bluuebunny/crossref_metadata_2025 huggingface dataset:
The ExaNeSt Prototype: Evaluation of Efficient HPC Communication Hardware in an ARM-based Multi-FPGA Rack
Authors: Ploumidis Manolis , Chaix Fabien , Chrysos Nikolaos , Assiminakis Marios , Kallimanis Nikolaos , Kossifidis Nikolaos , Nikoloudakis Mickael , Dimou Nikolaos , Gianioudis Michalis , Ieronymakis George , Ioannou Aggelos , Kalokerinos George , Xirouchakis Pantelis , Damianakis Astrinos , Ligerakis Mickael , Vavouris Theocharis , Katevenis Manolis , Papaefstathiou Vassilis , Marazakis Manolis , Mavroidis Iakovos
Published: February 2025

We present and evaluate the ExaNeSt Prototype, which compactly packages 128 Xilinx ZU9EG MPSoCs, 2 TBytes of DRAM, and 8 TBytes of SSD into a liquid-cooled rack, using a custom interconnection hardware based on 10 Gbps links. We developed this testbed in 2016-2019 in order to leverage the flexibility of FPGAs for experimenting with efficient hardware support for HPC communication among tens of thousands of processors and accelerators in the quest towards Exascale systems and beyond. In the years since then, we carefully studied this system, and we present our key design choices and insights resulting from our measurement and analysis.

We developed this testbed, from architecture to the PCBs and the runtime software, within the ExaNeSt project. It is fully operational in configurations with up to 8x4x4 MPSoC nodes. It achieves high density through tight board design, while also leveraging state-of-the-art liquid cooling technology. In this paper, we present a thorough architectural analysis, along with important aspects of our infrastructure development. Our custom interconnect includes a low-cost low-latency network interface, offering user-level, zero-copy RDMA, which we coupled with the ARMv8 processors in the MPSoCs. We further developed the corresponding runtimes that allow us to test real MPI applications on the large-scale testbed.

We evaluated our platform through MPI microbenchmarks, mini, and full MPI applications. Single hop, one way latency is

\(1.3\)

 

\(\mu\)

s; approximately

\(0.47\)

 

\(\mu\)

s out of these are attributed to network interface and the user-space library that exposes its functionality to the runtime. Latency over longer paths increases as expected, reaching

\(2.55\)

 

\(\mu\)

s for a five-hop path. Bandwidth tests show that, for single hop, link utilization reaches

\(82\%\)

of the theoretical capacity. Microbenchmarks based on MPI collectives reveal that broadcast latency scales as expected when the number of participating ranks increases. We also implemented a custom MPI_Allreduce accelerator in the network interface, which reduces the latency of such collectives by up to

\(88\%\)

. We assess performance scaling through weak and strong scaling tests for HPCG, LAMMPS, and the miniFE mini application; for all these tests, parallelization efficiency is at least

\(69\%\)

, or better.
A Survey of Research in Large Language Models for Electronic Design Automation
Authors: Pan Jingyu , Zhou Guanglei , Chang Chen-Chia , Jacobson Isaac , Hu Jiang , Chen Yiran
Published: February 2025

Within the rapidly evolving domain of Electronic Design Automation (EDA), Large Language Models (LLMs) have emerged as transformative technologies, offering unprecedented capabilities for optimizing and automating various aspects of electronic design. This survey provides a comprehensive exploration of LLM applications in EDA, focusing on advancements in model architectures, the implications of varying model sizes, and innovative customization techniques that enable tailored analytical insights. By examining the intersection of LLM capabilities and EDA requirements, the article highlights the significant impact these models have on extracting nuanced understandings from complex datasets. Furthermore, it addresses the challenges and opportunities in integrating LLMs into EDA workflows, paving the way for future research and application in this dynamic field. Through this detailed analysis, the survey aims to offer valuable insights to professionals in the EDA industry, AI researchers, and anyone interested in the convergence of advanced AI technologies and electronic design.
Non-conscious Detection of “Missed” Lung Nodules by Radiologists: Expanding the Boundaries of Successful Processing during the Visual Assessment of Chest CT Scans
Authors: DiGirolamo Gregory J. , Sorcini Federico , Zanewski Zachary , Kruskal Jonathan B. , Rosen Max P.
Published: February 2025

When the radiologists looked directly at the location of lung nodules on chest CT scans that they nevertheless failed to recognize or consider, their eye movements and pupil dilation changed, revealing nonconscious processes detecting the “missed” nodules.
Using AI to Select Women with Intermediate Breast Cancer Risk for Breast Screening with MRI
Authors: van Winkel Suzanne L. , Samperna Riccardo , Loehrer Elizabeth A. , Kroes Jaap , Rodriguez-Ruiz Alejandro , Mann Ritse M.
Published: February 2025

An artificial intelligence system at mammography effectively selected women with intermediate risk for breast cancer development (up to 50% lifetime risk) for supplemental MRI screening.
Foundation Models in Radiology: What, How, Why, and Why Not
Authors: Paschali Magdalini , Chen Zhihong , Blankemeier Louis , Varma Maya , Youssef Alaa , Bluethgen Christian , Langlotz Curtis , Gatidis Sergios , Chaudhari Akshay
Published: February 2025

This review focuses on foundation models in radiology and describes their key characteristics and methods for training, adapting, and evaluating; in addition, cautions and future directions associated with their responsible deployment in radiologic practices are discussed.
SARS-CoV-2 Infection Association with Atherosclerotic Plaque Progression at Coronary CT Angiography and Adverse Cardiovascular Events
Authors: Dai Neng , Tang Xianglin , Hu Yiqing , Lu Hao , Chen Zhangwei , Duan Shaofeng , Guo Weifeng , Edavi Pranav Prakash , Yu Yongfu , Huang Dong , Qian Juying , Ge Junbo
Published: February 2025

