bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer
Authors: Garrido-Castro Ana C , Graham Noah , Ali Lestat R , Herold Christina , Desrosiers Jennifer , Do Khanh , Parsons Heather , Li Tianyu , Goel Shom , DiLullo Molly , Wrabel Eileen , Williams Amy J , Liu Joyce F , Mittendorf Elizabeth A , Dougan Stephanie K , Tayob Nabihah , Shapiro Geoffrey I , Tolaney Sara M 
Published: February 2025

BackgroundPreclinical evidence suggests that cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors enhance antitumor immunity. We conducted a phase I trial of ribociclib (CDK4/6 inhibitor) plus spartalizumab (PD-1 inhibitor) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) or advanced ovarian cancer (AOC). The combination was also evaluated with fulvestrant in MBC.MethodsIn Cohort A, ribociclib was administered on Days 1–21 (28-day cycle) starting at 400 mg, and spartalizumab at 400 mg on Day 1. Dose escalation was followed by expansion in AOC. Fulvestrant was added (Cohort B) with a safety run-in followed by expansion in MBC. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and safety and tolerability of the combinations.Results33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600 mg. Treatment-related adverse events in >20% of patients in either cohort were neutropenia, fatigue, anemia, thrombocytopenia, hypertransaminasemia, maculopapular rash, fatigue, and nausea. Hypertransaminasemia occurred in 66.7% (AST) and 46.7% (ALT) of patients in Cohort B, including 46.7% and 40.0%, respectively, of grade 3 or 4 events. Two confirmed partial responses were observed (13.3%) in Cohort B, in patients with low baseline serum thymidine kinase activity, coupled with an increase on-treatment. Peripheral blood flow cytometry across patients demonstrated on-target drug binding with increases in PD-1 occupancy and activated CD8+T cells during treatment, irrespective of response. PD-L1-positivity, tumor-infiltrating lymphocytes, or tumor mutational burden did not correlate with progression-free survival (PFS). Several copy-number variations detected with next-generation sequencing correlated with PFS.ConclusionsRibociclib with spartalizumab and fulvestrant showed limited efficacy and elevated hepatotoxicity, precluding further development. Correlative analyses revealed treatment-induced immunological effects, and genomic alterations associated with PFS.
Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer
Authors: Roudko Vladimir , Del Valle Diane Marie , Radkevich Emir , Kelly Geoffrey , Hui Xie , Patel Manishkumar , Gonzalez-Kozlova Edgar , Tuballes Kevin , Streicher Howard , Atale Swati , Wang Lisa , CzinCzin Benito , Kim-Schulze Seunghee , Wistuba Ignacio I , Haymaker Cara L , Al-Atrash Gheath , Manyam Ganiraju , Zhang Jianjun , Thompson Ryan , Suarez-Farinas Mayte , Lheureux Stephanie , Gnjatic Sacha 
Published: February 2025

BackgroundAntiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104,NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.Methods and resultsUsing Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease <6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate <0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1).ConclusionsOverall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.
Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma
Authors: Zhang Pengpeng , Wang Dingli , Zhou Guangyao , Jiang Shuai , Zhang Ge , Zhang Lianmin , Zhang Zhenfa 
Published: February 2025

