bluuebunny/crossref_metadata_2025 huggingface dataset:
Intel Software Guard Extensions Applications: A Survey
Authors: Will Newton C. , Maziero Carlos A.
Published: April 2023

Data confidentiality is a central concern in modern computer systems and services, as sensitive data from users and companies are being increasingly delegated to such systems. Several hardware-based mechanisms have been recently proposed to enforce security guarantees of sensitive information. Hardware-based isolated execution environments are a class of such mechanisms, in which the operating system and other low-level components are removed from the trusted computing base. One of such mechanisms is the
Intel Software Guard Extensions
(Intel SGX), which creates the concept of
enclave
to encapsulate sensitive components of applications and their data. Despite being largely applied in several computing areas, SGX has limitations and performance issues that must be addressed for the development of secure solutions. This text brings a categorized literature review of the ongoing research on the Intel SGX architecture, discussing its applications and providing a classification of the solutions that take advantage of SGX mechanisms. We analyze and categorize 293 papers that rely on SGX to provide integrity, confidentiality, and privacy to users and data, regarding different contexts and goals. We also discuss research challenges and provide future directions in the field of enclaved execution, particularly when using SGX.
Electrochemical Imaging of Interfaces in Energy Storage via Scanning Probe Methods: Techniques, Applications, and Prospects
Authors: Mishra Abhiroop , Sarbapalli Dipobrato , Rodríguez Oliver , Rodríguez-López Joaquín
Published: April 2023

Developing a deeper understanding of dynamic chemical, electronic, and morphological changes at interfaces is key to solving practical issues in electrochemical energy storage systems (EESSs). To unravel this complexity, an assortment of tools with distinct capabilities and spatiotemporal resolutions have been used to creatively visualize interfacial processes as they occur. This review highlights how electrochemical scanning probe techniques (ESPTs) such as electrochemical atomic force microscopy, scanning electrochemical microscopy, scanning ion conductance microscopy, and scanning electrochemical cell microscopy are uniquely positioned to address these challenges in EESSs. We describe the operating principles of ESPTs, focusing on the inspection of interfacial structure and chemical processes involved in Li-ion batteries and beyond. We discuss current examples, performance limitations, and complementary ESPTs. Finally, we discuss prospects for imaging improvements and deep learning for automation. We foresee that ESPTs will play an enabling role in advancing EESSs as we transition to renewable energies.
5-Fluorouracil-Loaded PLGA Nanoparticles: Formulation, Physicochemical Characterisation, and In VitroAnti-Cancer Activity
Authors: Gahtani Reem M. , Alqahtani Ali , Alqahtani Taha , Asiri Saeed Ahmed , Mohamed Jamal Moideen Muthu , Venkatesa Prabhu S. , Muluneh Endalew Yaze
Published: April 2023

The major goal of this investigation was to prepare a drug delivery of polymeric nanoparticles (NPs) from 5-fluorouracil (FU) that could be delivered intravenously and improve the therapeutic index of the FU. In order to achieve this, interfacial deposition method was used to prepare FU entrapped poly-(lactic-co-glycolic acid) nanoparticles (FU-PLGA-NPs). The influence of various experimental settings on the effectiveness of FU integration into the NPs was assessed. Our findings show that the technique used to prepare the organic phase and the ratio of the organic phase to the aqueous phase had the greatest impact on the effectiveness of FU integration into NPs. The results show that the preparation process produced spherical, homogenous, negatively charged particles with a nanometric size of 200 nm that are acceptable for intravenous delivery. A quick initial release over 24 h and then slow and steady release of FU from the formed NPs, exhibiting a biphasic pattern. Through the human small cell lung cancer cell line (NCI-H69), the in vitro anti-cancer potential of the FU-PLGA-NPs was evaluated. It was then associated to the in vitro anti-cancer potential of the marketed formulation Fluracil®. Investigations were also conducted into Cremophor-EL (Cre-EL) potential activity on live cells. The viability of NCI-H69 cells was drastically reduced when they were exposed to 50 µg·mL−1 Fluracil®. Our findings show that the integration of FU in NPs significantly increases the drug cytotoxic effect in comparison to Fluracil®, with this potential effect being particularly important for extended incubation durations.
Combination of Astragalus membranaceus and Panax notoginseng as Main Components in the Treatment of Diabetic Nephropathy: A Systematic Review and Meta‐Analysis
Authors: An Xiaoning , Xu Youhua , Gui Dingkun
Published: April 2023