SARS-CoV-2 infection was associated with coronary atherosclerotic plaque progression, as assessed by coronary CT angiography, and worse cardiovascular outcomes.
CT Honeycombing and Traction Bronchiectasis Extent Independently Predict Survival across Fibrotic Interstitial Lung Disease Subtypes
Authors: Marinescu Daniel-Costin , Hague Cameron J. , Muller Nestor L. , Murphy Darra , Churg Andrew , Wright Joanne L. , Al-Arnawoot Amna , Bilawich Ana-Maria , Bourgouin Patrick , Cox Gerard , Durand Celine , Elliot Tracy , Ellis Jennifer , Fisher Jolene H. , Fladeland Derek , Grant-Orser Amanda , Goobie Gillian C. , Guenther Zachary , Haider Ehsan , Hambly Nathan , Huynh James , Johannson Kerri A. , Karjala Geoffrey , Khalil Nasreen , Kolb Martin , Lapointe-Shaw Lauren , Leipsic Jonathon , Lok Stacey , MacIsaac Sarah , McInnis Micheal , Manganas Helene , Marcoux Veronica , Mayo John , Morisset Julie , Scallan Ciaran , Sedlic Tony , Shapera Shane , Sun Kelly , Tan Victoria , Wong Alyson W. , Zheng Boyang , Ryerson Christopher J.
Published: February 2025

Extent of fibrosis, defined by the amount of honeycombing and traction bronchiectasis, was consistently associated with death or lung transplant across all interstitial lung disease subtypes in a dose-dependent fashion.
Lithium-Ion Battery State of Health Estimation Based on Model Interpretable Feature Extraction
Authors: Huang Guangshan , Fu Lijun , Liu Lang
Published: February 2025

This study proposes a lithium battery State of Health (SOH) estimation method that utilizes model interpretability feature extraction and the Equilibrium Optimizer (EO) algorithm to optimize Temporal convolutional neural networks (TCN), addressing issues of feature collinearity, noise interference, and the challenges of manual model parameter tuning. Initially, the battery’s incremental capacity (IC) curve is smoothed using Gaussian filtering, and the health features are extracted from the charging, discharging and IC curve to establish a TCN-based SOH estimation model. Subsequently, the SHAP interpretability method is employed to analyze the contribution of various features to the TCN model’s predictions, and the features were further screened based on these contributions; the EO algorithm is used to optimize the TCN model hyperparameters, enhancing the model’s prediction performance. Finally, this study builds an experimental platform for ageing tests to validate this method with experimental data and public datasets. The results show that SHAP analysis and the EO algorithm, based on the model’s real-time feedback mechanism, significantly improved the accuracy of feature selection and model prediction precision. The method proposed in this study achieves an RMSE of below 1.40% for the SOH prediction of six batteries, reducing it by 66.7% compared to the baseline model.
An Automated Electrochemical Noise Analysis for Corrosion Type Identification Using Random Forest: Features Selection and Cross-Material Performance
Authors: Bongiorno V. , Curioni M. , Zhou X.
Published: February 2025

Electrochemical noise has been used to monitor four materials undergoing uniform and localised corrosion and in passive conditions. The data are used to train a random forest (RF) model to classify the corrosion behaviours, achieving an accuracy of 96%, when training and testing the model with all materials and conditions. Key features, including current standard deviation and peak to peak difference, were identified as critical to obtain an accurate classification. The RF model was also trained on single metals and cross-validated on the others. The accuracy in the classification was generally maintained for similar materials, but decreased slightly for training and validation on significantly different materials.
Low-Temperature Synthesis of NiO Structures: Tailoring Morphology for Enhanced Dielectric Performance
Authors: Godlaveeti Sreenivasa Kumar , El-marghany Adel , Parandamaiah M. , Nasina Madhusudhana Rao , Gedi Sreedevi , Nagireddy Ramamanohar Reddy , Chinna Venkata Subbaiah G. , Chintaparty Rajababu
Published: February 2025

Nickel oxide (NiO) is a widely studied material for energy storage applications due to its excellent structural and functional properties. This study explores the effect of synthesis pH on the structural, optical, and dielectric properties of NiO nanoparticles to optimize their performance. NiO was synthesized via a hydrothermal method at pH 8 and 12, followed by calcination at 200 °C. At pH 12, X-ray diffraction confirmed the phase transition from β-Ni(OH)₂ to NiO, while TEM analysis revealed the formation of a one-dimensional (1D) structure. Optical studies using UV-visible spectroscopy and photoluminescence revealed defect states that contribute to improved energy storage performance. Dielectric studies revealed superior performance at pH 12. Electrochemical cyclic voltammetry confirmed the enhanced stability and energy storage capabilities of NiO with 1D structure. These findings establish NiO synthesized at pH 12 as a promising candidate for advanced energy storage technologies.
Cellular mechanisms underlying overreaching in skeletal muscle following excessive high-intensity interval training
Authors: Watanabe Daiki , Wada Masanobu
Published: February 2025

