services. With respect to these video services, we analyze two important video properties: image quality and response time. We discuss and present configurations of a Digital Video Delivery System (DVDS) from three general system components - servers, clients, and connectivities. Pertinent issues in developing each component are also analyze..