bluuebunny/crossref_metadata_2025 huggingface dataset:
MultiCBR: Multi-view Contrastive Learning for Bundle Recommendation
Authors: Ma Yunshan , He Yingzhi , Wang Xiang , Wei Yinwei , Du Xiaoyu , Fu Yuyangzi , Chua Tat-Seng
Published: January 2024

Bundle recommendation seeks to recommend a bundle of related items to users to improve both user experience and the profits of platform. Existing bundle recommendation models have progressed from capturing only user-bundle interactions to the modeling of multiple relations among users, bundles, and items. CrossCBR, in particular, incorporates cross-view contrastive learning into a two-view preference learning framework, significantly improving SOTA performance. It does, however, have two limitations: (1) the two-view formulation does not fully exploit all the heterogeneous relations among users, bundles, and items; and (2) the “early contrast and late fusion” framework is less effective in capturing user preference and difficult to generalize to multiple views.

In this article, we present MultiCBR, a novel
Multi
-view
C
ontrastive learning framework for
B
undle
R
ecommendation. First, we devise a multi-view representation learning framework capable of capturing all the user-bundle, user-item, and bundle-item relations, especially better utilizing the bundle-item affiliations to enhance sparse bundles’ representations. Second, we innovatively adopt an “early fusion and late contrast” design that first fuses the multi-view representations before performing self-supervised contrastive learning. In comparison to existing approaches, our framework reverses the order of fusion and contrast, introducing the following advantages: (1) Our framework is capable of modeling both cross-view and ego-view preferences, allowing us to achieve enhanced user preference modeling; and (2) instead of requiring quadratic number of cross-view contrastive losses, we only require two self-supervised contrastive losses, resulting in minimal extra costs. Experimental results on three public datasets indicate that our method outperforms SOTA methods. The code and dataset can be found in the github repo
https://github.com/HappyPointer/MultiCBR
.
Learning Failure-Inducing Models for Testing Software-Defined Networks
Authors: Ollando Raphaël , Shin Seung Yeob , Briand Lionel C.
Published: January 2024

Software-defined networks (SDN) enable flexible and effective communication systems that are managed by centralized software controllers. However, such a controller can undermine the underlying communication network of an SDN-based system and thus must be carefully tested. When an SDN-based system fails, in order to address such a failure, engineers need to precisely understand the conditions under which it occurs. In this article, we introduce a machine learning-guided fuzzing method, named FuzzSDN, aiming at both (1) generating effective test data leading to failures in SDN-based systems and (2) learning accurate failure-inducing models that characterize conditions under which such system fails. To our knowledge, no existing work simultaneously addresses these two objectives for SDNs. We evaluate FuzzSDN by applying it to systems controlled by two open-source SDN controllers. Furthermore, we compare FuzzSDN with two state-of-the-art methods for fuzzing SDNs and two baselines for learning failure-inducing models. Our results show that (1) compared to the state-of-the-art methods, FuzzSDN generates at least 12 times more failures, within the same time budget, with a controller that is fairly robust to fuzzing and (2) our failure-inducing models have, on average, a precision of 98% and a recall of 86%, significantly outperforming the baselines.
Enablers and Barriers of Empathy in Software Developer and User Interactions: A Mixed Methods Case Study
Authors: Gunatilake Hashini , Grundy John , Hoda Rashina , Mueller Ingo
Published: January 2024

Software engineering (SE) requires developers to collaborate with stakeholders, and understanding their emotions and perspectives is often vital. Empathy is a concept characterising a person’s ability to understand and share the feelings of another. However, empathy continues to be an under-researched human aspect in SE. We studied how empathy is practised between developers and end users using a mixed methods case study. We used an empathy test, observations, and interviews to collect data and socio-technical grounded theory and descriptive statistics to analyse data. We identified the nature of awareness required to trigger empathy and enablers of empathy. We discovered barriers to empathy and a set of potential strategies to overcome these barriers. We report insights on emerging relationships and present a set of recommendations and potential future works on empathy and SE for software practitioners and SE researchers.
Deepfake Detection Using Spatiotemporal Transformer
Authors: Kaddar Bachir , Fezza Sid Ahmed , Akhtar Zahid , Hamidouche Wassim , Hadid Abdenour , Serra-Sagristá Joan
Published: January 2024

