bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fourth order Hankel determinants for certain subclasses of modified sigmoid-activated analytic functions involving the trigonometric sine function
Authors: Srivastava Hari M. , Khan Nazar , Bah Muhtarr A. , Alahmade Ayman , Tawfiq Ferdous M. O. , Syed Zainab 
Published: June 2024

AbstractThe aim of this paper is to introduce two new subclasses $\mathcal{R}_{\sin }^{m}(\Im )$

R
sin
m

(
ℑ
)
and $\mathcal{R}_{\sin }(\Im )$

R
sin

(
ℑ
)
of analytic functions by making use of subordination involving the sine function and the modified sigmoid activation function $\Im (v)=\frac{2}{1+e^{-v}}$
ℑ
(
v
)
=

2

1
+

e

−
v

, $v\geq 0$
v
≥
0
in the open unit disc E. Our purpose is to obtain some initial coefficients, Fekete–Szego problems, and upper bounds for the third- and fourth-order Hankel determinants for the functions belonging to these two classes. All the bounds that we will find here are sharp. We also highlight some known consequences of our main results.
Nano-modifications of edible materials using ionizing radiation for potential application in active food safety
Authors: Aboulfotouh Maysara E. , Ali Hussein El-shahat , Mohamed Maha R. 
Published: June 2024

AbstractActive food packaging films from Carboxy methyl cellulose and starch (CMC-g-Starch) reinforced with Magnesium-oxide (MgO) NPs are created and characterized. The effect of different particle sizes, MgO NPs concentrations and different gamma irradiation doses on the preparation of (CMC-g-Starch-MgO) edible nanocomposite films were investigated to determine their properties. Several analytical methods, such as swelling behavior, FT-IR, TEM, TGA, and mechanical characteristics, are represented to investigate different characteristics of the prepared (CMC-g-Starch-MgO) edible nanocomposite films. Also, the prepared (CMC-g-Starch-MgO) edible nanocomposite films and their coating were subjected to the fresh Peaches fruits. Their effect on the Peach fruits' lifespan was evaluated. The anti-microbial property of the edible (CMC-g-Starch-MgO) nanocomposite films of gram (+ve) and gram (–ve) bacteria was reported. Results represented the thermal and mechanical characteristics of (CMC-g-Starch-MgO) edible nanocomposite films, which were enhanced by γ irradiation. Also, the irradiated (CMC-g-Starch-MgO) edible nanocomposite films and their coating extend the lifespan of Peaches fruits and exhibit resistance to pathogenic microorganisms. In conclusion, (CMC-g-Starch-MgO) edible nanocomposite films fulfilled the required behaviors for the application in the nanofood packaging era.
Organ-specific immune-related adverse events and survival in patients with cancer with immune checkpoint inhibitors.
Authors: Wang Jun , Han Xinyue , Chen Yingcui , Xie Hong , Zhang Yuekai , Cui Yu , Guan Yaping 
Published: June 2024

12124 Background: Immunotherapy with immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). This study was designed to assess whether the occurrence of irAEs or different irAE characteristics correlates with survival outcomes in advanced cancer patients treated with ICIs. Methods: This cohort study included a panel of patients with advanced cancer who received ICI therapy at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics. Results: A total of 238 patients were enrolled, and 83 (34.9%) patients developed at least one irAE. The irAE development was associated with prolonged OS (not reached vs 17.8 months, HR: 0.48, p < 0.001), PFS (8.7 vs 4.8 months, HR: 0.63, p = 0.003), and an improved objective response rate (24.1% vs 10.3%, p = 0.005). However, irAE characteristics, including severity, number of organs or systems affected, and timing of onset, were not associated with OS. Furthermore, we observed that only skin and endocrine toxicities independently protected against OS and PFS. Based on the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (HR: 0.24, p < 0.001) and PFS (HR: 0.43, p< 0.001). A prognostic irAE score based on organ-specific irAEs was developed to show the effect of total protective irAEs on patient outcomes. Conclusions: Not all irAEs are associated with prolonged survival. Identification of organ-specific irAEs but not other irAE characteristics is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.
Zotiraciclib for newly diagnosed or recurrent glioblastoma: Updated outcome and biomarker analysis.
Authors: Weller Michael , Gorlia Thierry , Felsberg Joerg , Jongen Joost , Maurage Claude-Alain , Ducray Francois , Gramatzki Dorothee , Hau Peter , Chinot Olivier L. , Preusser Matthias , Cartalat Stephanie , Roth Patrick , Van Den Bent Martin J. , Furtner Julia , Collienne Maike , Reifenberger Guido , Weiss Tobias , Le Rhun Emilie 
Published: June 2024

