bluuebunny/crossref_metadata_2025 huggingface dataset:
Androgen Receptor (AR) Depletion Underlies the Reproductive Dysfunctions in Male Rats Exposed to Alcohol and Combination Antiretroviral Therapy (cART)
Authors: Owembabazi Elna , Nkomozepi Pilani , Mbajiorgu Ejikeme F.
Published: April 2023

The prevalence of alcohol abuse and HIV/AIDS is high in males of reproductive age; unfortunately, a high incidence of alcohol intake has been reported in HIV/AIDS patients including those on combination antiretroviral therapy (cART). Incidentally, alcohol and cART use have each been implicated in male reproductive dysfunction. Therefore, the interactive effects of alcohol and cART on reproductive hormone levels, testicular connective tissue, and androgen receptor and Ki-67 expression were evaluated in HIV naïve adult male Sprague Dawley rats. Adult male rats were divided into four groups: control, alcohol (A), cART, and A+cART. Animals were terminated after 90 days of treatment; then, the blood and testis were extracted for analysis. Special staining for testicular connective tissue, immunoassay for reproductive hormones, and immunohistochemistry for androgen receptor and Ki-67 were conducted. The study found significantly (

p
<
0.05

) increased thickness of seminiferous tubule basement membrane in the cART group and testicular capsule in the A+cART group. Collagen, reticulin, and elastin fibers decreased significantly in all the treated groups, except for reticulin in the testis of A group animals. With exception of luteinizing hormone in the cART group, all the treated groups had significantly elevated levels of luteinizing and follicle-stimulating hormones, but no significant (

p
>
0.05

) difference was found in their testosterone and inhibin B levels. The number of Sertoli and Leydig cells expressing androgen receptor reduced significantly in all the treated groups, except for A group’s number of Sertoli cells expressing androgen receptor. Further, in all the treated groups, Ki-67 expression significantly reduced relative to control. In this study, with exception of seminiferous tubule basement membrane, all study parameters were greatly altered in the A+cART group; we suggest that the exacerbated androgen receptor depletion recorded in the A+cART group might have led to the observed severe testicular structural alteration and spermatogenesis derangement.
Pharmacodynamic Material Basis and Potential Mechanism Study of Spatholobi Caulis in Reversing Osteoporosis
Authors: Xiao Jianpeng , Shang Wei , Zhao Zhiming , Jiang Jun , Chen Jianping , Cai Hui , He Jinjin , Cai Zhihui , Zhao Zihan
Published: April 2023

Objective. To elucidate the mechanism of Spatholobi Caulis (SC) in treating osteoporosis (OP) integrated zebrafish model and bioinformatics. Methods. Skeleton staining coupled with image quantification was performed to evaluate the effects of SC on skeleton mineralization area (SSA) and total optical density (TOD). Zebrafish locomotor activity was monitored using the EthoVision XT. Bioactive compounds of SC and their corresponding protein targets were acquired from Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Potential therapeutic targets for OP were summarized through retrieving 5 databases, and then, the overlapping genes between SC and OP were acquired. The core genes were selected by CytoHubba. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional analysis of the intersection target genes were carried out by R software. Finally, the molecular docking simulation was manipulated between the ingredients and the hub genes. Results. Compared with the model group, SC significantly increased the SSA and TOD at 10 mg/mL and improved the locomotor activity in a dose‐dependent manner (p < 0.001). 33 components of SC were associated with 72 OP‐related genes including 10 core genes (MAPK1, VEGFA, MMP9, AKT1, AR, IL6, CALM3, TP53, EGFR, and CAT). Advanced Glycation End Product (AGE) Receptor for AGE (RAGE) signaling pathway was screened out as the principal pathway of SC in anti‐OP. The bioactive components (Aloe‐emodin, Emodin, Formononetin, Licochalcone A, Luteolin, and Lopac‐I‐3766) have excellent affinity to core genes (MAPK1, VEGFA, MMP9, AKT1, and IL6). Conclusion. SC had the hierarchical network characteristics of “multicomponents/multitargets/multifunctions/multipathways” in reversing OP, but AGE‐RAGE signaling pathway may be the main regulatory mechanism.
HLA‐HOD: Joint High‐Low Adaptation for Object Detection in Hazy Weather Conditions
Authors: Shen Yiyang , Yu Rongwei , Shu Ni , Qin Jing , Wei Mingqiang
Published: April 2023

