Bechtel (United States)

Abstract Background: HR+/HER2− tumors account for ∼70% of all breast cancers (BCs)1 and are responsible for most BC-related deaths. CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) have improved outcomes for HR+/HER2− BC2; however, patients eventually experience progressive disease and require new therapies. B-cell lymphoma 2 (BCL2) is an anti-apoptotic protein involved in regulation of the intrinsic apoptosis pathway that is often dysregulated in tumors. In BC, estrogen receptor signaling leads to upregulation of BCL2, which is overexpressed in 70-80% of HR+ BC.3-5 When administered in rational combinations with other anticancer agents, BCL2 inhibitors (BCL2i) are likely to enhance potential antitumor effects.5 In HR+ BC mouse xenograft models, the addition of a BCL2i to ET enhanced antitumor activity relative to single agent ET.6 Furthermore, the addition of a CDK4i or CDK4/6i to BCL2i + ET significantly augmented this antitumor activity, suggesting further exploration of the triplet is warranted.6-9 BGB-21447 is a novel, orally bioavailable, next-generation BH3 mimetic that was designed to be a highly potent inhibitor of both wild-type and mutant BCL2, which is also active against BCL-xL and is currently in clinical trials for hematologic cancers and BC. BGB-43395 is a selective CDK4i with improved CDK4 coverage and greater selectivity for CDK4 over CDK6, thus minimizing off-target toxicities. BGB-43395 is currently under development with ET in HR+ BC and other selected solid tumors (NCT06120283, NCT06253195). Here, we describe an ongoing phase 1 study of BGB-21447 + fulvestrant with and without BGB-43395 (NCT06756932). Methods: This is an open-label, international, multicenter, phase 1 dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-21447 in combination with fulvestrant without (Part A) or with BGB-43395 (Part B) in patients with previously treated HR+/HER2− metastatic BC. Sequential cohorts will receive ascending doses of BGB-21447 and fulvestrant. BGB-43395 will be added to the doublet combination dose-escalation component. Key eligibility criteria include patients ≥18 years with histologically or cytologically confirmed HR+HER2− metastatic BC, previous treatment in the advanced/metastatic setting, including prior treatment with CDK4/6i and ET in any setting, Eastern Cooperative Oncology Group Performance Status ≤1, and adequate organ function. Patients with prior BCL2i exposure are excluded. Primary objectives are to assess the safety and tolerability of BGB-21447 in combination with fulvestrant, with or without BGB-43395, and to determine the maximum tolerated dose, maximum administered dose, and recommended dose for expansion of both the doublet and triplet combination. Secondary objectives are preliminary antitumor activity (objective response rate, duration of response, and time to response per Response Evaluation Criteria in Solid Tumors v1.1), characterization of the PK (single dose and steady state), and the preliminary effect of food on PK. This study is currently recruiting patients, with sites open across Australia, China, and the United States (Part A only). Citation Format: 1. Burstein HJ. N Engl J Med. 2020;383:2557-2570. 2. Thill M and Schmidt M. Ther Adv Med Oncol. 2018;3:1758835918793326. 3. Kawiak A, Kostecka A. Cancers (Basel). 2022;14:279. 4. Dawson SJ et al. Br J Cancer. 2010;103 :668-675. 5. Lok SW, et al. Cancer Discov. 2019;9:354-369. 6. Vaillant F, et al. Cancer Cell. 2013;24:120-129. 7. Whittle JR, et al. Clin Cancer Res. 2020;26:4120-4134. 8. Lindeman G, et al. Clin Cancer Res. 2025;31(12_Supplement):P2-07-18. 9. BeOne Medicines. Data on file. Citation Format: G. Lindeman, C. Muttiah, P. Lau, N. Hunter, J. Zhang, Y. Liu, Y. Dong, P. Zhou, A. Kavi, K. Keyvanjah, Z. Shao. Trial in progress: a phase 1 dose-escalation study evaluating BGB-21447 (BCL2 inhibitor) in combination with fulvestrant with and without BGB-43395 (CDK4 inhibitor) in patients with previously treated HR+/HER2− metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-29.