An early sign of overtraining is a performance impairment known as overreaching (OR). This study revealed the cellular mechanism underlying OR by combining in vivo fatiguing contractions with mechanically skinned-fiber technique. Thirteen consecutive days of intense training result in myofibrillar force depression in OR. This study provides valuable insights not only for athletes and coaches but also for nonathletes who incorporate exercise into their daily activity.
AIM2 targeting of nuclear DNA leakage in dendritic cells exacerbates vasculitis in a murine model of Kawasaki disease
Authors: Baatarjav Chintogtokh , Komada Takanori , Gunji Yoshitaka , Komori Satoko , Aizawa Hidetoshi , Nagi-Miura Noriko , Karasawa Tadayoshi , Takahashi Masafumi
Published: February 2025

The AIM2 inflammasome in dendritic cells is a significant component of the murine model of Kawasaki disease-like vasculitis induced by CAWS injection. The AIM2 deficiency reduces vasculitis via reduced inflammatory cell infiltration and vascular fibrosis in CAWS-induced vasculitis. CAWS induces the damage and leakage of nuclear DNA in dendritic cells, which triggers AIM2 inflammasome activation, leading to an IL-1β-driven inflammatory response.
Resolution of Refractory Status Epilepticus With Ketamine Without Intubation in a Patient With Stroke‐Like Migraine Attacks After Radiation Therapy (SMART) Syndrome
Authors: Kaneko Kyle N. , Read Pablo , Eaton John M. , Umemura Yoshie , Hoskin Justin L.
Published: February 2025

Stroke‐like migraine attacks after radiation therapy (SMART) syndrome is an infrequently reported complication arising years after radiation therapy that manifests as a reversible syndrome marked by migraine‐like headaches, focal neurologic signs, and/or seizures. Refractory status epilepticus (RSE) associated with SMART syndrome is rare and can be challenging to treat. Valproic acid has been reported to improve seizures in RSE in SMART syndrome in a few case reports and may be ideal for SMART syndrome, given its use in the treatment of migraines and seizures. Ketamine has been used in RSE and a few instances in SMART syndrome. Here, we present a case of refractory focal status epilepticus in a patient with SMART syndrome who was treated with ketamine, which resolved seizures without the need for intubation.
Preoperative Hemoglobin Level Predicts Surgical Site Infections in Trauma Orthopedic Surgery: A Cohort Study
Authors: Walana Williams , Gyilbagr Fredrick , Buunaaim Alexis D. B.
Published: February 2025

Background: Surgical site infections resulting from trauma orthopedic surgery increase morbidity and mortality rates and generate additional costs for the healthcare system. Preoperative and postoperative blood parameters have been described as risk predictors for surgical site infection in other surgical areas. The purpose of this study was to assess the role of preoperative and postoperative hematological parameters in predicting the risk of surgical site infections in trauma orthopedic surgery.

Methods: Data on patients’ demographics were collected from their medical records and the operation reports. Preoperative and postoperative blood samples were collected for a complete blood count assay. The blood cell parameters as predictors of surgical site infection after trauma orthopedic surgery were determined by the Mann–Whitney U test to assess the differences in the median between the dependent and independent variables. p value < 0.05 was considered statistically significant.

Results: Out of the 210 patients who were followed postsurgery, 14 (6.7%) developed surgical site infection following trauma orthopedic surgery. The mean age of the study participants was 33.08 ± 19.23 (Mean ± SD), with a range of 86 to 0.67 years old. Low preoperative hemoglobin level was identified as a predictor of surgical site infection following trauma orthopedic surgery (p = 0.019). None of the postoperative blood parameters measured was significantly associated with surgical site infections after trauma orthopedic surgery in Northern Ghana.

Conclusion: In conclusion, our study demonstrates that preoperative hemoglobin level is a useful hematological parameter for predicting surgical site infection following trauma orthopedic surgery. These inexpensive and common hematological parameters could assist in guiding preventive efforts to reduce surgical site infections and improve outcomes for vulnerable patients undergoing trauma orthopedic surgery. Assessing preoperative hemoglobin levels is crucial in identifying patients at increased risk of developing surgical site infections. Preoperative optimization, including incorporating hemoglobin levels into predictive risk models can help to assess these at‐risk persons better. Educate patients on the need to optimize their hemoglobin levels before surgery and discuss potential interventions, including iron supplementation or transfusion.
Table S7 from Multiomics Analysis Reveals Molecular Changes during Early Progression of Precancerous Lesions to Lung Adenocarcinoma in Never-Smokers
Authors: Chen Yun-Ching , Hsu Chia-Lang , Wang Hui-Min , Wu Shang-Gin , Chang Yih-Leong , Chen Jin-Shing , Wu Yu-Ching , Lin Yen-Ting , Yang Ching-Yao , Lin Mong-Wei , Lee Jang-Ming , Kuo Shuenn-Wen , Chen Ke-Cheng , Hsu Hsao-Hsun , Huang Pei-Ming , Huang Yen-Lin , Yu Chong-Jen , Pirooznia Mehdi , Huang Bevan E. , Yang Rob , Shih Jin-Yuan , Yang Pan-Chyr
Published: February 2025

Table S7. The complete list of copy number alterations.
Table S3 from Multiomics Analysis Reveals Molecular Changes during Early Progression of Precancerous Lesions to Lung Adenocarcinoma in Never-Smokers
Authors: Chen Yun-Ching , Hsu Chia-Lang , Wang Hui-Min , Wu Shang-Gin , Chang Yih-Leong , Chen Jin-Shing , Wu Yu-Ching , Lin Yen-Ting , Yang Ching-Yao , Lin Mong-Wei , Lee Jang-Ming , Kuo Shuenn-Wen , Chen Ke-Cheng , Hsu Hsao-Hsun , Huang Pei-Ming , Huang Yen-Lin , Yu Chong-Jen , Pirooznia Mehdi , Huang Bevan E. , Yang Rob , Shih Jin-Yuan , Yang Pan-Chyr
Published: February 2025

