bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct numerical simulation of supersonic boundary layer transition induced by gap-type roughness
Authors: Liu Hongkang , Peng Kehui , Zhao Yatian , Yu Qian , Kong Zhiqiang , Chen Jianqiang 
Published: July 2024

AbstractThe transition of the supersonic boundary layer induced by roughness is a highly intricate process. Gaining a profound understanding of the transition phenomena and mechanisms is crucial for accurate prediction and control. In this study, to delve into the flow mechanisms of a transition in a supersonic boundary layer induced by the medium gap-type roughness, direct numerical simulation is employed to capture and analyze the transition process. Research indicates that as the flow over the flat plate passes the gap, the spanwise convergence effect leads to the formation of both upper and lower counter-rotating vortex pairs. As the flow progresses, these counter-rotating vortex pairs in the central region exhibit attenuation, with streamwise vortices developing on both sides. At a certain downstream distance, the boundary layer becomes unstable, triggering the formation of streamwise vortex legs. These streamwise vortex legs undergo further evolution, transforming into hairpin vortices and leg-buffer vortices. The formation of the central low-speed zone downstream of the roughness element is mainly attributed to the lift-up effect of the low-speed flow propelled by the central counter-rotating vortex pairs. The low-speed streaks on both sides are primarily influenced by the streamwise vortices. Through a meticulous analysis of the turbulent kinetic energy distribution and its generation mechanisms during the transition phase, this study infers that the primary sources of turbulent kinetic energy are the hairpin vortices, leg-buffer vortices, and their consequent secondary vortices. Combined with modal analysis, the study further elucidates the generation and breakdown of hairpin and leg-buffer vortices.
An assessment of workability, mechanical and durability properties of high-strength concrete incorporating nano-silica and recycled E-waste materials
Authors: Hinge Pawan , Shende Tushar , Ralegaonkar Rahul , Nandurkar Bhupesh , Raut Sanjay , Kamath Muralidhar , Tantri Adithya , Naganna Sujay Raghavendra 
Published: July 2024

Abstract
Background
Presently, the proper disposal of E-waste is a major challenge for all nations. Portland cement and aggregates continue to play a major role in the construction industry's operations. Meanwhile, natural resources like gravel (aggregates) are becoming scarce. Thus, E-waste is now offering the building industry a chance to replace traditional aggregates. The main goal of the current study is to determine the highest amount of E-waste that may be replaced with 10-mm coarse aggregates with a nano-silica associated ternary blend in M-60 grade high-strength concrete while still maintaining the designed concrete's mechanical, durability, microstructural and workability characteristics.

Results
When compared to normal concrete, concrete with 15% E-waste replacement maintained the design-required compressive, flexural and tensile strength properties. When the E-waste plastic component percentage is considerably high (15–30%), there is a significant decremental performance regarding the mechanical properties and the decremental rate is found to be in the range of 13–23%. Even the microstructure characteristics of concrete validate the mechanical performance of concrete. Nevertheless, the durability characteristics of E-waste incorporated concrete were found to be promising.

Conclusions
The overall outcome of the study recommends 15% as the optimal replacement percentage of E-waste for conventional concrete, and it is recommended to adopt for real-time practices.
CFD modeling of orthogonal wave-current interactions in a rectangular numerical wave basin
Authors: Wei Kai , Hu Kaiyu 
Published: July 2024