Objective. This meta‐analysis evaluated the curative effect of the compatibility of Astragalus membranaceus and Panax notoginseng (ARPN) as main components on diabetic nephropathy. Methods. We used various Chinese and English databases, including the Cochrane Library, PubMed, Embase, Web of Science, the China National Knowledge Infrastructure (CNKI), China Biology Medicine Disc (SinoMed), VIP, and Wanfang, to search for randomized controlled trials on the compatibility of Astragalus membranaceus and Panax notoginseng as main components. After data extraction, meta‐analysis was performed with Review Manager 5.4.0 and Stata 15, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the quality of the evidence. Result. A total of 17 studies involving 1342 patients with diabetic nephropathy were included. Compared with the control group, ARPN can significantly improve the clinical effective rate of diabetic nephropathy (OR 5.12, 95% CI 3.42 to 7.66, P < 0.00001), and the curative effect of reducing UAER (MD −26.67, 95% CI −31.30 to −22.04, P < 0.00001) and 24 h urinary protein (SMD −0.58, 95% CI −0.75 to −0.41, P < 0.00001) is also significantly better than that of the control group, and it can also improve the renal function(Scr: MD −13.78, 95% CI −25.39 to −2.17, P = 0.02; BUN: MD −0.74, 95% CI −1.27 to −0.20, P = 0.007). In addition, it can also reduce glycosylated hemoglobin (SMD −1.30, 95% CI −2.33 to −0.27, P = 0.01) and blood lipid(TC: SMD −0.62, 95% CI −0.95 to −0.29, P = 0.0002; TG: SMD −0.47, 95% CI −0.75 to −0.19, P = 0.0009; LDL: SMD −0.43, 95% CI −0.68 to −0.18, P = 0.0008), and improve the TCM syndrome score (MD −4.87, 95% CI −6.17 to −3.57, P < 0.00001). Subgroup analysis suggested that the treatment plan of the control group could be the sources of heterogeneity. All the included studies had no obvious adverse effects. Conclusions. The compatibility of Radix Astragali and Radix notoginseng as the main components can effectively improve the renal function of patients with diabetic nephropathy and delay the progress of diabetic nephropathy. However, the results of this study need further research to be confirmed because of the uncertainty of the evidence and the suboptimal risk bias.
Emissions and Performance of Diesel Engines Correlated with Biodiesel Properties
Authors: Surakasi Raviteja , Srinivasa Rao Yenda , Kalam Sd. Abdul , Begum Naziya
Published: April 2023

It has been demonstrated that B20 biodiesel can be used in diesel engines without modifying their specifications. It is still being developed to reduce dependence on diesel fuel by developing biodiesel with a higher percentage of palm oil. Alcohol is added to biodiesel to reduce problems with fuel injection due to its high viscosity. In this study, the biodiesel properties of diesel-palm cooking oil-methanol/ethanol/butanol blends are investigated in relation to diesel engine performance and potential exhaust emissions. The percentages of palm cooking oil used were 30%, 40%, 50%, 60%, 70%, 80%, and 85%. A 15% concentration of methanol, ethanol, and butanol alcohol was used. According to chemical and physical tests, biodiesel with a higher palm oil content had poorer properties. A biodiesel blend that combines diesel, palm oil, and methanol can perform almost as well as diesel fuel in terms of exhaust emissions and engine performance.
Molecular Cloning, Subcellular Localization, and Abiotic Stress Induction Analysis of a Polyamine Oxidase Gene from Oryza sativa
Authors: Samanta Ishita , Chaturvedi Shweta , Chanda Roy Pamela , Chowdhary Gopal
Published: April 2023