Table S3. Clinical phenotypes of 167 patients.
Characterization of an Enhancer RNA Signature Reveals Treatment Strategies for Improving Immunotherapy Efficacy in Cancer
Authors: Zhang Chenyang , Chen Yan-Yan , Chen Shuyu , Wang Yunzhe , Yuan Yifan , Yang Xiwen , Hu Wei , Chen Bo , Qi Zengxin , Huse Jason T. , Liu Yun , Wen Bo , Liu Xiuping , Han Leng , Wang Yuxiang , Zhang Zhao
Published: February 2025

Non-coding RNA transcribed from active enhancers, known as enhancer RNA (eRNA), is a critical element in gene regulation with a highly specific expression pattern in the regulatory networks of tumor-infiltrating cells. Therefore, eRNA signatures could potentially be applied to represent anti-tumor immune cells and to improve cancer immunotherapy. Herein, we identified thousands of eRNAs that were significantly correlated with infiltrating immune cell abundance in more than 10,000 patient samples across a variety of cancer types. The expression of these eRNAs was mediated by transcription factors with high expression in anti-tumor immune cells, as identified through single-cell assays. An eRNA immunotherapy signature (eRIS) developed using the anti-tumor eRNAs was highly associated with the objective response rate (ORR) of immunotherapy and was elevated in patients who benefited from immune checkpoint blockade (ICB) treatment. In comparison with a signature based on protein-coding genes, the eRIS was more effective in predicting the response to immunotherapy. Integration of the eRIS with pharmacogenomic data revealed hundreds of anti-cancer drugs that have the potential to enhance immunotherapy efficacy. Finally, treatment of a mouse model of IDH mutant glioma with the histone deacetylase inhibitor vorinostat improved the effects of anti-PD-1 immunotherapy through increased abundance of infiltrating immune cells. Taken together, this study developed an eRIS with demonstrated efficacy in predicting immunotherapy response and used the eRIS to identify a series of effective combination drugs, thus highlighting the clinical utility of the eRIS in immunotherapy enhancement.
Figure S3 from Harnessing the Potential of FAP-IL12mut TMEkine for Targeted and Enhanced Antitumor Responses
Authors: Lee Dahea , Kim Dongsu , Kim Donggeon , Kang Jisu , Lee Kiram , Lee Hyunji , Yoon Yujin , Lee Youngin , Kim Nahmju , Cho Byoung Chul , Chang Jihoon , Lee Byoung Chul
Published: February 2025

Supplementary Figure 3. FACS analysis of TILs. FACS analysis of tumor-infiltrating leukocyte populations from LLC1/NIH3T3-mFAP tumor-bearing mice on the indicated dates. LLC1/NIH3T3-mFAP tumor-bearing C57BL/6 mice were treated with 10 μg of mFAP-IL12mut once on day 0. For FACS analysis, tumors were harvested on the indicated dates after treatment initiation (n = 3 mice/group). The population of immune cell analysis of dissociated tumors was harvested on days 1, 3, 7, and 10 (n = 3/group). The population of NK cells (CD3−/CD49b+), macrophages (CD11b+/F4/80+), dendritic cells (CD11b+/CD11c+), CD4+ T cells (CD3+/CD4+), activated CD4+ T cells (CD44+/CD62L−/CD25+), effector memory CD4+ T cells (CD44+/CD62L−/CD25−), central memory CD4+ T cells (CD44+/CD62L+), CD8+ T cells (CD3+/CD8+), activated CD8+ T cells (CD44+/CD62L−/CD25+), effector memory CD8+ T cells (CD44+/CD62L−/CD25−), and central memory CD8+ T cells (CD44+/CD62L+) are shown. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ns., not significant, two-tailed unpaired t-test.
Figure S1 from Harnessing the Potential of FAP-IL12mut TMEkine for Targeted and Enhanced Antitumor Responses
Authors: Lee Dahea , Kim Dongsu , Kim Donggeon , Kang Jisu , Lee Kiram , Lee Hyunji , Yoon Yujin , Lee Youngin , Kim Nahmju , Cho Byoung Chul , Chang Jihoon , Lee Byoung Chul
Published: February 2025

Supplementary Figure 1. In vitro characterization of hFAP-IL12mut. A. Surface plasmon resonance of hFAP-IL12mut on the CM5 chip immobilized with the anti-human IgG antibody. Each protein reacted on the chips and was exposed to a diluted solution of recombinant human FAP protein (hFAP). B. Binding specificity of hFAP-IL12 and hFAP-IL12mut to target cells was confirmed using flow cytometry with human FAP overexpressed HEK293T–hFAP cells and U-87 MG. HEK293T served as a negative control. The target cells were treated with the indicated antibodies (each 1 µg/mL) and then analyzed using flow cytometry with anti-human IgG antibodies to detect the antibodies.
Supplementary Figure S5 from Characteristics of a CCL21 Gene–Modified Dendritic Cell Vaccine Utilized for a Clinical Trial in Non–Small Cell Lung Cancer
Authors: Oh Michael S. , Dumitras Camelia , Salehi-Rad Ramin , Tran Linh M. , Krysan Kostyantyn , Lim Raymond J. , Jing Zhe , Tappuni Shahed , Lisberg Aaron , Garon Edward B. , Dubinett Steven M. , Liu Bin
Published: February 2025