BackgroundLung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value in LUAD remains largely unexplored.MethodsWe developed a post-translational modification learning signature (PTMLS) using machine learning techniques, analyzing data from 1231 LUAD patients across seven global cohorts. The signature’s efficacy in predicting immunotherapy response was evaluated using 12 immunotherapy cohorts spanning multiple cancer types (n=1201). An in-house LUAD tissue cohort (n=171) was used to validate beta-1,4-galactosyltransferase 2’s (B4GALT2’s) prognostic significance. The role of B4GALT2 in immune exclusion was investigated through in vivo and in vitro experiments.ResultsThe established PTMLS exhibited exceptional predictive capabilities in LUAD patient outcomes, surpassing the efficacy of 98 existing LUAD prognostic indicators. The system’s predictive value was validated across diverse malignancy categories for immunotherapeutic response assessment. From a biological perspective, significant correlations were observed between PTMLS and immunological parameters, whereby elevated PTMLS levels were characterized by attenuated immune responses and immunologically cold neoplastic features. Within the PTMLS framework, B4GALT2 was identified as a crucial molecular component (r=0.82, p<0.05), and its heightened expression was linked to unfavorable clinical outcomes in LUAD cases, particularly in specimens exhibiting CD8-depleted phenotypes. The spatial distribution patterns between B4GALT2 and immune cell populations, specifically CD8+ T lymphocytes and CD20+ B lymphocytes, were elucidated through multiplexed immunofluorescence analysis. Laboratory investigations subsequently established B4GALT2’s regulatory influence on LUAD cellular expansion in both laboratory cultures and animal models. Significantly, suppression of B4GALT2 was found to enhance CD8+ T lymphocyte populations and their functional status, thereby potentiating anti-programmed cell death protein 1 immunotherapeutic efficacy in animal studies. This phenomenon was characterized by reduced CD62L+CD8 T lymphocyte levels alongside elevated GZMB+/CD44+/CD69+CD8 T cell populations.ConclusionThe developed PTMLS system represents an effective instrument for individualized prognostic evaluation and immunotherapy stratification in both LUAD and diverse cancer populations. The identification of B4GALT2 as a previously unrecognized oncogenic factor involved in immune exclusion presents a novel therapeutic avenue for LUAD treatment and immunotherapy optimization.
Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24
Authors: Liu Yu , Ma Jianhui , Ma Yiming , Wang Bing-zhi , Wang Yinong , Yuan Junhu , Zhang Fanyu , Zhao Xinhua , Chen Kun , Zhang Xiaoli , Wang Hongying 
Published: February 2025

BackgroundPhagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles.MethodsA lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays.ResultsNETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo.ConclusionsNET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.
Targeting mesothelin-CD24 axis repolarizes tumor-associated macrophages to potentiate PD-1 blockade therapy in high-grade serous ovarian cancer
Authors: Zhong Yujing , Wang Yiying , Wang Chenyang , Cao Kankan , Wang Xueling , Xu Xuyao , Yang Moran , Zhang Guodong , Liu Haiou , Lu Jiaqi 
Published: February 2025

BackgroundHigh-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy marked by an immunosuppressive tumor microenvironment that hinders effective immune responses. A key feature of this environment is the extensive infiltration of myeloid cells, which contributes to immune evasion. This study explored how mesothelin (MSLN), a tumor-associated antigen, modulates the expression of CD24, an emerging target for immune modulation, and its role in promoting immune evasion in HGSOC. Understanding these underlying mechanisms is crucial for enhancing the efficacy of immune checkpoint blockade (ICB) therapies and improving outcomes in patients with HGSOC.MethodsWe analyzed the expression of MSLN in HGSOC samples and examined its correlation with clinical outcome. In vitro and in vivo models were used to explore how MSLN influences CD24 expression and the polarization of tumor-associated macrophages (TAMs). We also investigated the role of MSLN in the activation of Wnt/β-catenin signaling and its impact on T-cell function and antitumor immunity. The effects ofMslnknockdown on CD24 expression and the response to anti-programmed cell death protein-1 (PD-1) therapy were evaluated in syngeneic mouse models.ResultsMSLN expression was found to be significantly elevated in HGSOC, with high MSLN levels correlating with poor prognosis and resistance to ICB. MSLN upregulated CD24 and promoted the protumorigenic polarization of TAMs, contributing to T-cell dysfunction. Mechanistically, MSLN activated Wnt/β-catenin signaling, which in turn enhanced CD24 expression. This activation forms a positive feedback loop that further promotes MSLN transcription. In contrast,Mslnknockdown reduced CD24 expression, relieved cytotoxic T-cell suppression, and significantly improved the efficacy of anti-PD-1 therapy in syngeneic models.ConclusionsThis study elucidates the critical role of MSLN in immune evasion in HGSOC and its underlying mechanisms. Targeting MSLN in combination with ICB is a promising strategy to enhance the efficacy of immunotherapy and improve patient outcomes in HGSOC.
An empirical analysis of the effect of COVID-19 on the Indian mutual funds industry
Authors: Mahapatra Rupsa , Das Kishore Kumar , Ali Shahnawaz , Banerjee Pradeepta 
Published: February 2025