Abiotic stress is a major bottleneck for crop productivity. To counter abiotic stresses, plants have developed several strategies, and the accumulation of polyamine (PA) serving as an osmolyte is one of them. The cellular pool of PAs is primarily regulated by polyamine oxidases (PAOs) either by terminal catabolism or by back conversion (BC) of polyamines. The role of PAO in abiotic stress tolerance has also been reported. Polyamine oxidases are primarily localized in the cytosol, cell wall, and apoplastic regions; however, lately, their peroxisomal localization has also been demonstrated. In this study, we reported the detection of polyamine oxidase isoform 3 from Oryza sativa (OsPAO3) in peroxisome as early as 12 h post-transformation under in vitro conditions using fluorescent microscopy. The gene was also found to be significantly upregulated by salinity, dehydration, cold, and heat stress. We have also demonstrated that the expression of OsPAO3 gene was mediated by a second messenger, calcium. The upregulation of OsPAO3 by salinity, dehydration, cold, and heat stresses suggests that it could be a suitable candidate for providing tolerance to plants against abiotic stress combination or stress matrix, which is a common feature in agricultural field conditions. Furthermore, the data provided here would be valuable in understanding the abiotic stress-mediated signal transduction network of PAOs.
Image-Based Malware Classification Method with the AlexNet Convolutional Neural Network Model
Authors: Zhao Zilin , Zhao Dawei , Yang Shumian , Xu Lijuan
Published: April 2023

In recent years, malware has experienced explosive growth and has become one of the most severe security threats. However, feature engineering easily restricts the traditional machine learning methods-based malware classification and is hard to deal with massive malware. At the same time, the dynamic analysis methods have the problems of complex operation and high cost, which are not suitable for efficiently classifying large quantities of malware. Therefore, we propose a novel static malware detection method based on this study’s AlexNet convolutional neural network (CNN). Unlike existing solutions, we convert all malware bytes into color images, propose an improved AlexNet architecture, and solve the unbalanced datasets with the data enhancement method. Extensive experiments are performed using the Microsoft malware dataset and the Google Code Jam (GCJ) dataset. The experimental results show that the accuracy of the Microsoft malware dataset reaches 99.99%, and the GCJ dataset reaches 99.38%. We also verify that our method can better extract the texture features of malware and improve the accuracy and detection efficiency.
A Special Mutation Operator in the Genetic Algorithm for Fixed Point Problems
Authors: Jalali Varnamkhasti Mohammad , Vali Masoumeh
Published: April 2023

Over the past century, the fixed point theory has emerged as a very useful and efficient tool in the study of nonlinear problems. This study introduced a progressed genetic algorithm (GA) based on a particular mutation operator applying on a subdivided search space where integer label and relative coordinates are used. This algorithm eventually categorizes each fixed point as its solution in appropriate set. Extensive computational experiments are conducted to assess the performance of the proposed technique with a standard GA for solving some nonlinear numerical functions from the literature.
Prehospital Emergency Service Use for Substance-Related Issues before and during COVID-19
Authors: Kabadayi Sahin Esra , Usul Eren
Published: April 2023

Objective. The COVID-19 pandemic disrupted the healthcare system and disproportionally affected individuals with substance use. This study aimed to evaluate the prehospital emergency medical service (EMS) use for substance-related health issues during the COVID-19 pandemic period and compare the changes with the pre-COVID-19 period. Methods. The prehospital EMS calls due to substance-related problems in overall Turkiye were analyzed retrospectively. The applications were categorized into the pre-COVID-19 period (May 11, 2019, to March 11, 2020) and the COVID-19 period (March 11, 2020, to January 4, 2021). These two periods were compared to if there were any changes in sociodemographic features of the applicants, the reason for EMS calls, and the dispatch results of the calls. Results. There were 6,191 calls in the pre-COVID-19 period and 4,758 calls in the COVID-19 period. According to the age groups, the number of applications of 18 years and under decreased, while the application of people 65 years and over increased during the COVID-19 period (

p
<
0.001

). Considering the reasons for the EMS application, there was an increase in the calls due to suicide and transfers during the COVID-19 period. Besides, the EMS applications for court-ordered treatment decreased in the COVID-19 period (

p
<
0.001

). There was no statistically significant difference in terms of dispatch results (

p
=
0.081

). Conclusions. This study shows that the elderly group is at higher risk for substance-related medical problems. Suicide is an important risk among individuals with substance use. The increase in demand for ambulance transfer services can place a significant burden on prehospital emergency care. There is a need for measures to provide emergency and transport services, especially for the elderly and suicide attempts during any future case of emergency.
[Retracted] Pan‐Cancer Analysis of Prognostic and Immune Infiltrates for the TMEM65, Especially for the Breast Cancer
Authors: Song Xinming , Wang Pintian , Feng Ruiling , Chetry Mandika , Li E , Wu Xiaohua , Liu Zewa , Liao Shasha , Lin Jing
Published: April 2023

