bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-scale Consistency Deep Lifelong Cross-modal Hashing
Authors: Xu Liming , Li Hanqi , Shao Jie , Zeng Xianhua , Li Weisheng
Published: November 2024

Deep cross-modal hashing methods provide effective and efficient solutions for large-scale cross-modal retrieval. However, existing cross-modal hashing methods fail to capture the dynamic changes of real-world data, and suffer from serious performance degradation when retrieving streaming data. In this paper, we propose a novel hashing method to achieve accurate cross-modal retrieval under continuous and streaming scenarios. Specifically, regularization-based lifelong learning module is introduced to balance plasticity for learning new knowledge and stability for maintaining old knowledge, and update incremental hash codes without retraining cumulative data. Then, multi-scale consistency network which employs multi-scale feature fusion module to extract fine-grained features among multi-scale modalities is introduced to learn multi-level semantic representations with consistency. Additionally, modality alignment with variational information bottleneck is designed to remove irrelevant information and obtain unified representation, which can be proved to be effective to yield high-quality hash code with new and old knowledge. Extensive experiments show that ours gains the advanced performance and the better adaptability to continuous and streaming environments.
Proposed Ninth Edition TNM Staging System for Lung Cancer: Guide for Radiologists
Authors: Klug Maximiliano , Kirshenboim Zehavit , Truong Mylene T. , Sorin Vera , Ofek Efrat , Agrawal Rishi , Marom Edith Michelle
Published: November 2024

A comprehensive understanding of the proposed updates in the ninth edition of the TNM staging system for lung cancer enables radiologists to provide accurate clinical radiologic staging, enhancing precision in predicting therapy outcomes and facilitating an individualized approach for each patient.
Accelerated Cardiac MRI with Deep Learning–based Image Reconstruction for Cine Imaging
Authors: Klemenz Ann-Christin , Reichardt Linda , Gorodezky Margarita , Manzke Mathias , Zhu Xucheng , Dalmer Antonia , Lorbeer Roberto , Lang Cajetan I. , Weber Marc-André , Meinel Felix G.
Published: November 2024

Deep learning–based cardiac cine sequences performed over three cardiac cycles led to substantially reduced acquisition time, while no differences in image quality and volumetric results compared with a standard clinical sequence could be detected.
Input-specific properties of excitatory synapses on oxytocin receptor-expressing neurons in the lateral septum
Authors: George Kiran , Ahmad Mohiuddin
Published: November 2024

This is the first identification and characterization of the cortical synaptic inputs that drive the oxytocin receptor (OXTR)-expressing neurons in the lateral septum (LS), which are involved in diverse affective behavior. The strongest cortical inputs to LS OXTR neurons are from the posteromedial amygdala cortex, an understudied cortical region that is beginning to gain prominence for its role in social behavior. The synapses from these projections show differences in properties compared to inputs from the ventral hippocampus.
Current Status, Challenges, and Opportunities of Evaporative Cooling for Building Indoor Thermal Comfort Using Water as a Refrigerant: A Review
Authors: Ishugah Tom Fred , Kiplagat Jeremiah , Madete June , Musango Jones
Published: November 2024

This study presents a review of advances made in evaporative cooling technologies, emphasizing their application in indoor thermal comfort. It highlights that the rising demand for cooling has primarily been met by conventional mechanical vapor compression systems. However, these systems face two significant issues: high electrical energy requirements and the use of refrigerants like chlorofluorocarbons (CFCs) and hydrofluorocarbons (HFCs), which contribute to ozone layer depletion and global warming. The findings indicate that evaporative cooling technology is a promising alternative due to its low energy demand and potential to integrate renewable energy, therefore enhancing its environmental benefits. The study also details various evaporative cooling technologies, recent improvements in their performance, practical applications, challenges, and opportunities for providing indoor thermal comfort.
Enhanced Accuracy and Real‐Time Monitoring: A Hybrid Communication Architecture for Fertility Monitoring
Authors: Siddiqui Shama , Khan Anwar Ahmed , Siddiqui Muhammad Shoaib , Dey Indrakshi
Published: November 2024

Human fertility monitoring, whether for natural conception or artificial insemination and fertilization, presents a significant challenge for both physicians and patients. Detecting the presence of eggs in the fallopian tube and timely communication of this information to the healthcare team and the patient remains an elusive goal; in this paper, we propose a novel, hybrid communication architecture for this purpose. Our architecture combines an intrabody nano‐sensor network for detecting the presence of eggs in the female fallopian tube with a body area network (BAN) to receive information from the intrabody network and transmit it over‐the‐air to the required point (physician, nurse, or patient). To investigate the system’s performance, we conducted preliminary simulations using a particle‐based stochastic simulator. The results revealed interesting relationships between information rates achievable, signal‐to‐noise ratio (SNR), distance, number of sensors, detection delay, viscosity, and temperature. Specifically, we found that increasing viscosity led to an increase in detection delay, while increasing temperature had the opposite effect. With data rates of up to 300 Mbps achievable at an SNR of 45, our proposed architecture ensures near‐zero latency, minimum energy consumption, and high throughput for efficient fertility monitoring. By integrating advanced communication technologies and sensor networks, our approach paves the way for improved fertility monitoring, enabling timely interventions and personalized care. These findings contribute to the development of a cooperative intra‐ to extra‐body network that enhances accuracy and enables real‐time monitoring for effective fertility management.
Evaluation of the Optimum Dietary Arachidonic Acid Level and Its Essentiality for Black Seabream (Acanthopagrus schlegelii): Based on Growth and Lipid Metabolism
Authors: Bao Yangguang , Shen Yuedong , Zhao Wenli , Yang Bingqian , Zhao Xiaoyi , Tao Shunshun , Sun Peng , Monroig Óscar , Zhou Qicun , Jin Min
Published: November 2024

The aim of this study was to investigate how dietary arachidonic acid (ARA) level affects growth performance and lipid metabolism in juvenile black seabream (Acanthopagrus schlegelii). A feeding trial was conducted for 8 weeks, during which the fish (0.99 ± 0.10 g) were fed six isonitrogenous and isolipidic diets with varying ARA levels of 0.1%, 0.59%, 1.04%, 1.42%, 1.94%, and 2.42%. Fish fed the diet with 1.42% ARA had significantly higher weight gain (WG) and specific growth rate (SGR) than the other groups (p < 0.05), except for the ARA1.04. As the ARA level increased, the liver and muscle effectively accumulated n−6 polyunsaturated fatty acids (n−6 PUFAs; p < 0.05). However, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and n−3 PUFA contents of liver and muscle significantly decreased by increasing dietary ARA level (p < 0.05). Results of liver histology showed dramatically increased vacuolar fat droplets leading to hepatic fat pathological changes in fish fed diets with ARA levels of 1.94% and 2.42% (p < 0.05). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities increased with increasing dietary ARA level which was accompanied with elevated liver lipid content (p < 0.05). Consistently, triglyceride (TG) and nonesterified fatty acid (NEFA) concentrations of serum and liver, and serum cholesterol (CHO) concentration increased (p < 0.05). As the level of dietary ARA increased, the indicators of lipid metabolism such as sirtuin 1 (sirt1) and peroxisome proliferator‐activated receptor α (pparα) also increased (p < 0.05). However, after reaching their peak in ARA1.04 group, the level of these indicators declined (p < 0.05). The same trend was observed for the expression of genes related to the downstream pathways. While the mRNA levels of sterol regulatory element–binding protein‐1 (srebp-1) and its downstream genes were markedly increased with the increase of dietary ARA level (p < 0.05). In conclusion, these data suggested that the optimum dietary ARA requirement of A. schlegelii is 1.03% of diet based on the WG. The study revealed that a diet containing 1.04% ARA can activate the expression levels of sirt1 and pparα leading to promoted lipolysis. However, dietary ARA levels of ≥1.42% induced lipid accumulation in the liver, as they suppressed the mRNA levels of sirt1 and pparα, while elevating the expression level of genes related to lipogenesis.
Prevalence of Intestinal Parasite Infection Among Prison Inmates and Their Associated Risk Factors at Hosanna Town, South–Central Ethiopia: A Cross‐Sectional Study
Authors: Mussema Abdulhakim , Tafesse Weynshet , Temam Leyla
Published: November 2024

Introduction: In developing countries, prisoners are one of the marginalized groups most susceptible to intestinal parasite infection due to inadequate living conditions, malnutrition, a lack of potable water, overcrowding, and poor hygiene. Thus, this study is aimed at assessing the prevalence and associated factors of intestinal parasitic infections among inmates of Hosanna town prison.

Materials and Methods: An institution‐based cross‐sectional study was conducted in Hosanna Town’s prisoners from June 1 to July 30, 2022, on a total of 420 inmates. The study participants were chosen using a simple random sampling technique. Sociodemographic, sanitation, hygienic, and related information were collected by using pretested questionnaires. In addition, about 5 g of stool sample was collected using a leak‐proof plastic stool cup and examined microscopically by using direct wet mount preparation and formalin–ether concentration techniques, and data were analyzed by using SPSS Version 25.

Results: This study indicated an overall 39.2% (95% CI: 34.6–44.1) prevalence of intestinal parasites (165/420). Entamoeba histolytica/dispar was the most prevalent intestinal parasite found, followed by Giardia lamblia, Ascaris lumbricoides, Hookworms, Taenia species, and Schistosoma mansoni. About 3.1% of participants had dual parasitic infections. In addition, there is a significant association in multivariable logistic regression analysis between intestinal parasitic infection and various hygiene practices such as not using soap when washing hands after using the toilet ((aOR 1.62 (95% CI: 1.06–2.48)), p ≤ 0.027), not regularly washing hands before meals ((aOR 2.83 (95% CI: 1.79–4.46)), p ≤ 0.001), poor hand hygiene overall ((aOR 3.18 (95% CI: 2.00–4.99)), p ≤ 0.001), not trimming fingernails ((aOR 2.09 (95% CI: 1.29–3.37)), p ≤ 0.003), and length of time in prison (aOR: 4.27, 95% CI: 22.62–6.96, p = 0.001).

Conclusions: The findings of the study indicated that the overall prevalence of intestinal parasitic infections was 39.2%, with 38.8% of the infected individuals falling within the 25–34 age range. Additionally, 67.3% of those infected had been imprisoned for over a year. Furthermore, the personal hygiene status of prisoners was found to be substantially correlated with the presence of parasites. Hosanna town prison should ensure sufficient sanitary supplies, promote personal hygiene, and implement health education. Regular medical checkups and routine nail‐clipping sessions are crucial for maintaining cleanliness and reducing parasite transmission among inmates.
Enhancing pH Modulation and Calcium Ions Release in External Resorption Artificial Defects
Authors: Kheradyar Azadeh , Adel Mamak , Sirati-Sabet Majid , Kolahdouzan Alireza , Shafagh Sahar
Published: November 2024

Background and Objectives: Diffusion of hydroxide (OH)− and calcium (Ca)++ ions through dentin may cease external root resorption. Calcium hydroxide (Ca(OH)2), mineral trioxide aggregate (MTA), and calcium‐enriched mixture (CEM) cement are the choices for this purpose due to their optimal properties. This study sought to analyze the effects of ultrasonic activation (UA) on pH and the release of calcium ions from Ca(OH)2, MTA, and CEM cement in external root resorption artificial defects.

Materials and Methods: This in vitro research involved the instrumentation and shaping of the root canals of 150 single‐rooted teeth (#F4). External defects were intentionally made on the middle one‐third of the root surface. Teeth were randomly assigned to a negative control group (n = 10), one positive control group (n = 20), and six experimental groups (each n = 20) according to the root canal filling material (Ca(OH)2 paste, MTA, CEM, gutta‐percha, Ca(OH)2 paste+ultrasonic, MTA + ultrasonic, and CEM + ultrasonic). Ultrasonic energy was transferred to the test materials using a #25 spreader. Ca++ concentration and pH were measured after 1, 7, 15, and 30 days in all groups. Statistical analysis involved the use of repeated measure analysis of variance (ANOVA) and paired‐sample T‐test (P ≤ 0.05).

Results: The levels of calcium ions and pH increased significantly over time in all groups (P < 0.001). There were significant differences between the experimental groups in terms of pH and the concentration of released calcium ions at different times (P < 0.001). The Ca(OH)2 plus ultrasonic energy group ranked first, while the gutta‐percha group ranked last in terms of release of calcium ions and pH.

Conclusion: The Ca(OH)2, MTA, and CEM cement groups showed an increase in pH and the release of calcium ions at the external root resorption defects. Additionally, the application of ultrasonic energy increased the release of calcium ions at these sites.
Comparison of Brachial Compression Versus Ulnar Compression on Radial Artery Diameter: A Randomized Controlled Trial
Authors: Bahrami Fatemeh , Mirshafiee Shayan , Mansouri Pejman , Eftekhari Mohammadreza , Vahidi Mohammad , Baharvand Fateme , Farsani Ehsan Moradi , Vahidi Hamed
Published: November 2024

Objectives: This study is aimed at comparing the effectiveness of ulnar compression and brachial compression in inducing radial artery dilatation.

Methods: This randomized crossover study included 30 patients undergoing elective diagnostic transradial coronary angiography. Ulnar compression and brachial compression maneuvers were performed in two groups. Radial artery diameter and cross‐sectional area were measured at baseline and remeasured every 30 s (up to 2 min) after the interventions.

Results: Both ulnar compression and brachial compression maneuvers successfully increased radial artery diameter for up to 60 s following the interventions. There were no statistically significant differences between the two groups after adjusting for baseline measurements. However, each treatment group showed a significant increase in indicators up to 60 s, followed by a subsequent decrease. The maximum radial artery diameter occurred at 60 s after the removal of compression in both groups.

Conclusion: Ulnar compression and brachial compression maneuvers demonstrated effectiveness in inducing radial artery dilation for a limited duration. These maneuvers may reduce the occurrence of access failure during radial artery cannulation. No significant differences were observed between the two maneuvers, indicating that they can be used interchangeably based on clinician preference. So, because the ulnar compression is simpler and more feasible for the patients, it can be considered instead of brachial compression.

Trial Registration:IRCT20230209057372N1.
Comparative Analysis of Big Five Personality Traits and Emotional Regulation as Predictors of Happiness Among Nursing Students in Jordan and Saudi Arabia
Authors: Shdaifat Emad , Shudayfat Tamadur , Alshowkan Amira
Published: November 2024

Background: Happiness is crucial for human wellbeing. Nursing students encounter distinct challenges such as stress, burnout, and emotional exhaustion, which can negatively impact their mental health. Cultural and societal factors also influence happiness.

Objective: This study conducted a comparative analysis of Big Five personality traits and emotional regulation (ER) as predictors of happiness among nursing students in Saudi Arabia and Jordan.

Methods: This cross‐sectional study included 739 nursing students from Jordan and Saudi Arabia who were selected using a multistage sampling technique. The instruments utilized in this study were the short version of the Big Five Inventory for assessing personality, Oxford Happiness Inventory for measuring happiness levels, and Emotional Regulation Questionnaire for evaluating ER. To identify the predictors of student happiness, stepwise regression analysis was conducted, and cross‐country comparisons were made using a “pool analysis” method.

Results: The findings indicated that 62.1% of the participants reported moderate levels of happiness, whereas 36.0% reported high levels. There were significant differences in happiness levels between Jordan and Saudi Arabia (p = 0.003), with Jordanian students reporting lower happiness levels. In Saudi Arabia, there were significant variations based on age (p = 0.049) and academic year (p = 0.013). Multiple regression analysis revealed that higher agreeableness, extraversion, and conscientiousness were positively associated with happiness while openness had a weak association. Conversely, higher Neuroticism, being in Jordan, and being male were negatively associated with happiness. Nominal regression analysis indicated that extraversion and agreeableness are significant predictors of higher levels of happiness, whereas neuroticism is associated with lower levels of happiness. Furthermore, males and non‐Saudis were more likely to report lower levels of happiness.

Conclusion: This study revealed notable determinants of happiness among nursing students in Saudi Arabia and Jordan. ER, Big Five personality traits, and demographic factors play influential roles. Overall, the robust regression model emphasized the dependability of these findings, providing valuable insights for nursing education and interventions aimed at improving student wellbeing. From a practical standpoint, these findings can guide the development of personalized mental health support programs and interventions designed to enhance the happiness and wellbeing of nursing students.
CD40 Agonist on Patient-Derived Xenograft Mice for the Treatment of B-Cell Acute Lymphoblastic Leukemia
Authors: Bellaye Pierre-Simon , Georgievski Aleksandra , Ballerini Paola , Bouslama Boutheina , Richard Corentin , Boidot Romain , Chevreux Guillaume , Legros Véronique , Guy Julien , Racine Jessica , Collin Bertrand , Garrido Carmen , Quéré Ronan
Published: November 2024

Purpose:

Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo.

Experimental Design:

The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft mouse models.

Results:

Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the ERK pathway, which led to the induction of apoptosis and disruption of cell-cycle progression. Cotreatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the proapoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in patient-derived xenograft mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre–B-ALL (EGIL B-III) that expressed CD40 than on common B-ALL (EGIL B-II) that lacked CD40 expression.

Conclusions:

These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.
Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex
Authors: Schultz Kris Ann P. , MacFarland Suzanne P. , Perrino Melissa R. , Mitchell Sarah G. , Kamihara Junne , Nelson Alexander T. , Mallinger Paige H.R. , Brzezinski Jack J. , Maxwell Kara N. , Woodward Emma R. , Gallinger Bailey , Kim Sun Young , Greer Mary-Louise C. , Schneider Kami Wolfe , Scollon Sarah R. , Das Anirban , Wasserman Jonathan D. , Eng Charis , Malkin David , Foulkes William D. , Michaeli Orli , Bauer Andrew J. , Stewart Douglas R.
Published: November 2024

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.
Abstract A006: Development of a syngeneic transplant rat model for the identification of an mRNA signature associated with metastatic hepatocellular carcinoma
Authors: Azcárraga Acosta Theresa G , Vazquéz Carolina Piña , Hernández Galdámez Hury V , Rubio Nava Karla M , Linares Josué Guzmán , Díaz Ivonne Ramírez , Barreto Guillermo , Aguilar Chaparro Mario A , Günther Stefan , Treviño Saul Villa , De la Garza Mireya , Téllez Teresita del niño Jesús Flores , Vásquez Garzón Veronica R
Published: November 2024

Approximately 70% of patients with hepatocellular carcinoma (HCC) die of metastasis, mainly in the lung, due in part to late diagnosis. Therefore, in vivo models that are representative of metastatic HCC biology in patients must include factors that are essential for metastasis development, such as an immunocompetent system and a tumor microenvironment with homotypic interactions. This will allow the identification of new prognostic biomarkers for patients with metastatic HCC that are efficient and accessible. We developed two hepatocellular carcinoma cell lines for syngeneic transplant models in immunocompetent rats: Samy (nonmetastatic) and Samy Met (metastatic). These cell lines allow the development of cancer and metastasis in a homotypic environment with a complete immune system; therefore, they are expected to be representative of what happens in patients with metastatic HCC. Both cell lines were biologically characterized, and the primary tumors they produced were used in a comparative transcriptomic study to identify a metastatic HCC molecular signature that may function as a prognostic biomarker. The differentially expressed genes (DEGs) were related to relevant biological processes, such as metastasis, cancer stem cells (CSCs), and tumor growth, and all of these processes are essential for cancer progression. Among the top 50 DEGs, an mRNA firm was assembled, including 3 upregulated genes (ITGB6, SEMA3F, and NDC80) and 7 downregulated genes (COL15A1, ATP13A4, C18ORF26, PRKG2, ITM2A, IGSF9B, and CNTN1). The firm was related to poor survival in patients with HCC and had good accuracy in predicting macrovascular invasion, which is a strong predictor of poor HCC outcome, both after surgical resection and after liver transplantation.

Citation Format: Theresa G Azcárraga Acosta, Carolina Piña Vazquéz, Hury V Hernández Galdámez, Karla M Rubio Nava, Josué Guzmán Linares, Ivonne Ramírez Díaz, Guillermo Barreto, Mario A Aguilar Chaparro, Stefan Günther, Saul Villa Treviño, Mireya De la Garza, Teresita del niño Jesús Flores Téllez, Veronica R Vásquez Garzón. Development of a syngeneic transplant rat model for the identification of an mRNA signature associated with metastatic hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A006.
Abstract A011: Binding of the exon junction complex shapes the landscape of m6A in RNA - a possible source of m6A dysregulation in cancer
Authors: Price Andrew , Sendinc Erdem , Purse Byron , Gregory Richard I , Stengel Gudrun
Published: November 2024

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNA. Increasing evidence shows that m6A is involved in the biological functions of cancer cells, including proliferation, invasion, metastasis, and drug resistance. Dysregulation of m6A deposition and its associated machinery, including writers, erasers and readers, is observed in multiple cancer types, and the dysregulation profiles have potential as diagnostic, prognostic and/or predictive biomarkers. In healthy cells, m6A modifications are installed co-transcriptionally by the writer enzyme METTL3, resulting in an enrichment of m6A in the 3’UTR of genes. For many years, the mechanistic origin for the m6A enrichment in the 3’UTR was unclear. Recently, the Gregory lab and others have developed a model where the exon junction complex (EJC) plays a key role in directing m6A deposition by hindering access of METTL3 to short exons and exon/intron junctions. In this study, we build on this model using a novel, proximity-barcoding based assay (EpiPlex™) for the simultaneous detection of m6A and inosine. Working with HEK293T cells, we modulated the activity of a central component of the EJC, the RNA helicase EIF4A3. Both genetic knockdown and chemical inhibition of EIF4A3 resulted in increased m6A levels and more diffuse localization at the 3’UTR. New m6A sites appear on short exons and near exon/intron junctions. These data corroborate the necessity of EIF4A3 for EJC assembly and confirm the model that the EJC prevents METTL3 from accessing and methylating exon junctions. Additionally, we find that blocking of the exon junction is reliant on EIF4A3’s helicase activity. Although the role of EJC in the cell cycle and cancer are still investigational, it is likely that m6A dysregulation is induced by aberrant EJC function, which presents a potential molecular mechanism for the dysregulation of multiple genetic pathways in cancer progression.

Citation Format: Andrew Price, Erdem Sendinc, Byron Purse, Richard I Gregory, Gudrun Stengel. Binding of the exon junction complex shapes the landscape of m6A in RNA - a possible source of m6A dysregulation in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A011.
Abstract A030: Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics
Authors: Berglund Peter
Published: November 2024

HDT Bio, a Seattle biotech company, has developed a platform technology based on self-amplifying RNA and a proprietary nanoparticle delivery system. mRNA have been increasingly used in the development of vaccines in both infectious diseases and oncology. Especially LNP- delivered mRNA has been deployed, following the success during the COVID pandemic, However, self-ampliying RNA (repRNA) possesses several features of particular relevance to cancer medicine. HDT has developed a nanoparticle technology named LION[TM] to safely and effectively deliver RNA to patients. In vivo studies showed that repRNA not only is capable of delivering robust cell-mediated immune responses but also doing so with a significanlty improved safety profile compared to administration using LNP-based formulations. These data will be presented in the context of clinical safety data with repRNA/LION. Furthermore, repRNA/LION was siuccessfully used to induce robust T-cell responses against tumor antigens, and will be discussed.

Citation Format: Peter Berglund. Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A030.
Abstract B001: CircRNA-derived neoantigen identification in cancer vaccine development
Authors: Zheng Yi-Cian , Chen Chun-Kan
Published: November 2024

Immunotherapy has been a popular topic in combating cancer for its great performance in specificity, versatility and durability recently. Cancer vaccines targeting neoantigens have shown clinical efficacy against cancer, eliciting long-lasting immune response and offering a more selective therapeutic approach with less side effects. However, rare mutation rates and low expression levels of neoantigen make it challenging to identify suitable neoantigens. Traditionally, researchers focus on the canonical mRNA transcriptome and proteome to find potential targets. Recent studies suggest that exploring the non-canonical transcriptome and proteome, particularly circular RNAs (circRNAs), can expand the search. CircRNAs, endogenously formed by the unique back-splicing events during pre-RNA processing, can serve as templates for protein synthesis. Some of these non-canonical peptides are specifically expressed in cancer cells, making circRNAs a valid source for neoantigen discovery. We have developed high-throughput circRNA reporter screening methods and mass spectrometry-based peptidomic workflow to pinpoint translating circRNAs and their derived peptides. Using these techniques, we have identified circRNA-derived neoantigens in breast cancer (BC) cell lines that can be used as possible targets for cancer vaccines. These circRNA-derived neoantigens are immunogenic and can trigger dendritic cell (DC) maturation and T cell activation in vitro. Next, we will test these findings by transferring to in vivo mouse system. We will assess cancer vaccine efficacy by targeting the neoantigens using syngeneic mouse tumor models. Our long- term goal is to apply the circRNA neoantigen identification technology to BC patient samples to facilitate cancer vaccine development and improve cancer immunotherapy. Our work will demonstrate the potential of circRNA-derived non canonical neoantigens in cancer vaccines, serving as a crucial first step to prove their effectiveness in therapy. By expanding our search beyond the traditional transcriptome and proteome, we will explore new targets and transform the neoantigen-based treatment. This innovative effort shifts the current understanding of neoantigen sources and opens up new possibilities for targeted cancer therapy strategies.

Citation Format: Yi-Cian Zheng, Chun-Kan Chen. CircRNA-derived neoantigen identification in cancer vaccine development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B001.
Abstract I001: Long noncoding RNAs at the intersection of cancer pathways
Authors: Dimitrova Nadya
Published: November 2024

There are thousands of long noncoding RNAs (lncRNAs) in mammalian genomes. Yet, their functional significance in health and disease states remains poorly understood. We investigate the intersection of lncRNAs and cancer biology. On the one hand, we dissect the molecular and cellular mechanisms by which lncRNAs modulate cancer pathways. On the other hand, we develop mouse models to interrogate the roles of lncRNAs in tumorigenesis at the organismal level. Our work has uncovered insights into the transcriptional regulatory roles of lncRNAs during the cellular response to genotoxic and oncogenic stress. In parallel, we have elucidated roles of lncRNAs as drivers of tumor progression and metastatic dissemination. The combined functional and mechanistic studies have revealed the importance of lncRNAs in cancer and suggest therapeutic approaches to target lncRNAs or their downstream effectors in cancer.

Citation Format: Nadya Dimitrova. Long noncoding RNAs at the intersection of cancer pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I001.
Abstract I005: Exploiting the immunoregulatory effect of double-stranded RNAs for cancer therapeutics
Authors: Lee Keonyong , Ku Jayoung , Widowati Tria Asri , Kim Namwook , Park Soo Young , Ryu Han Suk , Kim Yoosik
Published: November 2024

Introns are found in all eukaryotes and are one of the defining characteristics of eukaryotes. After transcription, pre-mRNAs undergo splicing, and introns are excised in the lariat structure. Since excised introns are degraded quickly after debranching, they have been considered as byproducts of gene expression, and their post-splicing role in the cells remains unclear. Here, we find that the inhibition of intron debranching process by depleting a debranching enzyme, DBR1, results in hyperactivation of protein kinase R (PKR) due to accumulation of intron lariat-derived transposable elements (TEs) that can adopt double-stranded secondary structure. Through in vitro PKR-binding assay, we show that PKR strongly binds to intron lariat RNAs harboring TEs, especially inverted Alu repeats. Interestingly, these TE-containing lariat RNAs are retained in the nucleus, but are released to the cytosol during mitosis, where they activate PKR, resulting in aberrant mitotic progression and apoptosis. We further exploit the lariat RNA-PKR interaction during mitosis and show that DBR1 depletion and anti-mitotic chemotherapy drugs can synergistically induce cancer cell death both in vitro and in vivo. Lastly, we perform docking simulation-based screening of DBR1-inhibitory small molecules. Collectively, our findings underscore the significance of intron turnover in avoiding innate immune activation and further suggest a potential strategy to enhance the efficacy of anti-mitotic drugs by targeting intron processing.

Citation Format: Keonyong Lee, Jayoung Ku, Tria Asri Widowati, Namwook Kim, Soo Young Park, Han Suk Ryu,Yoosik Kim. Exploiting the immunoregulatory effect of double-stranded RNAs for cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I005.
Abstract PR002: Hypoxia-induced epigenetic changes coordinate transcription start site selection and translational control through remodeling of 5’UTRs
Authors: Watt Kathleen , Dauber Bianca , Szkop Krzysztof J , Lee Laura , Jovanovic Predrag , Chen Shan , Masvidal Laia , Tandoc Kristofersson , Palia Ranveer , Topisirovic Ivan , Larsson Ola , Postovit Lynne-Marie
Published: November 2024

Adaptation to hypoxia enhances cancer cell malignancy and negatively impacts patient outcomes. Reprogramming of mRNA translation is an essential component of the hypoxia-adaptive response. During hypoxia, cells undergo a global decrease in protein synthesis. However, translation of subsets of transcripts encoding stress-response, survival and stemness factors is increased. This selective regulation is thought to be governed largely via the interactions between specific mRNA features and remodeling of the translational apparatus. However, our understanding of the mechanisms that govern translational perturbations under hypoxia remains incomplete. Here, we interrogated the effects of hypoxia on global changes in histone methylation and transcription start site (TSS) selection, coupled with monitoring corresponding alterations in total mRNA levels and translation efficiencies on a genome-wide scale in T47D breast cancer cells and H9 human embryonic stem cells. This revealed widespread epigenetic alterations leading to TSS switching and extensive remodeling of 5’UTRs, and allowed us to map the impact of specific 5’UTR features on translation efficiency under hypoxia. Pyruvate Dehydrogenase Kinase 1 (PDK1), a key enzyme in orchestrating metabolic adaption to hypoxia, undergoes TSS switching leading to increased availability of efficiently translated 5’UTR isoforms, and we show that this effect is coordinated at an epigenetic level. Therefore, our findings uncover a mechanism driving translational reprogramming under hypoxia, whereby alterations in translational apparatus are orchestrated with epigenetic perturbations that result in 5’UTR remodeling of the transcriptome.

Citation Format: Kathleen Watt, Bianca Dauber, Krzysztof J Szkop, Laura Lee, Predrag Jovanovic, Shan Chen, Laia Masvidal, Kristofersson Tandoc, Ranveer Palia, Ivan Topisirovic, Ola Larsson, Lynne-Marie Postovit. Hypoxia-induced epigenetic changes coordinate transcription start site selection and translational control through remodeling of 5’UTRs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR002.
Abstract PR013: Identification, therapeutic potential, and regulatory networks of tumor suppressing miRNAs in angiosarcoma
Authors: Liu Bozhi , Murphy Ant , Benton Annaleighh , Gartenhaus Lauren E. , Hanna Jason A
Published: November 2024

Angiosarcoma (AS) is an aggressive cancer of endothelial cells arising in the blood and lymphatic vasculature. Among all the rare soft tissue sarcomas, AS patients have some of the worst outcomes, with an estimated 5-year survival rate of only 30%. In mouse models, we discovered that endothelial loss of miRNAs through the conditional deletion of Dicer1 leads to AS development. Since most cells, and even most cancer cells require some level of miRNA expression for survival, this demonstrates that endothelial cells are uniquely sensitive to miRNA loss mediated transformation. Consistent with this finding we have found that Dgcr8 deletion with aP2-Cre phenocopies Dicer1 loss resulting in AS with 100% penetrance. This implicates miRNAs as critical tumor suppressors in AS. Thus, we tested the repurposing of the antibiotic, enoxacin as an anticancer therapeutic based on its known potential to enhance miRNA processing. Indeed, enoxacin significantly reduces AS cell proliferation and migration. Small RNA-sequencing revealed that several known tumor suppressing miRNAs were increased in abundance following enoxacin treatment. To discover other miRNAs critical in AS, we conducted an unbiased CRISPR-Cas9 screen with a miRNA specific gRNA library and identified several potential candidates. Among these, our preliminary data indicates miR-410 as a potent tumor suppressor. To determine the miRNA and mRNA target interactome of these miRNAs in AS, we are utilizing AgoTRIBE. This method fuses the Ago2 miRNA effector protein to the RNA editing domain of ADAR2 to generate RNA edits on transcripts that are associated with Ago2-miRNAs as determined by RNA-seq. This work will further utilize in vitro and in vivo tools to dissect the underlying biology and role of these tumor suppressing miRNAs in AS. We aim to leverage these findings to develop novel strategies for therapeutic interventions, including miRNA-based approaches that may improve patient outcomes.

Citation Format: Bozhi Liu, Ant Murphy, Annaleighh Benton, Lauren E. Gartenhaus, Jason A Hanna. Identification, therapeutic potential, and regulatory networks of tumor suppressing miRNAs in angiosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR013.
Table 1 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Model parameters.
Supplementary Figure S.4 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.4
Supplementary Figure S.32 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.32
Supplementary Figure S.3 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.3
Supplementary Figure S.28 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.28
Supplementary Figure S.23 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.23
Supplementary Figure S.22 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers
Authors: Kuznetsov Maxim , Adhikarla Vikram , Caserta Enrico , Wang Xiuli , Shively John E. , Pichiorri Flavia , Rockne Russell C.
Published: November 2024

Supplementary Figure S.22
Gadoxetic Acid-Enhanced Magnetic Resonance Imaging Features Can Predict Immune-Excluded Phenotype of Hepatocellular Carcinoma
Authors: Ueshima Eisuke , Sofue Keitaro , Kodama Takahiro , Yamamoto Shuhei , Komatsu Masato , Komatsu Shohei , Ishihara Nobuaki , Umeno Akihiro , Yamaguchi Takeru , Hori Masatoshi , Fukumoto Takumi , Takehara Tetsuo , Murakami Takamichi
Published: November 2024

Introduction: Immunotherapy is the first-line treatment for intermediate-advanced stage hepatocellular carcinoma (HCC), although its outcomes vary. This study aimed to identify imaging biomarkers of immunotherapy susceptibility linked to gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and immune phenotypes, particularly immune-excluded phenotypes, with a tumor immune barrier. Methods: We performed immunohistochemical staining with a CD8+ antibody, and samples were classified into immune-inflamed, -intermediate, -excluded, and -ignored phenotypes. We assessed EOB-MRI findings obtained from 104 patients who underwent hepatectomy for HCC and evaluated the relationship between MRI findings and immune phenotype. Spatial transcriptome analysis of tumor tissues in each immune phenotype was performed to characterize the MRI findings. For validation, we analyzed the treatment effect on 60 nodules in another cohort of 27 patients who received combined immunotherapy using anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies. Results: HCCs with rim arterial phase hyperenhancement (APHE) (odds ratio [OR] 17.3, p = 0.009), peritumoral enhancement in the arterial phase (OR: 8.6, p < 0.004), and intermediate intensity on the hepatobiliary phase (HBP) measured with a visual 3-point scale (OR: 28.2, p = 0.002) were associated with immune-excluded phenotype, where tumors tended to be larger and of the single nodular type with extranodular growth and confluent multinodular rather than the simple nodular type. Spatial transcriptome analysis revealed a spatial relationship among cytotoxic T lymphocytes, VEGF signals, and cancer-associated fibroblasts at the tumor-invasive margins in this phenotype. From the validation study, nodules with any one of these three imaging findings had a significantly prolonged time to-nodular progression (p = 0.007, median not reached vs. 226 days). Conclusion: HCCs with rim APHE, peritumoral enhancement in arterial phase, and intermediate intensity on HBP with visual 3-point scale could be non-invasive biomarkers to predict the immune-excluded phenotype with the tumor immune barrier. These HCCs were most likely to respond to combined immunotherapy.
Leber hereditary optic neuropathy “plus” with the m.14487 T>C mutation as the causality of hemidystonia: A Case Report
Authors: Takano Fumio , Ueda Kaori , Chihara Norio , Arai Mina , Sakamoto Mari , Kurimoto Takuji , Yamada-Nakanishi Yuko , Nakamura Makoto
Published: November 2024

Introduction: LHON complicated with extraocular symptoms is called LHON plus. We describe a case of Leber hereditary optic neuropathy (LHON) plus with a rare mutation, that also caused dystonia. Case Presentation: An 18-year-old male patient developed symptoms of dystonia at the age of 15 years. Two years later, he noticed decreased visual acuity and central scotoma in the left eye. One month later the same symptoms occurred in the right eye. Although the optic discs in both eyes revealed mildly redness and edematous change, no abnormal findings were detected on fluorescence fundus angiography and orbital magnetic resonance imaging. Mitochondrial deoxyribonucleic acid (mtDNA) sequencing detected the m.14487 T>C mutation. From clinical course and fundus findings, the case was diagnosed LHON. The optic nerve gradually atrophied and central scotoma remained. Conclusion: The m.14487 T>C mutation is one of the causative mutations in patients with dystonia or Leigh encephalopathy and a minor mutation in patients with LHON. However, in the present case, ocular symptoms were more severe than systematic symptoms and the disease course was consistent with LHON. For the above reasons, this case can be diagnosed as LHON plus. Whole mtDNA sequencing is important in diagnosing LHON if none of the three major mutations are detected.