Recent advances in generative models and the availability of large-scale benchmarks have made deepfake video generation and manipulation easier. Nowadays, the number of new hyper-realistic deepfake videos used for negative purposes is dramatically increasing, thus creating the need for effective deepfake detection methods. Although many existing deepfake detection approaches, particularly CNN-based methods, show promising results, they suffer from several drawbacks. In general, poor generalization results have been obtained under unseen/new deepfake generation methods. The crucial reason for the above defect is that CNN-based methods focus on the local spatial artifacts, which are unique for every manipulation method. Therefore, it is hard to learn the general forgery traces of different manipulation methods without considering the dependencies that extend beyond the local receptive field. To address this problem, this article proposes a framework that combines Convolutional Neural Network (CNN) with Vision Transformer (ViT) to improve detection accuracy and enhance generalizability. Our method, namedHCiT, exploits the advantages of CNNs to extract meaningful local features, as well as the ViT’s self-attention mechanism to learn discriminative global contextual dependencies in a frame-level image explicitly. In this hybrid architecture, the high-level feature maps extracted from the CNN are fed into the ViT model that determines whether a specific video is fake or real. Experiments were performed on Faceforensics++, DeepFake Detection Challenge preview, Celeb datasets, and the results show that the proposed method significantly outperforms the state-of-the-art methods. In addition, the HCiT method shows a great capacity for generalization on datasets covering various techniques of deepfake generation. The source code is available at:https://github.com/KADDAR-Bachir/HCiT
Alcohol Use Disorder Treatment: Problems and Solutions
Authors: Koob George F.
Published: January 2024

Alcohol use disorder (AUD) afflicts over 29 million individuals and causes more than 140,000 deaths annually in the United States. A heuristic framework for AUD includes a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that provides a starting point for exploring the heterogeneity of AUD with regard to treatment. Effective behavioral health treatments and US Food and Drug Administration–approved medications are available but greatly underutilized, creating a major treatment gap. This review outlines challenges that face the alcohol field in closing this treatment gap and offers solutions, including broadening end points for the approval of medications for the treatment of AUD; increasing the uptake of screening, brief intervention, and referral to treatment; addressing stigma; implementing a heuristic definition of recovery; engaging early treatment; and educating health-care professionals and the public about challenges that are associated with alcohol misuse. Additionally, this review focuses on broadening potential targets for the development of medications for AUD by utilizing the three-stage heuristic model of addiction that outlines domains of dysfunction in AUD and the mediating neurobiology of AUD.
Structural and Temperature Dependent-Magnetic and Dielectric Properties of CoNd
x
Fe2−x
O4 (0 ≤ x ≤ 0.1) Nanoparticles
Authors: Singh Bittu , Babu Kuppam Mohan , Bhaskaraiah M. , Kavuluri Pushpalatha , Joshi Rajendra , Chandra Bhuwan
Published: January 2024

We present an investigation into the structural and magnetic properties of neodymium-doped cobalt ferrites, described by the general formula CoNd
x
Fe2−x
O4 (where x = 0, 0.02, 0.04, 0.06, 0.08 & 0.10). CoNd
x
Fe2−x
O4 nanoparticles were synthesized using sol-gel auto-combustion method with tartaric acid employed as a chelating agent. The strength of the X-ray diffraction (XRD) peak diminishes as the concentration of Nd3+ increases from 0 to 0.10 mol%, implying that crystallization is hindered due to relatively large ion radii. The crystallite size decreases from 22 nm to 12 nm, with an increase in Nd3+ concentration from 0 to 0.1 mol% in CoFe2O4. Scanning electron microscopy (SEM) studies reveal irregularly shaped particles with a homogenous distribution. The hysteresis loop obtained from the Vibrating-sample magnetometer (VSM) indicates the formation of soft magnetic materials, with magnetization values decreasing from 53 emu g−1 (x = 0) to 40 emu g−1 (x = 0.10) at 3 K and from 32 emu g−1 (x = 0) to 20 emu g−1 (x = 0.10) at 300 K. Interestingly, the highest coercivity and highest anisotropy constant (K) were observed for the sample x = 0.04.
NADPH oxidase 1 promotes hepatic steatosis in obese mice and is abrogated by augmented skeletal muscle mass
Authors: Larion Sebastian , Padgett Caleb A. , Mintz James D. , Thompson Jennifer A. , Butcher Joshua T. , Belin de Chantemèle Eric. J. , Haigh Stephen , Khurana Sandeep , Fulton David J. , Stepp David W.
Published: January 2024

This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.
Quantification of smooth muscle in human airways by polarization-sensitive optical coherence tomography requires correction for perichondrium
Authors: Hackmann Michael J. , Cairncross Alvenia , Elliot John G. , Mulrennan Siobhain , Nilsen Kris , Thompson Bruce R. , Li Qingyun , Karnowski Karol , Sampson David D. , McLaughlin Robert A. , Cense Barry , James Alan L. , Noble Peter B.
Published: January 2024

Polarization-sensitive optical coherence tomography (PS-OCT) may facilitate in vivo measurement of airway smooth muscle (ASM). We present a quantitative validation correlating absolute ASM area from PS-OCT to directly matched histological cross sections using human tissue. A major confounder for ASM quantification was observed and resolved: fibrous perichondrium surrounding hyaline cartilage in human airways presents a PS-OCT signature similar to ASM for birefringence and optic axis orientation. Findings impact the development of automated methods for ASM segmentation.
Financial Openness, Bank Systematic Risk, and Macroprudential Supervision
Authors: Chen Yanling , Deng Liangyu , Peng Chengliang
Published: January 2024