Introduction. Transmembrane protein 65 (TMEM65) is an inner mitochondrial membrane protein, which played important role in mediating autophagy, smooth muscle contraction, protein glycosylation, and immune response. In recent years, the interest had risen for exploring the function of the TMEM genes in the cancer fields. As a consequence, in our pan‐cancer research of the TMEM65, we explored the function of the gene in kinds of database and tried to apply the finding in the clinical practice. Methods. In this research, we provide a comprehensive investigation of TMEM65 expression in a pan‐cancer manner containing 33 cancer types. We evaluated the association of TMEM65 with the prognosis, immune infiltration, drug sensitivity analysis, GSVA enrichment analysis, TMB, MSI, NEO, and hotspot mechanisms. Results. TMEM65 was abnormally expressed in 24 types of cancers and showed correlation with the OS for 6 cancers and PFI for 9 cancers and kpI for 3 types. Moreover, the TME score, CD8 T effector, and immune checkpoint scoring systems showed a close correlation with the TMEM65. Moreover, TMEM65 was strongly correlated with some of the most common tumor‐related genes and certain pathways (TGF beta signaling, TNFA signaling, hypoxia, pyroptosis, DNA repairing, autophagy, ferroptosis, and other related genes). Additionally, the TMEM65 showed correlations with the tumor mutational burden (TMB), microsatellite instability (MSI), NEO, and drug sensitivity. Finally, we confirmed several pathways by the GSEA and GSVA for the TMEM65 at the breast cancer aspects. Nomogram prediction model was also established for the breast tumors based on the TMEM65 level and other variables. Conclusion. Above all, the TMEM65 played important roles in predicting the prognosis of the cancers and correlated with the tumor immunity in the pan‐cancer analysis.
Supplementary Data from FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung
Authors: Tomoshige Koichi , Stuart William D. , Fink-Baldauf Iris M. , Ito Masaoki , Tsuchiya Tomoshi , Nagayasu Takeshi , Yamatsuji Tomoki , Okada Morihito , Fukazawa Takuya , Guo Minzhe , Maeda Yutaka
Published: April 2023

Supplementary Tables
Supplementary Data from FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung
Authors: Tomoshige Koichi , Stuart William D. , Fink-Baldauf Iris M. , Ito Masaoki , Tsuchiya Tomoshi , Nagayasu Takeshi , Yamatsuji Tomoki , Okada Morihito , Fukazawa Takuya , Guo Minzhe , Maeda Yutaka
Published: April 2023

Supplementary Materials and Methods and Supplementary Figures
Supplementary Fig. S5 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Spatial expression of stemness genes in tumor areas.
Supplementary Fig. S3 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Quality control analysis of scRNA-seq.
Supplementary Fig. S2 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Spatial gene expression of ECM molecules in mouse brain tumors.
Supplementary Fig. S10 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Survival analysis of GBM patients in public databases.
Supplementary Fig. S1 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Quality control analysis of spatial transcriptomics.
Graphical abstract from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: April 2023

Graphical abstract. A multi-omics analysis of the glioblastoma tumor microenvironment revealed that biglycan, predominantly expressed by inflammatory BTICs, drives tumor growth. The graphics were generated with Biorender.com.
Data from FOXA2 Cooperates with Mutant KRAS to Drive Invasive Mucinous Adenocarcinoma of the Lung
Authors: Tomoshige Koichi , Stuart William D. , Fink-Baldauf Iris M. , Ito Masaoki , Tsuchiya Tomoshi , Nagayasu Takeshi , Yamatsuji Tomoki , Okada Morihito , Fukazawa Takuya , Guo Minzhe , Maeda Yutaka
Published: April 2023