Object detection remains challenging in hazy weather conditions due to the poor visibility of captured images. There are currently two types of detectors capable of adapting to varying weather conditions: (i) low‐level adaptation methods that combine one detector with an additional dehazing network and (ii) high‐level adaptation methods that explore various kinds of domain adaptation knowledge. However, neither of these approaches can achieve desirable performance due to their inherent limitations. We raise an intriguing question—if combining both low‐level adaptation and high‐level adaptation, can improve the generalization ability of a detector in hazy weather conditions? To answer it, we propose a Joint High‐Low Adaptation Object Detection paradigm (HLA‐HOD) in hazy weather conditions. By combining both low‐level adaptation and high‐level adaptation, HLA‐HOD achieves superior performance on hazy images without requiring ground‐truth bounding boxes or clean images. Extensive experiments demonstrate that our method outperforms state‐of‐the‐art low‐level and high‐level adaptation methods by a large margin both quantitatively and qualitatively.
Deep Learning-Based Business Recommendation System in Intelligent Vehicles
Authors: Yu Kyungho , Lim Kiho , Kim Pankoo
Published: April 2023

The advancements in intelligent vehicle technologies are facilitating the growth of information technology (IT) platforms, unlike conventional automobiles. In-vehicle-infotainment (IVI) is becoming an appealing element in intelligent vehicles as it offers various experiences to users; however, it requires personalized services to provide even more sophisticated user experiences. It is supposed that passengers search for businesses that provide products or services they found interesting in videos played via IVIs while the vehicle is driving autonomously. In that case, it could be more effective to use images that can express the user’s preference as a query for the search than to utilize texts such as product names. Accordingly, this study proposes a recommendation system that informs users of businesses near an intelligent vehicle when a passenger inputs an image of a product or service into an IVI system. The proposed recommendation system involves training deep learning-based image classification models with the user’s interest images to classify the category, measure the similarity with the business category using Word2vec, and finally provide the locations of the businesses with a high degree of similarity via IVI, using a smartphone. The experimental results indicated that the user’s interest image exhibited 85% accuracy for category classification via the EfficientNet B0 model, while the similarity between the image and business categories using Word2vec was particularly high in the business category similar to the actual image category.
The Role of Cytosolic Lipid Droplets in Hepatitis C Virus Replication, Assembly, and Release
Authors: Awadh Abdullah A.
Published: April 2023

The hepatitis C virus (HCV) causes chronic hepatitis by establishing a persistent infection. Patients with chronic hepatitis frequently develop hepatic cirrhosis, which can lead to liver cancer—the progressive liver damage results from the host’s immune response to the unresolved infection. The HCV replication process, including the entry, replication, assembly, and release stages, while the virus circulates in the bloodstream, it is intricately linked to the host’s lipid metabolism, including the dynamic of the cytosolic lipid droplets (cLDs). This review article depicts how this interaction regulates viral cell tropism and aids immune evasion by coining viral particle characteristics. cLDs are intracellular organelles that store most of the cytoplasmic components of neutral lipids and are assumed to play an increasingly important role in the pathophysiology of lipid metabolism and host‐virus interactions. cLDs are involved in the replication of several clinically significant viruses, where viruses alter the lipidomic profiles of host cells to improve viral life cycles. cLDs are involved in almost every phase of the HCV life cycle. Indeed, pharmacological modulators of cholesterol synthesis and intracellular trafficking, lipoprotein maturation, and lipid signaling molecules inhibit the assembly of HCV virions. Likewise, small‐molecule inhibitors of cLD‐regulating proteins inhibit HCV replication. Thus, addressing the molecular architecture of HCV replication will aid in elucidating its pathogenesis and devising preventive interventions that impede persistent infection and prevent disease progression. This is possible via repurposing the available therapeutic agents that alter cLDs metabolism. This review highlights the role of cLD in HCV replication.
An Optimized Framework of the Integrated Renewable Energy and Power Quality Model for the Smart Grid
Authors: Kumar Naveen , Singh Gopal , Kebede Hailemichael
Published: April 2023