Supplementary Figure S5. Functional impact of lymphocyte subpopulations in CCL21-DC vaccines.
Supplementary Figure S9 from Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82
Authors: Najera Susana S. , Ricketts Christopher J. , Schmidt Laura S. , Medina Julia I. , Saito Keita , Ileva Lilia , Brender Jeffrey R. , James Amy M. , Peer Cody J. , Gouker Brad , Karim Baktiar O. , Chernova Olga , Wells Catherine , Wei Ming-Hui , Yang Youfeng , Zhang Xiaohu , Klumpp-Thomas Carleen , Travers Jameson , Chen Lu , Wilson Kelli M. , Issaq Sameer H. , Figg William D. , Difilippantonio Simone , Kalen Joseph D. , Krishna Murali C. , Thomas Craig J. , Ceribelli Michele , Heske Christine M. , Crooks Daniel R. , Meier Jordan L.
Published: February 2025

Expression levels of NAD+ biosynthetic and salvage pathway genes in HLRCC tumors, normal kidney samples and pan-kidney data from TCGA. (A) Overview of NAD+ biosynthetic and salvage pathways. (B-E) Box plots for selected NAD+ biosynthetic genes derived from RNA-seq analysis of HLRCC tumors and normal kidney specimens. (F) Box plots for selected NAD+ biosynthetic genes derived from RNA-seq TCGA pan-kidney data. NAMPT (nicotinamide phosphoribosyltransferase), NAPRT (nicotinate phosphoribosyltransferase ), QPRT (quinolinate phosphoribosyltransferase), NMNAT (nicotinamide mononucleotide adenylyl transferase), KIRP (kidney renal papillary cancer), CIMP (CpG island methylator phenotype), PRCC T1/T2 (papillary renal cell carcinoma type 1/type 2), ccRCC (clear cell renal cell carcinoma), ChRCC (chromophobe renal cell carcinoma).
Supplementary Figure S7 from Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82
Authors: Najera Susana S. , Ricketts Christopher J. , Schmidt Laura S. , Medina Julia I. , Saito Keita , Ileva Lilia , Brender Jeffrey R. , James Amy M. , Peer Cody J. , Gouker Brad , Karim Baktiar O. , Chernova Olga , Wells Catherine , Wei Ming-Hui , Yang Youfeng , Zhang Xiaohu , Klumpp-Thomas Carleen , Travers Jameson , Chen Lu , Wilson Kelli M. , Issaq Sameer H. , Figg William D. , Difilippantonio Simone , Kalen Joseph D. , Krishna Murali C. , Thomas Craig J. , Ceribelli Michele , Heske Christine M. , Crooks Daniel R. , Meier Jordan L.
Published: February 2025

In vivo effects of NAMPT inhibitors in HLRCC xenograft models. Mean body weights are constant throughout the drug study for animals harboring UOK262 xenografts (A) and UOK365 xenografts (B; study shown in Figure 3A-B, n = 10 mice per arm, 95mg/kg OT-82 for 8 week duration). (C-D) H&E stained sections of retinas obtained from NSG mice treated with vehicle or 95mg/kg OT-82 for 5 days. (E-F) Caspase 3 stained sections of retinas obtained from NSG mice treated with vehicle or 95 mg/kg OT-82 for 5 days. Histological sections were evaluated for signs of retinal toxicity by a trained veterinary pathologist. No overt signs of retinal toxicity were observed (n=3 NSG mice).
Supplementary Figure S4. from Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82
Authors: Najera Susana S. , Ricketts Christopher J. , Schmidt Laura S. , Medina Julia I. , Saito Keita , Ileva Lilia , Brender Jeffrey R. , James Amy M. , Peer Cody J. , Gouker Brad , Karim Baktiar O. , Chernova Olga , Wells Catherine , Wei Ming-Hui , Yang Youfeng , Zhang Xiaohu , Klumpp-Thomas Carleen , Travers Jameson , Chen Lu , Wilson Kelli M. , Issaq Sameer H. , Figg William D. , Difilippantonio Simone , Kalen Joseph D. , Krishna Murali C. , Thomas Craig J. , Ceribelli Michele , Heske Christine M. , Crooks Daniel R. , Meier Jordan L.
Published: February 2025

NAD+ and NADH analysis of UOK365 cells. Analysis of the relative levels of NAD+ and NADH and their ratio after 24 hour treatment of the UOK365 cell line model with a range of concentrations (0.5-100 nM) of either GNE-618 (A-B) or OT-82 (C-D). All levels were compared to cells treated with the amount of DMSO present in the highest concentration of the utilized drugs.
Figure S3 from OBI-992, a Novel TROP2-Targeted Antibody–Drug Conjugate, Demonstrates Antitumor Activity in Multiple Cancer Models
Authors: Li Wan-Fen , Chiang Ming-Feng , Weng Hao-Cheng , Yang Jhih-Jie , Wu Hsin-Shan , Wu Szu-Yu , Chen Yu-Jung , Lu Chi‐Huan , Tu Jyy-Shiuan , Hsu Ren-Yu , Shia Chi-Sheng , Huang Teng-Yi , Lai Ming-Tain
Published: February 2025