The dual-radiator Imaging Cherenkov detector (dRICH) is a key component of the forward particle identification system for the ePIC experiment at the Electron-Ion Collider (EIC). This study evaluates the dRICH performance using Geant4 simulations in the context of the global ePIC simulation stack, focusing on the optimization of the aerogel radiator and the impact of sensor noise. We compare two aerogel configurations: the initial design (n=1.019) and the current default (n=1.026). The latter, characterized by improved optical properties and a higher refractive index, demonstrates enhanced $π-K$ separation at high momenta, effectively extending the operational overlap with the $\mathrm{C_2F_6}$ gas radiator. Additionally, the study investigates the impact of Silicon Photomultiplier (SiPM) dark noise, showing that a 300 kHz noise rate per channel leads to a moderate reduction (approximately 1.5 GeV/c) in the $3σ$ separation threshold. These results validate the current dRICH design and quantify the purity levels achievable for both radiators under expected experimental conditions.

Abstract Material selection for low partial pressure CO2 service in presence of moisture is well understood. A full understanding of corrosion in supercritical CO2 (sCO2) systems is not well understood. Factors influencing corrosion of steel in sCO2 service are temperature, pressure, flow conditions, and trace impurities, and water concentration (ppm range). Additionally, fracture mitigation needs consideration, as depressurization of sCO2 can provide sufficient driving force to propagate ductile fracture in pipeline steels. Historical data indicates that while carbon steel has been the primary choice of material for supercritical CO2 pipelines, corrosion failures have occurred. This paper discusses material integrity risks to pipeline steel and options for alternate materials.

This proceeding presents recent advances in the study of hyperon physics using data from the BESIII experiment. The BESIII detector has been in full operation at the BEPCII collider since 2008, providing excellent resolution, particle identification (PID), and large coverage for both neutral and charged particles. Leveraging the outstanding capability of the detector, the BESIII experiment has collected 10 billion $J/\psi$ and 2.7 billion $\psi(3686)$ events. In recent years, BESIII has conducted a series of analyses focusing on hyperon physics, utilizing the pair production of quantum-entangled hyperon-antihyperon pairs from these charmonium decays. The transverse polarizations of the $\Lambda$, $\Sigma^{+,0}$, and $\Xi^{-,0}$ hyperons have been observed in $J/\psi$ and $\psi(3686)$ decays, providing excellent opportunities to search for the CP violation in hyperon decays. Additionally, BESIII investigates weak radiative hyperon decays, semi-leptonic hyperon decays, and hyperon-nucleon interactions.

Ciprofloxacin is among the most commonly prescribed Fluoroquinolones. Side effects of Fluoroquinolones include tendinopathies, ar-rhythmias, gastrointestinal discomfort, and neurological symptoms. The definition of a "Fluoroquinolone-associated disability" includes dis-ability, symptoms in several body systems and duration of symptoms after discontinuation of the antibiotic. The pathophysiology of this disease is probably due to a damage to the redox system. We report on a 41-year-old patient who felt pain in his Achilles tendons three days after starting to take ciprofloxacin (of a total of 3 g) and presented as an emergency. In the course of the disease, the pain became chronically disabling and the patient developed paresthesia of both extremities and intermittent heart palpitations. The only tolerated pain medication was Pregabalin. Several MRI examinations showed minimal peritendinitis and irritation of the Achilles tendons. Blood samples indicated probable intracellular damage at low intracellular ATP and coenzyme Q10 values.

Abstract The 2025 Edition of ASME Section VIII, Division 2 contains the most substantial revision since the entire Section VIII, Division 2 was rewritten in the 2007 Edition. Below are the highlights of the changes made. The entirety of Part 5 underwent a significant editorial revision. The entire Part is brought into conformance with the ASME Style Guide. Cross-references to paragraphs, equations, figures, and tables have been fixed. Variables in the nomenclature have been cleaned up. And a variety of paragraphs have been simplified using the “Clarity Rewrite” approach that other portions of the Section VIII Code are undergoing. In paragraph 5.2, two stress limits that were in the Code prior to the 2007 rewrite are reinstated: Bearing Stress Limits and Shear Stress Limits. These limits are identical to the limits previously contained in the 2004 Edition. The fatigue screening methods in paragraph 5.5 are also updated. Method B had been updated in the 2023 Edition. A new Method C is introduced, which is almost identical to Method B, except that instead of the smooth-bar fatigue curves, the Structural Stress welded fatigue curves are used. The fatigue analysis methods themselves are also updated, in order to bring them into harmony with API 579-1/ASME FFS-1 (2021), as well as proposed and approved changes that are not yet published in that document. The ratcheting assessment is also updated substantially. The elastic analysis ratcheting limits are changed. Additionally, a new elastic analysis method, based on the Bree Diagrams, is also introduced. A new Section is inserted into Paragraph 5.6, titled, “Protection Against Creep Damage”. This new section details new damage modes that require demonstrating protection against. The first subsection is “Protection Against Stress Rupture From Load-Controlled Loads”. Design-By-Rule methods are referenced, as is an elastic stress analysis method. The second subsection is “Protection Against Stress Rupture From Load-Controlled Loads Plus Occasional Loads”. Again, Design-By-Rules methods are referenced. The third subsection is “Protection Against Creep Buckling”. In this subsection, the analyst is referred to Method B in paragraph 5.4, with modification appropriate for creep - namely using an isochronous stress-strain curve instead of the elastic-plastic curve. The fourth subsection is “Protection Against Failure from Creep Fatigue”. Here, creep-fatigue screening methods are introduced. A specific creep-fatigue analysis methodology has not yet been introduced, although the framework for one is laid out in the form of the paragraph. The fifth and final subsection is “Protection Against Creep Ratcheting”. In this subsection, an elastic analysis methodology is presented. Note that these subsections generally follow the flow of the prior paragraphs in Part 5.

Abstract Coke drums experience one of the most severe cyclic services of any common pressure vessel type in the process or heavy industries. While the severe loading is thermal in nature, with an inherently random and statistical aspect to it, the end results are very predictable. Namely that cracking adjacent to the girth (or circumferential) weld seams, initiating overwhelmingly from the inside surface, tends to set the economic life of the drums. The concept of calibrating loading to known cracking can be leveraged, but to do so requires meaningful fatigue initiation and crack growth data for typical coke drum welded joints. Such data is reviewed and analyzed, and property recommendations made for both the inside (with clad restoration) and outside (simple matching weld joint) including appropriate test-based fatigue strength reduction factors. Focus is given to the common coke drum material SA-387 Grade 11 Cl. 2 (1.25Cr-0.5Mo) due to the volume of data available for it, and typical coke drum welded joints. Coke drum thermal loading is reviewed to develop realistic load ranges for use with the property recommendations to validate that they are capable of giving meaningful life predictions.

Abstract The draft ASME Plant Systems Design standard integrates systems engineering, risk evaluation, and probabilistic design practices into traditional plant engineering processes. This standard provides a framework through which plant owners, designers, and other stakeholders may execute projects in a manner that minimizes errors and omissions in the design process and produces optimal cost and schedule outcomes for its users. Integration of classic systems engineering processes into plant design provides a uniform framework for communicating design requirements, design information, and acceptance criteria throughout the lifecycle of a plant design project. Traditional plant design processes emphasize the use of separate engineering disciplines, which often create information silos that cause errors and omissions in design. The use of a systems engineering process ensures that the plant, its systems, and its infrastructure are designed holistically and consider all requirements for productivity, safety, and the plant lifecycle. This paper provides an introduction and overview of the Systems Engineering and Design Integration (SEDI) portion of the new standard that is targeted for publication in 2025.