2058 Background: There has been little progress in the treatment of newly diagnosed glioblastoma in decades and standards of care for recurrent glioblastoma remain poorly defined. The multi-cyclin dependent kinase inhibitor Zotiraciclib (TG02) depletes short-lived survival proteins such as c-MYC and MCL-1 which are overexpressed in glioblastoma. The mode of action is thought to be specific inhibition of cyclin-dependent kinase (CDK) 9. Methods: EORTC 1608 was a three parallel group (A,B,C) phase Ib, non-randomized, multicenter study in isocitrate dehydrogenase wildtype newly diagnosed glioblastoma or anaplastic astrocytoma. In groups A and B, the maximum tolerated dose (MTD) of Zotiraciclib in elderly patients, in combination with radiotherapy alone (group A) or temozolomide alone (group B), stratified by O6-methylguanine DNA methyltransferase promoter methylation status, were determined. In group C, we explored single agent activity of TG02 at first relapse with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry. Tumor-related extracellular vesicles were quantified according to the minimal information for studies of extracellular vesicles 2018 (MISEV2018) guidelines. Results: Main toxicities of zotiraciclib were neutropenia, gastrointestinal disorders and hepatotoxicity. The MTD was 150 mg twice weekly in group A (weekly) or twice weekly in alternating weeks in group B. PFS-6 in group C was 6.7%. The tumor expression of c-MYC and MCL-1 was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. The levels of tumor-related extracellular vesicles in the blood correlated with tumor volumes determined by MRI and increased from baseline to recurrence. Conclusions: Zotiraciclib exhibits overlapping toxicity with alkylating agents which are the cornerstone of medical treatment for glioblastoma. Its single agent clinical activity in the recurrent setting was low. The role of c-MYC and MCL-1 as therapeutic targets and the diagnostic value of extracellular vesicles in peripheral blood in glioblastoma warrant further study.
Identification of molecular subtypes for integrated multi-omics analysis for use in guiding precision medicine in hepatocellular carcinoma.
Authors: Chen Yihong , Han Ying , Cai Changjing , Peng Yinghui , Ma Jiayao , Shen Hong , Zeng Shan 
Published: June 2024

2576 Background: Tumor microenvironment (TME) heterogeneity leads to the discrepancy of survival prognosis and clinical treatment response for HCC patients. Although the documented molecular subtypes moderately describe the TME heterogeneity and characteristics, their clinical application is constrained by several issues. Methods: We integrated three single-cell datasets from 39 HCC patients to describe the TME landscape and identified prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers (SSMs) was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and Xiangya real-world HCC cohort with patients who received immune checkpoint blockade (ICB) therapy. Cancer stemness was estimated using bioinformatic methods and in vivo and in vitro experiments. The features of TME were further validated using single-cell RNA-seq and immune repertoire sequencing, mass cytometry (CyTOF) and multiplex immunofluorescence (mIF). Ultimately, we constructed prognosis-related score (PRS)based on machine learning algorithm, and identified the potential therapeutic targets and agents for high-PRS patients. Results: The comprehensive single-cell analysis provided a high-resolution depiction of TME heterogeneity in HCC and confirmed 6 cell subclusters of prognostic relevance. Five transcriptomic subtypes were constructed using SSMs, which possessed different clinical prognosis, stemness characteristics, immune landscape and therapeutic responses. Class 1 indicated an inflamed phenotype with better clinical outcomes, while Class 2 and class 4 demonstrated immune-deserted phenotypes lacking T cells infiltration. Class 5 and class 3 indicated inhibitory tumor immune microenvironment enriched regulatory T cells and suppressive immune checkpoints. Multiple therapeutic cohorts suggested that Class 5 and class 3 were sensitive to ICB and targeted therapy, while Class 1 and Class 2 were more responsive to transcatheter arterial chemoembolization treatment (TACE). Class 4 displayed resistant to all conventional HCC therapies. The PRS performed well in prognostic prediction in multiple HCC cohorts. Four potential therapeutic agents and four targets were further identified for high-PRS HCC patients. Conclusions: Our study generated a clinically valid molecular classification, thereby providing guidance for precision medicine in HCC patients.
SH2B3 mutation as a potential resistance mechanism to oncolytic virus therapy.
Authors: Costa Philippos Apolinario , Ishizuka Jeffrey Joseph , Olino Kelly , Frey Alexander , Lee Daniel 
Published: June 2024