Supplementary Figure S3
Supplementary Figure S12 from Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82
Authors: Najera Susana S. , Ricketts Christopher J. , Schmidt Laura S. , Medina Julia I. , Saito Keita , Ileva Lilia , Brender Jeffrey R. , James Amy M. , Peer Cody J. , Gouker Brad , Karim Baktiar O. , Chernova Olga , Wells Catherine , Wei Ming-Hui , Yang Youfeng , Zhang Xiaohu , Klumpp-Thomas Carleen , Travers Jameson , Chen Lu , Wilson Kelli M. , Issaq Sameer H. , Figg William D. , Difilippantonio Simone , Kalen Joseph D. , Krishna Murali C. , Thomas Craig J. , Ceribelli Michele , Heske Christine M. , Crooks Daniel R. , Meier Jordan L.
Published: February 2025

In vitro analysis of NAMPT inhibition on glycolysis in FH-deficient tumor cells. (A) Effects of the NAMPT inhibitor OT-82 (100 nM) on the extracellular acidification rate (ECAR) in the UOK262 and UOK365 HLRCC cell lines and the RPTEC normal cell line. (B) Representation of the different effects of OT-82 versus DMSO at time point 5 (designated by a star) after the injection of glucose in UOK262, UOK365, and RPTEC. 2-DG, 2-deoxyglucose.
Figure S7 from Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody–Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors
Authors: Wang Zeng , Zheng Meijun , Li Mengyao , Lu Huaqing , Liu Nanxi , Chen Yongdong , Yang Nian , Zeng Wanqin , Dong Yijun , Li Jia , Zhu Zhixiong , Yang Chen , Zhang Zongliang , Lu Qizhong , Li Hexian , Zhou Liangxue , Yang Hui , Tong Aiping
Published: February 2025

Supplementary Figure 7. Molecular structure of SLC3A2/PD-L1 BsADC. VcMMAE, mc-vc-PAB-MMAE. Drug payload, MMAE, monomethyl auristatin E; Linker, mc-vc-PAB, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl.
Figure S6 from Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody–Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors
Authors: Wang Zeng , Zheng Meijun , Li Mengyao , Lu Huaqing , Liu Nanxi , Chen Yongdong , Yang Nian , Zeng Wanqin , Dong Yijun , Li Jia , Zhu Zhixiong , Yang Chen , Zhang Zongliang , Lu Qizhong , Li Hexian , Zhou Liangxue , Yang Hui , Tong Aiping
Published: February 2025

Supplementary Figure 6. SLC3A2/PD-L1 BsADC inhibited tumor growth efficacy in SNU-899 xenograft models (A), NCI-H460 xenograft models (B), and A375 xenograft models (C), with or without human PBMCs engraftment in vivo. D, H&E staining of important organ sections from MC38 mice at the endpoint treatment. Scale bar, 20 μm.
Figure S5 from Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody–Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors
Authors: Wang Zeng , Zheng Meijun , Li Mengyao , Lu Huaqing , Liu Nanxi , Chen Yongdong , Yang Nian , Zeng Wanqin , Dong Yijun , Li Jia , Zhu Zhixiong , Yang Chen , Zhang Zongliang , Lu Qizhong , Li Hexian , Zhou Liangxue , Yang Hui , Tong Aiping
Published: February 2025

Supplementary Figure 5. Flow cytometry analysis for apoptosis. A, Flow cytometric analysis for cell apoptosis in SNU-899 cells. B, Flow cytometric analysis for cell apoptosis in H460 cells. C, Flow cytometric analysis for cel
Figure S4 from Preclinical Characterization of XB002, an Anti–Tissue Factor Antibody–Drug Conjugate for the Treatment of Solid Tumors
Authors: Kantak Seema , Faggioni Raffaella , Cai Allen G. , Bhatti Maryam M. , Li Jing , Vainshtein Inna , Cheng Jackie , Mendelsohn Brian A. , Gaudreault Jacques , Migone Thi-Sau , Theunissen Jan-Willem
Published: February 2025

Cleavage of XB002 with cathepsin B – release of ZD02044 payload
Figure S3 from Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody–Drug Conjugate for Enhanced Antitumor Efficacy in Solid Tumors
Authors: Wang Zeng , Zheng Meijun , Li Mengyao , Lu Huaqing , Liu Nanxi , Chen Yongdong , Yang Nian , Zeng Wanqin , Dong Yijun , Li Jia , Zhu Zhixiong , Yang Chen , Zhang Zongliang , Lu Qizhong , Li Hexian , Zhou Liangxue , Yang Hui , Tong Aiping
Published: February 2025

Supplementary Figure 3. SLC3A2/PD-L1 BsAb showed Neutralizing activities and T cells activation. A, SLC3A2/PD-L1 BsAb blocked the interaction between PD-L1-His and biotinylated PD-1-His protein by ELISA. IC50, half-maximal inhibitory concentration. B, ADCC activities of SLC3A2/PD-L1 BsAb to A375 using human PBMCs as effector cells. Supernatants were harvested to measure the LDH release by ELISA. C, SLC3A2/PD-L1 BsAb induced IFN-γ secretion in mixed leukocyte reaction (MLR). PD-L1 mAb was used as a positive control. SLC3A2 mAb was used as a negative control. D, SLC3A2/PD-L1 BsAb reversed PD-L1-mediated inhibition of T-cell proliferation. T cell numbers were quantified with CCK-8. *P < 0.05, **P < 0.01 and ***P < 0.001 by unpaired t-test and two-way ANOVA with Tukey’s multiple comparison test. Data = mean ± SEM of three independent experiments.
Supplementary Figure S1 from Modeling the Acute Mucosal Toxicity of Fractionated Radiotherapy Combined with the ATM Inhibitor WSD0628
Authors: Garcia Darwin A. , Rathi Sneha , Connors Margaret A. , Grams Michael , Vaubel Rachael A. , Bakken Katrina K. , Ott Lauren L. , Carlson Brett L. , Hu Zeng , Decker Paul A. , Eckel-Passow Jeanette E. , Burgenske Danielle M. , Zhong Wei , Trzasko Joshua D. , Herman Michael G. , Elmquist William F. , Remmes Nicholas B. , Sarkaria Jann N.
Published: February 2025