The smart grid’s structure is distinctive because it incorporates numerous cutting-edge communication and sensor technologies. It is challenging to manage smart grids using conventional power grids’ unified optimum delivery strategy effectively. This work offers a smart grid power production and maintenance collaborative optimization framework with renewable energy based on power generation and maintenance analysis. The operating costs of conventional units, the price of generating solar or wind power, and the cost of maintaining units are the problems of objective functions; the constraints taken into account are primarily system constraints. The genetic algorithm (GA) is used in this research to examine the optimization solution strategy. Depending on the properties of the system, various loads, power sources, and constraints are considered. The difficulty of adjusting load scheduling is transformed into a control problem by developing an efficient objective function. When uncertain system components are considered, the real-time control system can dynamically alter load scheduling to meet the needs of the actual system. In this study, the real-time algorithm put forward in this research is based on a strategy that satisfies the load optimization requirement and achieves dynamic compensation for unpredictable changes in renewable energy power generation. Moreover, the simulation compares the proposed algorithm capabilities with the existing algorithms/study, demonstrating the effectiveness of the suggested approach.
Self-Care Behaviors among Patients after Cardiac Surgery in Saudi Arabia: Application of Orem’s Theory of Self-Care
Authors: Jamil Alkuwaisi Mohannad , Hamdan Alsargri Salman , Kamel Aldalaykeh Mohammed , Abdu Hamid Mokhtar , Hamdan Alsargri Fatimah
Published: April 2023

Aims. To examine the self-care behaviors of Saudi patients who had cardiac surgery after hospital discharge and to investigate how much variation in self-care behavior may be attributed to patients’ basic conditioning factors (BCFs). Background. Self-care behaviors following cardiac surgery should be appropriate for the patient’s circumstances to decrease hospital readmissions and maintain good health. Design. A cross-sectional design guided this study. Orem’s Theory of Self-Care was applied as a theoretical framework. Materials & Methods. The Self-Care Behavior Scale (SCBS) was used to gather data from 150 patients who experienced cardiac surgery after they were discharged from cardiac centers in two large cities in Saudi Arabia. Results. The two self-care behaviors performed most frequently concerned taking medications as prescribed. The other three self-care behaviors frequently performed were avoiding any strain, assessing all incisions for signs of infection, and contacting a physician if any signs of infection appeared. There was a statistically significant difference between patients’ total self-care behaviors according to their BCFs. Married patients reported significantly more self-care behaviors than single patients. Patients with only valve replacement (VR) surgery performed more self-care behaviors than the coronary artery bypass graft (CABG) and VR groups. These factors positively influence (61.2%) self-care behavior and performance. Conclusion. Cardiac surgery patients showed moderate self-care behavior after being discharged from hospital. Furthermore, the results of this study showed statistically significant variation in patients' self-care behaviors based on their BCFs.
Resilience-Oriented Scheduling of Shared Autonomous Electric Vehicles: A Cooperation Framework for Electrical Distribution Networks and Transportation Sector
Authors: Amirioun Mohammad Hassan , Jafarpour Saeid , Abdali Ali , Guerrero Josep M. , Khan Baseem
Published: April 2023

As autonomous electric vehicles and car-sharing services are becoming more popular, the contribution of shared autonomous electric vehicles (SAEVs) to the future of urban transportation is getting more achievable. Like conventional electric vehicles, SAEVs can provide power grids with ancillary services. This article proposes a new scheduling scheme for SAEV fleets within a cooperative plan to let power distribution networks benefit from the energy storage of vehicle batteries in recovering critical loads after a predictable extreme event. According to a long-term contract, the detailed request of the distribution system operator (DSO), together with desired constraints and perquisites, is sent to the SAEVs aggregator (SA) prior to the landfall of a predictable extreme event. Afterward, SA runs a targeted algorithm to schedule trip assignments and charging cycles of SAEVs so that the required constraints of DSO are satisfied. The SAEV participants will continue carrying passengers within the scheduled time horizon in addition to delivering energy to the distribution network at the scheduling deadline declared by DSO. This deadline is the time instant when the capacity of the SAEV fleet may be no more applicable to enhance the system preparedness against the approaching event. Numerical results illustrated that the proposed scheme helps improve the power grid resilience by delivering 2396.1 kWh of energy to the distribution network in addition to increasing the total income of each participant SAEV by about 130%. Thus, it is implied that the proposed method offers a win-win situation for both entities.
Characterization and Mapping of Soil-Landscape for Site-Specific Soil Management in Ayiba Watershed, Northern Highlands of Ethiopia
Authors: Seifu Weldemariam , Elias Eyasu , Gebresamuel Girmay , Feyisa Gudina Legese , Tefera Wolde
Published: April 2023