International experiences have underscored the dual implications of financial openness. Given China’s unique circumstances and its escalating level of financial openness, it is crucial to assess potential impacts on the country’s bank systemic risk. This paper uses the quarterly data of 37 listed banks in China from 2010 to 2022 to explore the relationship between financial openness and systemic risk of the banking system, the mechanism of action, and the moderating effect of macroprudential policy on the two. The findings indicate an inverted “U”-shaped correlation between financial openness and bank systemic risk. On one side of this shape, financial openness primarily exacerbates funding mismatch, thereby increasing the systemic risk of banks. Conversely, on the other side, it primarily alleviates systemic risk by optimizing capital management. Moreover, with the help of macroprudential supervision, the inverted “U”-shaped relationship between financial openness and bank systemic risk leads to a lower level of systemic risk and, at the same time, promotes the early arrival of the inverted “U”-shaped inflection point between financial openness and bank systemic risk. Notably, the impact of financial openness on the systemic risk of joint-stock commercial banks, urban commercial banks, and rural commercial banks is more significant. The above research results provide a regulatory reference for effectively preventing and resolving systemic risk while achieving high-quality openness to the outside world. In deepening financial openness, the banking industry needs to pay attention to the funding mismatch and the efficiency of capital management and implement differential risk supervision and prevention mechanisms for banks with different ownership, which is conducive to the reduction of bank systematic risk.
Assessing the Potential of Adenosine and L‐Theanine as Metabolic Suppressants for Improving Shipping of the New Zealand Scampi (Metanephrops challengeri)
Authors: Willis Jaime R. , Jeffs Andrew G. , Heasman Kevin , Hickey Anthony J. R.
Published: January 2024

Live crustaceans, especially lobsters, crabs, and shrimp, fetch premium prices in many international seafood markets, especially in parts of Asia. To access these market opportunities, live crustaceans frequently need to be transported over long distances, which can involve prolonged air exposure resulting in elevated stress and increased morbidity and mortality. Interventions which deliver metabolic suppression to live crustaceans during their transport have the potential to improve outcomes from live shipping. In this study, the administration of adenosine (Ado) and L‐theanine (L‐th) were assessed for metabolic suppression in the New Zealand scampi, Metanephrops challengeri, a deep sea lobster which is highly prized as seafood, and with excellent prospects for supply into premium live seafood markets. The administration to scampi of Ado and L‐th in isolation or as a mixture (Ado/L‐th), caused a significant decrease in heart rate (HR) with a lasting effect for the 4 hr experimental period. However, this depression of HR did not translate into a systemic downregulation of metabolism, as measured by the key metabolites, i.e., glycogen utilization and the accumulation of lactate and ammonia. The lack of systematic metabolic downregulation would preclude the potential use of Ado and L‐th for commercial application in live shipping of crustaceans.
Graphene Quantum Dots: Green Synthesis, Characterization, and Antioxidant and Antimicrobial Potential
Authors: Kadyan Pooja , Thillai Arasu Ponnusamy , Kataria Sudhir Kumar
Published: January 2024

Antibiotic resistance is becoming more common, emphasising the demand for novel antibacterial treatments. The current investigation describes the green synthesis of graphene quantum dots (GQDs) using M. indica leaves and characterization via Fourier-transform infrared spectra (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), and ultraviolet-visible (UV-Vis) spectrophotometer. The results showed that GQDs are spherical in shape. In vitro antioxidant and antimicrobial studies indicate that the biological efficacy of synthesized GQDs was higher than the ethanolic leaf extract. GQDs exhibited the highest scavenging efficacy with lowest IC50 (half-maximal inhibitory concentration) value. However, antimicrobial study showed more inhibitory activity of GQDs against all screened microorganisms, i.e., Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa, and fungi, i.e., Aspergillus niger and Aspergillus flavus. Graphene quantum dots facilitate reactive oxygen species (ROS) which ultimately lead to antioxidant and antibacterial activity. This approach would provide an efficient alternate method for tackling microorganisms.
Dynamics Analysis of a Delayed Crimean‐Congo Hemorrhagic Fever Virus Model in Humans
Authors: Al-Jubouri Karrar Qahtan , Naji Raid Kamel
Published: January 2024