Abstract
The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation.
Significance:
FOXA2 expression combined with mutant KRAS drives invasive mucinous adenocarcinoma of the lung by synergistically promoting a mucous transcriptional program, suggesting strategies for targeting this lung cancer type that lacks effective therapies.
Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer
Authors: Blanc-Durand Félix , Tang Roseline , Pommier Margaux , Nashvi Marzieh , Cotteret Sophie , Genestie Catherine , Le Formal Audrey , Pautier Patricia , Michels Judith , Kfoury Maria , Hervé Robert , Mengue Sylvie , Wafo Estelle , Elies Antoine , Miailhe Gregoire , Uzan Jennifer , Rouleau Etienne , Leary Alexandra
Published: April 2023

Purpose:

Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance.

Experimental Design:

This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.

Results:

Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.

Conclusions:

Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.

See related commentary by Garg and Oza, p. 2957
Data from Preclinical Evaluation of ON203, A Novel Bioengineered mAb Targeting Oxidized Macrophage Migration Inhibitory Factor as an Anticancer Therapeutic
Authors: Rossmueller Gregor , Mirkina Irina , Maurer Barbara , Hoeld Verena , Mayer Julia , Thiele Michael , Kerschbaumer Randolf J. , Schinagl Alexander
Published: April 2023

Abstract
High levels of macrophage migration inhibitory factor (MIF) in patients with cancer are associated with poor prognosis. Its redox-dependent conformational isoform, termed oxidized MIF (oxMIF), is a promising tumor target due to its selective occurrence in tumor lesions and at inflammatory sites. A first-generation anti-oxMIF mAb, imalumab, was investigated in clinical trials in patients with advanced solid tumors, where it was well tolerated and showed signs of efficacy. However, imalumab has a short half-life in humans, increased aggregation propensity, and an unfavorable pharmacokinetic profile. Here, we aimed to optimize imalumab by improving its physicochemical characteristics and boosting its effector functions. Point mutations introduced into the variable regions reduced hydrophobicity and the antibodies’ aggregation potential, and increased plasma half-life and tumor accumulation in vivo, while retaining affinity and specificity to oxMIF. The introduction of mutations into the Fc region known to increase antibody-dependent cellular cytotoxicity resulted in enhanced effector functions of the novel antibodies in vitro, whereas reduced cytokine release from human peripheral blood mononuclear cells in the absence of target antigen by the engineered anti-oxMIF mAb ON203 versus imalumab reveals a favorable in vitro safety profile. In vivo, ON203 mAb demonstrated superior efficacy over imalumab in both prophylactic and established prostate cancer (PC3) mouse xenograft models. In summary, our data highlight the potential of the second-generation anti-oxMIF mAb ON203 as a promising immunotherapy for patients with solid tumors, warranting clinical evaluation.
Preclinical Evaluation of ON203, A Novel Bioengineered mAb Targeting Oxidized Macrophage Migration Inhibitory Factor as an Anticancer Therapeutic
Authors: Rossmueller Gregor , Mirkina Irina , Maurer Barbara , Hoeld Verena , Mayer Julia , Thiele Michael , Kerschbaumer Randolf J. , Schinagl Alexander
Published: April 2023

High levels of macrophage migration inhibitory factor (MIF) in patients with cancer are associated with poor prognosis. Its redox-dependent conformational isoform, termed oxidized MIF (oxMIF), is a promising tumor target due to its selective occurrence in tumor lesions and at inflammatory sites. A first-generation anti-oxMIF mAb, imalumab, was investigated in clinical trials in patients with advanced solid tumors, where it was well tolerated and showed signs of efficacy. However, imalumab has a short half-life in humans, increased aggregation propensity, and an unfavorable pharmacokinetic profile. Here, we aimed to optimize imalumab by improving its physicochemical characteristics and boosting its effector functions. Point mutations introduced into the variable regions reduced hydrophobicity and the antibodies’ aggregation potential, and increased plasma half-life and tumor accumulation in vivo, while retaining affinity and specificity to oxMIF. The introduction of mutations into the Fc region known to increase antibody-dependent cellular cytotoxicity resulted in enhanced effector functions of the novel antibodies in vitro, whereas reduced cytokine release from human peripheral blood mononuclear cells in the absence of target antigen by the engineered anti-oxMIF mAb ON203 versus imalumab reveals a favorable in vitro safety profile. In vivo, ON203 mAb demonstrated superior efficacy over imalumab in both prophylactic and established prostate cancer (PC3) mouse xenograft models. In summary, our data highlight the potential of the second-generation anti-oxMIF mAb ON203 as a promising immunotherapy for patients with solid tumors, warranting clinical evaluation.
Table S3 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

