bluuebunny/crossref_metadata_2025 huggingface dataset:
Ensemble reservoir computing for dynamical systems: prediction of phase-space stable region for hadron storage rings
Authors: Casanova Maxime , Dalena Barbara , Bonaventura Luca , Giovannozzi Massimo
Published: June 2023

We investigate the ability of an ensemble reservoir computing approach to predict the long-term behaviour of the phase-space region in which the motion of charged particles in hadron storage rings is bounded, the so-called dynamic aperture. Currently, the calculation of the phase-space stability region of hadron storage rings is performed through direct computer simulations, which are resource- and time-intensive processes. Echo State Networks (ESN) are a class of recurrent neural networks that are computationally effective, since they avoid backpropagation and require only cross-validation. Furthermore, they have been proven to be universal approximants of dynamical systems. In this paper, we present the performance reached by ESN based on an ensemble approach for the prediction of the phase-space stability region and compare it with analytical scaling laws based on the stability-time estimate of the Nekhoroshev theorem for Hamiltonian systems. We observe that the proposed ESN approach is capable of effectively predicting the time evolution of the extent of the dynamic aperture, improving the predictions by analytical scaling laws, thus providing an efficient surrogate model.
Deep Learning for Zero-day Malware Detection and Classification: A Survey
Authors: Deldar Fatemeh , Abadi Mahdi
Published: June 2023

Zero-day malware is malware that has never been seen before or is so new that no anti-malware software can catch it. This novelty and the lack of existing mitigation strategies make zero-day malware challenging to detect and defend against. In recent years, deep learning has become the dominant and leading branch of machine learning in various research fields, including malware detection. Considering the significant threat of zero-day malware to cybersecurity and business continuity, it is necessary to identify deep learning techniques that can somehow be effective in detecting or classifying such malware. But so far, such a comprehensive review has not been conducted. In this article, we study deep learning techniques in terms of their ability to detect or classify zero-day malware. Based on our findings, we propose a taxonomy and divide different zero-day resistant, deep malware detection and classification techniques into four main categories: unsupervised, semi-supervised, few-shot, and adversarial resistant. We compare the techniques in each category in terms of various factors, including deep learning architecture, feature encoding, platform, detection or classification functionality, and whether the authors have performed a zero-day evaluation. We also provide a summary view of the reviewed papers and discuss their main characteristics and challenges.
Electrochemical CO2 Reduction on Au Cluster-based Electrodes: Investigating the Role of Nafion Ionomer
Authors: Sharma Shailendra Kumar , Johannessen Bernt , Golovko Vladimir B. , Marshall Aaron T.
Published: June 2023

The performance of electrocatalytic CO2 reduction (CO2RR) depends not only on the catalytic material but also on the neighbouring chemical environment around the active sites. The surrounding local environment can perturb the electronic properties of active sites and alter the adsorption/desorption behaviour of reactant/intermediate/product, thus changing CO2RR characteristics. Herein, we studied electrochemical reduction of CO2 onto supported atomically precise [Au9(PPh3)8](NO3)3 clusters and observed an unusual increase in catalytic activity over time. Additionally, electrochemical activation of the electrodes by applying a more negative potential was found to improve activity of the electrode. Investigations using UV–vis and X-ray absorption spectroscopy revealed that these observations may be attributed to the interaction of the Nafion ionomer with the catalytic Au9 clusters. These interactions may cause partial blocking of the Au9 active sites, and the prolonged application of negative potentials leads to favourable interface reconstructions. In addition, a method was developed to minimise the interaction between the Au9 clusters and Nafion ionomer by first depositing a layer of carbon black followed by dropcasting the active catalyst. Our study highlights that polymeric binders modulate the electronic properties of the electrocatalysts, which can change the product distribution during CO2 electrolysis.
Reports from the Frontier: Electrifying Chemical Transformations and Separations to Valorize Wastewater Nitrogen
Authors: Liu Matthew , Tarpeh William
Published: June 2023

