bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternating phase focusing beam dynamics for drift tube linacs
Authors: Lauber Simon , Barth Winfried , Basten Markus , Dziuba Florian D. , List Julian , Miski-Oglu Maksym , Podlech Holger , Yaramyshev Stepan 
Published: April 2024

AbstractIn contrast to conventional E-mode resonance accelerators, H-mode DTLs provide for compact linac sections and have been established as highly efficient resonators during the last decades. Thus, H-mode structures are widely applied for heavy-ion acceleration with medium beam energies because of their outstanding capability to provide high acceleration gradients with relatively low energy consumption. To build upon those advantages, an alternating phase focusing beam dynamics layout has been applied to provide for a resonance accelerator design without internal lenses, which allows for eased commissioning, routine operation, maintenance, and potential future upgrades. The features of such a channel are going to be demonstrated on the example of two interdigital H-mode cavities, separated by an external quadrupole triplet. This setup provides for heavy ion (mass-to-charge ratio $A/z\le 6$
A
/
z
≤
6
) acceleration from 300 keV/u to 1400 keV/u and is used as an injector part of the superconducting continuous wave accelerator HELIAC. Hence, this promising approach generally enables effective and compact routine operation for various applications, such as super heavy ion research, material science, and radio biological applications such as heavy-ion tumor therapy.
There are no post-quantum weakly pseudo-free families in any nontrivial variety of expanded groups
Authors: Anokhin Mikhail 
Published: April 2024

Let [Formula: see text] be a finite set of finitary operation symbols and let [Formula: see text] be a nontrivial variety of [Formula: see text]-algebras. Assume that for some set [Formula: see text] of group operation symbols, all [Formula: see text]-algebras in [Formula: see text] are groups under the operations associated with the symbols in [Formula: see text]. In other words, [Formula: see text] is assumed to be a nontrivial variety of expanded groups. In particular, [Formula: see text] can be a nontrivial variety of groups or rings. Our main result is that there are no post-quantum weakly pseudo-free families in [Formula: see text], even in the worst-case setting and/or the black-box model. In this paper, we restrict ourselves to families [Formula: see text] of computational and black-box [Formula: see text]-algebras (where [Formula: see text]) such that for every [Formula: see text], each element of [Formula: see text] is represented by a unique bit string of length polynomial in the length of d. In our main result, we use straight-line programs to represent nontrivial relations between elements of [Formula: see text]-algebras. Note that under certain conditions, this result depends on the classification of finite simple groups. Also, we define and study some types of post-quantum weak pseudo-freeness for families of computational and black-box [Formula: see text]-algebras.
New Means and Challenges in the Targeting of BTK
Authors: Nawaratne Vindhya , Sondhi Anya K. , Abdel-Wahab Omar , Taylor Justin 
Published: April 2024

Abstract
Bruton's tyrosine kinase (BTK) is central to the survival of malignant and normal B lymphocytes and has been a crucial therapeutic target of several generations of kinase inhibitors and newly developed degraders. These new means for targeting BTK have added additional agents to the armamentarium for battling cancers dependent on B-cell receptor (BCR) signaling, including chronic lymphocytic leukemia and other non–Hodgkin lymphomas. However, the development of acquired resistance mutations to each of these classes of BTK inhibitors has led to new challenges in targeting BTK as well as novel insights into BCR signaling. The first-generation covalent BTK inhibitor ibrutinib is susceptible to mutations affecting the covalent binding site, cysteine 481 (C481). Newer noncovalent BTK inhibitors, such as pirtobrutinib, overcome C481 mutation–mediated resistance but are susceptible to other kinase domain mutations, particularly at residues Threonine 474 and Leucine 528. In addition, these novel BTK inhibitor resistance mutations have been shown biochemically and in patients to cause cross-resistance to some covalent BTK inhibitors. Importantly, newer generation covalent BTK inhibitors zanubrutinib and acalabrutinib are susceptible to the same mutations that confer resistance to noncovalent inhibitors. The BTK L528W mutation is of particular interest as it disrupts the kinase activity of BTK, rendering it kinase dead. This observation suggests that BTK may act independently of its kinase activity as a scaffold. Thus, the timely development of BTK degrading proteolysis targeting drugs has allowed for degradation, rather than just enzymatic inhibition, of BTK in B-cell lymphomas, and early clinical trials to evaluate BTK degraders are underway.
Abstract CT287: LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715)
Authors: Gordon Erlinda M. , Omelchenko Nadezhda , Jeffrey Samantha , Kumar Vaishali , Chawla Neal S. , Seetharam Mahesh , Chua Victoria , Moradkhani Ania , Quon Doris , Wong Steven , Chawla Sant 
Published: April 2024