Purpose: This research aims to examine and study the direct impact of change in COVID-19 cases and IIP index on the performance of NIFTY and selected mutual funds NAV performance for one year from the date WHO declared COVID-19 pandemic on 11 March 2020. Approach/Methodology/Design: The study applies using daily NAV series of four mutual funds across sectors. ANOVA, Correlation, Regression, Descriptive Statistics. Findings: There is a strong relation among NIFTY 50 and all the four mutual funds’ NAV performance, however, the relation between daily reported COVID-19 cases and NAV performance couldn’t be established. Practical Implications: Economic turmoil has affected the disposable income of investors, the capital market is very volatile. This study will help the researchers and analysts to understand the relationship between COVID-19, NIFTY 50 index and select mutual funds NAV movements. And they can make a better decision under a similar situation.
XpuTEE: A High-Performance and Practical Heterogeneous Trusted Execution Environment for GPUs
Authors: Fan Shulin , Hua Zhichao , Xia Yubin , Chen Haibo 
Published: February 2025

AI applications are employed in diverse scenarios, including data centers, personal computers, smart cars, and so on. Their privacy is threatened by the intricate software stacks and the potential malfeasance of system maintainers. The Trusted Execution Environment (TEE) has become popular for safeguarding applications from untrusted system software. However, AI applications are always speeded up with heterogeneous accelerators, e.g., GPU, which requires the TEE to be heterogeneous. A heterogeneous TEE should satisfy three requirements: 1) the joint heterogeneous abstraction that covers the CPU and GPUs and minimizes cooperation overhead among enclaves on them; 2) the high performance for supporting high-speed GPUs and introducing limited performance overhead; and 3) the compatibility with existing CPUs and GPUs so that existing machines can directly benefit from it.
To meet the above requirements, this paper introduces XpuTEE, a practical and high-performance heterogeneous TEE system. XpuTEE provides a new abstraction called XpuEnclave, comprising the CEnclave to protect CPU-side logic and numerous XEnclaves to guard GPU tasks. XpuEnclave is a joint TEE crossing the CPU and connected GPUs, and it removes all cryptographic operations and extra memory copies for CPU-GPU communication, which allows XpuTEE to achieve high performance. The results demonstrate that XpuTEE has an average performance overhead of 2.48% for common AI applications.
A Hybrid Statistical and Rule-based Approach to Extremely Low-resource Machine Transliteration
Authors: Connor Patrick Charles 
Published: February 2025

Machine transliteration work has focused primarily on languages with large volumes of parallel corpus, and between language pairs whose orthographies are very different. In contrast, a large proportion of the world’s languages have vastly fewer resources and employ Roman-like alphabets often with large degrees of orthographic overlap with high-resource languages. We propose that machine transliteration between languages with few training examples can be accomplished by a noisy-channel-like statistical model captured in a human editable format with practical rule-based capabilities built-in. This hybrid approach allows users to take advantage of an algorithm to find and apply common transformations in context while providing rigorous control over the output. Effectiveness is evaluated on the Bible names translation matrix dataset of Wu et al. (2018), covering 591 languages that involve 590 names on average per language pair. Our approach slightly exceeds past results and explores several features targeted at benefiting the extremely low-resource language domain.
Modeling the Dynamics of Cylindrical Lithium-ion Battery Aging Due to Evolving Solid Electrolyte Interphase Layer
Authors: Zhao Jin , Abu Qahouq Jaber A. 
Published: February 2025