2578 Background: Oncolytic viruses (OV) are viruses that preferentially destroy cancer cells while sparing healthy cells. Currently, talimogene laherparepvec (TVEC) is the sole FDA-approved OV product; however, resistance to therapy often emerges. To further understand OV resistance mechanisms, we performed transcriptome and mutational analysis on patient samples using a discordant lesion approach. Methods: An 80-year-old woman was diagnosed with Merkel cell carcinoma of the right lower extremity and underwent wide local excision. Her disease recurred, and she developed multiple metastatic lesions over three years. During that time, she was further treated with radiation, immunotherapy, and intralesional TVEC. Despite the different treatments, her disease eventually progressed, leading to her death. We analyzed the primary lesion and four discordant lesions that either persisted or recurred following treatment. Treatment data were extracted from medical records, and lesions were classified based on their resistance to therapies. DNA and RNA were extracted from tissue, and whole exome sequencing and bulk RNA sequencing were performed. Whole exome data was compared between specimens to determine mutation enrichment over time. Gene Set Enrichment Analysis was used to interpret bulk RNA sequencing data and compare transcriptional states of lesions. Results: Lesions four and five recurred following TVEC treatment and were, therefore, classified as TVEC resistant. Whole exome sequencing of all five lesions identified a heterozygous point mutation (P521L) in the SH2B3 gene in lesions four and five only. Additionally, the variant allelic fraction of this point mutation increased from 33% in lesion four to 44% in lesion five, where it was the highest frequency variant. When comparing lesion five to lesion one, Gene Set Enrichment Analysis showed an increase in both the hallmark inflammatory response gene signature and the hallmark interferon alpha response gene signature. SH2B3 is a gene that encodes the LNK protein, which functions as a negative regulator of the JAK-STAT signaling pathway and is, therefore, a negative regulator of interferon signaling. A mutation leading to a loss of function in SH2B3 would conceptually lead to upregulation of interferon signaling, which has previously been shown to promote an antiviral state within the tumor microenvironment and limit the effectiveness of OV treatment. Conclusions: Sequencing of discordant MCC lesions revealed enrichment in the mutational fraction of SH2B3 associated with an increase in interferon alpha and inflammatory signaling among lesions that were resistant to TVEC treatment. This is the first study to report a possible genetic driver for OV resistance. We introduced using CRISPR-HDR P521L SH2B3 in MCC cell lines to investigate its impact on LNK expression and its role as a mechanism of OV treatment resistance, with results to be presented.
AI based PD-L1 CPS quantifier software to identify more patients for checkpoint therapy in gastric cancer at pathologist-level interobserver concordance.
Authors: Badve Sunil S , Kumar George Louis , Lang Tobias , Mulder David , Calvopiña Diego , Frey Patrick , Karasarides Maria 
Published: June 2024

2633 Background: To determine whether gastric cancer (GC) patients are eligible for immunotherapy, PD-L1 expression is analyzed by immunohistochemistry (IHC) using the “Combined Positive Score” (CPS). This requires quantification of PD-L1 stained tumor and tumor-associated immune cells as well as all viable tumor cells. However, manual CPS scoring on whole-slide images (WSIs) is time-consuming and prone to error as evidenced by low interobserver concordance. While the use of artificial intelligence (AI) holds the promise to ameliorate this key challenge in clinical practice, AI models have not yet met the required accuracy thresholds for PD-L1 CPS scoring on GC biopsies. Methods: We investigated the use of an AI-based PD-L1 CPS quantifier software to support pathologists in standardized PD-L1 IHC assessment on GC biopsies.An AI software for automated PD-L1 CPS scoring was deployed on WSIs from GC biopsies (n = 97) stained for PD-L1 with the 28-8 pharmDx assay and scanned on a 3DHistech P1000 scanner. Manual CPS scores from 12 pathologists on all 97 slides were available for comparison. Pairwise correlation was calculated for continuous values using Lin’s concordance correlation coefficient (CCC). Pairwise concordance was measured for scores binarized at the clinically relevant positivity cutoff of CPS ≥ 5 using unweighted Cohen’s kappa. Results: For continuous CPS scores, the CCC between AI scores and pathologists’ scores was higher (0.59) than the mean correlation among pathologists (0.56). In the majority of cases, the AI scores were found to be within the range of all pathologists, but slightly above the pathologist median. At a cutoff of CPS≥5, the concordance between AI scores and pathologists’ manual scores (κ=0.45) was higher than the mean concordance among pathologists’ manual scores (κ=0.39) (p<0.05). Substantial variability is seen among pathologists when categorizing patients as positive (CPS≥5), with approximately 30.3 ±5.0 patients classified as positive on average by manual scoring and 46 patients (>50% more) categorized as positive by the AI model. Conclusions: An AI model for the assessment of PD-L1 expression in GC using CPS was applied successfully without human intervention. The correlation in continuous CPS scores as well as the concordance in clinical categories with all pathologists was higher for the AI model than for individual pathologists on average, while at the same time, the AI model found more positive patients. This shows that by using AI more positive patients eligible for PD-L1 targeted treatment might be identified while simultaneously ensuring a level of concordance that is non-inferior to pathologists.
Effect of continued immunotherapy on survival of extensive-stage small cell lung cancer: A retrospective analysis.
Authors: Sun Zhuoran , Tian Yaru , Lu Shuangqing , Zhu Hui 
Published: June 2024