Differentially Expressed Genes
Table S2 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

Clinical Characteristics by Patient
Table S1 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

RNA Sequencing QC Metrics
Supplementary Figures 1-6 from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

S1. Heatmap of unsupervised hierarchical clustering of the top 1000 most variable genes.S2. Violin plots showing the expression levels of genes previously identified as differentially expressed genes between primary and recurrent tumors in Haltia et al., 2020.S3. Gene set enrichment analysis performed with GO terms and KEGG pathways showing that primarily immune-related and hormone-regulated gene sets expression are altered between primary and recurrent aGCTs.S4. Gene set enrichment analysis results showing that top enriched gene sets are significantly enriched in recurrent tumors in comparison with primary tumors.S5. Boxplot showing the fraction of each noncancerous cell type identified by CIBERSORTx (A) and xCell (B) in primary and recurrent tumor samples.S6. Heatmap showing the correlation between immune cells fractions.
Data from BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis
Authors: Agarwal Sumit , Afaq Farrukh , Bajpai Prachi , Behring Michael , Kim Hyung-Gyoon , Varambally Amith , Chandrashekar Darshan S. , Peter Shajan , Diffalha Sameer Al , Khushman Moh'd , Seeber Andreas , Varambally Sooryanarayana , Manne Upender
Published: April 2023

Abstract
Because survival of patients with metastatic colorectal cancer remain poor, there is an urgent need to identify potential novel druggable targets that are associated with colorectal cancer progression. One such target, basic leucine zipper and W2 domains 2 (BZW2), is involved in regulation of protein translation, and its overexpression is associated with human malignancy. Thus, we investigated the expression and regulation of BZW2, assessed its role in activation of WNT/β-catenin signaling, identified its downstream molecules, and demonstrated its involvement in metastasis of colorectal cancer. In human colorectal cancers, high mRNA and protein expression levels of BZW2 were associated with tumor progression. BZW2-knockdown reduced malignant phenotypes, including cell proliferation, invasion, and spheroid and colony formation. BZW2-knockdown also reduced tumor growth and metastasis; conversely, transfection of BZW2 into BZW2 low-expressing colorectal cancer cells promoted malignant features, including tumor growth and metastasis. BZW2 expression was coordinately regulated by microRNA-98, c-Myc, and histone methyltransferase enhancer of zeste homolog 2 (EZH2). RNA sequencing analyses of colorectal cancer cells modulated for BZW2 identified P4HA1 and the long noncoding RNAs, MALAT1 and NEAT1, as its downstream targets. Further, BZW2 activated the Wnt/β-catenin signaling pathway in colorectal cancers expressing wild-type β-catenin. In sum, our study suggests the possibility of targeting BZW2 expression by inhibiting EZH2 and/or c-Myc.
Implications:
FDA-approved small-molecule inhibitors of EZH2 can indirectly target BZW2 and because BZW2 functions as an oncogene, these inhibitors could serve as therapeutic agents for colorectal cancer.
Data from Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

Abstract
Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets.
Implications:
Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.
Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler
Published: April 2023

Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets.