Supplementary Figure S1 includes repeats of immunofluorescence images and an example of H&E staining from untreated oral mucosa.
Suppl Figure 6 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Suppl Figure 5 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Suppl Figure 2 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Suppl Figure 13 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Supplementary Figure S5 from Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling
Authors: Volat Fanny , Medhi Ragini , Maggs Lauren Z. , Deken Marcel A. , Price Alice , Andrews Lauren , Clark Jonathan , Taylor Diane , Carruthers Alan , Taylor-Smith Ewan , Pacheco Natalia , Rudge Simon A. , Fraser Amy , Lopez-Clavijo Andrea F. , Sousa Bebiana C. , Johnson Zoë , Di Conza Giusy , van der Veen Lars , Shah Pritom , Sandig Hilary , Sharpe Hayley J. , Farrow Stuart
Published: February 2025

Supplementary Figure S5 shows RNA-seq analysis of 0082T CAFs after treatment with ATX inhibitors.
Suppl Figure 12 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Supplementary Figure S4 from Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling
Authors: Volat Fanny , Medhi Ragini , Maggs Lauren Z. , Deken Marcel A. , Price Alice , Andrews Lauren , Clark Jonathan , Taylor Diane , Carruthers Alan , Taylor-Smith Ewan , Pacheco Natalia , Rudge Simon A. , Fraser Amy , Lopez-Clavijo Andrea F. , Sousa Bebiana C. , Johnson Zoë , Di Conza Giusy , van der Veen Lars , Shah Pritom , Sandig Hilary , Sharpe Hayley J. , Farrow Stuart
Published: February 2025

Supplementary Figure S4 shows LPAR expression in PDAC cell lines and ATX-mediated pro-tumorigenic stimulation by 0082T conditioned media.
Suppl Figure 11 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Suppl Figure 1 from Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors: Interest of a Combined Antibody-Based Therapy
Authors: Joshkon Ahmad , Traboulsi Wael , Terme Magali , Bachelier Richard , Fayyad-Kazan Hussein , Dignat-George Françoise , Foucault-Bertaud Alexandrine , Leroyer Aurelie S. , Bardin Nathalie , Blot-Chabaud Marcel
Published: February 2025

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Data from Harnessing the Potential of FAP-IL12mut TMEkine for Targeted and Enhanced Antitumor Responses
Authors: Lee Dahea , Kim Dongsu , Kim Donggeon , Kang Jisu , Lee Kiram , Lee Hyunji , Yoon Yujin , Lee Youngin , Kim Nahmju , Cho Byoung Chul , Chang Jihoon , Lee Byoung Chul
Published: February 2025

Abstract
Although cancer immunotherapy has yielded encouraging outcomes in hematologic malignancies, it has faced challenges in achieving the same level of effectiveness in numerous solid tumors, primarily because of the presence of immunosuppressive tumor microenvironments (TME). The immunosuppressive qualities of the TME have generated considerable interest, making it a focal point for treatments aimed at enhancing immune responses and inhibiting tumor progression. Fibroblast activation protein (FAP), an attractive candidate for targeted immunotherapy, is prominently expressed in the TME of various solid tumors. IL12, recognized as a key mediator of immune responses, has been explored as a potential candidate for cancer treatment. Nevertheless, initial efforts to administer IL12 systemically demonstrated limited efficacy and notable side effects, emphasizing the necessity for innovation. To address these concerns, our molecules incorporated specific IL12 mutations, called IL12mut, which reduced toxicity. This study explored the therapeutic potential of the FAP-IL12mut TMEkine—a novel immunotherapeutic agent selectively engineered to target FAP-expressing cells in preclinical cancer models. Our preclinical results, conducted across diverse murine cancer models, demonstrated that FAP-IL12mut significantly inhibits tumor growth, enhances immune cell infiltration, and promotes a shift toward a cytotoxic immune activation profile. These findings suggest that FAP-IL12mut could offer effective cancer treatment strategies.
Data from Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82
Authors: Najera Susana S. , Ricketts Christopher J. , Schmidt Laura S. , Medina Julia I. , Saito Keita , Ileva Lilia , Brender Jeffrey R. , James Amy M. , Peer Cody J. , Gouker Brad , Karim Baktiar O. , Chernova Olga , Wells Catherine , Wei Ming-Hui , Yang Youfeng , Zhang Xiaohu , Klumpp-Thomas Carleen , Travers Jameson , Chen Lu , Wilson Kelli M. , Issaq Sameer H. , Figg William D. , Difilippantonio Simone , Kalen Joseph D. , Krishna Murali C. , Thomas Craig J. , Ceribelli Michele , Heske Christine M. , Crooks Daniel R. , Meier Jordan L.
Published: February 2025