Given that the Crimean and Congo hemorrhagic fever is one of the deadly viral diseases that occur seasonally due to the activity of the carrier “tick,” studying and developing a mathematical model simulating this illness are crucial. Due to the delay in the disease’s incubation time in the sick individual, the paper involved the development of a mathematical model modeling the transmission of the disease from the carrier to humans and its spread among them. The major objective is to comprehend the dynamics of illness transmission so that it may be controlled, as well as how time delay affects this. The discussion of every one of the solution’s qualitative attributes is included. According to the established basic reproduction number, the stability analysis of the endemic equilibrium point and the disease‐free equilibrium point is examined for the presence or absence of delay. Hopf bifurcation’s triggering circumstance is identified. Using the center manifold theorem and the normal form, the direction and stability of the bifurcating Hopf bifurcation are explored. The next step is sensitivity analysis, which explains the set of control settings that have an impact on how the system behaves. Finally, to further comprehend the model’s dynamical behavior and validate the discovered analytical conclusions, numerical simulation has been used.
Identification of Senescence‐Associated Biomarkers in Diabetic Glomerulopathy Using Integrated Bioinformatics Analysis
Authors: Zhang Li , Wang Zhaoxiang , Tang Fengyan , Wu Menghuan , Pan Ying , Bai Song , Lu Bing , Zhong Shao , Xie Ying
Published: January 2024

Background. Cellular senescence is thought to play a significant role in the onset and development of diabetic nephropathy. The goal of this study was to explore potential biomarkers associated with diabetic glomerulopathy from the perspective of senescence. Methods. Datasets about human glomerular biopsy samples related to diabetic nephropathy were systematically obtained from the Gene Expression Omnibus database. Hub senescence‐associated genes were investigated by differential gene analysis and Least Absolute Shrinkage and Selection Operator analysis. Cluster analysis was employed to identify senescence molecular subtypes. A single‐cell dataset was used to validate the above findings and further evaluate the senescence environment. The relationship between these genes and the glomerular filtration rate was explored based on the Nephroseq database. These gene expressions have also been explored in various kidney diseases. Results. Twelve representative senescence‐associated genes (VEGFA, IQGAP2, JUN, PLAT, ETS2, ANG, MMP14, VEGFC, SERPINE2, CXCR2, PTGES, and EGF) were finally identified. Biological changes in immune inflammatory response, cell cycle regulation, metabolic regulation, and immune microenvironment have been observed across different molecular subtypes. The above results were also validated based on single‐cell analysis. Additionally, we also identified several significantly altered cell communication pathways, including COLLAGEN, PTN, LAMININ, SPP1, and VEGF. Finally, almost all these genes could well predict the occurrence of diabetic glomerulopathy based on receiver operating characteristic analysis and are associated with the glomerular filtration rate. These genes are differently expressed in various kidney diseases. Conclusion. The present study identified potential senescence‐associated biomarkers and further explored the heterogeneity of diabetic glomerulopathy that might provide new insights into the diagnosis, assessment, management, and personalized treatment of DN.
Modeling and Parametric Analysis of a Large-Scale Solar-Based Absorption Cooling System
Authors: Abdullah Ali , AlZahrani Abdullah A.
Published: January 2024

This study investigates the thermodynamic performance of a solar-powered absorption cooling system. The system uses a lithium bromide-water (LiBr-H2O) absorption refrigeration system (ARS) integrated with evacuated solar collectors (ETSC) and thermal energy storage (TES) to provide a 3 kTR cooling capacity for a university campus. The paper examines the performance of the integrated system under different design and operating conditions as well as the performance of each subsystem, i.e., ETSC, TES, and ARS. Furthermore, a parametric energy and exergy analysis is applied, where different parameters are studied, such as the temperatures of the generator, the condenser, the evaporator, and the absorber. In addition, the system performance is examined with the variation in environmental conditions. The coefficient of performance (COP), exergetic efficiency, exergy destruction, and fuel depletion ratio (FDR) are used to evaluate the system’s performance. The ETSC and the TES are studied under the variation in solar radiation through the day in two seasons: summer and winter. The results revealed that the increase in generator temperature positively impacts the COP of the ARS while lowering the condenser and absorber temperature gives the same positive effect. Furthermore, the main reason for the exergy destruction is found to be the solar collector, which is responsible for destroying 89% of the input solar exergy. Additionally, 4.7% of the inlet exergy is destroyed in the generator, which makes 4.5% of the total exergy loss. The TES destroyed 4.8% of the total solar exergy input. The energy analysis shows that the ARS achieves an energetic COP of about 0.77, while the exergy analysis revealed that the exergetic COP is 0.21.
Adverse Social Determinants of Health in Children with Newly Diagnosed Type 1 Diabetes: A Potential Role for Community Health Workers
Authors: Lai Charlene W. , Craven Meghan , Hershey Jennifer A. , Lipman Terri H. , Hawkes Colin P.
Published: January 2024