Implications:

Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.
Supplemental Table 1 from Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W.
Published: April 2023

Supplemental Table 1: Describes the Stressful Life Events and Social Support scales used in the study.
Supplemental Figure 1 from Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W.
Published: April 2023

Supplemental Figure 1: Presents the flow chart of women that participated in the observational study that were included in the analytical sample.
Data from Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W.
Published: April 2023

Abstract
Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. Using the Women's Health Initiative study, we included 76,951 postmenopausal women followed for events for a median of 16.7 years to investigate the association between baseline self-reported stressful life events and incident breast cancer by ER status and whether the association was modified by social support. We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate HRs and 95% confidence intervals (95%CI). The mean age was 63 (SD, 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared with women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs. Quartile 1; HR = 1.30; 95%CI, 1.01–1.68; Ptrend = 0.050). Moreover, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR = 2.39; 95%CI, 1.29–4.44; Pinteraction<0.001). Association between stressful life events and ER-negative breast cancer was not modified by social support. In this cohort of postmenopausal women, higher experiences of prediagnostic stressful life events were associated with increased risk of ER-negative breast cancer.
Prevention Relevance:
Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.
Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W.
Published: April 2023

Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. Using the Women's Health Initiative study, we included 76,951 postmenopausal women followed for events for a median of 16.7 years to investigate the association between baseline self-reported stressful life events and incident breast cancer by ER status and whether the association was modified by social support. We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate HRs and 95% confidence intervals (95%CI). The mean age was 63 (SD, 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared with women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs. Quartile 1; HR = 1.30; 95%CI, 1.01–1.68; Ptrend = 0.050). Moreover, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR = 2.39; 95%CI, 1.29–4.44; Pinteraction<0.001). Association between stressful life events and ER-negative breast cancer was not modified by social support. In this cohort of postmenopausal women, higher experiences of prediagnostic stressful life events were associated with increased risk of ER-negative breast cancer.

Prevention Relevance:

Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.
Supplementary Tables S1-S3 from A View on Drug Development for Cancer Prevention
Authors: Reynolds Andrew R. , Moschetta Michele , Yohannes Alula R. , Walcott Farzana , Ashford Marianne , Szucs Zoltan , Sarbajna Tina , Hadfield James , Harrison Eden , Challis Benjamin G. , Hernandez Amaya Gasco , Schiavon Gaia , Germa Caroline , Zorenyi Gyorgy , Crean Barry , Galbraith Susan
Published: April 2023

Tables that provide additional information to support the main article
Supplementary Tables S1-S11 and Figure S1 from Opportunities for Achieving the Cancer Moonshot Goal of a 50% Reduction in Cancer Mortality by 2047
Authors: Shiels Meredith S. , Lipkowitz Stanley , Campos Nicole G. , Schiffman Mark , Schiller John T. , Freedman Neal D. , de González Amy Berrington
Published: April 2023

Supplemental Table 1. 15 leading causes of cancer death in the U.S. in 2019.
Supplemental table 2. Trends in total cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 3. Trends in lung cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 4. Trends in colorectal cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 5. Trends in pancreatic cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 6. Trends in female breast cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 7. Trends in prostate cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 8. Trends in liver/IHBD cancer mortality rates, incidence rates and relative survival in the U.S.
Supplemental table 9. Trends in cancer mortality rates in the U.S., 2000-2019 for selected sites.
Supplemental Table 10. US breast cancer incidence-based mortality*.
Supplemental Table 11. U.S. breast cancer incidence-based mortality by age at death.
Supplemental Figure 1. Liver cancer incidence (1992-2019), survival (2000-2019) and mortality (2000-2019 projected through 2047). This figure excludes cases of intrahepatic bile duct cancer.
Supplementary Table 1 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

Summary of GOF vs. LOF activities of p53(A347D) in U2OS cells
Supplementary Figures from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

Supplementary Figures 1-9 demonstrating the GOF and LOF activities of p53(A347D)
Supplementary Data 6 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

p53 ChIPseq peaks from osteoblasts derived from normal and LFS individuals
Supplementary Data 5 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

p53 ChIPseq peaks from U2OS cells varying in p53 allelic status
Supplementary Data 4 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

p53 ChIPseq peaks from U2OS cells varying in p53 allelic status
Supplementary Data 3 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

Differentially expressed genes in osteoblasts derived from normal and LFS individuals
Supplementary Data 1 from Li–Fraumeni Syndrome–Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Obradovic Aleksandar Z. , Low-Calle Ana Maria , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol
Published: April 2023

Differentially expressed genes in U2OS cells varying in p53 allelic status