bluuebunny/crossref_metadata_2025 huggingface dataset:
Bowel cancer diagnosis experiences as a predictor of overall care rating: evidence from the English Cancer Patient Experience Survey
Authors: Owais Syeda Somyyah , Arnolda Gaston , Lamprell Klay , Liauw Winston , Delaney Geoff P , Olver Ian , Karnon Jonathan , Braithwaite Jeffrey
Published: November 2024

Objective

To investigate whether and which negative diagnosis-related experiences of patients newly diagnosed with colorectal cancer (CRC) are associated with a poorer overall rating of care, to help prioritise interventions.

Methods

A secondary data analysis was conducted using the English National Cancer Patient Experience Survey 2018. Analysis was restricted to responses by patients with CRC diagnosed within 12 months of survey, through pathways other than population screening. Nine diagnosis-related questions were selected (six objective and three feelings-based). The primary analysis used multivariable logistic regression to predict poorer overall care rating from negative experience responses to the six objective questions, adjusted for confounders. The sensitivity analysis additionally included the three feelings-based questions. Predictors of poorer overall rating with a significance level at p<0.01 were retained in the final models.

Results

4069 CRC patient survey responses were analysed. In the primary analysis, negative experiences were reported between 4% (‘Enough information about diagnostic test’) and 21% (‘Given written information about your cancer type’) of respondents. In multivariable analysis, all six objective questions were predictive of poorer overall rating, with ORs ranging from 1.6 to 3.5. In the multivariable sensitivity analysis, eight of nine negative experiences were predictive.

Conclusion

Negative experiences reported on diagnosis-related questions were almost always associated with a higher likelihood of a poorer overall care rating. To reduce negative diagnostic experiences, the most apt interventions to incorporate into workflows may be informing patients to bring someone to their diagnosis consultation and routine provision of tumour-specific information relevant to patient circumstances.
Prevalence of epilepsy: a population-based cohort study in Denmark with comparison to Global Burden of Disease (GBD) prevalence estimates
Authors: Christensen Jakob , Trabjerg Betina B , Wagner Ryan G , Newton Charles R , Kwon Churl-Su , Aaberg Kari Modalsli , Trinka Eugen , Wiebe Samuel , Cross Judith Helen , Vegrim Håkon Magne , Vos Theo , Steinmetz Jaimie , Dreier Julie Werenberg
Published: November 2024

Background

The Global Burden of Disease Study (GBD) produces prevalence estimates for ‘idiopathic epilepsy’ (ie, of unknown aetiology) and ‘secondary epilepsy’ (ie, with known aetiology) but does not report prevalence by underlying aetiologies for ‘secondary epilepsy’.

Methods

We used nationwide, population-based register data from Denmark to identify underlying causes of epilepsy and their contribution to prevalence of ‘secondary epilepsy’ and compared with global prevalence data from GBD 2019. We identified all persons with a hospital-based epilepsy diagnosis and a filled prescription for antiseizure medication between 1 January 2009 and 31 December 2018. Epilepsy was categorised into ‘idiopathic’ or ‘secondary’ and ‘total epilepsy’ as the sum of the two epilepsy categories.

Results

On 31 December 2018, a total of 5 784 284 individuals (49.7% males) were living in Denmark including 40 336 with epilepsy (51.5% males). Perinatal conditions, traumatic brain injury, brain tumours and stroke were prominent underlying causes of ‘secondary epilepsy’. The prevalence of ‘total epilepsy’ in Denmark was 697 (95% CI 691 to 704) per 100 000 population (264 (95% CI 260 to 269) for ‘secondary epilepsy’ and 433 (95% CI 428 to 438) for ‘idiopathic epilepsy’). In the GBD 2019 Study, the prevalence of ‘total epilepsy’ in 2018 was 682 (95% uncertainty interval (UI) 586 to 784) per 100 000 population (359 (95% UI 324–397) for ‘secondary epilepsy’ and 324 (95% UI 249 to 404) for ‘idiopathic epilepsy’).

Conclusions

Prevalence estimates of ‘total epilepsy’, ‘idiopathic epilepsy’ and ‘secondary epilepsy’ in Denmark align with the GBD 2019 estimates. In future studies, it is suggested to explicitly include all types of epilepsy, including ‘secondary epilepsy’, which is currently estimated as sequelae (consequences) of underlying diseases.
Skeletal muscle relaxant for the treatment of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials
Authors: Shing Chung Hin , Wang Fengfeng , Lau Lai Ning Lydia , Lam Pui Ming , Ho Hung Chak , Wong Stanley Sau Ching
Published: November 2024

Background/importance

Fibromyalgia is a complex chronic pain disorder that significantly impairs patient well-being. Evaluating the efficacy of muscle relaxants for treating fibromyalgia is crucial for improving patient care.

Objective

This study aimed to evaluate the analgesic efficacy of muscle relaxants in patients with fibromyalgia.

Evidence review

A comprehensive literature search was conducted using PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and the Cochrane Library. The search included randomized controlled trials (RCTs) comparing skeletal muscle relaxants with placebo/active analgesics for fibromyalgia. The primary outcome was pain intensity, measured by standardized mean difference (SMD) in pain scores. The risk of bias of included RCTs was assessed using the Cochrane Risk of Bias Assessment Instrument for Randomized Controlled Trials.

Findings

14 RCTs (1851 participants) were included. Muscle relaxants were associated with a small but statistically significant reduction in pain scores compared with placebo or active treatment (SMD=–0.24, 95% CI=–0.32 to –0.15, p<0.001, 95% prediction interval=–0.40 to –0.08), with no significant inconsistency (I2=0, 95% CI=0% to 50.79%) and a moderate Grading of Recommendation, Assessment, Development and Evaluation rating. Secondary outcomes showed small, but statistically significant improvements in depression, fatigue and sleep quality. Muscle relaxants were associated with increased incidence of overall adverse effects, fatigue, abnormal taste, and drug withdrawal due to adverse effects.

Conclusions

Moderate quality evidence showed that muscle relaxants were associated with a small reduction in pain intensity for patients with fibromyalgia.
KANQAS: Kolmogorov-Arnold Network for Quantum Architecture Search
Authors: Kundu Akash , Sarkar Aritra , Sadhu Abhishek
Published: November 2024

Quantum architecture Search (QAS) is a promising direction for optimization and automated design of quantum circuits towards quantum advantage. Recent techniques in QAS emphasize Multi-Layer Perceptron (MLP)-based deep Q-networks. However, their interpretability remains challenging due to the large number of learnable parameters and the complexities involved in selecting appropriate activation functions. In this work, to overcome these challenges, we utilize the Kolmogorov-Arnold Network (KAN) in the QAS algorithm, analyzing their efficiency in the task of quantum state preparation and quantum chemistry. In quantum state preparation, our results show that in a noiseless scenario, the probability of success is 2× to 5× higher than MLPs. In noisy environments, KAN outperforms MLPs in fidelity when approximating these states, showcasing its robustness against noise. In tackling quantum chemistry problems, we enhance the recently proposed QAS algorithm by integrating curriculum reinforcement learning with a KAN structure. This facilitates a more efficient design of parameterized quantum circuits by reducing the number of required 2-qubit gates and circuit depth. Further investigation reveals that KAN requires a significantly smaller number of learnable parameters compared to MLPs; however, the average time of executing each episode for KAN is higher.
Tectonic and climatic controls on plant biodiversity in the Hengduan Mountains, China
Authors: Chang Yaquan , Gelwick Katrina , Fang Xianjun , Luo Ao , Wang Zhiheng , Pellissier Loïc , Willett Sean D.
Published: November 2024

Mountainous regions contain some of the most dynamic landscapes in the world and host a majority of the world's biodiversity hotspots. The Hengduan Mountains, located at the syntax of Eurasia and India, have a complex geological history associated with a hyperdiverse assemblage of species. Tectonic, geomorphic and climatic processes in the Hengduan Mountains may have jointly caused the emergence of high biodiversity. We propose three mechanisms that may promote high-level montane biodiversity: habitat creation, habitat disruption and habitat oscillations. We mapped species richness patterns for seed plants and computed phylogenetic endemism across the entire Hengduan region. We developed a set of geomorphic metrics regarding these mechanisms to link plant richness and phylogenetic endemism patterns. By estimating the component of species richness that is attributable to habitat heterogeneity, we isolate the component that is the result of tectono-geomorphic processes. We found that regions of exceptionally high species richness are explained by a combination of habitat heterogeneity and tectono–geomorphic processes, whereas glaciation and high climate change velocity are associated with low richness, thus contributing to extinctions. We interpret the richness of biodiversity hotspots in the Hengduan Mountains in terms of climatic and tectonic processes.
Demystifying React Native Android Apps for Static Analysis
Authors: Liu Yonghui , Chen Xiao , Liu Pei , Samhi Jordan , Grundy John , Chen Chunyang , Li Li
Published: November 2024

React Native, an open-source framework, simplifies cross-platform app development by allowing JavaScript-side code to interact with native-side code. Previous studies disregarded React Native, resulting in insufficient static analysis of React Native app code. This study initiates the investigation of challenges when statically analyzing React Native apps. We propose
ReuNify
to improve Soot-based static analysis coverage for JavaScript-side and native-side code.
ReuNify
converts Hermes bytecode to Soot’s intermediate representation. Hermes bytecode, compiled from JavaScript code and integrated into React Native apps, possesses a unique syntax that eludes current JavaScript analyzers. Additionally, we investigate opcode distribution and conduct in-depth analyses of the usage of opcode between popular apps and malware. We also propose a benchmark consisting of 97 control-flow-related cases to validate the control-flow recovery of the generated intermediate representation. Furthermore, we model the cross-language communication mechanisms of React Native to expand the static analysis coverage for native-side code. Our evaluation demonstrates that
ReuNify
enables an average increase of 84% in reached nodes within the call graph and further identifies an average of two additional privacy leaks in taint analysis. In summary, this paper demonstrates that
ReuNify
significantly improves the static analysis for the React Native Android apps
Applications and Challenges of AI in PCB X-ray Inspection: A Comprehensive Study
Authors: Roy Antika , Al Hasan MD Mahfuz , Ghosh Shajib , Varshney Nitin , Julia Jake , Forghani Reza , Asadizanjani Navid
Published: November 2024

As printed circuit boards (PCBs) continue to evolve in complexity and miniaturization, the demand for robust and efficient inspection techniques has become paramount in ensuring the quality and reliability of electronic devices. The application of machine learning and deep learning techniques has revolutionized PCB inspection in recent years, enabling the ability to automate and improve numerous elements of the process. In this article, a comprehensive analysis is performed on the applications and challenges of AI, encompassing techniques of deep learning and machine learning, in the domain of PCB X-ray scrutiny. The main focus of this research centers around defect detection, identification of components and layers, deep learning algorithms for image reconstruction, as well as the identification of defects and features in advanced packaging. This study examines the current cutting-edge advancements in each of these areas, closely examining the existing methodologies and technologies employed. Furthermore, it delves into the limitations and challenges inherent in PCB X-ray inspection, such as the unavailability of data, computational demands, and the interpretability of models. In addition, this article offers prospective insights and presents promising avenues like application of generative adversarial networks and deep learning reconstruction methods for future exploration.
Representing Geospatial Knowledge in Narratives
Authors: Bartalesi Valentina , Pratelli Nicolò
Published: November 2024

This article explores the representation of geospatial knowledge within narratives through a Semantic Web approach. We introduce the NOnt

\(+\)

Space (NOnt

\(+\)

S) model, an extension of the CIDOC CRM-based Narrative Ontology, which allows the representation of narratives and their geospatial aspects. By leveraging standards such as CRMgeo and GeoSPARQL, NOnt

\(+\)

S ensures systematic and interoperable geospatial representation in narratives, enabling geospatial queries on knowledge graphs. We present an assessment of NOnt

\(+\)

S utilizing data from the H2020 MOVING European project (2021–2024), which collected knowledge about European mountain value chains intended as Cultural Heritage. We have represented this knowledge as geospatial narratives using NOnt

\(+\)

S. GeoSPARQL queries and semantic reasoning applied to the created KG reveal the ontology ability to infer new geospatial knowledge. Our work contributes to the ongoing efforts in the Semantic Web community to integrate and represent geospatial information within narratives, promoting collaboration and interoperability across various scientific domains.
Diagnostic Accuracy of Dual-Energy CT for Bone Stress Injury of the Lower Limb
Authors: Foti Giovanni , Sanfilippo Lorenza , Longo Chiara , Oliboni Eugenio , De Santis Nicoletta , Iacono Venanzio , Serra Gerardo , Guerriero Massimo , Filippini Roberto
Published: November 2024

Dual-energy CT helped to accurately diagnose bone stress fractures and stress reactions of the lower limb (leg, ankle, and foot) using MRI as the reference standard.
Changes in Reader Performance During Sequential Reading of Breast Cancer Screening Digital Breast Tomosynthesis Examinations
Authors: Abbey Craig K. , Bandos Andriy I. , Parthasarathy Mohana K. , Webster Michael A. , Zuley Margarita L.
Published: November 2024

Observational cross-sectional data from a large academic screening practice show significant changes in false-positive rates and interpretation times during batch reading of digital breast tomosynthesis images.
Aquaporin-4 Immunoglobulin G–seropositive Neuromyelitis Optica Spectrum Disorder MRI Characteristics: Data Analysis from the International Real-World PAMRINO Study Cohort
Authors: Chien Claudia , Cruz e Silva Vera , Geiter Emanuel , Meier Dominik , Zimmermann Hanna , Bichuetti Denis B. , Idagawa Marcos I. , Altintas Ayse , Tanriverdi Uygur , Siritho Sasitorn , Pandit Lehka , Dcunha Anitha , Sá Maria J. , Figueiredo Rita , Qian Peiqing , Tongco Caryl , Lotan Itay , Khasminsky Vadim , Hellmann Mark A. , Stiebel-Kalish Hadas , Rotstein Dalia L. , Waxman Lindsay , Ontaneda Daniel , Nakamura Kunio , Abboud Hesham , Subei M. Omar , Mao-Draayer Yang , Havla Joachim , Asgari Nasrin , Skejø Pernille B. , Kister Ilya , Ringelstein Marius , Broadley Simon , Arnett Simon , Marron Brie , Jolley Anna M. , Wunderlich Michael , Green Sean , Cook Lawrence J. , Yeaman Michael R. , Smith Terry J. , Brandt Alexander U. , Wuerfel Jens , Paul Friedemann ,   for the Guthy-Jackson Charitable Foundation International Clinical Consortium for NMOSD
Published: November 2024

Large, international, real-world MRI assessments showed high heterogeneity in the data collected from patients with aquaporin-4 immunoglobulin G–seropositive neuromyelitis optica spectrum disorder and frequent cerebral and lower spinal cord abnormalities.
Myocardial Fibrosis Assessment at 3-T versus 5-T Myocardial Late Gadolinium Enhancement MRI: Early Results
Authors: Guo Yubo , Lin Lu , Zhao Shihai , Sun Gan , Chen Yuyan , Xue Ke , Yang Yuxin , Chen Shuo , Zhang Yan , Li Guobin , Zhu Yanjie , Vliegenthart Rozemarijn , Wang Yining
Published: November 2024

Fibrosis assessment performed using 5-T myocardial late gadolinium enhancement MRI had higher signal-to-noise and contrast-to-noise ratios compared with assessment performed at 3-T MRI, with no evidence of differences in subjective image quality and quantitative assessment.
The Treasure Trove Hidden in Plain Sight: The Utility of GPT-4 in Chest Radiograph Evaluation
Authors: Tayebi Arasteh Soroosh , Siepmann Robert , Huppertz Marc , Lotfinia Mahshad , Puladi Behrus , Kuhl Christiane , Truhn Daniel , Nebelung Sven
Published: November 2024