Abstract
Background: Sarcoma cells are most immunogenic earlier in the course of the disease. Therefore, immune checkpoint inhibitors such as ipilimumab (ipi) and nivolumab (nivo), that promote sustained T-cell activation by suppressing T regs would be most effective when given as first line therapy, together with a tumoricidal agent, such as lurbinectedin, whose plausible mechanism of action is not only to destroy the cancer cells and expose the tumor neoantigens for immune recognition, but also to destroy growth promoting factors in the tumor microenvironment. In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. 15, 906, 2023). Lurbinectedin is a synthetic marine-derived agent and an analog of trabectedin. Therefore, we expect that lurbinectedin will be as effective as trabectedin when used together with ipi and nivo as first line therapy for advanced STS.
Methods: Objective 1: Assess MTD of lurbinectedin. Objective 2: Evaluate PFS, OS, incidence and severity of adverse events; Correlative: Correlate response with ctDNA using Signatera. This is an open label, dose-seeking phase 1/2 study. The phase 1 part employs standard “cohort of three” design with a DLT window of 6 weeks. Treatment schedule: Ipi 1 mg/kg IV q 12 weeks; Nivo 3 mg/kg IV q 2 weeks; escalating doses of lurbinectedin from 2.6 mg/m2 to 3.2 mg/m2 IV q 3 weeks. Phase 2 part follows completion of phase 1 part wherein additional 28-34 participants will receive lurbinectedin at the MTD with fixed doses of Ipi and Nivo. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed.
Citation Format: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla. LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT287.
Abstract LB010: Identification of malignant lung indeterminate pulmonary nodules with Plasma WGS using exon read depth of short DNA fragments
Authors: Yip Shun H. , Swarup Neeti , Hyun Jason C. , Cheng Jordan C. , Ramamurthy Raghuraman , Wong Edmund , Choi Irene , Arora Akanksha , Aberle Denise , Wong David TW , Tang Cheuk Y. 
Published: April 2024

Abstract
Background: Plasma WGS for non-invasive cancer detection has been an active area of research, where fragmentomics studies have been gaining attention for its promising results. Previous studies showed that the quantity of short and long fragments could be used for the prognosis of malignant tumor. In this study, the efficacy of short fragment read depth on the reference genome for malignant nodule detection was evaluated.
Methods: Plasma samples from 40 patients with Indeterminate Pulmonary Nodules (IPN) (20 with Benign nodule, 20 Malignant) were collected for WGS. Low quality samples were filtered, and 31 patients (15 Benign, 16 Cancer) remained. Short fragments in each sample were extracted (30-99 bp) and exon read depth for each sample was obtained through human reference genome alignment. A proprietary data analytic machine learning pipeline using XGBoost was trained and tested using 10 fold cross validation.
Results: XGBoost model testing accuracy was 96.77% in differentiating Benign and Cancer samples using read depth information from only 3 exons. GPR35’s ENSE00003591008.1, ZNF594-DT’s ENSE00002678218.2 and IGHGP’s ENSE00001819760.2 were the 3 exons used in the model. Hierarchical clustering using top features with differential read depth (p&lt;0.001) was able to perfectly cluster the samples into the Benign group and the Malignant group.
Conclusion: Read depth information of exon by short fragments from WGS plasma was able to differentiate patients with Lung benign nodules from patients with malignant nodules. This analysis demonstrates promises of developing diagnosis tools using exon read depths from plasma samples.
Citation Format: Shun H. Yip, Neeti Swarup, Jason C. Hyun, Jordan C. Cheng, Raghuraman Ramamurthy, Edmund Wong, Irene Choi, Akanksha Arora, Denise Aberle, David TW Wong, Cheuk Y. Tang. Identification of malignant lung indeterminate pulmonary nodules with Plasma WGS using exon read depth of short DNA fragments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB010.
Abstract LB034: First-in-class compounds targeting the MIEN1 signaling pathway: A breakthrough approach for breast and prostate cancer therapy
Authors: Tripathi Amit Kumar , Vishwanatha Jamboor K. 
Published: April 2024