The characterization of soil landscapes is becoming increasingly important for making decisions regarding site-specific agriculture systems and soil management. This study was initiated for the purpose of identifying landscape-scale spatial soil variation using a toposequence model so that site-specific fertilization could be achieved. According to the finding, the soils were shallow to very deep in depth, moderately acidic to moderately alkaline in soil reaction, nonsaline in salinity, and clay to sandy loam in texture. The soils were found very low to low levels in most soil nutrients, very low to very high levels of base saturation, and deficient in zinc but have adequate levels of iron, copper, and manganese. The soil exchange complex was mainly dominated by Ca and Mg where the order of occurrence was Ca > mg > K > Na. The CEC values were in high to very high range. Following the field survey and soil analytical results, five main reference soil groups of the World Soil Resource Base—Leptosols (56%), Luvisols (8.5%), Fluvisols (14.4%), Vertisols (13%), and Cambisol (8.2%)—were identified and mapped. Leptosols cover the largest landmass of the watershed and mostly found at the summit and hill back slopes. On the other hand, Luvisols, Fluvisols, Vertisols, and Cambisols were found on the middle and foot slopes. According to the findings, the variation in soil source indicating that topography is the primary pedogenic element in the formation of the soil in the watershed that was under research. Therefore, having local-scale-specific soil information can assist the site-specific application of soil nutrients and amendments based on spatial variability which is tailored to the soil requirements.
A Spatio‐Temporal Siamese Neural Network for Multimodal Handwriting Abnormality Screening of Parkinson’s Disease
Authors: Zhao Aite , Wu Huimin , Chen Ming , Wang Nana
Published: April 2023

Currently, hand motion recognition of single‐modality data has been extensively explored for the analysis of various contact and noncontact sensors, and it is recognized that all the existing technologies have both strengths and limitations. As a significant motor symptom, hand tremor is usually utilized for the diagnosis and evaluation of Parkinson’s disease; furthermore, a multimodal analysis of the handwriting pattern of the patient has made up for the one‐sided way of learning the hand movement in a single measurement dimension. Especially, considering a variety of measurement resources, it shows promising performance in recognizing handwriting patterns of Parkinson’s disease. In this work, a novel Spatio‐temporal Siamese neural network (ST‐SiamNN) is proposed to learn the handwriting differences between healthy individuals and patients with Parkinson’s disease, process data onto multiple sensors, and enhance the characteristics of handwriting in Parkinson’s disease. Uniquely, it is a discriminative model of multilabel and multinetwork constructed by a Siamese network, which consists of four modules: a preprocessor for handwritten data enhancement, a Siamese bidirectional memory neural network (SiamBiMNN) for temporal and texture feature extraction and difference enhancement, a Siamese octave convolutional neural network (SiamOctCNN) for spatial feature extraction and difference enhancement, and a decision‐making layer to rejudge the output features of the Siamese networks to obtain more accurate auxiliary diagnosis results. The framework proposed in this article is verified on two handwritten datasets of multiple modalities, i.e., images, smart pen signals, and graphics tablet signals, which are compared with several state‐of‐the‐art studies.
Data from Bayesian machine learning enables identification of transcriptional network disruptions associated with drug-resistant prostate cancer
Authors: Blatti Charles , de la Fuente Jesús , Gao Huanyao , Marín-Goñi Irene , Chen Zikun , Zhao Sihai D. , Tan Winston , Weinshilboum Richard , Kalari Krishna R. , Wang Liewei , Hernaez Mikel
Published: April 2023