Ammonia is an essential compound to modern society, underpinning fertilizer production and chemical manufacturing. Global ammonia demand currently exceeds 150 million tons a year and is projected to increase over 2% annually. Over 96% of ammonia is currently generated through the Haber-Bosch (HB) process, in which steam-reformed hydrogen reacts with nitrogen under reaction conditions that consume 1–2% of global energy and contribute 1.2–1.4% of anthropogenic CO2 emissions every year. In an environmental context, ammonia is a form of reactive nitrogen. Large amounts of reactive nitrogen, such as HB ammonia, accumulate in the biosphere because 80% of wastewater globally is discharged without treatment. The resulting skew in the global nitrogen cycle leads to imbalanced ecosystems and threatens water quality. Conventional water treatment removes reactive nitrogen by converting it to N2 (biological nitrification–denitrification); at HB facilities, the N2 is then cycled back to produce ammonia. Directly valorizing reactive nitrogen in waste streams would shortcut the use of N2 as an intermediate in water remediation and ammonia production, allowing savings in energy, emissions, and costs. Indeed, treating nitrogen as a resource to recover rather than simply a pollutant to remove aligns with the US National Academy of Engineering’s call to manage the nitrogen cycle, a challenge central to chemical manufacturing and ecosystem protection.
Quantum Efficiency Measurement of Single-Particle Phosphor by Proximity Method
Authors: Takahashi Kohsei , Todoroki Shin-ichi , Takeda Takashi , Hirosaki Naoto
Published: June 2023

In this study, a technique for measuring the quantum efficiency of single-particle phosphors was developed. For this purpose, a proximity measurement technique capable of measuring the photoluminescence of a single particle with a high signal-to-noise ratio was adopted. Single optical fibers were combined with a commercially available spectrofluorometer to directly measure the light distribution near the phosphor. The number of photons absorbed by the phosphor can be evaluated by focusing the Xe light down to 18 μm, which is equivalent to the particle diameter. By eliminating the optical parts as much as possible and performing spectral sensitivity calibration over a wide wavelength range, an internal quantum efficiency evaluation similar to a powder measurement was established.
Electrochemical Energy Storage Properties of Sm2FeCuO6 Double Perovskite Synthesized via Sol-Gel Route
Authors: Devi Manju , Rogge Irina , Singh Jashandeep , Sharma Amit L. , Kumar Ashavani , Kumar Ashok
Published: June 2023

The rare Earth-based double perovskites have been widely studied due to their exceptional physical properties and wide range of technological applications. Despite the extensive investigation of copper-based rare Earth double perovskites and a limited study of samarium-based double perovskites, no reports on the synthesis and characterization of Sm2FeCuO6 have been found in the literature. This work presents the experimental investigation on the synthesis of Sm2FeCuO6 via a wet chemical sol-gel route and the characterization of its structural and electrochemical properties using various techniques. The results showed that Sm2FeCuO6 have good electrochemical properties, making it a promising candidate for use in electrochemical energy storage applications.
The Impact of Silicon Dioxide Nanoparticle Size on the Viscosity and Stability of Nanofluids: A Comprehensive Study
Authors: Payzullaev A. N. , Allaev B. A. , Mirzaev S. Z. , Abdiev J. M. , Urinov J. , Parkash A.
Published: June 2023

This study investigated the impact of silicon dioxide nanoparticle size on the viscosity and stability of nanofluids. A comprehensive study was conducted, including the synthesis and characterization of silicon dioxide nanoparticles of varying sizes, as well as the preparation and testing of nanofluids with different nanoparticle concentrations. The results show that nanoparticle size has a significant effect on both the viscosity and stability of nanofluids, with smaller nanoparticles leading to higher viscosity and improved stability. Silicon dioxide nanoparticles were dispersed in deionized water at mass fractions of 0.5% and 3% and average particle diameters of 12 nm and 40 nm using an ultrasonic disperser. The rheological properties of the obtained nanofluids at 304 K were studied depending on the mass concentration and linear size of nanoparticles in the liquid. An analysis of the results showed that the viscosity of the nanofluids increased with decreasing linear size of the nanoparticles. These findings have important implications for the development and optimization of nanofluid-based applications in various industries, such as electronics, energy, and biomedical engineering.
Extensively Invasive Gallbladder Cancer from Intracholecystic Papillary Neoplasm Treated with Pylorus-Preserving Pancreaticoduodenectomy and Extended Cholecystectomy: A Case Report and Literature Review
Authors: Kumagai Hideki , Umemura Akira , Nitta Hiroyuki , Katagiri Hirokatsu , Nishiya Masao , Uesugi Noriyuki , Sugai Tamotsu , Sasaki Akira
Published: June 2023