Abstract
We report the identification and complete characterization of first-in-class molecules targeting the MIEN1 signaling pathway in cancer. Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved ITAM and prenylation motifs within MIEN1, we identified potent anti-cancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and EMT pathways, concurrently suppressing EGF-induced NF-kB nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and circular dichroism spectroscopy indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK-SCR and RP-7-SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high peptide doses of up to 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anti-cancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo.
Citation Format: Amit Kumar Tripathi, Jamboor K. Vishwanatha. First-in-class compounds targeting the MIEN1 signaling pathway: A breakthrough approach for breast and prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB034.
Abstract LB052: PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer
Authors: Neel Benjamin G. , Bhardwaj Abhishek , Antonelli Maria , Ueberheide Beatrix 
Published: April 2024

Abstract
Dual PTP1B/TC-PTP (PTPN1/2) inhibitors are in clinical trials for multiple cancer types, primarily because they augment anti-tumor immunity, but they can also have cancer cell-autonomous effects. Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency/inhibition promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ~600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. We now report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD-deleted HER2+ cell-derived xenografts phencopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning “cold” tumors “hot”, thereby increasing the potential clinical utility of PTP1B inhibitors.
Citation Format: Benjamin G. Neel, Abhishek Bhardwaj, Maria Antonelli, Beatrix Ueberheide. PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB052.
Abstract LB055: IBI3001: A potentially first-in-class site-specifically conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors
Authors: Guan Jian , Zhang Xiao , Wu Weiwei , Cao Lei , Liao Zhengguang , Zhu Tianyu , Liu Chentao , Zhou Shuaixiang , Lu Jia , Li Ninghuan , Luo Nana , Zhang Ying , Dian Kang , Chia Tiong Sun , Chen Bingliang , He Kaijie 
Published: April 2024

Abstract
B7-H3 and EGFR are both clinically validated TAAs in solid tumors. We previously demonstrated in IBI334 (B7-H3/EGFR bsAb) study that (1) B7-H3 and EGFR are co-expressed in multiple solid tumors; (2) B7-H3-aided EGFR signaling inhibition was significantly more potent than Zalutumumab (EGFR mAb) and Amivantamab (c-met/EGFR bsAb); and (3) IBI334 has favorable safety profile in cynomolgus monkey at 120 mg/kg/week. Building on this optimized bispecific antibody, we site-specifically conjugated IBI334 with Exatecan (drug-antibody-ratio = 4) using the clinically validated SyntecanE platform. The resulting bispecific ADC, IBI3001, has multiple mechanism of actions: (1) enhanced EGFR signaling blockage; (2) EGFR- and B7-H3-aided payload internalization and cytotoxicity; and (3) bystander killing effects of ADC. More importantly, the optimized B7-H3 arm not only enhances the EGFR signaling blockage but also reduces EGFR on-target toxicities. IBI3001 demonstrated potent in vitro cytotoxicity in all B7-H3LowEGFRLow, B7-H3HighEGFRLow, B7-H3LowEGFRHigh and B7-H3HighEGFRHigh cancer cells across multiple solid tumors, including lung cancer, colorectal cancer, pancreatic cancer, breast cancer, head and neck cancer, and stomach cancer. In addition, it had strong bystander effects, killing both EGFR+ B7-H3+ cancer cells and EGFR- B7-H3- cancer cells. All in vitro studies were further validated in vivo with robust tumor growth inhibition in NCI-H508 (colorectal cancer), JIMT-1 (breast cancer), BxPC3 (pancreatic cancer) and NCI-1975 (lung cancer) xenograft models. IBI3001 has a favorable PK profile in BALB/c mice with the half-life at 282 hours, and is well-tolerated in cynomolgus monkeys up to 90 mg/kg/week. In conclusion, IBI3001 is a novel bispecific ADC that demonstrated strong anti-tumor efficacy cross multiple solid tumors, and has excellent PK and safety profile.
Citation Format: Jian Guan, Xiao Zhang, Weiwei Wu, Lei Cao, Zhengguang Liao, Tianyu Zhu, Chentao Liu, Shuaixiang Zhou, Jia Lu, Ninghuan Li, Nana Luo, Ying Zhang, Kang Dian, Tiong Sun Chia, Bingliang Chen, Kaijie He. IBI3001: A potentially first-in-class site-specifically conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB055.
Abstract LB140: Age difference in cervical cancer stigma among Caribbean population
Authors: Thomas-Purcell Kamilah , Song Gaole , Sealy Diadrey-Anne , Bailey Althea , Ashing Kimlin T. 
Published: April 2024

Abstract
Introduction Cervical cancer (CCA) is the second most common cancer and one of the leading causes of death among women in the Caribbean region. CCA stigma impedes women from seeking and obtaining relevant healthcare. This study aimed to evaluate age difference in cancer stigma among non-patient populations in Jamaica, Grenada, and Trinidad and Tobago, utilizing a culturally trans-created scale.
Methods A cross-sectional study involving 1207 participants was conducted. The survey comprised the adapted Cancer Stigma Scale, supplemented with questions on cervical cancer knowledge and beliefs. Participants' knowledge and attitudes towards the HPV vaccine were also assessed. Data was collected online from October 2022 to March 2023. Statistical analysis was performed using SAS.
Results This study included 33.4% of total participants aged 18-25 years, 23.4% aged 26-35 years, 21.4 aged 36-45 years, 10.7% aged 46-55 years, 7.5% aged 56-65 years, and 3.6% aged 65+ years. Chi-squared tests showed age is significantly related to respondents’ opinions on women with CCA are treated with less respect than usual by others (p&lt;.0001), women with CCA must keep it a secret (p=0.03), women with CCA are rejected by family members (p=0.0007), women with CCA are rejected by intimate partners (p&lt;.0001), and intimate partners blame women for having CCA (p=0.003). Additionally, age has significant associations with agreements on negative views of cervical cancer from the community (p&lt;.0001) and family (p&lt;.0001) may discourage women from seeking and obtaining screening and treatment and community members believe CCA is viewed as shameful (p=.0001). Notably, there are more younger respondents (18-25 years) who agreed that women with CCA are rejected by intimate partners (32.3%), and the fear of family reaction and rejection may discourage women from getting further diagnosis after an abnormal Pap smear (48.1%).
Discussion Age is an important factor that influences cervical cancer stigma even in Caribbean contexts. Findings of this study indicate younger people may have a more serious stigma, which calls for proper educational programs for cervical cancer screening and treatment.
Citation Format: Kamilah Thomas-Purcell, Gaole Song, Diadrey-Anne Sealy, Althea Bailey, Kimlin T. Ashing. Age difference in cervical cancer stigma among Caribbean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB140.
Abstract LB147: Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer
Authors: Li an , Xing Tongyu , Zhao Yanrui , Chen Kexin , Zheng Hong 
Published: April 2024

Abstract
Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. Genome-wide association study(GWAS) identified a novel variant on chromosome 9q22.33as a susceptibility locus of epithelial ovarian cancer (EOC) in Han Chinese population. However, the underline mechanism of this region was still unknown. In this study, we conducted a fine-mapping analysis of 130kb region including 1,039 variants in 200 health women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants were significantly associated with ovarian cancer risk (rs7027650, P=1.91 × 10−7; rs1889268, P=3.71 × 10−2). Expression quantitative trait locus (eQTL) analysis found thatrs7027650was significantly correlated with COL15A1 gene expression (P=0.009). Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1 to reduce its activity. Electrophoretic Mobility ShiftAssay (EMSA) showed theallele-specific binding capacity of rs7027650. These findings revealed that rs7027650 may be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study provided a clue for the molecular mechanism of potential causal variantaffecting the risk of ovarian cancer.
Citation Format: an Li, Tongyu Xing, Yanrui Zhao, Kexin Chen, Hong Zheng. Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB147.