Abstract
Survival rates of patients with metastatic castration-resistant prostate cancer (mCRPC) are low due to lack of response or acquired resistance to available therapies, such as abiraterone (Abi). A better understanding of the underlying molecular mechanisms is needed to identify effective targets to overcome resistance. Given the complexity of the transcriptional dynamics in cells, differential gene expression analysis of bulk transcriptomics data cannot provide sufficient detailed insights into resistance mechanisms. Incorporating network structures could overcome this limitation to provide a global and functional perspective of Abi-resistance in mCRPC. Here, we developed TraRe, a computational method using sparse Bayesian models to examine phenotypically-driven transcriptional mechanistic differences at three distinct levels: transcriptional networks, specific regulons, and individual transcription factors. TraRe was applied to transcriptomic data from 46 mCRPC patients with Abi-response clinical data and uncovered abrogated immune response transcriptional modules that showed strong differential regulation in Abi-responsive compared to Abi-resistant patients. These modules were replicated in an independent mCRPC study. Further, key rewiring predictions and their associated transcription factors were experimentally validated in two prostate cancer cell lines with different Abi resistance features. Among them, ELK3, MXD1, and MYB played a differential role in cell survival in Abi-sensitive and Abi-resistant cells. Moreover, ELK3 regulated cell migration capacity, which could have a direct impact on mCRPC. Collectively, these findings shed light on the underlying transcriptional mechanisms driving abiraterone response, demonstrating that TraRe is a promising tool for generating novel hypotheses based on identified transcriptional network disruptions.
Data from DNA methylation landscapes of prostate cancer brain metastasis are shaped by early driver genetic alterations
Authors: Gallon John , Rodriguez-Calero Antonio , Benjak Andrej , Akhoundova Dilara , Maletti Sina , Amstutz Ursula , Hewer Ekkehard , Genitsch Vera , Fleischmann Achim , Rushing Elisabeth J. , Grobholz Rainer , Fischer Ingeborg , Jochum Wolfram , Cathomas Gieri , Osunkoya Adeboye O. , Bubendorf Lukas , Moch Holger , Thalmann George , Feng Felix Y. , Gillessen Silke , Ng Charlotte K.Y. , Rubin Mark A. , Piscuoglio Salvatore
Published: April 2023

Abstract
Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.
Data from Germline cancer gene expression quantitative trait loci are associated with local and global tumor mutations
Authors: Liu Yuxi , Gusev Alexander , Kraft Peter
Published: April 2023

Abstract
Somatic mutations drive cancer development and are relevant to patient responses to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline-somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene (“local impact”) or a set of recurrently mutated cancer genes across the genome (“global impact”) through their regulatory effect on gene expression. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline-somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes.
Data from Germline Cancer Gene Expression Quantitative Trait Loci Are Associated with Local and Global Tumor Mutations
Authors: Liu Yuxi , Gusev Alexander , Kraft Peter
Published: April 2023

Abstract
Somatic mutations drive cancer development and are relevant to patient responses to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline–somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene (“local impact”) or a set of recurrently mutated cancer genes across the genome (“global impact”) through their regulatory effect on gene expression. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline–somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes.
Significance:
Analysis of associations between the germline genetic background and somatic mutations in patients with cancer suggests that germline variants can influence local and global tumor mutations by altering expression of cancer-related genes.

See related commentary by Kar, p. 1165.
Data from AKT blocks SIK1-mediated repression of STAT3 to promote breast tumorigenesis
Authors: Sun Zhicheng , Jiang Qiwei , Gao Bing , Zhang Xiaomei , Bu Lang , Wang Lei , Lin Ying , Xie Wei , Li Jie , Guo Jianping
Published: April 2023

Abstract
The PI3K-AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. While inhibitors directly targeting the PI3K-AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2-STAT3 axis as a strategy to treat AKT-driven breast cancer.
Data from AKT Blocks SIK1-Mediated Repression of STAT3 to Promote Breast Tumorigenesis
Authors: Sun Zicheng , Jiang Qiwei , Gao Bing , Zhang Xiaomei , Bu Lang , Wang Lei , Lin Ying , Xie Wei , Li Jie , Guo Jianping
Published: April 2023

Abstract
The PI3K–AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. Although inhibitors directly targeting the PI3K–AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry–based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2–STAT3 axis as a strategy to treat AKT-driven breast cancer.
Significance:
AKT binds and phosphorylates SIK1 to overcome SIK1-mediated repression of STAT3, indicating that STAT3 is a potential therapeutic target in breast cancer with hyperactive AKT signaling.
Data from Dysregulation of Mitochondrial Translation Caused by CBFB Deficiency Cooperates with Mutant PIK3CA and Is a Vulnerability in Breast Cancer
Authors: Malik Navdeep , Kim Young-Im , Yan Hualong , Tseng Yu-Chou , du Bois Wendy , Ayaz Gamze , Tran Andy D. , Vera-Ramirez Laura , Yang Howard , Michalowski Aleksandra M. , Kruhlak Michael , Lee Maxwell , Hunter Kent W. , Huang Jing
Published: April 2023