e20114 Background: Immunotherapy has shown significant survival advantages in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC),and the second-line treatment options for ES-SCLC are gradually attracting wider attention. The aim of this study was to evaluate the clinical efficacy of continued immunotherapy as the second-line treatment for ES-SCLC. Methods: Between September 2020 and August 2023, the study included 207 patients diagnosed with ES-SCLC, all of whom progressed after first-line immunotherapy plus chemotherapy. The primary endpoints was progression-free survival (PFS) from the first disease progression to the second progression or date cutoff. And the second endpoints were overall survival(OS) from diagnosis to death or date cutoff and adverse events (AEs).OS and PFS were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: Overall, 124 patients were included in the continued immunotherapy group, and 83 patients in the control immunotherapy group. The basic characteristics of patients included age: 62.3% below 65 years old and 37.7% over or equal 65 years old; Most patients had KPS scores≥80 (85%),138 patients (66.7%) had baseline liver metastases, and 146 patients(70.5%) had baseline brain metastases.The continued second-line immunotherapy (including PD-L1 inhibitors and PD-1 inhibitors) did not prolong OS (median:18.03 vs. 21.34 months, HR=1.15,p=0.47) and PFS (median:4.30 vs. 4.43 months,HR=1.29,p=0.19) compared with the control. In the subgroup analysis, there were no significant differences in PFS among patients with partial response (PR, median:4.46 vs 4.43 months, HR=1.35,p=0.10) and stable disease (SD, median:4.75 vs 3.08 months HR=0.81, p=0.56), as well as in OS among patients with partial response (PR, median:18.43 vs 21.34 months, HR=1.15,p=0.53) and stable disease (SD, median:14.98 vs 17.80 months HR=0.95,p=0.90).I n the continued immunotherapy group, PFS was not significantly different between continued PD-L1 inhibitor group and PD-1 inhibitor group (median: 4.26 vs 4.59 months HR=1.04,p=0.17). There was no significant difference in adverse effects between the groups. Conclusions: Continued immunotherapy did not prove survival of ES-SCLC patients progressed after the standard first-line immunotherapy plus chemotherapy, neither efficacy nor type of immune checkpoint inhibitors produces benefit after progression in ES-SCLC patients.
Efficacy and safety of anti-angiogenic therapy plus immunotherapy as later-line treatment for small cell lung cancer: A real-world study.
Authors: Chen Tong , Wang Mingzhao , Chen Yanchao , Cao Yang , Liu Yutao 
Published: June 2024

e20125 Background: Small cell lung cancer (SCLC) is an highly aggressive malignancy with a poor prognosis, and current therapeutic options for relapsed SCLC are limited. This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents in patients (pts) with previously treated SCLC, and to initially explore biomarkers for the response prediction of combination therapy. Methods: In this single-center study, medical records and follow-up data of pts with SCLC who received antiangiogenic therapy plus immunotherapy (combination therapy) or antiangiogenic monotherapy as second or later-line treatment were retrospectively analyzed. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Additionally, plasma was collected from pts in the combination therapy cohort before and after two cycles of treatment. The samples were tested for extracellular vesicles (EVs) membrane protein expression profiles. Potential biomarkers for the therapeutic effect were screened and then evaluated for their predictive performance. Results: A total of 61 pts were enrolled, including the combination therapy group (n = 40) and the antiangiogenic monotherapy group (n = 21). Baseline characteristics of the two groups were comparable. Kaplan-Meier (K-M) curve demonstrated superior PFS in combination therapy group than in monotherapy group (mPFS: 4.0 vs.2.7 months, P = 0.029). Both univariate (HR 0.634, 95%CI: 0.420-0.959, P = 0.031) and multivariate Cox regression (HR 0.554, 95%CI: 0.345-0.888, P = 0.014) proved that combination therapy, compared to antiangiogenic monotherapy, was correlated with markedly improved PFS. The combination group had higher DCR than the monotherapy group (77.5% vs. 52.4%, P = 0.044). No significant difference in the incidence of AEs between the two groups was observed. Plasma EV membrane protein detection and differential expression analysis suggested that IL-12 served as a prognostic marker for adverse outcomes in combination therapy. The Receiver Operating Characteristic (ROC) curve and K-M curve showed that IL-12 possessed favorable efficacy prediction performance (Area Under Curve, AUC = 0.85), and pts with high IL-12 expression exhibited significantly shorter PFS in contrast to those with low expression (P < 0.0001). In pts experiencing progression within 3 months, higher levels of IL-12 were detected compared to those who did not (P = 0.002). Conclusions: ICIs plus antiangiogenic therapy has demonstrated superior efficacy in disease control and delayed progression over antiangiogenic monotherapy as later-line treatment in pts with SCLC. Serum EV membrane proteins showed promising predictive value for the efficacy of combination therapy.