Abstract
The solid electrolyte interphase (SEI) layer plays a critical role in the aging and degradation of lithium-ion batteries (LIBs), directly influencing their performance and longevity. This paper presents a physics-based model that quantitatively characterizes SEI layer growth in cylindrical LIBs by incorporating ionic current density as a governing parameter. The presented approach captures localized SEI dynamics by coupled state-space equations (SSEs) within an convex optimization framework. The model accounts for both uniform and nonlinear SEI growth phases, predicting capacity fade and impedance evolution over cycling aging. Validation against experimental charge-discharge profiles, electrochemical impedance spectroscopy (EIS) characterization, and equivalent circuit modeling demonstrates the model’s precision in tracking SEI-related degradation. The proposed framework offers a robust, interpretable, and computationally efficient tool for battery diagnostics and lifetime prediction.
Aeroallergen Sensitization Patterns and Related Factors in Children With Allergic Rhinitis in Guangzhou
Authors: Zeng Qingxiang , Yang Chao , Li Jinyuan , Qiu Xiangqian , Liu Wenlong 
Published: February 2025

Background: Certain patterns of children’s serum immunoglobulin E (IgE) sensitivity to aeroallergens may offer useful clinical insight into forecasting the course and prognosis of allergic rhinitis (AR). The study aimed to investigate the changes in aeroallergen sensitization patterns in children with AR during the last decade and compare the sensitization pre‐ and post‐coronavirus disease 2019 (COVID‐19) pandemic in Children who visited our center.Methods: This is a retrospective study, examining the serum IgE of nine aeroallergens from 21,362 children (1–12 years old) from AR who visited Guangzhou Women and Children’s Medical Center from June 2013 to June 2023.Result: The dust mites were the most prevalent aeroallergen in Guangzhou, with positive sensitization rates of 74.30% for Dermatophagoides farinae (D. farinae), 73.30% for Dermatophagoides pteronyssinus (D. pteronyssinus), and common ragweed (1.6%) was the lowest. After the COVID‐19 pandemic, the sensitization rates to D. farinae were consistent and D. pteronyssinus was slightly decreased while German cockroach, cat, and dog dander were increased. Most of the aeroallergens other than common ragweed were increased in school‐age children than preschool stage. Boys have a higher positive rate than girls for D. farinae and D. pteronyssinus.Conclusions: With the unraveling of allergens’ sensitization rates in various conditions, avoidance from D. farinae and D. pteronyssinus should still be the most important objectives to maintain in reducing AR episodes.
Patterns of associations with epidemiologic factors by high grade serous ovarian cancer gene expression subtypes
Authors: Collin Lindsay J. , Cushing-Haugen Kara L. , Terry Kathryn L. , Goode Ellen L. , Wu Anna H. , Harris Holly R. , Sasamoto Naoko , Cramer Daniel W. , Modugno Francesmary , Elishaev Esther , Fu Zhuxuan , Moysich Kirsten B. , Fasching Peter A. , Pearce Celeste Leigh. , Menon Usha , Gentry-Maharaj Aleksandra , Gayther Simon A. , Wentzensen Nicolas , Goodman Marc T. , George Joshy , Talhouk Aline , Anglesio Michael S. , Ramus Susan J. , Bowtell David DL. , Tworoger Shelley S. , Schildkraut Joellen M. , Webb Penelope M. , Doherty Jennifer A. 
Published: February 2025

Abstract
Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes. Methods: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis Consortium. The PrOTYPE validated NanoString-based 55 gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models. Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. Key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking (OR=1.25, 95%CI: 1.03, 1.51) and genital powder use (OR=1.42, 95%CI: 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR=1.46, 95%CI: 0.98, 2.16) and C4.DIF (OR=1.27, 95%CI: 0.94, 1.71) only. Family history of breast cancer (OR=1.44, 95%CI: 1.16, 1.78) and current smoking (OR=1.40, 95%CI: 1.11, 1.76) were associated with C4.DIF only. Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes. Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.