OpenAI’s GPT-4 with Advanced Data Analysis autonomously performed basic statistical analyses and built machine learning–based models to evaluate a large chest radiography dataset, performing similarly to its manually crafted counterpart.
Impact of Jellyroll Tapes on Performance of Layered Oxide/Hard Carbon Sodium-Ion Pouch Cells
Authors: Ye Ziwei , Hijazi Hussein , Black William , Adamson Anu , Tang Ben , Zhang Libin , Johnson Michel , Dahn J. R. , Metzger Michael
Published: November 2024

This study investigates the influence of jellyroll tape materials on the cycle life and self-discharge of layered oxide/hard carbon sodium-ion pouch cells. Jellyroll tapes made of polyethylene terephthalate (PET) or polypropylene (PP) polymer were used in this study. Severe PET tape decomposition was observed in additive-free electrolyte. The use of solid-electrode interphase forming additives suppressed PET tape decomposition effectively and resulted in a competitive performance comparable to that of cells with PP tape. Replacing PET tape with PP tape led to sodium-ion pouch cells with substantial improvements of capacity retention, coulombic efficiency, and charge endpoint slippage. The superior chemical stability of PP tape in sodium-ion batteries allows for long cycle life and low self-discharge even in the absence of additives.
Cognitive effect of passively induced kinesthetic perception associated with virtual body augmentation modulates spinal reflex
Authors: Okada Kohsuke , Okawada Megumi , Yoneta Masaki , Kuwahara Wataru , Unai Kei , Kawakami Michiyuki , Tsuji Tetsuya , Kaneko Fuminari
Published: November 2024

Neural effects in visual-induced kinesthetic illusion expand into the spinal reflex. Kinesthetic illusion inhibits the monosynaptic reflex in an antagonistic muscle via reciprocal and presynaptic inhibition. Visually induced kinesthetic illusion is a suitable treatment for spasticity in patients with stroke.
The Association Between Diabetes and the Outcome of COVID‐19 Infection in Bethlehem, Palestine: A Case–Control Study
Authors: Abu-Helu Rasmi Fayiz , Zeer Mohammad Jumah , Adwan Ghaleb Mohammad
Published: November 2024

The severity of COVID‐19’s outcomes has been positively correlated with an increased risk of respiratory failure and death, especially in patients with chronic illnesses. This case–control design study aims to examine the correlation in the Palestinian population in light of its impact on diabetic patients. The study was conducted from March 2020 to June 2021 on 417 patients admitted to the Palestinian National Center for Rehabilitation. Of them, 198 cases were tested positive for COVID‐19 and had diabetes, whereas the remaining 219 were those who tested positive for COVID‐19 but were not diagnosed with diabetes and acted as controls. Data from patient files were collected to address the study questions. Patients’ ages ranged from 17 to 98 years, with a mean age of 58. Male participants represented 53.5% of the total. The results of the current study indicated that the case fatality rate (CFR) was 14.2% for all participants and 19.7% for patients with diabetes. In regard to patients’ health conditions, 5.7% had cardiovascular diseases (CVD), 33.6% had hypertension, 6.5% had kidney diseases, and 47.4% had diabetes. According to the multivariate analysis, diabetic patients had a 1.63 times higher risk for COVID‐19 infection compared to nondiabetic patients (adjustment of odds ratio of 1.63 and confidence interval [CI] = 0.354–1.856). This is the first study to investigate the relationship between the severity of COVID‐19 outcomes in Palestine and the diabetes status, and the majority of its findings are consistent with other research studies that assessed the impact of COVID‐19 on diabetic patients (with minor variations in the number and percentage). The study confirms that along with diabetes, age, hypertension, kidney diseases, shortness of breath, requirement of oxygen, D‐dimer, C‐reactive protein (CRP), kidney function test (KFT), and days of hospitalization were also associated with severe COVID‐19 outcomes, whereas gender, CVDs, and liver function test (LFT) were not associated with severe COVID‐19 outcomes.
COVID‐19 Infection Risk Assessment in a Kindergarten Utilizing Continuous Air Quality Monitoring Data
Authors: Chen Chung-Yen , Chen Jia-Kun , Chio Chia-Pin , Chen Pau-Chung , Su Ta-Chen , Chan Chang-Chuan
Published: November 2024

Researchers and transnational public health organizations have recognized aerosol transmission as an essential route of COVID‐19 transmission. Therefore, improving ventilation systems is now adopted as a core preventive measure. As young children aged 2–6 in kindergartens generally lack vaccine protection and multiple infection clusters have been identified during the pandemic, we aimed to quantify the risk of aerosol transmission in kindergartens in Taipei, Taiwan. From August to November 2021, we conducted on‐site visits and continuously monitored indoor air quality indicators including carbon dioxide (CO2) in a kindergarten located in northern Taiwan. We utilized the Wells–Riley model to estimate the basic reproduction number (R0) of each classroom and staff office, with input parameters including the number of occupants, duration of their stay, and indoor/outdoor CO2 concentration. Contagious settings were defined as those where the R0 estimate exceeded 1. We conducted a scenario/sensitivity analysis to assess the effect of simulated improvement measures. During school hours, the average concentration of CO2 in each classroom and the staff office was often more than 400 ppm higher than the outdoor levels. The R0 estimates gradually increased from Monday to Friday and throughout school hours, corresponding to the hourly and daily distribution of the CO2 concentration, which could not dissipate completely during off‐duty time. The R0 estimates during school hours ranged from 3.01 to 3.12 in classrooms with a maximum of 30 occupants. To lower the R0 estimate, it is imperative to substantially reduce the number of occupants, the duration of their stay, and indoor CO2 concentration. The risk of outbreaks of cluster infections in kindergartens should not be underestimated. Feasible strategies to mitigate this risk should include improving ventilation systems through engineering control and limiting the number of indoor occupants and their time staying indoor through administrative control.
Iron Administration Partially Ameliorates Cadmium‐Induced Oxidative Damage in the Liver and Kidney of Rats
Authors: Ezim Ogechukwu E. , Kidi Lilian , Ndufeiya-Kumasi Lauritta C. , Abarikwu Sunny O.
Published: November 2024

The protective effect of Fe against Cd‐induced toxicity in the liver and kidney of rats during concurrent administration of both metals was investigated in this study. Fifty female rats (130–150 g) were distributed into five groups of 10 rats each (n = 10): Group I (control), received normal saline solution; Group II (1.2 mg CdCl2/kg b.w.); Group III (1.2 mg CdCl2 + 0.25 mg FeCl2/kg b.w.); Group IV (1.2 mg CdCl2 + 0.75 mg FeCl2/kg b.w.); and Group V (1.2 mg CdCl2 + 1.5 mg FeCl2/kg b.w.). Administration of both tested substances lasted for 47 days. Cd was injected intraperitoneally once a week, while Fe was administered to the Cd‐exposed animals by oral gavage thrice weekly. The animals were killed at the end of the study, their blood was collected, and their liver and kidneys were harvested for biochemical and histological analysis. Following Cd administration, the kidney and liver showed a significant increase in Cd concentration, while Fe concentration in the kidney decreased. However, cotreatment with Fe decreased Cd concentration in the kidney and liver and increased Fe concentration in the kidney but not the liver, and the effect was more pronounced in the higher than lower doses. In the kidney, cotreatment with Fe especially at higher doses inhibited Cd‐induced lipid peroxidation and plasma uric acid concentration. In the liver, lipid peroxidation which Cd did not alter was found to be elevated after cotreatment with the highest dose Fe. Inflammatory cell infiltrations of the central vein and renal tubular and glomeruli injury induced by Cd were not obviated by Fe cotreatment. It seems that both tissues respond differently to the concurrent administration of these metals and that Fe protected the kidney against oxidative injury‐induced by Cd but not histopathological changes in both tissues.
Multitime Scale Reactive Power and Voltage Optimal Regulation for Transmission Network With Wind Power Cluster Based on Model Predictive Control
Authors: Wang Hong , Yuan Chao , Gu Wen , Yang Chun , Kong Minhao , Yu Jian
Published: November 2024

In order to solve the problem of voltage fluctuation caused by the grid integration of wind power cluster, a multitime scale reactive power and voltage optimal regulation method based on model predictive control (MPC) is proposed in this paper. In the day‐ahead stage, the reduction of network active power loss is mainly achieved through the regulation of discrete reactive power compensation devices and generator units, focusing on the economic operation of the power system. In the intraday stage, considering the rapid response characteristics of continuous reactive power compensation devices, the optimal regulation aiming to minimize voltage control deviation is carried out under 15‐ and 5‐min time scale based on the MPC algorithm with the adjustment of continuous reactive power compensation devices. In the feedback correction stage, a fast calculation method considering reactive power partitioning is adopted instead of solving the 5‐min optimization model for 288 periods, avoiding excessive adjustment of reactive compensation devices. While effectively improving voltage fluctuations caused by wind power prediction deviation, it also alleviated the computational and communication burden on the system. Finally, the effectiveness of the proposed regulation method in this paper is verified with the improved IEEE‐39 test case.
Conditional Activation of c-MYC in Distinct Catecholaminergic Cells Drives Development of Neuroblastoma or Somatostatinoma
Authors: Wang Tingting , Liu Lingling , Fang Jie , Jin Hongjian , Natarajan Sivaraman , Sheppard Heather , Lu Meifen , Turner Gregory , Confer Thomas , Johnson Melissa , Steinberg Jeffrey , Ha Larry , Yadak Nour , Jain Richa , Picketts David J. , Ma Xiaotu , Murphy Andrew , Davidoff Andrew M. , Glazer Evan S. , Easton John , Chen Xiang , Wang Ruoning , Yang Jun
Published: November 2024

c-MYC is an important driver of high-risk neuroblastoma. A lack of c-MYC–driven genetically engineered mouse models (GEMM) has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and to develop effective therapies. In this study, we showed that conditional c-MYC induction via Cre recombinase driven by a tyrosine hydroxylase promoter led to a preponderance of PDX1+ somatostatinoma, a type of pancreatic neuroendocrine tumor. However, c-MYC activation via an improved Cre recombinase driven by a dopamine β-hydroxylase promoter resulted in neuroblastoma development. The c-MYC murine neuroblastoma tumors recapitulated the pathologic and genetic features of human neuroblastoma and responded to anti-GD2 immunotherapy and difluoromethylornithine, an FDA-approved inhibitor targeting the MYC transcriptional target ODC1. Thus, c-MYC overexpression results in different but related tumor types depending on the targeted cell. The GEMMs represent valuable tools for testing immunotherapies and targeted therapies for these diseases.

Significance: The development of c-MYC–driven genetically engineered neuroblastoma and somatostatinoma mouse models provides useful tools for understanding the tumor cell origin and investigating treatment strategies.
Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade Uterine Cancer
Authors: Haanen Terrance J. , Boock Sophie , Callahan Catherine G. , Peris Irene , Zawacki Kaitlin P. , Raines Brynne , Nino Charles A. , Tran Brian , Harold Alexis , Hodges Onishi Gabrielle , Hinderman Matthew , Dowdican Amanda , Huang Wei , Taylor Derek J. , Taylor Sarah E. , Jackson Mark W. , DiFeo Analisa , O’Connor Caitlin M. , Narla Goutham
Published: November 2024

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal plasticity phenotype, and elevated secretion of the tumorigenic cytokine insulin growth factor (IGF) binding protein 2 (IGFBP2). Therapeutic targeting of the IGFBP2/IGF receptor 1 signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.

Significance: Elevated IGFBP2 secretion by uterine cancer cells with heterozygous PPP2R1A mutations supports tumor progression and confers a vulnerability to IGFBP2/IGF1R inhibition as a therapeutic approach for this highly aggressive cancer subtype.
Phase II Trial of Induction Chemotherapy for Advanced Sinonasal Squamous Cell Carcinoma
Authors: Contrera Kevin J. , Ferrarotto Renata , Gunn Brandon , Su Shirley Y. , Kies Merrill S. , Glisson Bonnie S. , Garden Adam S. , Roberts Dianna , Habna Curtis , Hoff Camilla O. , El-Naggar Adel , Williams Michelle D. , Raza Shaan M. , DeMonte Franco , Chen Melissa M. , Chambers Mark S. , Hanna Ehab Y.
Published: November 2024

Purpose:

Outcomes after primary surgery for advanced sinonasal squamous cell carcinoma (SCC) are poor. We tested whether induction chemotherapy (IC) can improve disease control or organ preservation.

Patients and Methods:

A phase II trial evaluated previously untreated patients with stage II to IV, M0 sinonasal SCC. Patients received IC with docetaxel, cisplatin, and fluorouracil, followed by chemoradiotherapy (CRT) for responders and surgery with adjuvant radiotherapy or CRT for nonresponders. The primary endpoints were overall response rate and locoregional control. Secondary endpoints included progression-free survival (PFS), overall survival (OS), organ preservation, and treatment toxicity.

Results:

Of the 31 patients enrolled between 2008 and 2020, 28 were evaluated for efficacy. Disease was T4a, T4b, and N+ in 57%, 21%, and 36% of patients, respectively. The overall response rate was 82.1%; 17.9% of patients had stable disease, and 0% had progressive disease. Grade 3 and 4 adverse events occurred in 54% and 18% of patients, respectively; there were no grade 5 adverse events. The 2-year locoregional control and PFS rates were 64.3% [95% confidence interval (CI), 40.4–77.6) and 52.4% (95% CI, 32.3–69.0), respectively. The median PFS was 25.8 months. The median OS was 47.4 months, with a 2-year OS rate of 69.4% (95% CI, 44.9–80.4). No survival difference was observed between surgery versus CRT (HR, 1.07; 95% CI, 0.9–3.84). Of patients alive at 2 years, 63% achieved organ preservation, avoiding maxillectomy (38%), craniotomy (13%), or orbital exenteration (38%).

Conclusions:

IC and response-directed local treatment achieved promising disease control and added organ preservation for patients with advanced sinonasal SCC.
A Phase II Study of Acimtamig (AFM13) in Patients with CD30-Positive, Relapsed, or Refractory Peripheral T-cell Lymphomas
Authors: Kim Won Seog , Shortt Jake , Zinzani Pier Luigi , Mikhailova Natalia , Radeski Dejan , Ribrag Vincent , Domingo Domenech Eva , Sawas Ahmed , Alexis Karenza , Emig Michael , Elbadri Riham , Hajela Pallavi , Ravenstijn Paulien , Pinto Sheena , Garcia Linta , Overesch Andre , Pietzko Kerstin , Horwitz Steven
Published: November 2024

Purpose:

Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options. This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL.

Patients and Methods:

Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was the overall response rate by fluorodeoxyglucose-PET per independent review committee; secondary and exploratory endpoints included duration of response, safety, progression-free survival, and overall survival.

Results:

The overall response rate in 108 patients was 32.4% [95% confidence interval (CI), 23.7, 42.1] with a complete response rate of 10.2% (95% CI, 5.2, 17.5); the median duration of response was 2.3 months (95% CI, 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses [53.3% (95% CI, 34.3, 71.7)]. Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint.

Conclusions:

The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic NK cells.
Phase Ib Clinical and Pharmacodynamic Study of the TIE2 Kinase Inhibitor Rebastinib with Paclitaxel or Eribulin in HER2-Negative Metastatic Breast Cancer
Authors: Anampa Jesus D. , Flynn Daniel L. , Leary Cynthia , Oh Sun , Xue Xiaonan , Oktay Maja H. , Condeelis John S. , Sparano Joseph A.
Published: November 2024

Purpose:

Breast cancer cells disseminate to distant sites via tumor microenvironment of metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC).

Patients and Methods:

This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib orally twice daily in combination with weekly paclitaxel 80 mg/m2 (if ≤2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 and 8 (if ≥1 prior regimen). Safety, tolerability, and pharmacodynamic parameters indicating TIE2 kinase inhibition and TMEM doorway function were evaluated.

Results:

No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). Adverse events attributed to rebastinib include muscular weakness and myalgias. Intraocular pressure increased at the 100-mg rebastinib dose level, whereas angiopoietin-2 levels increased at both dose levels, providing pharmacodynamic evidence for TIE2 blockade. Circulating tumor cells decreased significantly with the combined treatment. Objective response occurred in 5/23 (22%) evaluable patients.

Conclusions:

In patients with MBC, the recommended phase II dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg orally twice daily in combination with paclitaxel or eribulin.
Targeting of Tumoral NAC1 Mitigates Myeloid-Derived Suppressor Cell–Mediated Immunosuppression and Potentiates Anti–PD-1 Therapy in Ovarian Cancer
Authors: Dong Shunli , Ye Cong , Li Bin , Lv Fanglin , Zhang Lu , Yang Shumin , Wang Fang , Zhu Mingxian , Zhou Mingxuan , Guo Fanfan , Li Zhenyun , Peng Lei , Ji Cheng , Lu Xialiang , Cheng Yan , Ren Xingcong , Chen Youguo , Zhou Jinhua , Yang Jinming , Zhang Yi
Published: November 2024

Epithelial ovarian cancer is the most common type of ovarian cancer with a low rate of response to immunotherapy such as immune checkpoint blockade therapy. In this study, we report that nucleus accumbens–associated protein 1 (NAC1), a putative driver of epithelial ovarian cancer, has a critical role in immune evasion. We showed in murine ovarian cancer models that depleting or inhibiting tumoral NAC1 reduced the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, led to significant increases of cytotoxic tumor-infiltrating CD8+ T cells, and promoted antitumor immunity and suppressed tumor progression. We further showed that tumoral NAC1 directly enhanced the transcription of CXCL16 by binding to CXCR6, thereby promoting MDSC recruitment to the tumor. Moreover, lipid C20:1T produced by NAC1-expressing tumor cells fueled oxidative metabolism of MDSCs and promoted their immune-suppressive function. We also showed that NIC3, a small-molecule inhibitor of NAC1, was able to sensitize mice bearing NAC1-expressing ovarian tumors to anti–PD-1 therapy. Our study reveals a critical role for NAC1 in controlling tumor infiltration of MDSCs and in modulating the efficacy of immune checkpoint blockade therapy. Thus, targeting of NAC1 may be exploited to sensitize ovarian cancer to immunotherapy.
Clotting Promotes Glioma Growth and Infiltration Through Activation of Focal Adhesion Kinase
Authors: Knowles Lynn M. , Wolter Carolin , Linsler Stefan , Müller Simon , Urbschat Steffi , Ketter Ralf , Müller Andreas , Zhou Xiangda , Qu Bin , Senger Sebastian , Geisel Jürgen , Schmidt Tim , Eichler Hermann , Pilch Jan
Published: November 2024

The tumor architecture of high-grade gliomas is shaped by tumor cell necrosis, invasive growth, and the leakage of a fibrin-rich edema from poorly organized tumor blood vessels. In this study, we demonstrate a marked upregulation of clot formation in the interstitial spaces of tumor tissues from patients with glioblastoma (GBM) whereas a tumor-free brain is essentially devoid of fibrin. The accumulation of fibrin in tumor interstitial spaces is functionally relevant as we demonstrate increased infiltration and growth of primary GBM cells after embedding in a 3-dimensional matrix made of fibrin ex vivo. Additionally, we detected accelerated tumor growth after implanting GBM cells together with clotted plasma in brains of immunodeficient mice whereas GBM development in clotting-deficient hemophilia mice was delayed. GBM growth correlated with the outgrowth of invadopodia and their adhesive interactions with the 3-dimensional clot matrix, which was mediated by integrins β1 and β3 and their common downstream target focal adhesion kinase (FAK). Knocking down FAK with CRISPR Cas9 caused an upregulation of p21/p27 cell-cycle inhibitors, strong growth inhibition in cultured GBM cells, and sustained antitumorigenic effects in orthotopic GBM xenografts in vivo. These results go hand in hand with genomic data from The Cancer Genome Atlas that indicate increased clotting activity and reduced patient survival in glioma subgroups with high integrin β1 and β3 expression. We therefore conclude that clotting in glioma interstitial spaces provides tumor cells with a potent proliferative stimulus that can be reversed by targeting the adhesive machinery of GBM cells via inhibition of FAK.

Significance:

High-grade gliomas are associated with intratumoral thrombosis, tumor cell necrosis, and hemorrhage. The resulting blood clot serves as an adhesive matrix for glioma cell integrins that activate FAK. Knocking down FAK with CRISPR cas9, on the other hand, is highly effective at halting GBM growth in mice.
The Role of Esophageal Physiologic Tests in Eosinophilic Esophagitis
Authors: Wakim El-Khoury Jeanine , Safroneeva Ekaterina , Schoepfer Alain M.
Published: November 2024

Background: In patients with eosinophilic esophagitis (EoE), the correlation between symptoms of esophageal dysfunction and endoscopic and histologic disease activity is generally poor and probably related to multiple causes such as esophageal remodeling processes that might go undetected using endoscopy and histology as well as esophageal hypervigilance and symptom-specific anxiety. Hence, there is a need for a holistic management of patients that goes beyond the control of eosinophilia and symptoms. Summary and Key Messages: Physiological esophageal testing using high-resolution manometry, functional lumen imaging probe, pH-impedance, wireless pH monitoring, and mucosal impedance may unveil the effects of chronic transmural fibro-inflammatory changes of the esophageal wall as well as esophageal hypervigilance, thereby assisting to phenotype patients, predict therapeutic response to therapy, and identify motility disorders that may need a specific targeted therapy to ameliorate patients’ outcomes. This article discusses the role of functional esophageal examinations in the diagnosis and management of EoE.
Utilising retinal phenotypes to predict cerebrovascular disease and detect related risk factors in multi-ethnic populations: a narrative review
Authors: Injety Ranjit J. , Shenoy Riddhi , Free Robert C. , Minhas Jatinder S. , Thomas Mervyn G.
Published: November 2024

Background: Cerebrovascular diseases (CBVDs) are a major cause of mortality and disability, with significant ethnic variations suggesting specific risk factors. Early detection of these risk factors is critical, and retinal imaging offers a non-invasive method to achieve this.
Summary: Retinal phenotypes can serve as early markers for CBVDs. Racial differences in retinal and vascular morphometric characteristics have been described. Examining these characteristics in the context of racial differences could improve early detection and targeted interventions for CBVDs. This review discusses the role of retinal imaging in predicting CBVDs and highlights the importance of ethnicity-specific approaches.
Key Messages: Understanding ethnic variations in retinal features can enhance the precision of CBVD prediction and enable personalised treatment strategies.
Exploring the Critical Role of Tight Junction Proteins in Kidney Disease Pathogenesis
Authors: Jayne David , Herbert Corentin , Anquetil Vincent , Teixeira Geoffrey
Published: November 2024

Background: Kidney disease poses a significant global health challenge, marked by a rapid decline in renal function due to a variety of causative factors. A crucial element in the pathophysiology of kidney disease is the dysregulation of epithelial cells, which are vital components of renal tissue architecture. The integrity and functionality of these cells are largely dependent on tight junctions (TJ) proteins, complex molecular structures that link adjacent epithelial cells. These TJ not only confer cellular polarity and maintain essential barrier functions but also regulate epithelial permeability. Summary: TJ proteins are pivotal in their traditional role at cell junctions and in their non-junctional capacities. Recent research has shifted the perception of these proteins from mere structural elements to dynamic mediators of kidney disease, playing significant roles in various renal pathologies. This review explores the multifaceted roles of TJ proteins, focusing on their functions both within and external to the renal epithelial junctions. It highlights how these proteins contribute to mechanisms underlying kidney disease, emphasizing their impact on disease progression and outcomes. Key Messages: TJ proteins have emerged as significant players in the field of nephrology, not only for their structural role but also for their regulatory functions in disease pathology. Their dual roles in maintaining epithelial integrity and mediating pathological processes make them promising therapeutic targets for kidney disease. Understanding the intricate contributions of TJ proteins in kidney pathology offers potential for novel therapeutic strategies, aiming to modulate these proteins to halt or reverse the progression of kidney disease.
Ultrasonographic characterization of abdominal organs of baby opossums
Authors: Cavalcanti Eduarda Aléxia Nunes Louzada Dias , Cavalcanti Guilherme Albuquerque de Oliveira , França Raqueli Teresinha
Published: November 2024

A ultrassonografia abdominal é um importante recurso para o diagnóstico de inúmeras afecções na medicina veterinária. A descrição dos achados ultrassonográficos dos órgãos abdominais considerados normais é importante para o direcionamento do diagnóstico e acompanhamento da terapêutica. Especialmente na medicina de animais silvestres, poucos estudos são realizados nesta área, por exemplo os gambás, embora amplamente distribuídos pelas Américas e frequentemente encaminhados para os centros de atendimento de animais silvestres, pouco se sabe na área da ultrassonografia. Desta forma, o objetivo deste trabalho foi avaliar os órgãos abdominais de gambás filhotes saudáveis. Foram avaliados 38 gambás (19 machos e 19 fêmeas) com peso entre 110 e 180 gramas. Não houve diferença significativa entre os sexos, entretanto, foi observado diferença entre as classes de pesos na mensuração dos rins e a parede da vesícula urinária. A espessura média, em centímetros, da parede gástrica foi de 0,13 (±0,01), da vesícula biliar foi de 0,05 (±0,01) e do cólon foi de 0,15 (±0,17). Na avaliação subjetiva, as características dos órgãos como ecotextura e ecogenicidade foram similares as descritas na literatura estudada e as medidas obtidas são específicas para a espécie.
O vídeo, as ONGs cariocas e a solidariedade como princípio – entrevista com Mauricio Lissovsky
Authors: França Andréa
Published: November 2024

Entrevista feita com Mauricio Lissovsky sobre sua trajetória, ainda jovem, no movimento cineclubista nos anos 1970; Mauricio fala da prática e da produção de vídeo junto às Organizações não governamentais (Ongs) cariocas nos anos 1980 e 1990; discute o papel político do vídeo e das Ongs junto aos movimentos populares e sociais no contexto de fim da ditadura no país e, ainda, o lugar estratégico do vídeo na ação política pela disputa dos meios de comunicação.