Abstract
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted tricarboxylic acid cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted a high-throughput drug screen in HLRCC cell lines, which identified a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Human HLRCC tumors and HLRCC-derived cell lines exhibited elevated NAMPT expression compared with controls. FH-deficient HLRCC cells, but not FH-restored HLRCC or normal kidney cells, were sensitive to NAMPT inhibition. HLRCC cell line viability was significantly decreased in both 2D and 3D in vitro cultures in response to the clinically relevant NAMPT inhibitor OT-82. NAMPT inhibition in vitro significantly decreased the total amount of NAD+, NADH, NADP, NADPH, and poly-ADP-ribose levels, and the effects of NAMPT inhibition could be rescued by the downstream NAD precursor nicotinamide mononucleotide (NMN), confirming the on-target activity of OT-82. Moreover, NAMPT inhibition by OT-82 in two HLRCC xenograft models resulted in severely reduced tumor growth. OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated RCC.
Supplemental Figure S4 from Ternary Complex Components Responsible for Rapid LDL Internalization as Biomarkers for Breast Cancer Associated with Proliferation and Early Recurrence
Authors: McDonald Elizabeth S. , Pan Tien-Chi , Pant Dhruv K. , Troester Melissa A. , Kossenkov Andrew V. , Mankoff David A. , Mach Robert H. , Chodosh Lewis A.
Published: February 2025

This shows that the association of TK1 with breast cancer relapse is dependent on proliferation.
Supplemental Figure S2 from Ternary Complex Components Responsible for Rapid LDL Internalization as Biomarkers for Breast Cancer Associated with Proliferation and Early Recurrence
Authors: McDonald Elizabeth S. , Pan Tien-Chi , Pant Dhruv K. , Troester Melissa A. , Kossenkov Andrew V. , Mankoff David A. , Mach Robert H. , Chodosh Lewis A.
Published: February 2025

This shows the association of TK1 with early breast cancer relapse segregated by molecular subtype.
Das «Ballerina»-Anzeichen: Posteriore Kapselruptur während der Kataraktoperation
Authors: Ramon Dan , Shemesh Nadav , Achiron Asaf
Published: February 2025

Einleitung: In dieser Fallstudie stellen wir das «Ballerina»-Anzeichen als potenziell wertvollen klinischen Indikator für die Erkennung einer posterioren Kapselruptur (PCR) während einer Katarakt­operation vor. Ziel dieser Studie ist es, die Bedeutung der PCR im Kontext der Kataraktchirurgie aufzuzeigen und dieses neuartige Anzeichen vorzustellen. Fallvorstellung: Während der Kataraktoperation an einem 70-jährigen Patienten haben wir ein spiralförmiges Nucleus-Fragment beobachtet, das mit einem Glaskörperstrang verbunden war. Im Anschluss wurde ohne weitere intraoperative Komplikationen eine anteriore Vitrektomie erfolgreich durchgeführt, gefolgt von der Einführung einer 3-teiligen Linse in den Sulcus. Während der postoperativen Termine zur Nachuntersuchung, die nach 1 Tag, 2 Wochen und 3 Monaten erfolgten, wurden positive visuelle Ergebnisse festgestellt.
Outcomes of Intermittent Hemodialysis vs. Continuous Kidney Replacement Therapy in Hemodynamically Stable Patients with Acute Kidney Injury: A Prospective, Observational, Multicenter Study
Authors: AlSahow Ali , Alkandari Omar , Bahbahani Yousif , Alyousef Anas , AlHelal Bassam , AlRajab Heba , AlQallaf Ahmed , AlSharekh Monther , AlKandari Abdulrahman , Nessim Gamal , Mashal Bassem , Mazroue Ahmad , Abdelmoteleb Alaa , Elabbadi Mohamed , Abdelzaher Ali , Abdallah Emad , Abdellatif Mohamed , ElHusseini Ziad , Abdelrady Ahmed
Published: February 2025

Introduction: Continuous dialysis in hemodynamically stable patients with acute kidney injury (AKI) may impact outcomes differently than intermittent dialysis. We evaluated differences in patient and kidney outcomes between the two modalities. Methods: Clinical and 30-day outcome data for inpatients with AKI who were hemodynamically stable and not on ventilation and who received intermittent hemodialysis (IHD) or continuous kidney replacement therapy (CKRT) in public hospitals in Kuwait from January 1 to December 31, 2021, were prospectively collected. Results: We recruited 229 patients (age: 59.9 years; males, 60.3%; baseline eGFR, 56 ml/min). CKRT accounted for 72.9% of cases due to lack of access to water treatment. No statistically significant differences were observed between groups in terms of age, baseline eGFR, sex, comorbidities, cause of AKI, or fluid administration. Intensive care unit contributed 21% of cases, with no significant difference between groups. More IHD patients received diuretics (62.9% vs. 43.1% for CKRT, p = 0.008). At 30 days, 21.8% of patients had died. There was no statistically significant difference in mortality between groups (16.1% for IHD vs. 24% for CKRT, p = 0.2). Final eGFR was 53.2 ml/min, with no difference between groups. Complete kidney recovery was greater with CKRT (33.1% vs. 13.5%, p = 0.009). Baseline eGFR < 60 ml/min did not influence mortality or kidney recovery. Conclusion: Compared with IHD, CKRT did not lower mortality at 30 days, which is similar to that of randomized trials; however, it was associated with better complete kidney recovery, which was reported in observational studies.
Cabozantinib in the Treatment of Neuroendocrine Neoplasms: Insights Across Different Tumor Origins
Authors: Vitale Giovanni , Rybinska Ilona , Arrivi Giulia , Marotta Vincenzo , Di Iasi Gianfranco , Filice Alessia , Nardi Christopher , Colao Annamaria , Faggiano Antongiulio ,   NIKE Group
Published: February 2025

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviours from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis. Summary: This review provides a comprehensive analysis of cabozantinib’s therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer. Key Messages: The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogues, peptide receptor radionuclide therapy, temozolomide and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs