bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating small extracellular vesicle-based vaccination across heterologous
Salmonella
strains isolated from wastewater
Authors: Emerson Lisa E. , Bhimani Saloni , Rainey Andrew L. , Maurelli Anthony T. , Ferraro Mariola J.
Published: January 2025

Salmonella
infections pose significant public health challenges worldwide. The diversity of
Salmonella
strains, particularly those isolated from environmental and clinical sources, necessitates innovative approaches to prevention and treatment. Previous research has shown that small extracellular vesicles (sEVs) produced by macrophages during
Salmonella
Typhimurium infection can induce robust immune responses when used as a vaccine, offering complete protection in systemic infection models. In this study, we isolated 120
Salmonella
strains from qPCR
invA
-positive wastewater samples collected in Gainesville, FL. These strains underwent enrichment, selection, and biochemical confirmation, followed by serotyping and whole genome sequencing. Two isolates,
Salmonella enterica
subsp. diarizonae (Diarizonae) and
S. enterica
serovar Enteritidis, were selected for further analysis based on community prevalence and clinical severity. We also assessed the ability of sEVs produced by
S
. Typhimurium-infected macrophages to induce immune responses against these heterologous and circulating strains in mice. Immunization with sEVs induced robust antigen-specific SIgA and IgG responses against
S
. Typhimurium, Enteritidis, and Diarizonae, with high titers observed in sera and fecal samples. Proteomic analysis revealed differential expression of proteins in these strains, including antigenic proteins present in sEVs such as OmpA, FliC, or OmpD. Moreover, this study highlights the role of wastewater-based epidemiology (WBE) as a tool for environmental surveillance, offering a complementary perspective on
Salmonella
dynamics within a population. Integrating WBE with traditional surveillance methods, along with the promising results of sEV-based vaccination, provides a pragmatic strategy for developing effective preventative measures against
Salmonella
infections, addressing the diversity of non-typhoidal
Salmonella
strains.
On-land evidence for subduction of the proto−South China Sea beneath northern Borneo and tectonic reconstruction of Southeast Asia during the early Permian–Oligocene
Authors: Zhang Xin-Chang , Li Hong-Yan , Yao Yongjian , Chen Wen-Huang
Published: January 2025

The development of the Mesozoic proto−South China Sea was closely related to the tectonic evolution of the Tethys and Paleo-Pacific domains and may have been a key driving mechanism for the opening of the South China Sea. Despite its importance, direct geologic evidence for the proto−South China Sea remains limited, and its development is debated between two primary models: intra-oceanic subduction and oceanic-continental subduction. Here, we present petrographic, geochronologic, and geochemical data from tuffs and Eocene−Pliocene sedimentary records in Sabah, northern Borneo. The results reveal that these tuffs, formed ca. 28 Ma, possess geochemical characteristics indicative of oceanic arc origins. Combined with changes in sediment provenance since the Oligocene and various subduction timelines around Borneo, we suggest that these tuffs resulted from the subduction of the proto−South China Sea. This oceanic arc, along with Eocene mid-ocean-ridge−like mafic rocks in Sabah, indicates that a younger oceanic basin had formed within the proto−South China Sea. This aligns with observations in Palawan, Philippines, illustrating the transition from an oceanic spreading center to a subduction zone and indicating the proto−South China Sea extended from eastern Sabah to Palawan. In addition, inherited zircons (ca. 280 Ma) in the tuffs exhibit geochemical signatures typical of continental arcs. Combined with the Permian−Cretaceous arc-related igneous rocks in Southeast Asia, this suggests that southern Sabah was part of the Paleo-Tethys Ocean before integrating into the Paleo-Pacific domain since the Triassic. By shedding light on these processes, our research provides critical insights into the existence, extent, and evolution of the proto−South China Sea and reconstructs the multiphase transitions between different tectonic domains in Southeast Asia.
Single-molecule localisation microscopy (SMLM) is feasible in human and animal formalin fixed paraffin embedded (FFPE) tissues in medical renal disease
Authors: Brockmoeller Scarlet F , Slaney Hayley , Curd Alistair , Bono Aurora , Felce James H , Arora Deep , Lewington Andrew , Miklosi Andras G , Quirke Philip
Published: January 2025

Aims

Establishment of a protocol for routine single-molecule localisation microscopy (SMLM) imaging on formalin fixed paraffin embedded (FFPE) tissue using medical renal disease including minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS).

Methods

Protocol for normal and diseased renal FFPE tissue was developed to investigate the clinical diagnostic potential of SMLM. Antibody concentrations were determined for confocal microscopy and transferred to SMLM. Different fixatives and lengths of fixation were studied. To reduce autofluorescence, additional quenching and UV bleaching steps were compared. Optimal SMLM acquisition settings were established. SMLM data were imaged, digitally captured, stored, visually inspected and analysed quantitatively.

Results

Protocol was established on normal renal FFPE tissue and then applied to clinical diseased tissue with single and multiple markers. Antibodies against key diagnostic proteins including podocin, nephrin, collagen, laminin, synaptopodin, CD31, IgG, IgM and IgA antibodies were established for MCD, FSGS and immune-mediated renal disease. We found important characteristic differences in the renal diseases listed above.

Conclusions

We established a routine super-resolution microscopy protocol for clinical FFPE material on medical renal biopsies, which could visualise fluorescently labelled proteins in all glomeruli present with a precision of approximately 10–20 nm, with a turnaround under 48 hours. We visualised and quantitated specific protein distributions in different conditions. SMLM opens subcellular microscopy in FFPE to histopathologists on routine FFPE tissue, which can in the future be an adjunct and, in some aspects, a rapid superior alternative to electron microscopy.
Geometric design and safety outcomes of roundabouts in the Canadian context: a case study in the region of Waterloo
Authors: Miyake Ryoto , Fu Liping
Published: January 2025

Road safety remains a critical concern in Canada and worldwide. In response, roundabouts have emerged as a safer intersection design under certain road, traffic, and environmental conditions, with extensive research highlighting the critical role of geometric design in their safety effect. However, such geometric effects remain relatively unexplored in Canada, where roundabouts are a recent addition. Moreover, it is unknown whether the underlying relationship varies over time due to the evolution in driver behaviour. This study attempts to address these questions by utilizing data from the Region of Waterloo and constructing negative binomial models. Results indicate that geometric design significantly impacts collision frequency, with effects generally consistent but showing some temporal variability. The study also highlights unique relationships between geometries and safety in Canada, advocating for tailored roundabout designs and cautioning against direct application of findings from other regions.
Intelligent Identification of Security Threats in Long-Distance Communication Networks Based on Embedded AI Perception
Authors: Liu Hong-Xia , Song Lina
Published: January 2025

In the context of network security, when threats exhibit spatial similarities — such as attacks originating from the same or nearby geographic locations or using similar methods within a specific region — it can complicate the identification of security threats in long-distance communication networks. To address this challenge and improve both the efficiency and accuracy of threat identification, we propose an intelligent method for detecting long-distance communication network security threats based on embedded AI perception. This method takes spatial similarities into account by comparing sensing data between nodes within the network to assess their real-time status. Using a group decision-making mechanism, we correlate the data collection points of vulnerable network nodes to gather security log data. The network logs are then preprocessed using the Grubbs statistical algorithm to extract key security threat features. By incorporating machine learning algorithms from the field of AI, and leveraging the edge computing capabilities of the NVIDIA Jetson series as the embedded AI platform, we construct an intelligent perception model to detect security threats in real-time. Experimental results demonstrate that the proposed method can effectively detect the actual state of different nodes within the network, with a maximum state deviation of only 0.2. Additionally, the method achieved an [Formula: see text]1 score of 0.986, a recall value of 0.979, and a precision value of 0.981, indicating strong robustness and comprehensive threat identification performance.
Design and Analysis of Green Building Solar Energy Utilization System Based on BIM
Authors: Qi Pan
Published: January 2025

In order to intuitively present the layout and design of the solar energy utilization system, improve the integrity, and consistency of the design. Design and analyze the solar energy utilization system of green buildings based on Building Information Model (BIM). The data acquisition layer collects relevant data of green buildings and solar energy utilization system in RFID and WSN mode and transmits them to the data processing layer; the data processing layer filters the data related to green buildings and solar energy utilization system according to IPC construction standards, and transmits them to the model layer through the Internet of Things; the model layer uses the REVIT software combined with the filtered data to build and update the BIM model of green buildings and solar energy utilization system, intuitively present the layout and design of the solar energy utilization system, and improve the integrity and consistency of the design; the application layer uses the fuzzy comprehensive evaluation model, combined with the green building and solar energy utilization system BIM model, to simulate and analyze the solar energy utilization system environment of green buildings; the user layer provides users with human–computer interaction functions to view the design and analysis process of the solar energy utilization system of green buildings. Experiments show that this method can effectively collect relevant data of green buildings and establish a BIM model of solar energy utilization system; this method can effectively design the solar energy utilization system of green buildings; the solar energy utilization system designed by this method can effectively reduce the electric heating capacity of green buildings, and has an excellent energy-saving effect.
Optimization of English Grammar Error Automatic Detection Algorithm Based on Natural Language Processing
Authors: Wang Bihai
Published: January 2025

A text’s grammatical errors (GEs) are passages that are broken down to accept grammar standards. Resolving grammatical faults and inconsistencies in a document is the aim of GEs. Different strategies can focus on varying textual spans, from individual phrases to whole documents. Common GEs include improper word choice, punctuation, and syntax. The development of natural language processing (NLP) has fundamentally changed the way textual data is analyzed and processed, leading to notable advancements in automated grammatical mistake detection systems. In this study, we proposed a novel starling murmuration-optimized dense recurrent neural network (SMO-DRNN) model for the detection of English grammar errors. In this study, we collected text samples that were analyzed by marking different types of GEs. Automatic reading also involves converting textual data from English compositions into numerical values for further computation. Data pre-processing techniques include tokenization, stop word removal, stemming, and lemmatization. To extract relevant information from the pre-processing data, term frequency-inverse document frequency (TF-IDF) feature extraction was used for accurate grammar detection. The proposed approach is compared to the traditional algorithms. The overall results show that the proposed approach performed better than the existing method in terms of accuracy and loss, ROC (0.95), recall (92%), precision (96%), and F-0.5 score (94%), for identifying English grammar errors. The suggested method effectively combines current NLP strategies to offer a highly accurate method for identifying grammar mistakes in English.
Level Up with ML Vulnerability Identification: Leveraging Domain Constraints in Feature Space for Robust Android Malware Detection
Authors: Bostani Hamid , Zhao Zhengyu , Liu Zhuoran , Moonsamy Veelasha
Published: January 2025

Machine Learning (ML) promises to enhance the efficacy of Android Malware Detection (AMD); however, ML models are vulnerable to realistic evasion attacks—crafting realizable Adversarial Examples (AEs) that satisfy Android malware domain constraints. To eliminate ML vulnerabilities, defenders aim to identify susceptible regions in the feature space where ML models are prone to deception. The primary approach to identifying vulnerable regions involves investigating realizable AEs, but generating these feasible apps poses a challenge. For instance, previous work has relied on generating either feature-space norm-bounded AEs or problem-space realizable AEs in adversarial hardening. The former is efficient but lacks full coverage of vulnerable regions, whereas the latter can uncover these regions by satisfying domain constraints but is known to be time consuming. To address these limitations, we propose an approach to facilitate the identification of vulnerable regions. Specifically, we introduce a new interpretation of Android domain constraints in the feature space, followed by a novel technique that learns them. Our empirical evaluations across various evasion attacks indicate effective detection of AEs using learned domain constraints, with an average of 89.6%. Furthermore, extensive experiments on different Android malware detectors demonstrate that utilizing our learned domain constraints in adversarial training outperforms other adversarial training based defenses that rely on norm-bounded AEs or state-of-the-art non-uniform perturbations. Finally, we show that retraining a malware detector with a wide variety of feature-space realizable AEs results in a 77.9% robustness improvement against realizable AEs generated by unknown problem-space transformations, with up to 70× faster training than using problem-space realizable AEs.
LIA: Latency-Improved Adaptive routing for Dragonfly networks
Authors: Benito Mariano , Vallejo Enrique , Beivide Ramón
Published: January 2025

Low-diameter network topologies require non-minimal routing, such as Valiant routing, to avoid network congestion under challenging traffic patterns like the so-called adversarial. However, this mechanism tends to increase the average path length, base latency, and network load. The use of shorter non-minimal paths has the potential to enhance performance, but it may also introduce congestion depending on the traffic patterns. This paper introduces
LIA
(Latency-Improved Adaptive), a routing mechanism for Dragonfly networks which dynamically exploits minimal and non-minimal paths.
LIA
harnesses the traffic counters already present in contemporary switches to determine when it is safe to shorten non-minimal paths and to adjust routing decisions based on their information about the network conditions. Evaluations reveal that
LIA
achieves nearly optimal latency, outperforming state-of-the-art adaptive routing mechanisms by reducing latency by up to 30% while maintaining stable throughput and fairness.
Unveiling and Evaluating Vulnerabilities in Branch Predictors via a Three-Step Modeling Methodology
Authors: Wang Quancheng , Tang Ming , Xu Ke , Wang Han
Published: January 2025

With the emergence and proliferation of microarchitectural attacks targeting branch predictors, the once-established security boundary in computer systems and architectures is facing unprecedented challenges. This paper introduces an innovative branch predictor modeling methodology that abstractly characterizes 19 states and 53 operations of branch predictors, aiming to assist hardware designers in addressing overlooked security concerns during the microarchitecture design phase. Building upon this modeling discipline, we develop a symbolic execution-based framework to analyze and derive potential vulnerabilities in branch predictors. This framework finally yields 156 valid three-step attack patterns against branch predictors, including 89 novel variants not discovered in previous work. Subsequently, we extend the framework to automatically generate a benchmark suite for assessing the practical feasibility of derived attacks in real-world scenarios. Evaluation across five commercial Intel processors underscores the substantial threat posed by branch predictor attacks, with 130 of the 156 derived attacks proving viable on at least one processor. Finally, we theoretically model and evaluate 12 secure designs related to branch predictors. The evaluation results demonstrate that existing secure branch predictors can offer better security guarantees than secure speculation schemes, indicating that secure branch predictor designs are promising solutions to maintain the confidentiality and integrity of computer systems.
KINDRED: Heterogeneous Split-Lock Architecture for Safe Autonomous Machines
Authors: Gan Yiming , Leng Jingwen , Yu Bo , Zhu Yuhao
Published: January 2025

With the increasing practicality of autonomous vehicles and drones, the importance of reliability requirements has escalated substantially. In many instances, traditional system designs tend to overlook reliability issues, emphasizing primarily on performance constraints. On the other hand, certain designers may opt for a lock-step (redundant) system design, duplicating every component, which in turn can result in significant performance, energy, and cost overheads. In software for autonomous machines, such as self-driving vehicles, performance degradation can increase reaction time, posing safety risks and reducing mission success rates.

This paper introduces a novel multi-domain lock-step system design,
Kindred
, which places a strong emphasis on maximizing reliability while minimizing performance overhead. The proposed approach capitalizes on the inherent diversity in fault tolerance among various tasks within autonomous machine software, intelligently scheduling only the vulnerable nodes in the lock-domain. The primary challenge addressed in this study involves the intelligent task scheduling across different domains, complemented by efficient error detection and correction in the lock-domain. In a real system demonstration, we illustrate the effectiveness of
Kindred
, showcasing its ability to attain the same level of reliability as a full lock-step system while incurring only a mere 2.8% overhead, as opposed to a fully split system, indicating the advantages and potential of our multi-domain lock-step system design in achieving high reliability without compromising performance.
How Low Can We Go? Minimizing Interaction Samples for Configurable Systems
Authors: Krupke Dominik , Moradi Ahmad , Perk Michael , Keldenich Phillip , Gehrke Gabriel , Krieter Sebastian , Thüm Thomas , Fekete Sándor P.
Published: January 2025

Modern software systems are typically configurable, a fundamental prerequisite for wide applicability and reusability. This flexibility poses an extraordinary challenge for quality assurance, as the enormous number of possible configurations makes it impractical to test each of them separately. This is where
t-wise interaction sampling
can be used to systematically cover the configuration space and detect unknown feature interactions. Over the last two decades, numerous algorithms for computing small interaction samples have been studied, providing improvements for a range of heuristic results; nevertheless, it has remained unclear how much these results can still be improved.

We present a significant breakthrough: a fundamental framework, based on the mathematical principle of
duality
, for combining near-optimal solutions with provable lower bounds on the required sample size. This implies that we no longer need to work on heuristics with marginal or no improvement, but can certify the solution quality by establishing a limit on the remaining gap; in many cases, we can even prove optimality of achieved solutions. This theoretical contribution also provides extensive practical improvements: Our algorithm SampLNS was tested on 47 small and medium-sized configurable systems from the existing literature. SampLNS can reliably find samples of smaller size than previous methods in 85 % of the cases; moreover, we can achieve and prove optimality of solutions for 63 % of all instances. This makes it possible to avoid cumbersome efforts of minimizing samples by researchers as well as practitioners, and substantially save testing resources for most configurable systems.
Development of a Novel Prognostic Model for Lung Adenocarcinoma Utilizing Pyroptosis‐Associated LncRNAs
Authors: Bai Hong-Yan , Li Tian-Tian , Sun Li-Na , Zhang Jing-Hong , Kang Xiu-He , Qu Yi-Qing
Published: January 2025

Lung cancer is a highly prevalent and fatal cancer that seriously threatens the safety of people in various regions around the world. Difficulty in early diagnosis and strong drug resistance have always been difficulties in the treatment of lung cancer, so the prognosis of lung cancer has always been the focus of scientific researchers. This study used genotype‐tissue expression (GTEx) and the cancer genome atlas (TCGA) databases to obtain 477 lung adenocarcinoma (LUAD) and 347 healthy individuals’ samples as research subjects and divided LUAD patients into low‐risk and high‐risk groups based on prognostic risk scores. Differentially expressed gene (DEG) analysis was performed on 25 pyroptosis‐related genes obtained from GeneCards and MSigDB databases in cancer tissues of LUAD patients and noncancerous tissues of healthy individuals, and seven genes were significantly different in cancer tissues and noncancerous tissues among them. Coexpression analysis and differential expression analysis of these genes and long noncoding RNAs (lncRNAs) found that three lncRNAs (AC012615.1, AC099850.3, and AO0001453.2) had significant differences in expression between cancer tissues and noncancerous tissues. We used Cox regression and the least absolute shrinkage sum selection operator (LASSO) regression to construct a prognostic model for LUAD patients with these three pyroptosis‐related lncRNAs (pRLs) and analyzed the prognostic value of the pRLs model by the Likaplan–Meier curve and Cox regression. The results show that the risk prediction model has good prediction ability. In addition, we also studied the differences in tumor mutation burden (TMB), tumor immune dysfunction and rejection (TIDE), and immune microenvironment with pRLs risk scores in low‐risk and high‐risk groups. This study successfully established a LUAD prognostic model based on pRLs, which provides new insights into lncRNA‐based LUAD diagnosis and treatment strategies.
Typhoid Fever as a Cause of Liver Failure in the United States: A Case Report
Authors: Baqir Syed Mujtaba , Sharma Neha , Lutaf Aruge , Ghitan Monica , Lin Yu Shia
Published: January 2025

Background: Typhoid fever is a multisystemic illness caused by Salmonella typhi and Salmonella paratyphi, transmitted fecal orally through contaminated water and food. It is a rare diagnosis in the US, with most cases reported in returning travelers. Hepatitis and cholestasis are rare sequelae of salmonella infection. However, acute liver failure (ALF) is exceptionally uncommon. We report a case of typhoid fever in a returning traveler to the US progressing to ALF.

Case Presentation: A 48‐year‐old man presented with high‐grade fever, abdominal pain, vomiting, acholic stools, dark urine, and yellowish discoloration of skin and sclera for one week. He was immune to hepatitis A and B, with no recent change in medications. He had no history of alcohol consumption. On presentation, the patient was tachycardic but well perfused with diffuse abdominal tenderness. Laboratory results showed leukocytosis, elevated creatinine, mixed hepatocellular and cholestatic pattern of raised liver enzymes, elevated ammonia levels, and negative hemolytic parameters. Viral, autoimmune, and metabolic causes of hepatitis were negative. Ultrasound of the abdomen revealed a normal biliary system and a computerized tomography (CT) scan of the abdomen showed multiple liver cysts, mesenteric and porta‐hepatis lymphadenopathy, and mild thickening of the terminal ileum. Intravenous (IV) ceftriaxone and metronidazole were initiated. Blood cultures grew S. typhi. The patient clinically deteriorated and developed altered mental status, respiratory distress, and an up‐trending Model for End‐Stage Liver Disease (MELD) score and was upgraded to the intensive care unit. IV meropenem was initiated, resulting in clinical recovery and negative repeat blood cultures. The patient completed 2 weeks of meropenem and was discharged.

Conclusion: Typhoid fever can cause life‐threatening liver failure which is rare. Clinicians should be aware of this due to the rapid progression and life‐threatening clinical course, as well as the rise of multidrug‐resistant and extensively drug‐resistant typhoid causing delays in starting the right antibiotic.
A Rare Case of Colorectal Cancer With Delayed Metastasis to the Duodenum
Authors: Chaudhary Ammad Javaid , Saleem Abdulmalik , Shahzil Muhammad , Hafeez Nosheen , Jamali Taher , Ginnebaugh Brian
Published: January 2025

Colorectal cancer (CRC) continues to be a significant global health issue contributing to a high mortality rate. Despite advancements in treatment, the risk of recurrence remains due to inherent mutations and the rapid turnover of intestinal mucosa. We present an exceptionally rare case of CRC metastasis to the duodenum in a 42‐year‐old female who has been compliant with postsurgical surveillance. Despite previous negative surveillance results, elevated CEA levels and a 3‐cm mesenteric mass were detected, raising concerns for carcinoma, which was later confirmed by biopsy. The tumor board deemed her ineligible for surgery due to vascular involvement, leading to palliative care and an attempt at neoadjuvant therapy. Vigilant monitoring is crucial for early detection and intervention.
Anterior Uveitis and Uveal Depigmentation in a Dog With Vitiligo
Authors: Ledbetter Eric C. , Lamkin Irini D. , Peters-Kennedy Jeanine
Published: January 2025

Objective: The objective of this study is to describe the clinical and histologic features of a dog that developed anterior uveitis and uveal depigmentation in association with vitiligo.

Animal Studied: A 3‐year‐old, female‐spayed, Bernese Mountain Dog with a history of bilateral idiopathic anterior uveitis developed iris depigmentation, leukotrichia, and skin depigmentation.

Procedures: The initial diagnostic evaluation for uveitis was unremarkable, including general bloodwork, urinalysis, infectious disease testing, thoracic radiographs, and abdominal ultrasound. After the development of dermatologic disease, uveodermatologic syndrome was clinically suspected and cutaneous biopsy specimens were collected for histopathology.

Results: Cutaneous histopathology was consistent with vitiligo. Progressive and diffuse skin and hair depigmentation occurred over several years, but the dog’s anterior uveitis remained well controlled on relatively minimal topical anti‐inflammatory medications. No posterior segment ocular lesions developed, and the dog remained visual.

Conclusions and Clinical Relevance: This report indicates that anterior uveitis and uveal depigmentation can develop in dogs associated with vitiligo. The presence of bilateral uveitis and uveal depigmentation, concurrent with skin and hair depigmentation, is often considered suggestive of uveodermatologic syndrome in a dog. This report illustrates the importance of cutaneous histopathology to confirm a clinical suspicion even in the most suggestive of clinical presentations.
ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer
Authors: Stojanovic Lora , Abbotts Rachel , Tripathi Kaushelendra , Coon Collin M. , Rajendran Saranya , Abbasi Farid Elnaz , Hostetter Galen , Guarnieri Joseph W. , Wallace Douglas C. , Liu Sheng , Wan Jun , Calendo Gennaro , Marker Rebecca , Gohari Zahra , Inayatullah Mohammed M.A. , Tiwari Vijay K. , Kader Tanjina , Santagata Sandro , Drapkin Ronny , Kommoss Stefan , Pfisterer Jacobus , Konecny Gottfried E. , Coopergard Ryan , Issa Jean-Pierre J. , Winterhoff Boris J.N. , Topper Michael J. , Sandusky George E. , Miller Kathy D. , Baylin Stephen B. , Nephew Kenneth P. , Rassool Feyruz V.
Published: January 2025

DNA methyltransferase and poly (ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian and other cancers. Here, we showed that combining DNMTis and PARPis upregulates expression of the nucleic-acid sensor NFX1-type zinc finger-containing 1 protein (ZNFX1). ZNFX1 mediated induction of PMR in mitochondria, serving as a gateway for STING-dependent interferon/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase 3 trial for therapy-resistant ovarian cancer patients receiving bevacizumab in combination with chemotherapy. RNA-sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 as a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in ovarian cancer patients.
Supplementary Table S7 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers
Authors: Belmontes Brian , Slemmons Katherine K. , Su Chun , Liu Siyuan , Policheni Antonia N. , Moriguchi Jodi , Tan Hong , Xie Fang , Aiello Daniel Andrew , Yang Yajing , Lazaro Raul , Aeffner Famke , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Vestergaard Mikkel , Cowland Sanne , Andersson Jan , Sarvary Ian , Chen Qing , Sharma Pooja , Lopez Patricia , Tamayo Nuria , Pettus Liping H. , Ghimire-Rijal Sudipa , Mukund Susmith , Allen Jennifer R. , DeVoss Jason , Coxon Angela , Rodon Jordi , Ghiringhelli François , Penel Nicolas , Prenen Hans , Glad Sanne , Chuang Chen-Hua , Keyvanjah Kiana , Townsley Danielle M. , Butler John R. , Bourbeau Matthew P. , Caenepeel Sean , Hughes Paul E.
Published: January 2025

Supplementary Table S7: HuTRIAL TGI
Supplementary Table S5 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers
Authors: Belmontes Brian , Slemmons Katherine K. , Su Chun , Liu Siyuan , Policheni Antonia N. , Moriguchi Jodi , Tan Hong , Xie Fang , Aiello Daniel Andrew , Yang Yajing , Lazaro Raul , Aeffner Famke , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Vestergaard Mikkel , Cowland Sanne , Andersson Jan , Sarvary Ian , Chen Qing , Sharma Pooja , Lopez Patricia , Tamayo Nuria , Pettus Liping H. , Ghimire-Rijal Sudipa , Mukund Susmith , Allen Jennifer R. , DeVoss Jason , Coxon Angela , Rodon Jordi , Ghiringhelli François , Penel Nicolas , Prenen Hans , Glad Sanne , Chuang Chen-Hua , Keyvanjah Kiana , Townsley Danielle M. , Butler John R. , Bourbeau Matthew P. , Caenepeel Sean , Hughes Paul E.
Published: January 2025

Supplementary Table S5: MTAP-deleted splicing atlas
Supplementary Figure S9 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers
Authors: Belmontes Brian , Slemmons Katherine K. , Su Chun , Liu Siyuan , Policheni Antonia N. , Moriguchi Jodi , Tan Hong , Xie Fang , Aiello Daniel Andrew , Yang Yajing , Lazaro Raul , Aeffner Famke , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Vestergaard Mikkel , Cowland Sanne , Andersson Jan , Sarvary Ian , Chen Qing , Sharma Pooja , Lopez Patricia , Tamayo Nuria , Pettus Liping H. , Ghimire-Rijal Sudipa , Mukund Susmith , Allen Jennifer R. , DeVoss Jason , Coxon Angela , Rodon Jordi , Ghiringhelli François , Penel Nicolas , Prenen Hans , Glad Sanne , Chuang Chen-Hua , Keyvanjah Kiana , Townsley Danielle M. , Butler John R. , Bourbeau Matthew P. , Caenepeel Sean , Hughes Paul E.
Published: January 2025

Supplementary Figure S9. AMG 193 chemotherapy combinations are synergistic in the H292 MTAP-deleted NSCLC cell line
Supplementary Figure S7 from AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers
Authors: Belmontes Brian , Slemmons Katherine K. , Su Chun , Liu Siyuan , Policheni Antonia N. , Moriguchi Jodi , Tan Hong , Xie Fang , Aiello Daniel Andrew , Yang Yajing , Lazaro Raul , Aeffner Famke , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Vestergaard Mikkel , Cowland Sanne , Andersson Jan , Sarvary Ian , Chen Qing , Sharma Pooja , Lopez Patricia , Tamayo Nuria , Pettus Liping H. , Ghimire-Rijal Sudipa , Mukund Susmith , Allen Jennifer R. , DeVoss Jason , Coxon Angela , Rodon Jordi , Ghiringhelli François , Penel Nicolas , Prenen Hans , Glad Sanne , Chuang Chen-Hua , Keyvanjah Kiana , Townsley Danielle M. , Butler John R. , Bourbeau Matthew P. , Caenepeel Sean , Hughes Paul E.
Published: January 2025

Supplementary Figure S7. Time course SDMA analysis, CDX models versus AMG 193, and AM-9747 PDX trial
Supplementary Figure 5 from Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers
Authors: Wilding Birgit , Woelflingseder Lydia , Baum Anke , Chylinski Krzysztof , Vainorius Gintautas , Gibson Neil , Waizenegger Irene C. , Gerlach Daniel , Augsten Martin , Spreitzer Fiona , Shirai Yukina , Ikegami Masachika , Tilandyová Sylvia , Scharn Dirk , Pearson Mark A. , Popow Johannes , Obenauf Anna C. , Yamamoto Noboru , Kondo Shunsuke , Opdam Frans L. , Bruining Annemarie , Kohsaka Shinji , Kraut Norbert , Heymach John V. , Solca Flavio , Neumüller Ralph A.
Published: January 2025

High-throughput zongertinib PRISM drug sensitivity screen and biomarker analysis.
Supplementary Figure 4 from Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers
Authors: Wilding Birgit , Woelflingseder Lydia , Baum Anke , Chylinski Krzysztof , Vainorius Gintautas , Gibson Neil , Waizenegger Irene C. , Gerlach Daniel , Augsten Martin , Spreitzer Fiona , Shirai Yukina , Ikegami Masachika , Tilandyová Sylvia , Scharn Dirk , Pearson Mark A. , Popow Johannes , Obenauf Anna C. , Yamamoto Noboru , Kondo Shunsuke , Opdam Frans L. , Bruining Annemarie , Kohsaka Shinji , Kraut Norbert , Heymach John V. , Solca Flavio , Neumüller Ralph A.
Published: January 2025

High-throughput PRISM drug sensitivity screen in cancer cell lines.
Figure S6 from Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model
Authors: Liu Yonghong , Han Jincheng , Hsu Wen-Hao , LaBella Kyle A. , Deng Pingna , Shang Xiaoying , Tallón de Lara Paulino , Cai Li , Jiang Shan , DePinho Ronald A.
Published: January 2025

Relapsed tumors undergoing sustained treatment with MRTX1133 plus triple IO showed activation of ERK, NF-κB, mTOR and/or YAP signaling pathways.
Table S23 from TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Pieri Valentina , Hernández-Oliver Carolina , Álvaro-Espinosa Laura , Rojas Andrea , Sánchez Oliva , Steindl Ariane , Caleiras Eduardo , García Fernando , García-Martín Santiago , Graña-Castro Osvaldo , García-Mulero Sandra , Serrano Diego , Velasco-Beltrán Paloma , Jiménez-Lasheras Borja , Egia-Mendikute Leire , Rupp Luise , Stammberger Antonia , Meinhardt Matthias , Chaachou-Charradi Anas , Martínez-Saez Elena , Bertero Luca , Cassoni Paola , Mangherini Luca , Pellerino Alessia , Rudà Roberta , Soffietti Riccardo , Al-Shahrour Fatima , Saftig Paul , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J. , Calvo Alfonso , Palazón Asís , Valiente Manuel
Published: January 2025

Antibodies used for immunohistochemistry. Detailed information of antibodies used for immunohistochemistry stainings.
Table S15 from TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Pieri Valentina , Hernández-Oliver Carolina , Álvaro-Espinosa Laura , Rojas Andrea , Sánchez Oliva , Steindl Ariane , Caleiras Eduardo , García Fernando , García-Martín Santiago , Graña-Castro Osvaldo , García-Mulero Sandra , Serrano Diego , Velasco-Beltrán Paloma , Jiménez-Lasheras Borja , Egia-Mendikute Leire , Rupp Luise , Stammberger Antonia , Meinhardt Matthias , Chaachou-Charradi Anas , Martínez-Saez Elena , Bertero Luca , Cassoni Paola , Mangherini Luca , Pellerino Alessia , Rudà Roberta , Soffietti Riccardo , Al-Shahrour Fatima , Saftig Paul , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J. , Calvo Alfonso , Palazón Asís , Valiente Manuel
Published: January 2025

Patient-derived organotypic cultures (PDOC) treated with anti-TIMP1. Results from the Patient-derived organotypic brain cultures (PDOCs) of human brain metastasis treated with Anti-TIMP1 or Anti-TIMP1 and CD8 blockade. The table contains information corresponding to Figure 4F-G.
Figure S6 from TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Pieri Valentina , Hernández-Oliver Carolina , Álvaro-Espinosa Laura , Rojas Andrea , Sánchez Oliva , Steindl Ariane , Caleiras Eduardo , García Fernando , García-Martín Santiago , Graña-Castro Osvaldo , García-Mulero Sandra , Serrano Diego , Velasco-Beltrán Paloma , Jiménez-Lasheras Borja , Egia-Mendikute Leire , Rupp Luise , Stammberger Antonia , Meinhardt Matthias , Chaachou-Charradi Anas , Martínez-Saez Elena , Bertero Luca , Cassoni Paola , Mangherini Luca , Pellerino Alessia , Rudà Roberta , Soffietti Riccardo , Al-Shahrour Fatima , Saftig Paul , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J. , Calvo Alfonso , Palazón Asís , Valiente Manuel
Published: January 2025

TIMP1 through CD63 alters relevant properties of CD8+ T cells. Supplementary Figure 6 shows additional data corresponding to Figure 6.
Figure S5 from TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Pieri Valentina , Hernández-Oliver Carolina , Álvaro-Espinosa Laura , Rojas Andrea , Sánchez Oliva , Steindl Ariane , Caleiras Eduardo , García Fernando , García-Martín Santiago , Graña-Castro Osvaldo , García-Mulero Sandra , Serrano Diego , Velasco-Beltrán Paloma , Jiménez-Lasheras Borja , Egia-Mendikute Leire , Rupp Luise , Stammberger Antonia , Meinhardt Matthias , Chaachou-Charradi Anas , Martínez-Saez Elena , Bertero Luca , Cassoni Paola , Mangherini Luca , Pellerino Alessia , Rudà Roberta , Soffietti Riccardo , Al-Shahrour Fatima , Saftig Paul , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J. , Calvo Alfonso , Palazón Asís , Valiente Manuel
Published: January 2025

TIMP1 mediates brain metastasis in a CD8+ T cell-dependent manner. Supplementary Figure 5 shows additional data corresponding to Figure 4.
Figure S1 from TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
Authors: Priego Neibla , de Pablos-Aragoneses Ana , Perea-García María , Pieri Valentina , Hernández-Oliver Carolina , Álvaro-Espinosa Laura , Rojas Andrea , Sánchez Oliva , Steindl Ariane , Caleiras Eduardo , García Fernando , García-Martín Santiago , Graña-Castro Osvaldo , García-Mulero Sandra , Serrano Diego , Velasco-Beltrán Paloma , Jiménez-Lasheras Borja , Egia-Mendikute Leire , Rupp Luise , Stammberger Antonia , Meinhardt Matthias , Chaachou-Charradi Anas , Martínez-Saez Elena , Bertero Luca , Cassoni Paola , Mangherini Luca , Pellerino Alessia , Rudà Roberta , Soffietti Riccardo , Al-Shahrour Fatima , Saftig Paul , Sanz-Pamplona Rebeca , Schmitz Marc , Crocker Stephen J. , Calvo Alfonso , Palazón Asís , Valiente Manuel
Published: January 2025

Heterogeneity within the brain metastasis microenvironment. Supplementary Figure 1 shows additional data corresponding to Figure 1.
Taking a Swing at TIMP1-Armed Immunosuppressive Astrocytes Unleashes T cell Immunity against Brain Metastases
Authors: Lorger Mihaela , James Fiona
Published: January 2025

Priego and colleagues identify a secreted glycoprotein TIMP1, expressed downstream of the transcription factor STAT3, in a subpopulation of STAT3+ reactive astrocytes as a mediator of immunosuppression in late-stage brain metastases. The STAT3 inhibitor silibinin enhances the preclinical efficacy of the combined PD-1/CTLA4 immune checkpoint blockade, providing a rationale to translate the combination therapy into clinical use for this underserved patient group with poor prognosis.

See related article by Priego et al., p. 179
Supplementary Tables from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Supplementary Table file to be published with manuscript
Suppl Figure 7 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Supplementary Figure 7
Suppl Figure 6 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Supplementary Figure 6
Suppl Figure 4 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Supplementary Figure 4
Suppl Figure 1 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Supplementary Figure 1
Data from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia
Authors: Sonowal Himangshu , Rice William G. , Bejar Raphael , Byun Joo-Yun , Jung Seung Hyun , Sinha Ranjeet , Howell Stephen B.
Published: January 2025

Abstract
Tuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia (AML). Nonclinical studies show that TUS targets key prosurvival kinases with IC50 values in the low nmol/L range, including SYK, wild-type (WT) and mutant forms of FLT3, mutant but not WT forms of KIT, RSK2, and TAK1–TAB1 kinases, and indirectly suppresses expression of MCL1. Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3-mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax (VEN) or 5-azacytidine. In vitro, TUS demonstrated potent killing of AML lines [concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) = 1.3–5.2 nmol/L] and Ba/F3 cells expressing WT (GI50 = 9.1 nmol/L) or various mutant forms of FLT3 (GI50 = 2.5–56 nmol/L). In AML lines, the multikinase targeting capacity of TUS suppressed phosphorylation of SYK, FLT3, STAT5, MEK, ERK, AKT, mTOR, 4E-BP1, and S6K kinases. Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to VEN (1900 fold), navitoclax, and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to VEN, yet the TUS/VEN combination exhibited synergy in the NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.
Significance:
This article reports preclinical development of TUS, an oral kinase inhibitor currently in clinical development for treatment of AML. The article covers the studies of TUS activities on cellular targets and the nonclinical studies that supported the advancement of TUS to a phase I/II trial of TUS/VEN in refractory AML and a phase I/II trial of TUS/VEN/5-azacytidine in newly diagnosed patients with AML (NCT03850574).
Nicotine Metabolism-Related Genetic Polymorphisms Associated with Smoking Cessation in Korean Men: A Candidate Gene Association Study in a Korean Cohort
Authors: Park Jae-Min , Choi Ja-Eun , Lee Ji-Won , Hong Kyung-Won
Published: January 2025

Introduction: Smoking cessation is influenced by genetic and environmental factors, particularly genetic polymorphisms influencing nicotine metabolism. This study investigated the association between specific nicotine metabolism-related genetic variants and smoking cessation among Korean men.
Methods: A candidate gene association study was performed targeting single nucleotide polymorphisms (SNPs) within nicotine metabolism-related genes. Participants were categorized as never, former, or current smokers. A Genetic Risk Score (GRS) was computed using significant SNPs to evaluate cumulative genetic influence.
Results: Six SNPs showed significant association with smoking cessation in a Korean cohort. A higher GRS was associated with increased odds of current smoking compared to former smoking (OR = 1.18, 95% CI: 1.12–1.25, P < 0.001).
Conclusion: This study indicates a substantial genetic component in smoking cessation, highlighting the importance of population-specific approaches, and may aid personalized smoking cessation strategies based on genetic predisposition among Koreans.