Objective. There are significant socioeconomic and racial disparities in glycemic control among children with type 1 diabetes (T1D). Community health workers (CHWs) have been shown to improve outcomes in marginalized, high-risk populations. The purpose of this qualitative study was to describe the prevalence and the impact of adverse social determinants of health (SDOH) on diabetes care soon after a diagnosis of pediatric T1D, and investigate the potential supportive role of a CHW. Research Design and Methods. Caregivers of youth <17-year old, with new onset T1D, and government insurance at the time of diagnosis were enrolled. Baseline demographic and SDOH questionnaires were administered at the time of enrollment. Semistructured interviews were performed at 3 months after diagnosis to explore the effect of SDOH on diabetes care and the impact of a CHW. Results. Seventeen caregivers were enrolled, 10 were randomly assigned to a CHW. Two-thirds of caregivers identified at least one SDOH need at enrollment; 35% of caregivers identified two SDOH needs. Interviews revealed that the two major themes identified as barriers to diabetes care were caregivers’ employment and financial issues. Social support was identified as a facilitator. The transition from hospital to home after the diagnosis of T1D was improved for families working with a CHW, and the CHW was identified as a strong source of support. Conclusions. There is a high prevalence of adverse SDOH in families from lower socioeconomic status at the time of diagnosis of pediatric T1D. These SDOH have a significant impact on families’ abilities to care for their children. Preliminary data suggest that CHWs can be a facilitator to the diabetes care. This trial is registered with NCT04238949.
Large Section of Soft Rock Gob‐Side Entry Retaining Surrounding Rock Control
Authors: Wang Xizhi , Zhu Yongjian , Wang Ping , Ren Heng , Li Peng , He Xianwen , Lv Jianhua
Published: January 2024

When cutting roof and pressure relief, the impact of blasting is especially obvious on the integrity of the roof of a large‐section soft‐rock roadway. The reasonable parameters of blasting roof cutting were studied through using Xiaohezui coal mine ‐12110 roadway as the engineering background. The LS‐Dyna simulation results show that: Interval blasting is beneficial to the expansion of interhole cracks and the damage to the perimeter of the hole is smaller than that of adjacent blasting, the lower the charge uncoupling factor, the larger the perimeter of the hole fragmentation zone. The mechanical model of the large‐section soft‐rock roadway after retrieval was established, the support resistance equation of the roadway side support and the gangue in the extraction area was derived, and the minimum support force required for the roadway side support was solved. According to the site situation, the roadway support scheme for different areas was proposed, and after continuous delamination monitoring of the roof plate, it was found that the amount of roof‐plate delamination was finally stabilized within 180 mm after the working face was advanced, and the effect of leaving the roadway was good.
Association of Fibroids, Endometriosis, and Gynecologic Surgeries with Breast Cancer Incidence and Hormone Receptor Subtypes
Authors: Zeldin Jordan , Sandler Dale P. , Ogunsina Kemi , O'Brien Katie M.
Published: January 2024

Background:

Fibroids and endometriosis are sex hormone–mediated and exhibit cancer-like behavior. Breast cancer may be more common in women who have had these conditions, but the literature is conflicting and does not always address factors like hysterectomy/oophorectomy status, race/ethnicity, menopause, and hormone receptor subtypes.

Methods:

Data are from the Sister Study, a cohort of 50,884 U.S. women enrolled in 2003 to 2009 and followed through 2020. Cox proportional hazards models with time-varying exposures and covariates assessed the relationship of fibroids or endometriosis with breast cancer. Logistic regression examined the association with estrogen receptor (ER) status among cases.

Results:

Fibroids (19,932 cases) were positively associated with breast cancer [fully adjusted HR: 1.07; 95% confidence interval (CI): 1.01–1.14], notably among Black participants (HR: 1.34; 95% CI: 1.07–1.69) and women who had a hysterectomy (HR: 1.18; 95% CI: 1.05–1.31). Endometriosis (3,970 cases) was not associated with breast cancer (HR: 0.99; 95% CI: 0.91–1.08). Among 4,419 breast cancer cases, fibroids were positively associated with ER+ subtypes (OR: 1.34; 95% CI: 1.10–1.65), while endometriosis was negatively associated with ER+ subtypes (OR: 0.78; 95% CI: 0.61–1.01).

Conclusions:

We observed a modest positive association between fibroids and breast cancer, particularly ER+ breast cancer. No relationship with endometriosis and breast cancer incidence was found.

Impact:

Fibroids, even in those with a family history of breast cancer, might modify breast cancer risk stratification tools. Future studies should further assess this link and interrogate shared risk factors.
Germline USP36 Mutation Confers Resistance to EGFR-TKIs by Upregulating MLLT3 Expression in Patients with Non–Small Cell Lung Cancer
Authors: Guan Shaoxing , Chen Xi , Wei Yuru , Wang Fei , Xie Wen , Chen Youhao , Liang Heng , Zhu Xia , Yang Yunpeng , Fang Wenfeng , Huang Yan , Zhao Hongyun , Zhang Xiaoxu , Liu Shu , Zhuang Wei , Huang Min , Wang Xueding , Zhang Li
Published: January 2024

Purpose:

Although somatic mutations were explored in depth, limited biomarkers were found to predict the resistance of EGFR tyrosine kinase inhibitors (EGFR-TKI). Previous studies reported N6-methyladenosine (m6A) levels regulated response of EGFR-TKIs; whether the germline variants located in m6A sites affected resistance of EGFR-TKIs is still unknown.

Experimental Design:

Patients with non–small cell lung cancer (NSCLC) with EGFR-activating mutation were enrolled to investigate predictors for response of EGFR-TKIs using a genome-wide-variant-m6A analysis. Bioinformatics analysis and series of molecular biology assays were used to uncover the underlying mechanism.

Results:

We identified the germline mutation USP36 rs3744797 (C > A, K814N) was associated with survival of patients with NSCLC treated with gefitinib [median progression-free survival (PFS): CC vs. CA, 16.30 vs. 10.50 months, P < 0.0001, HR = 2.45] and erlotinib (median PFS: CC vs. CA, 14.13 vs. 9.47 months, P = 0.041, HR = 2.63). Functionally, the C > A change significantly upregulated USP36 expression by reducing its m6A level. Meanwhile, rs3744797_A (USP36 MUT) was found to facilitate proliferation, migration, and resistance to EGFR-TKIs via upregulating MLLT3 expression in vitro and in vivo. More importantly, MLLT3 and USP36 levels are tightly correlated in patients with NSCLC, which were associated with prognosis of patients. Mechanistically, USP36 MUT stabilized MLLT3 by deubiquitinating MLLT3 in nucleoli and consequently activating its downstream signaling (HIF1α and Snai). Furthermore, inhibition of MLLT3 alleviated USP36 variant–induced EGFR-TKIs resistance in EGFR-mutant NSCLC.

Conclusions:

These findings characterized rs3744797 as an oncogenic variant in mediating EGFR-TKI resistance and tumor aggressiveness through deubiquitinating MLLT3, highlighting the variant as a predictive biomarker for EGFR-TKI response in NSCLC.
Data from The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation
Authors: Kim Mijung , Rooper Lisa , Xie Jia , Rayahin Jamie , Burdette Joanna E. , Kajdacsy-Balla Andre A. , Barbolina Maria V.
Published: January 2024

Abstract
Chemokine receptor-ligand interactions are important to support functioning of both normal and pathologic cells. The expression and function of chemokine receptors in epithelial ovarian carcinoma (EOC) is largely unknown. Here, we report that the lymphotactin receptor (XCR1) was expressed in primary and metastatic human epithelial ovarian carcinoma (EOC) specimens and cell lines. In contrast, expression of XCR1 was not detected in the normal ovary or in human normal ovarian surface epithelial cells. Our data indicate that XCL1 and XCL2 are either present in the malignant ascites or expressed by the ovarian carcinoma cells. The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1-positive cells. Reduction of XCR1 expression in ovarian carcinoma cell line SKOV-3 resulted in abrogated diaphragm and peritoneal wall tumor formation and in reduced frequency of colonic, splenetic, and liver nodules in an in vivo xenograft mouse model. Taken together, our data suggest that XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of EOC cells. Mol Cancer Res; 10(11); 1419–29. ©2012 AACR.
Data from STAT3-RANTES Autocrine Signaling Is Essential for Tamoxifen Resistance in Human Breast Cancer Cells
Authors: Yi Eun Hee , Lee Chang Seok , Lee Jin-Ku , Lee Young Ju , Shin Min Kyung , Cho Chung-Hyun , Kang Keon Wook , Lee Jung Weon , Han Wonshik , Noh Dong-Young , Kim Yong-Nyun , Cho Ik-Hyun , Ye Sang-kyu
Published: January 2024

Abstract
The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3–RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3–RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3–RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors. Mol Cancer Res; 11(1); 31–42. ©2012 AACR.
Data from Radiation Survivors: Understanding and Exploiting the Phenotype following Fractionated Radiation Therapy
Authors: Makinde Adeola Y. , John-Aryankalayil Molykutty , Palayoor Sanjeewani T. , Cerna David , Coleman C. Norman
Published: January 2024

Abstract
Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors, focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing the cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145, and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multifraction (MF) radiation of 0.5, 1, and/or 2 Gy fraction to 10 Gy total dose, and a single dose of 5 and 10 Gy. The resulting changes in mRNA, miRNA, and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell-cycle arrest, TGF-β, survival, and apoptotic signal transduction. The radiation-induced stress response will set forth a unique platform for exploiting the effects of radiation therapy as “focused biology” for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome. Mol Cancer Res; 11(1); 5–12. ©2012 AACR.
Data from The Role of Versican in Modulating Breast Cancer Cell Self-renewal
Authors: Du William Weidong , Fang Ling , Yang Xiangling , Sheng Wang , Yang Bing L. , Seth Arun , Zhang Yaou , Yang Burton B. , Yee Albert J.
Published: January 2024

Abstract
Versican is highly expressed during the early stages of tissue development and its expression is elevated during wound repair and tumor growth. There is little literature on the potential role of breast cancer stem cells on the cellular–extracellular matrix interactions involving versican. An anti-versican short hairpin RNA (shRNA) was used to observe the effect of reduction of versican on breast cancer self-renewal. A versican G3 construct was exogenously expressed in breast cancer cell lines. Colony formation and mammosphere formation assays were conducted; flow cytometry was applied to analyze the prevalence of side population cells. The versican G3- and vector-transfected 66c14 cells were injected transdermally into BALB/c mice as a 10-fold dilution series from 1 × 105 to 1 × 102 cells per mouse. Versican G3 domain enhanced breast cancer self-renewal in both experimental in vitro and in vivo models. Versican G3–transfected cells contained high levels of side population cells, formed more mammospheres when cultured in the serum-free medium, and formed a greater number and larger colonies. Reduction of versican's functionality through anti-versican shRNA or knocking out the EGF-like motifs reduced the effect of versican on enhancing mammosphere and colony formation. Versican-enhanced self-renewal played a role in enhanced chemotherapeutic drug resistance, relating partly to the upregulated expression of EGF receptor (EGFR) signaling. Versican is highly expressed in breast cancer progenitor cells and was maintained at high levels before cell differentiation. Overexpression of versican enhanced breast cancer self-renewal through EGFR/AKT/GSK-3β (S9P) signaling and conferred resistant to chemotherapeutic drugs tested. Mol Cancer Res; 11(5); 443–55. ©2013 AACR.
Data from Synergistic Effect of Olaparib with Combination of Cisplatin on PTEN-Deficient Lung Cancer Cells
Authors: Minami Daisuke , Takigawa Nagio , Takeda Hiromasa , Takata Minoru , Ochi Nobuaki , Ichihara Eiki , Hisamoto Akiko , Hotta Katsuyuki , Tanimoto Mitsune , Kiura Katsuyuki
Published: January 2024

Abstract
PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non–small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650PTEN+) and knocked down PTEN expression in the PC-9 cells (PC-9PTEN−) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9PTEN− cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650PTEN+ and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair. Mol Cancer Res; 11(2); 140–8. ©2012 AACR.
Data from SUZ12 Promotes Human Epithelial Ovarian Cancer by Suppressing Apoptosis via Silencing HRK
Authors: Li Hua , Cai Qi , Wu Hong , Vathipadiekal Vinod , Dobbin Zachary C. , Li Tianyu , Hua Xiang , Landen Charles N. , Birrer Michael J. , Sánchez-Beato Margarita , Zhang Rugang
Published: January 2024

Abstract
Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here, we show that SUZ12 is expressed at significantly higher levels in human EOC (n = 117) compared with either normal human ovarian surface epithelium (n = 35, P < 0.001) or fallopian tube epithelium (n = 15, P < 0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (P < 0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (P < 0.001), and predicts shorter overall survival (P = 0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified Harakiri (HRK), a proapoptotic gene, as a novel SUZ12 target gene, and showed that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown. Mol Cancer Res; 10(11); 1462–72. ©2012 AACR.
Data from Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma
Authors: Yoon Joon Won , Gallant Marisa , Lamm Marilyn LG , Iannaccone Stephen , Vieux Karl-Frederic , Proytcheva Maria , Hyjek Elizabeth , Iannaccone Philip , Walterhouse David
Published: January 2024

Abstract
Although Hedgehog signaling plays a major role in GLI1 transcription, there is now evidence suggesting that other pathways/genes, such as c-MYC, may also regulate GLI1 expression. We initiated studies in Burkitt lymphoma cells, which constitutively express c-MYC due to a chromosomal translocation, to determine whether Hedgehog or c-MYC regulates GLI1 expression. We show that all Burkitt lymphoma cell lines tested express GLI1, PTCH1, and SMO and that five of six Burkitt lymphomas express GLI1. Exposure to Sonic or Indian Hedgehog or cyclopamine (SMO inhibitor) does not modulate GLI1 expression, cell proliferation, or apoptosis in most Burkitt lymphoma cell lines. Sequence analysis of PTCH1, SMO, and SuFu failed to show mutations that might explain the lack of Hedgehog responsiveness, and we did not detect primary cilia, which may contribute to it. We show that c-MYC interacts with the 5′-regulatory region of GLI1, using chromatin immunoprecipitation (ChIP) assay, and E-box–dependent transcriptional activation of GLI1 by c-MYC in NIH3T3 and HeLa cells. The c-MYC small-molecule inhibitor 10058-F4 downregulates GLI1 mRNA and protein and reduces the viability of Burkitt lymphoma cells. Inhibition of GLI1 by GANT61 increases apoptosis and reduces viability of some Burkitt lymphoma cells. Collectively, our data provide evidence that c-MYC directly regulates GLI1 and support an antiapoptotic role for GLI1 in Burkitt lymphoma. Burkitt lymphoma cells do not seem to be Hedgehog responsive. These findings suggest a mechanism for resistance to SMO inhibitors and have implications for using SMO inhibitors to treat human cancers. Mol Cancer Res; 11(6); 604–15. ©2013 AACR.
Data from The Invasion Inhibitor Sarasinoside A1 Reverses Mesenchymal Tumor Transformation in an E-Cadherin–Independent Manner
Authors: Austin Pamela , Freeman Spencer A. , Gray Christopher A. , Gold Michael R. , Vogl A. Wayne , Andersen Raymond J. , Roberge Michel , Roskelley Calvin D.
Published: January 2024

Abstract
During metastatic progression, an aberrant epithelial-to-mesenchymal transformation (EMT) that is most often driven by the loss of the cell–cell adhesion molecule E-cadherin generates noncohesive tumor cells that are highly invasive. We used mesenchymally transformed, E-cadherin–negative MDA-MB-231 breast carcinoma cells in a natural product screen and determined that the triterpenoid saponin sarasinoside A1 inhibited their invasion and the invasion of a number of other tumor cell lines. Sarasinoside A1 also caused MDA-MB-231 cells to become cohesive in a three-dimensional basement membrane and collagen gel cultures. In two-dimensional culture, sarasinoside A1 initiated a morphologic re-epithelialization of MDA-MB-231 cells wherein preexisting nonepithelial cadherins and the junction-associated proteins β-catenin and ZO-1 all relocalized to sites of cell–cell contact. In addition, the intercellular space between neighboring cells narrowed considerably, the stability of polymerized actin at cell-cell contact sites increased, and there was a recruitment and stabilization of nectin-based adhesion complexes to these sites, all of which strongly suggested that functional cell–cell junctions had formed. Importantly, sarasinoside A1 induced nascent cell–cell junction formation that did not require changes in gene expression and was not associated with an induction of E-cadherin but resulted in increased activation of Rap GTPases. Therefore, our findings with sarasinoside A1 suggest that it may be possible to re-epithelialize metastatic tumor cells with phenotypic consequence even when E-cadherin is completely absent. Mol Cancer Res; 11(5); 530–40. ©2013 AACR.
Data from Multiple Functions of Sushi Domain Containing 2 (SUSD2) in Breast Tumorigenesis
Authors: Watson Allison P. , Evans Rick L. , Egland Kristi A.
Published: January 2024

Abstract
Routinely used therapies are not adequate to treat the heterogeneity of breast cancer, and consequently, more therapeutic targets are desperately needed. To identify novel targets, we generated a breast cancer cDNA library enriched for genes that encode membrane and secreted proteins. From this library we identified SUSD2 (Sushi Domain Containing 2), which encodes an 822-amino acid protein containing a transmembrane domain and functional domains inherent to adhesion molecules. Previous studies describe the mouse homolog, Susd2, but there are no studies on the human gene associated with breast cancer. Immunohistochemical analysis of human breast tissues showed weak or no expression of SUSD2 in normal epithelial cells, with the endothelial lining of vessels staining positive for SUSD2. However, staining was observed in pathologic breast lesions and in lobular and ductal carcinomas. SUSD2 interacts with galectin-1 (Gal-1), a 14-kDa secreted protein that is synthesized by carcinoma cells and promotes tumor immune evasion, angiogenesis, and metastasis. Interestingly, we found that localization of Gal-1 on the surface of cells is dependent on the presence of SUSD2. Various phenotype assays indicate that SUSD2 increases the invasion of breast cancer cells and contributes to a potential immune evasion mechanism through induction of apoptosis of Jurkat T cells. Using a syngeneic mouse model, we observed accelerated tumor formation and decreased survival in mice with tumors expressing Susd2. We found significantly fewer CD4 tumor infiltrating lymphocytes in mice with tumors expressing Susd2. Together, our findings provide evidence that SUSD2 may represent a promising therapeutic target for breast cancer. Mol Cancer Res; 11(1); 74–85. ©2012 AACR.
Data from MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma
Authors: Castro Inês C. , Breiling Achim , Luetkenhaus Katharina , Ceteci Fatih , Hausmann Simone , Kress Sebastian , Lyko Frank , Rudel Thomas , Rapp Ulf R.
Published: January 2024

Abstract
Human lung cancer is a disease with high incidence and accounts for most cancer-related deaths in both men and women. Metastasis is a common event in non–small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis from NSCLC, but the mechanism underlying this switch remained to be identified. Here, we focus on GATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of the MYC-associated zinc finger protein (MAZ) from the GATA4 promoter, which leads to GATA4 expression. Histone modification analysis of the GATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy. Mol Cancer Res; 11(2); 161–72. ©2012 AACR.