AbstractSea-crossing bridges are subject to long-term simultaneous wave and current loadings throughout thier life cycle. The wave-current interaction makes the hydrodynamic load calculation difficult and challenging, especially in simulating the noncollinear wave-current interactions between waves and currents due to potential disturbances such as wall reflections within the observational zone. Therefore, in this study, a numerical flume was built based on the Reynolds time-average (RANS) equation and k-ε turbulence model using the computational fluid dynamics (CFD) software Flow-3D to investigate noncollinear wave-current interaction numerical simulation methods. The collinear wave-current interactions were then numerically simulated using the inflow boundary and mass source wave generation method, and the developed numerical flume was validated with experimental results based on a large-scale wave-current flume. Furthermore, a three-dimensional numerical simulation of complex noncollinear wave-current interactions was developed. The developed rectangular numerical basin based on the collinear wave-current flume was validated with theoretical results regarding wavelength variations in a noncollinear wave-current interaction field. Finally, the effective observation zone of orthogonal wave-current interactions was explored. This study is important for advancing bridge hydrodynamic research into noncollinear wave-current interactions.
Impacts of micro- and nanoplastics on early-life health: a roadmap towards risk assessment
Authors: Christopher Emily A. , Christopher-de Vries Yvette , Devadoss Anitha , Mandemaker Laurens D.B. , van Boxel Jeske , Copsey Helena M. , Dusza Hanna M. , Legler Juliette , Meirer Florian , Muncke Jane , Nawrot Tim S. , Saenen Nelly D. , Scholz-Böttcher Barbara M. , Tran Lang , Weckhuysen Bert M. , Zou Runyu , Zimmermann Lisa , Galea Karen S. , Vermeulen Roel , Boyles Matthew S. P. 
Published: July 2024

AbstractMicro- and nanoplastics (MNPs) are ubiquitous environmental pollutants representing a concern for human health. MNPs have been detected in human placentas, indicating that during pregnancy maternal exposure may lead to placental transfer and foetal exposure, with potential for adverse effects on early-life development. However, a comprehensive risk assessment (RA) framework, specific to early-life is lacking. Here, we propose a novel roadmap to assist the development of an early-life health RA of MNPs. This roadmap is designed based on established chemical, mixture, particle, and MNP assessment strategies aligned with standard RA components (problem formulation, hazard identification, hazard characterisation, exposure assessment, risk characterisation). We systematically work through these stages to identify what is needed to progress a RA for the early-life impacts of MNPs, including what information is missing, and what may be used in the interim. While challenges such as complex physicochemical properties of MNPs, limited toxicity data at relevant exposure levels, and uncertainties related to characterising complex exposures have been described elsewhere, our work discusses how these challenges specifically impact early-life stages such as the significance of MNP presence in biological samples and factors influencing bioaccumulation and placental transfer. Additionally, we introduce the development of new technology readiness levels for methods used in the detection of MNPs in complex matrices. Importantly, this review integrates a broad scope of relevant information into one comprehensive document, providing a unified resource. We highlight specific requirements and areas for targeted research, including the development of dose-response relationships specific to early-life stages and novel strategies for assessing bioaccumulation and placental transfer of MNPs. By addressing these gaps, our roadmap aims to advance the development of a robust framework, ultimately enhancing the understanding and mitigation of risks associated with early-life exposure to MNPs.
A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.
Authors: Yap Timothy A. , Plummer Elizabeth Ruth , Tolcher Anthony W. , Szucs Zoltan , Gounaris Ioannis , Locatelli Giuseppe , Enderlin Marta , Hicking Christine , Kaur Mukker Jatinder , De Bono Johann S. 
Published: July 2024

3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight <77kg or platelet count <150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .
YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.
Authors: Cheng Ying , Zhang Xiaochen , Liu Jian , Huang Zhangzhou , Lv Dongqing , Zhang Yiping , Wang Xiaojia , Chaudhry Arvind , Amin Harshad , Damodaran Senthil , Patel Shiven B. , Assad Hadeel , Lee Arielle Shebay , Zhao Hui , Bai Jinyun , Xue Tongtong , Chin Steve 
Published: July 2024

3034 Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (>20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]
Safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: A first-in-human, dose-escalation, multicenter, open-label, phase I study.
Authors: Park John J. , Gao Bo , Beecroft Claire , Wilkinson Kate Jessica , Parsonson Andrew , Zhang Karl , Yan Xiangyun , Wang Ni 
Published: July 2024

3038 Background: JSKN003 is a biparatopic HER2-directed ADC conjugated to a topoisomerase I inhibitor with an average DAR 4. Preclinical studies showed that JSKN003 had a good serum stability and strong anti-tumor activity. Hence JSKN003 could be effective in HER2 expressing tumors with a potentially broader therapeutic window. Methods: JSKN003-101 is a first-in-human, dose-escalation and -expansion study in Australian pts with advanced solid tumors. Pts (ECOG 0-1) with histologically documented HER2-expressing (HER2-positive defined as IHC 2+ or 2+/ISH+, HER2 low defined as IHC 1+ pr 2+/ISH-) or HER2-mutation by local testing who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, tolerability, MTD or RP2D, PK, and preliminary antitumor activity. Here the results from dose-escalation part were reported. Results: As of 15 Dec 2023, 32 pts were enrolled and received JSKN003 across 7 dose levels (1.0-8.4 mg/kg, Q3W). Among the 32 pts, 9 were IHC 1+, 16 were IHC 2+, and 7 were IHC 3+. Most pts (22/32, 68.8%) received ≥ 3 prior lines of therapy. The median duration of treatment was 15.8 (range, 6-54) weeks, and 19 pts (59.4%) remain on treatment. TRAEs occurred in 27 pts (84.4%) and 2 pts (6.3%) in 4.2mg/kg and 7.3mg/kg experienced grade 3 TRAE (anemia and fatigue); the most common TRAEs were diarrhea (62.5%) and nausea (50.0%), which were all grade 1-2. Only 1 pt experienced ILD/pneumonia (7.3mg/kg, grade 2). To date, no DLT events were found yet, and no TRAE led to death or treatment discontinuation. MTD has not been reached in 8.4 mg/kg. Following a single dose, exposures (Cmax and AUC) of JSKN003 and released TOP1i increased proportionally over a dose range of 4.2 mg/kg to 8.4 mg/kg. T1/2 of JSKN003 is approximately 5-6 days for 6.3 mg/kg and higher doses and increases with dose escalation. Accumulation of JSKN003 was minimal within the range of 1.1-1.5. The exposure of released payload was significantly lower than JSKN003 ADC, demonstrating the stability of the JSKN003 in circulation. All pts had at least one post-baseline tumor assessment. 16 pts achieved PR per RECIST 1.1 by investigator. Thus, ORR and DCR was 50.0% (95%CI: 31.9%, 68.1%) and 90.6% (95%CI: 75.0%, 98.0%), respectively. The ORR in pts with IHC 1+, 2+ and 3+ was 55.6% (5/9), 37.5% (6/16), and 71.4% (5/7), respectively. As for the efficacy of the HER2-positive and HER2-low breast cancer, the ORR was 80% (4/5) and 40.0% (4/10), respectively. Conclusions: JSKN003 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2 expressed tumors. As of the cut-off date, no DLT was observed, MTD has not been reached yet. Clinical trial information: NCT05494918 .
Subclonal mutational signatures in breast cancer brain metastases.
Authors: Varuzza Muriele Bertagna , Winata Helena , Patel Yash , Mootor Mohammed Faizal Eeman , Souza Cristiano de Padua , Boutros Paul Christopher , Silveira Marcia Maria Chiquitelli Marques 
Published: July 2024

e13108 Background: Breast cancer is the leading cause of cancer-related deaths among women in Brazil and the cancer type with highest incidence. When diagnosed at early stages, it has an overall five-year survival rate of up to 90%. However, in advanced stages, survival rate is reduced to about 24%, and 90% of women in stage IV die of metastatic complications. Brain is one of the most common metastatic sites in breast cancer patients, and even though it is a site with poor prognosis, the mutational profile of brain tumors is poorly described in the literature. Therefore, we understand that the identification of this profile may contribute to elucidate mechanisms associated with tumor progression. The aim of this study was to reconstruct the subclonal evolution of breast cancer metastases in the brain. Methods: To carry out this study, the whole exome was accessed through Next Generation Sequencing (NGS) using the Illumina platform in DNA samples extracted from buffy coat cryopreserved and paraffin material of breast tumors and paired brain metastases (n=10). The median read coverage was 68x. DNA was aligned to a Human Reference Genome using the Burrows–Wheeler Aligner, Genome Analysis Toolkit was used for germline short variants calling, and Mutect2 and MuSE were used for variant calling with somatic character (SNVs and INDELs). FACETS was used for assessing the somatic DNA copy number (Copy Number Aberrations). PyClone-VI tool was used for the subclonal reconstruction and to infer the phylogeny it was considered the mutation loci, Cancer Cell Fraction (CCF) and clustering assignments, using R Statistical Environment and Stats, Argparse, and Devtools packages. Results: We identified the mutational signature in these patients with subclonal and clonal mutations that segregated in approximately two clusters with a median between ten and forty variants related with tumor progression process. Conclusions: These findings show a set of variants with driver potential for breast cancer brain metastasis, bringing new perspectives in identifying mechanisms associated with disease progression.
Survival analysis of brain metastases secondary to breast cancer: A single-center experience.
Authors: Chun Brie , Oyogoa Emmanuella , Kaempf Andy , Levy Julia , Padilla Lazos Thalia , Rounsavill Teyhana , Nguyen Mai-Loan , Stefanik Fiona , Eichten Victoria , Kornachuk Tana , Duong Jessica , Goodyear Shaun M. , Zimmer Alexandra Dos Santos 
Published: July 2024

e13111 Background: Brain metastasis (BM) contributes to substantial morbidity and mortality for breast cancer (BCa) patients (pts). Advances in systemic therapies have improved survival following BM diagnosis; however, other factors such as age, timing of BM development, and molecular features may also affect outcomes. Here we characterize the overall survival (OS) of pts with BM secondary to BCa treated at our institution with the aim of identifying predictors that can used to improve treatment and management. Methods: In an electronic medical record of “brain metastasis” and “breast cancer”, we identified pts aged >18 years treated between 2015 and 2022. All cases were manually reviewed by ≥2 reviewers. Cases with second metastatic (met) solid tumors, hematologic malignancies, or insufficient data were excluded. Only cases with intraparenchymal and/or leptomeningeal disease attributed to met BCa were included. Kaplan-Meier estimation and Cox regression were applied to OS. Results: Of 344 cases reviewed, 229 (1 male) were appropriate for inclusion. The median age at BM diagnosis (dx) was 58 years. 28% underwent surgical resection and 81% received radiation treatment for BM. With a median follow-up of 5 years, 82% of pts died and median OS (mOS) following BM dx was 14 months (95% CI: 9-19). Among 208 pts without de novo BM, time to BM development (mTBM) from primary BCa varied by subtype: mTBM (IQR) HR+HER2- of 6.4 years (3.9-10.5), HR+HER2+ of 3.5 years (2.0-9.1), HR-HER2+ of 2.1 years (1.2-3.1), TNBC of 2.4 years (1.1-4.9). mOS varied by BCa subtype (table, log-rank p=0.029). 41 cases had de novo met disease (met dx ≤2 months of BCa dx) with 21 (9%) having de novo BM. HER2+ BCa and shorter mTBM were associated with longer mOS (table). Pts with BM dx in 2nd or later met relapse vs. earlier BM (de novo or 1st met relapse), OS HR was 1.67 (95% CI: 1.24-2.25; p=0.001). OS did not vary by age at BM diagnosis. Conclusions: Our findings build on prior work showing differential BM survival by subtype. We observe significantly shorter post-BM survival among pts who develop BM after a second or later line of met treatment. Ongoing work will expand our database and explore molecular features of resected brain tumors. [Table: see text]