Abstract
Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain‐of-function (GOF) and CBFB loss‐of‐function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moonlighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient‐derived xenografts carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer.
Significance:
CBFB-regulated mitochondrial translation is a regulatory step in breast cancer metabolism and synergizes with mutant PI3K in breast cancer progression.
Data from G-quadruplex structures are key modulators of somatic structural variants in cancers
Authors: Zhang Rongxin , Shu Huiling , Wang Yuqi , Tao Tiantong , Tu Jing , Wang Cheng , Mergny Jean-Louis , Sun Xiao
Published: April 2023

Abstract
G-quadruplexes (G4s) are non-canonical secondary genome structures. Aberrant formation of G4s can impair genome integrity. Investigation of the relationship between G4s and somatic structural variants (SVs) in cancers could provide a better understanding of the role of G4 formation in cancer development and progression. In this study, we combined bioinformatic approaches and multi-omics data to investigate the connection between G4s and the somatic SVs. Somatic SV breakpoints were significantly enriched in G4 regions, regardless of SV subtypes. This enrichment was only observed in regions demonstrated to form G4s in cells (“active quadruplexes”), rather than in regions with a sequence compatible with G4 formation but without confirmed G4 formation (“potential quadruplexes”). Several genomic features impacted the connection between G4s and SVs, with the enrichment being notably strengthened at the boundary of topologically associated domains. Somatic breakpoints were also preferentially associated with G4 regions with earlier replication timing and open chromatin status. In cancer patients with homologous recombination repair defects, G4s and somatic breakpoints were substantially more strongly associated. Machine learning models were constructed that showed that G4 propensity is a potent feature for predicting the density of SV breakpoints. Altogether, these findings suggest that the G4 structures play a critical role in modulating the production of somatic SVs in cancers.
DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations
Authors: Gallon John , Rodriguez-Calero Antonio , Benjak Andrej , Akhoundova Dilara , Maletti Sina , Amstutz Ursula , Hewer Ekkehard , Genitsch Vera , Fleischmann Achim , Rushing Elisabeth J. , Grobholz Rainer , Fischer Ingeborg , Jochum Wolfram , Cathomas Gieri , Osunkoya Adeboye O. , Bubendorf Lukas , Moch Holger , Thalmann George , Feng Felix Y. , Gillessen Silke , Ng Charlotte K.Y. , Rubin Mark A. , Piscuoglio Salvatore
Published: April 2023

Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.

Significance:

DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases
Authors: Wood Colin S. , Pennel Kathryn A.F. , Leslie Holly , Legrini Assya , Cameron Andrew J. , Melissourgou-Syka Lydia , Quinn Jean A. , van Wyk Hester C. , Hay Jennifer , Roseweir Antonia K. , Nixon Colin , Roxburgh Campbell S.D. , McMillan Donald C. , Biankin Andrew V. , Sansom Owen J. , Horgan Paul G. , Edwards Joanne , Steele Colin W. , Jamieson Nigel B.
Published: April 2023

Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFβ signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype.

Significance:

Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.
A New Frontier for Cancer Genetics: Identification of Germline–Somatic Associations
Authors: Kar Siddhartha P.
Published: April 2023

Studies of the inherited or germline genome have identified rare mutations with large effects and common polymorphisms of more modest effect sizes that are associated with cancer risk. This research has substantially illuminated the etiology and development of cancer, with particular relevance to cancer prevention. In parallel, studies of the somatic or tumor genome have been instrumental in identifying the key drivers of cancer progression, significantly informing modern cancer therapy. While these studies have thus far largely been performed separately, integrative studies where the germline and somatic genomes are mapped in the same individuals have the potential to yield novel and holistic insights into cancer biology. In this issue of Cancer Research, Liu and colleagues report the results of integrative germline–somatic analyses in over 12,000 patients with cancer and 11 cancer types, identifying several associations where inherited variants that regulate the expression of a nearby gene in normal tissues are associated with tumor mutations in the same gene or with genome-wide somatic traits such as the tumor mutational burden. Although considerable follow-up work is required, the study is an important contribution to an emerging body of evidence that is demonstrating that the germline has a vital role in shaping the tumor genome.