Background. Intracholecystic papillary neoplasm (ICPN) is a rare tumor first classified by the World Health Organization in 2010. ICPN is a counterpart of the intraductal papillary mucinous neoplasm of the pancreas and intraductal papillary neoplasm of the bile duct. Previous reports on ICPN are limited; thus, the diagnosis, surgical intervention, and prognosis are controversial. Here, we report an extensively invasive gallbladder cancer arising in ICPN treated with pylorus-preserving pancreaticoduodenectomy (PPPD) and extended cholecystectomy. Case Presentation. A 75-year-old man presented to another hospital with jaundice for 1 month. Laboratory findings showed elevated total bilirubin, 10.6 mg/dL and carbohydrate antigen 19-9, 54.8 U/mL. Computed tomography showed a well-enhanced tumor located in the distal bile duct and dilated hepatic bile duct. The gallbladder wall was thickened and homogeneously enhanced. Endoscopic retrograde cholangiopancreatography revealed a filling defect in the distal common bile duct, and intraductal ultrasonography showed a papillary tumor in the common bile duct, indicating tumor invasion of the bile duct subserosa. Subsequent bile duct brush cytology revealed adenocarcinoma. The patient was referred to our hospital for surgical treatment and underwent an open PPPD. Intraoperative findings showed a thickened and indurated gallbladder wall, suggesting concurrent gallbladder cancer; thus, the patient subsequently underwent PPPD and extended cholecystectomy. Histopathological findings confirmed gallbladder carcinoma originating from ICPN, which extensively invaded the liver, common bile duct, and pancreas. The patient started adjuvant chemotherapy (tegafur/gimeracil/oteracil) 1 month after surgery and had no recurrence at follow-up after 1 year. Conclusions. Accurate preoperative diagnosis of ICPN, including the extent of tumor invasion is challenging. To ensure complete curability, the development of an optimal surgical strategy considering preoperative examinations and intraoperative findings is essential.
Adsorption of Cu(II) and Zn(II) onto Activated Carbon from Oil Palm Empty Fruit Bunch Prepared by Two-Step Acid Treatment and Microwave-Assisted Pyrolysis
Authors: Somsiripan Thotsaporn , Sangwichien Chayanoot , Tohdee Kanogwan , Semmad Surat
Published: June 2023

This study explores the feasibility of biochar-based activated carbon derived from oil palm empty fruit bunch (EFB) as a potential precursor for the preparation of activated carbon via 2-step H3PO4 activation under microwave-assisted pyrolysis (2ACEFB). The characterization of EFB and 2ACEFB was observed by FTIR and BET, and chemical composition was determined using proximate and elemental analysis data. The adsorptive removal of Cu(II) and Zn(II) from an aqueous solution was studied, and the effects of metal concentration and solution pH were also investigated. The pseudo-second-order equation was properly described, providing the best fit to the observed experimental data. The adsorption capacities of Cu(II) and Zn(II) onto the EFB were 20.28 and 18.06 mg/g, respectively, and improved by 2.04- and 1.89-fold onto the 2ACEFB. The potential of 2ACEFB was also proved by adsorbent reusability with five consecutive circles of the batch experiment without regeneration or treatment. This study demonstrated that 2ACEFB is an efficient adsorbent for eliminating heavy metals from aqueous solutions.
Asymptotic Expansions for Large Degree Tangent and Apostol-Tangent Polynomials of Complex Order
Authors: Corcino Cristina B. , Corcino Roberto B. , Casquejo Jeremar
Published: June 2023

This paper provides asymptotic expansions for large values of

n

of tangent

T

n

μ

z

and Apostol-tangent

T

n

μ

z
;
λ

polynomials of complex order. The derivation is done using contour integration with the contour avoiding branch cuts.
Supplementary Table 1 from N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer
Authors: Zhang Haisheng , Zhou Jiawang , Li Jiexin , Wang Zhaotong , Chen Zhuojia , Lv Ziyan , Ge Lichen , Xie Guoyou , Deng Guoming , Rui Yalan , Huang Hongbing , Chen Likun , Wang Hongsheng
Published: June 2023

Table S1
Supplementary Data from N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer
Authors: Zhang Haisheng , Zhou Jiawang , Li Jiexin , Wang Zhaotong , Chen Zhuojia , Lv Ziyan , Ge Lichen , Xie Guoyou , Deng Guoming , Rui Yalan , Huang Hongbing , Chen Likun , Wang Hongsheng
Published: June 2023

The detailed procedures of methods and eight figures are attached in supplementary.
Table S4 from Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

GO analysis of genes up-regulated in the Simvastatin plus mevalonate group vs. the simvastatin group.
Table S3 from Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

GO analysis of genes down-regulated by simvastatin
Supplementary Table S2 from Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

Simvastatin responsive genes
Supplementary Data from TGFβ Antagonizes IFNγ-Mediated Adaptive Immune Evasion via Activation of the AKT–Smad3–SHP1 Axis in Lung Adenocarcinoma
Authors: Ye Fan , Cai Zihao , Wang Boyu , Zeng Chenxi , Xi Yu , Hu Shaojie , Qu Rirong , Yuan Zhiwei , Yue Jiaqi , Tian Yitao , Wang Xue , Fu Xiangning , Li Lequn
Published: June 2023

Table S2
Supplementary Table S1 from Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

qRT-PCR primers
Supplementary Data from Genetic Modulation of BET1L Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification
Authors: Li Shuwei , Du Mulong , Xu Kaili , Ben Shuai , Zhu Tianru , Guo Mengfan , Xin Junyi , Zhu Lingjun , Gu Dongying , Zhang Zhengdong , Wang Meilin
Published: June 2023

Supplementary Figures 1-13
Supplementary Data from Attenuation of Sialylation Augments Antitumor Immunity and Improves Response to Immunotherapy in Ovarian Cancer
Authors: Cao Kankan , Zhang Guodong , Yang Moran , Wang Yiying , He Mengdi , Zhang Chen , Huang Yan , Lu Jiaqi , Liu Haiou
Published: June 2023

Supplementary Tables S1 to S9 for multiple supplementary tables
Supplementary Table 5_Marker genes all and some per cluster no cell cycle_GO and curated pathways per cluster no cell cycle from A Rare Subset of Primary Tumor Cells with Concomitant Hyperactivation of Extracellular Matrix Remodeling and dsRNA-IFN1 Signaling Metastasizes in Breast Cancer
Authors: Roda Niccolò , Cossa Andrea , Hillje Roman , Tirelli Andrea , Ruscitto Federica , Cheloni Stefano , Priami Chiara , Dalmasso Alberto , Gambino Valentina , Blandano Giada , Polazzi Andrea , Falvo Paolo , Gatti Elena , Mazzarella Luca , Luzi Lucilla , Migliaccio Enrica , Pelicci Pier Giuseppe
Published: June 2023

Supplementary Table including Marker genes (ALL and SOME settings) per cluster upon cell cycle regression, and GO and curated pathways per cluster upon cell cycle regression
Data from Metabolic reprogramming driven by IGF2BP3 promotes acquired resistance to EGFR inhibitors in non-small cell lung cancer
Authors: Lin Ziyou , Li Jingwei , Zhang Jian , Feng Weineng , Lu Jiaye , Ma Xiaofan , Ding Wen , Ouyang Shumin , Lu Jin-Jian , Yue Peibin , Wan Guohui , Liu Peiqing , Zhang Xiaolei
Published: June 2023

Abstract
Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by IGF2BP3-dependent crosstalk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. IGF2BP3 was upregulated in TKI-resistant non-small cell lung cancer patients, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3’-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3-COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.
Data from Caffeine supplementation and FOXM1 inhibition enhance the antitumor effect of statins in neuroblastoma
Authors: Tran Gia-Buu , Ding Jane , Ye Bingwei , Liu Mengling , Yu Yajie , Zha Yunhong , Dong Zheng , Liu Kebin , Sudarshan Sunil , Ding Han-Fei
Published: June 2023