See related article by Liu et al., p. 1191
Fueling the Tumor Microenvironment with Cancer-Associated Adipocytes
Authors: Bouche Caroline , Quail Daniela F.
Published: April 2023

Despite their abundance throughout the body, adipocytes are often ignored for their contributions within the tumor microenvironment (TME). However, their role in fueling cancer is becoming increasingly apparent as interest in the TME has seen remarkable advances in recent years. A seminal study by Dirat and colleagues highlighted the essential impact of the peritumoral adipose tissue in breast cancer progression and was among the first to demonstrate that tumor cells can reprogram adipocytes within their immediate niche to adopt unique characteristics. These “cancer-associated adipocytes” (CAA) were found to exchange cytokines and lipids with tumor cells, leading to their metabolic rewiring and acquisition of proinflammatory and invasive phenotypes. These important discoveries have represented a breakthrough in understanding the bidirectional metabolic dialog between adipocytes and tumor cells, and have contributed renewed perspectives on the functional contributions of adipocytes within the TME. Moreover, the effects of CAA may be further amplified in the setting of obesity as lipids dramatically accumulate, providing insights into the link between breast cancer and its more advanced clinical state in obese conditions. Thus, the different molecular actors involved in the dialog between tumor cells and CAA represent promising therapeutic targets that may have particular relevance in improving prognosis in obese patients with cancer.

See related article by Dirat and colleagues, Cancer Res 2011;71:2455–65.
Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma
Authors: Thiesler Hauke , Gretenkort Lina , Hoffmeister Leonie , Albers Iris , Ohlmeier Luisa , Röckle Iris , Verhagen Andrea , Banan Rouzbeh , Köpcke Nora , Krönke Nicole , Feuerhake Friedrich , Behling Felix , Barrantes-Freer Alonso , Mielke Dorothee , Rohde Veit , Hong Bujung , Varki Ajit , Schwabe Kerstin , Krauss Joachim K. , Stadelmann Christine , Hartmann Christian , Hildebrandt Herbert
Published: April 2023

Purpose:

Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell–associated polySia on glioblastoma outcome.

Experimental Design:

Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16–positive or Siglec-16–negative macrophages, and by exposing Siglec-16–positive or Siglec-16–negative macrophages to glioblastoma cell–derived membrane fractions.

Results:

Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16–expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell–derived membranes.

Conclusions:

Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.
TIL Therapy: Facts and Hopes
Authors: Monberg Tine J. , Borch Troels H. , Svane Inge M. , Donia Marco
Published: April 2023

After a positive phase III trial, it is evident that treatment with tumor-infiltrating lymphocytes (TIL) is a safe, feasible, and effective treatment modality for patients with metastatic melanoma. Further, the treatment is safe and feasible in diverse solid tumors, regardless of the histologic type. Still, TIL treatment has not obtained the regulatory approvals to be implemented on a larger scale. Therefore, its availability is currently restricted to a few centers worldwide. In this review, we present the current knowledge of TIL therapy and discuss the practical, logistic, and economic challenges associated with implementing TIL therapy on a larger scale. Finally, we suggest strategies to facilitate the widespread implementation of TIL therapy and approaches to develop the next generation of TILs.
Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238
Authors: Larkin James , Del Vecchio Michele , Mandalá Mario , Gogas Helen , Arance Fernandez Ana M. , Dalle Stéphane , Cowey Charles Lance , Schenker Michael , Grob Jean-Jacques , Chiarion-Sileni Vanna , Marquez-Rodas Ivan , Butler Marcus O. , Di Giacomo Anna Maria , Middleton Mark R. , Lutzky Jose , de la Cruz-Merino Luis , Arenberger Petr , Atkinson Victoria , Hill Andrew G. , Fecher Leslie A. , Millward Michael , Nathan Paul D. , Khushalani Nikhil I. , Queirolo Paola , Ritchings Corey , Lobo Maurice , Askelson Margarita , Tang Hao , Dolfi Sonia , Ascierto Paolo A. , Weber Jeffrey
Published: April 2023

Purpose:

In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB–C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings.

Patients and Methods:

Patients with resected stage IIIB–C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS.

Results:

At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60–0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value.

Conclusions:

Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome.

See related commentary by Augustin and Luke, p. 3253