Abstract
High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and non-sterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and non-sterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins with implications for treatment of high-risk neuroblastoma
Data from Genetic Modulation of BET1L Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification
Authors: Li Shuwei , Du Mulong , Xu Kaili , Ben Shuai , Zhu Tianru , Guo Mengfan , Xin Junyi , Zhu Lingjun , Gu Dongying , Zhang Zhengdong , Wang Meilin
Published: June 2023

Abstract
Genetic variants in regions encoding 3′ untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single-nucleotide polymorphism rs11245997 in the BET1L 3′UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140–3p binding. It also reduced BET1L m6A modification, which upregulated BET1L expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140–3p overexpression. RNA sequencing and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1, and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer.
Significance:
The integration of miRNA expression profiles and genetic variants identified rs11245997 as a colorectal cancer risk-related variant that reduces miR-140–3p binding and m6A modification, leading to BET1L upregulation to promote colorectal tumorigenesis.
Data from A Rare Subset of Primary Tumor Cells with Concomitant Hyperactivation of Extracellular Matrix Remodeling and dsRNA-IFN1 Signaling Metastasizes in Breast Cancer
Authors: Roda Niccolò , Cossa Andrea , Hillje Roman , Tirelli Andrea , Ruscitto Federica , Cheloni Stefano , Priami Chiara , Dalmasso Alberto , Gambino Valentina , Blandano Giada , Polazzi Andrea , Falvo Paolo , Gatti Elena , Mazzarella Luca , Luzi Lucilla , Migliaccio Enrica , Pelicci Pier Giuseppe
Published: June 2023

Abstract
Metastatic breast cancer has a poor prognosis and is largely considered incurable. A better understanding of the molecular determinants of breast cancer metastasis could facilitate development of improved prevention and treatment strategies. We used lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during breast cancer metastasis and showed that metastases derive from rare prometastatic clones that are underrepresented in primary tumors. Both low clonal fitness and high metastatic potential were independent of clonal origin. Differential expression and classification analyses revealed that the prometastatic phenotype was acquired by rare cells characterized by the concomitant hyperactivation of extracellular matrix remodeling and dsRNA-IFN signaling pathways. Notably, genetic silencing of key genes in these pathways (KCNQ1OT1 or IFI6, respectively) significantly impaired migration in vitro and metastasis in vivo, with marginal effects on cell proliferation and tumor growth. Gene expression signatures derived from the identified prometastatic genes predict metastatic progression in patients with breast cancer, independently of known prognostic factors. This study elucidates previously unknown mechanisms of breast cancer metastasis and provides prognostic predictors and therapeutic targets for metastasis prevention.
Significance:
Transcriptional lineage tracing coupled with single-cell transcriptomics defined the transcriptional programs underlying metastatic progression in breast cancer, identifying prognostic signatures and prevention strategies.
ESRRB Inhibits the TGFβ Signaling Pathway to Drive Cell Proliferation in Cervical Cancer
Authors: Li Qin-Shu , Zheng Peng-Sheng
Published: June 2023

Estrogen-related receptor β (ESRRB) is a member of the orphan nuclear receptor family and mediates stem cell self-renewal and early embryonic development. Previous studies have also reported that ESRRB plays a role in the development and progression of breast cancer and prostate cancer. In this study, we observed that ESRRB was highly expressed in cervical cancer and was associated with disease progression. Knocking out ESRRB using CRISPR/Cas9 gene editing in cervical cancer cells induced cell-cycle arrest at the transition from the G0–G1 phase to the S phase, resulting in inhibition of cell proliferation in vitro and reduced tumor growth in vivo. Conversely, ectopic expression of ESRRB significantly promoted the proliferation of cervical cancer cells. ESRRB activated transcription of SMAD7, a TGFβ pathway inhibitor, which blocked phosphorylation and nuclear translocation of SMAD2/3 to the nucleus, thereby downregulating CDKN1A and upregulating CCNA2 and MYC. In turn, MYC transactivated ESRRB and upregulated SMAD7, thus forming a positive feedback loop with ESRRB. Together, these findings identify the tumor-promoting function of ESRRB in cervical cancer and reveal a mechanism by which ESRRB stimulates cell proliferation to promote cancer progression.

Significance:

The ESRRB/SMAD7/MYC-positive feedback loop inhibits TGFβ signaling to activate cell-cycle progression and promote proliferation in cervical cancer, thereby driving tumor growth.
Cross-talk between Myeloid and B Cells Shapes the Distinct Microenvironments of Primary and Secondary Liver Cancer
Authors: Chen Zhihang , Zhang Guopei , Ren Xiaoxue , Yao Zhijia , Zhou Qian , Ren Xuxin , Chen Shuling , Xu Lixia , Sun Kaiyu , Zeng Qianwen , Kuang Ming , Kuang Dong-Ming , Peng Sui
Published: June 2023

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC, whereas IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3–CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10–CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.

Significance:

The immunomodulatory patterns of tumor-infiltrating B cells are distinct in primary and secondary liver cancer, with plasma cells mediating important physiologic processes that drive cancer progression.
Preexisting Immunity Drives the Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma
Authors: Arbore Giuseppina , Albarello Luca , Bucci Gabriele , Punta Marco , Cossu Andrea , Fanti Lorella , Maurizio Aurora , Di Mauro Francesco , Bilello Vito , Arrigoni Gianluigi , Bonfiglio Silvia , Biancolini Donatella , Puccetti Francesco , Elmore Ugo , Vago Luca , Cascinu Stefano , Tonon Giovanni , Rosati Riccardo , Casorati Giulia , Dellabona Paolo
Published: June 2023

Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathologic complete response to nCT, which correlates with increased 5-year survival compared with nonresponders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multidimensional profiling of pretreatment tumor biopsies and blood from 68 patients with EAC (34 prospectively and 34 retrospectively collected), comparing complete responders versus nonresponders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative antitumor tissue-resident memory CD39+ CD103+ CD8+ T cells, and reduced immunosuppressive T regulatory cells (Treg) and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+ CD11c+ HLA-DRhigh cells, and reduced programmed cell death ligand 1–positive (PD-L1+) monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (proinflammatory) and low IL4, CXCL10, C3a, and C5a (suppressive). Plasma proinflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+ CD103+ CD8+ T cells. These results suggest that preexisting immunity in baseline tumor drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens.

Significance:

Multidimensional profiling of pretreatment esophageal adenocarcinoma shows patient response to nCT is correlated with active preexisting immunity and indicates molecular pathways of resistance that may be targeted to improve clinical outcomes.
Sources of Disparities in Surveillance Mammography Performance and Risk-Guided Recommendations for Supplemental Breast Imaging: A Simulation Study
Authors: Hubbard Rebecca A. , Pujol Toyya A. , Alhajjar Elie , Edoh Kossi , Martin Melissa L.
Published: June 2023

Background:

Surveillance mammography is recommended for all women with a history of breast cancer. Risk-guided surveillance incorporating advanced imaging modalities based on individual risk of a second cancer could improve cancer detection. However, personalized surveillance may also amplify disparities.

Methods:

In simulated populations using inputs from the Breast Cancer Surveillance Consortium (BCSC), we investigated race- and ethnicity-based disparities. Disparities were decomposed into those due to primary breast cancer and treatment characteristics, social determinants of health (SDOH) and differential error in second cancer ascertainment by modeling populations with or without variation across race and ethnicity in the distribution of these characteristics. We estimated effects of disparities on mammography performance and supplemental imaging recommendations stratified by race and ethnicity.

Results:

In simulated cohorts based on 65,446 BCSC surveillance mammograms, when only cancer characteristics varied by race and ethnicity, mammograms for Black women had lower sensitivity compared with the overall population (64.1% vs. 71.1%). Differences between Black women and the overall population were larger when both cancer characteristics and SDOH varied by race and ethnicity (53.8% vs. 71.1%). Basing supplemental imaging recommendations on high predicted second cancer risk resulted in less frequent recommendations for Hispanic (6.7%) and Asian/Pacific Islander women (6.4%) compared with the overall population (10.0%).

Conclusions:

Variation in cancer characteristics and SDOH led to disparities in surveillance mammography performance and recommendations for supplemental imaging.

Impact:

Risk-guided surveillance imaging may exacerbate disparities. Decision-makers should consider implications for equity in cancer outcomes resulting from implementing risk-guided screening programs.

See related In the Spotlight, p. 1479
Data from Cost-Effectiveness of p16/Ki-67 Dual-Stained Cytology Reflex Following Co-Testing with hrHPV Genotyping for Cervical Cancer Screening
Authors: Harper Diane M. , Anderson Rye J. , Baker Ed , Yu Tiffany M.
Published: June 2023

Abstract
The first biomarker-based cervical cancer screening test, p16/Ki-67 dual-stained cytology (DS), has been clinically validated and approved in the United States for triage of women being screened for cervical cancer who test positive for high-risk human papillomavirus (hrHPV). The primary aim of this work is to evaluate the cost-effectiveness of DS triage after co-testing findings of positive non-16/18 HPV types and atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) cytology. A payer-perspective Markov microsimulation model was developed to assess the impact of DS reflex testing. Each comparison simulated 12,250 screening-eligible women through health states defined by hrHPV status and genotype, cervical intraepithelial neoplasia (CIN) grades 1-3, invasive cervical cancer (ICC) by stage, and cancer-related or non-cancer death. Screening test performance data were from the IMPACT clinical validation trial. Transition probabilities were from population and natural history studies. Costs of baseline medical care, screening visits, tests, procedures, and ICC were included. DS reflex after co-testing was cost-effective with incremental cost-effectiveness ratios (ICER) per quality-adjusted-life-year (QALY) gained of $15,231 (95% CI $10,717-$25,400) compared to co-testing with hrHPV pooled primary and genotyped reflex testing, and $23,487 (95% CI $15,745-$46,175) compared to co-testing with hrHPV genotyping with no reflex test. Screening and medical costs and life-years increased, while ICC costs and risk of ICC death decreased. Incorporating DS reflex into co-testing cervical cancer screening algorithms is projected to be cost-effective.
Data from Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer
Authors: Wan Ledong , Lin Kuang-Ting , Rahman Mohammad Alinoor. , Ishigami Yuma , Wang Zhikai , Jensen Mads A. , Wilkinson John E. , Park Youngkyu , Tuveson David A. , Krainer Adrian R.
Published: June 2023

Abstract
Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling—partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas, and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas-cell homeostasis. This negative-feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target.
Data from Feasibility and Safety of Personalized, Multi-Target, Adoptive Cell Therapy (IMA101): First-in-Human Clinical Trial in Patients with Advanced Metastatic Cancer
Authors: Tsimberidou Apostolia M. , Guenther Kerstin , Andersson Borje S. , Mendrzyk Regina , Alpert Amir , Wagner Claudia , Nowak Anna , Aslan Katrin , Satelli Arun , Richter Fabian , Kuttruff-Coqui Sabrina , Schoor Oliver , Fritsche Jens , Coughlin Zoe , Mohamed Ali S. , Sieger Kerry , Norris Becky , Ort Rita , Beck Jennifer , Vo Henry Hiep , Hoffgaard Franziska , Ruh Manuel , Backert Linus , Wistuba Ignacio I. , Fuhrmann David , Ibrahim Nuhad K. , Morris Van Karlyle , Kee Bryan K. , Halperin Daniel M. , Nogueras-Gonzalez Graciela M. , Kebriaei Partow , Shpall Elizabeth J. , Vining David , Hwu Patrick , Singh Harpreet , Reinhardt Carsten , Britten Cedrik M. , Hilf Norbert , Weinschenk Toni , Maurer Dominik , Walter Steffen
Published: June 2023

Abstract
IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 predefined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose IL2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n = 6; Grade 2, n = 4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in posttreatment tumor tissue. Individual T-cell receptors (TCR) contained in T-cell products exhibited broad variation in TCR avidity, with the majority being low avidity. High-avidity TCRs were identified in some patients’ products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs.

See related Spotlight by Uslu and June, p. 865
Data from Circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma
Authors: Saliby Renee Maria , El Zarif Talal , Bakouny Ziad , Shah Valisha , Xie Wanling , Flippot Ronan , Denize Thomas , Kane M. Harry , Madsen Katrine N. , Ficial Miriam , Hirsch Laure , Wei Xiao X. , Steinarter John A. , Harshman Lauren C. , Vaishampayan Ulka N. , Severgnini Mariano , McDermott David F. , Lee Gwo-Shu Mary. , Xu Wenxin , Van Allen Eliezer M. , McGregor Bradley A. , Signoretti Sabina , Choueiri Toni K. , McKay Rana R. , Braun David A.
Published: June 2023

Abstract
Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an “inflammatory module” that was increased in International Metastatic RCC Database Consortium (IMDC)-poor risk patients and was associated with worse progression-free survival (PFS) (p=0.028). At baseline, an elevated circulating VEGF-A level was associated with a lack of response (p=0.03) and worse PFS (p=0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (p=0.01) and improved overall survival (p=0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (p=0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.
Supplemental Table 2 from Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L , Fonseca Jairo A , Zhou Chengjing , Evans Alysa N , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M , Rafiq Sarwish , Langermann Solomon , Liu Linda N , Henry Curtis J , Porter Christopher C
Published: June 2023

All antibodies used for flow cytometry analysis.
Supplemental Figure 5 from Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L , Fonseca Jairo A , Zhou Chengjing , Evans Alysa N , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M , Rafiq Sarwish , Langermann Solomon , Liu Linda N , Henry Curtis J , Porter Christopher C
Published: June 2023

Flow cytometry gating schemes.
Supplemental Figure 2 from Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L , Fonseca Jairo A , Zhou Chengjing , Evans Alysa N , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M , Rafiq Sarwish , Langermann Solomon , Liu Linda N , Henry Curtis J , Porter Christopher C
Published: June 2023

Sig15 is regulated by NF-κB activation in B-ALL.
Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L. , Fonseca Jairo A. , Zhou Chengjing , Evans Alyssa N. , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M. , Rafiq Sarwish , Langermann Solomon , Liu Linda N. , Henry Curtis J. , Porter Christopher C.
Published: June 2023

Siglec-15 (Sig15) has been implicated as an immune checkpoint expressed in solid tumor-infiltrating macrophages and is being targeted in clinical trials with mAbs to normalize the tumor immune microenvironment and stimulate antitumor immunity. However, the role of Sig15 in hematologic malignancies remains undefined. Sig15 mRNA and protein expression levels in hematologic malignancies were determined from publicly available databases, cell lines, and primary patient samples. Human B-cell acute lymphoblastic leukemia (B-ALL) cell lines were used to identify signaling pathways involved in the regulation of Sig15 expression. Secreted/soluble Sig15 and cytokine levels were measured from the plasma of children with leukemia and healthy controls. Knockdown and knockout of Siglec15 in a murine model of B-ALL was used to evaluate the effect of leukemia-derived Sig15 on the immune response to leukemia. We observed pathologic overexpression of Sig15 in a variety of hematologic malignancies, including primary B-ALL samples. This overexpression was driven by NFκB activation, which also increased the surface localization of Sig15. Secreted/soluble Sig15 was found to circulate at elevated levels in the plasma of children with B-ALL and correlated with an immune-suppressive cytokine milieu. Genetic inhibition of Sig15 in murine B-ALL promoted clearance of the leukemia by the immune system and a marked reversal of the immune-privileged leukemia bone marrow niche, including expanded early effector CD8+ T cells and reduction of immunosuppressive cytokines. Thus, Sig15 is a novel, potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate T lymphocytes against leukemia cells.

Significance:

We demonstrate that Sig15 is overexpressed in hematologic malignancies driven by NFκB, is required for immune evasion in a mouse model of leukemia, and, for the first time, that it circulates at high levels in the plasma of children with leukemia.