bluuebunny/crossref_metadata_2025 huggingface dataset:
A colorimetric biosensor with infrared sterilization based on CuSe nanoparticles for the detection of
E. coli
O157:H7 in food samples
Authors: Guo Yulan , Zhao Jinbin , Ma Xueer , Cai Ming , Liu Shitong , Sun Chunmeng , Chi Yuyang , Xu Kun
Published: July 2024

It is critical to develop quick, accurate, and efficient sterilization for detecting
Escherichia coli
O157:H7 in order to prevent infections and outbreaks of foodborne illnesses. Herein, we established a colorimetric biosensor with sterilizing properties using copper selenide nanoparticles to detect
E. coli
O157:H7. The sample was mixed with magnetic nanoprobes and nanozyme probes to form a sandwich structure, and then the unbound nanozyme probes were collected by magnetic separation. Finally, the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate)-hydrogen peroxide (H
2
O
2
) reporting system was added for signal amplification. The change from colorless to green can be seen with the naked eye. Under the optimal conditions, the detection range of
E. coli
O157:H7 was 10
2
–10
6
CFU/mL, and the detection limit was 0.35 × 10
2
CFU/mL. The total detection time was 80 minutes, which can be successfully applied to milk and mineral water. In addition, the colorimetric sensor can kill the target bacteria by irradiating it under a 980-nm laser for 5 minutes. In conclusion, this sensor is a promising tool for rapidly detecting foodborne pathogens and promptly eliminating bacteria.

IMPORTANCE

Escherichia coli
O157:H7 is a major threat to public health. At present, the detection methods for
E. coli
O157:H7 mainly include traditional bacterial culture, immunology (enzyme-linked immune-sorbent assay) and molecular biology techniques (polymerase chain reaction). These methods have the limitations of professional operation, waste of time and energy, and high cost. Therefore, we have developed a simple, fast, bactericidal colorimetric biosensor to detect
E. coli.
O157:H7. The entire process was completed in 80 minutes. The method has been successfully applied to milk and mineral water samples with satisfactory results, proving that the method is an effective method for real-time detection and inactivation of bacteria.
Bell’s Inequality, Its Physical Origins, and Generalization
Authors: Zorich V. A.
Published: July 2024

A mathematical generalization is given of the famous Bell inequality, which arose in connection with the analysis of the classical Einstein–Podolsky–Rosen paradox.
Secondary Linburg-Comstock syndrome post-trapeziectomy surgery
Authors: Lim Brandon , Clement Adeline , Sen Suddhajit
Published: July 2024

Linburg-Comstock syndrome is an acquired symptomatic restrictive thumb index finger flexor tenosynovitis involving a hypertrophic tenosynovium between flexor pollicis longus and flexor digitorum profundus. Patients may report synkinetic movement of the thumb and index finger, pain and swelling. We present the case of a woman in her 80s who presented with painless Linburg-Comstock syndrome after a trapeziectomy 4 months earlier for trapeziometacarpal arthritis. A literature review of PubMed-indexed case reports found that Linburg-Comstock syndrome has never been described in a post-trapeziectomy patient. This unusual presentation that arose as a side effect of hand surgery remains unreported in the literature. We present this unique complication as the first such case in the world. This case report is a valuable addition to the existing knowledge on the complications of trapeziectomy surgery.
Successful transvaginal repair of a vesicouterine fistula with delayed presentation
Authors: Love Grace , White Madeline , Herrell Howard
Published: July 2024

A G4P4 woman in her 30s with a type II vesicouterine fistula, as defined by the Jozwik classification system, presented with symptoms of menouria, vaginal menses and urinary incontinence 8 years after caesarean delivery, the time of probable origination of the fistula tract. Transvaginal ultrasound identified a fistula tract communicating between the bladder and uterus, a rare finding that many years remote from caesarean delivery. Traditional surgical technique includes laparoscopic, abdominal and endoscopic methods of repair, sometimes using a transvesical approach. Transvesical repair can be associated with subsequent inpatient hospital stays and prolonged catheterisation. Our technique proposes a transvaginal surgical approach as an outpatient procedure with decreased operating time (40 min), postoperative pain and catheterisation requirement. It is the authors’ belief that a transvaginal approach is less invasive and allows for better preservation of the uterus for future pregnancies and vaginal deliveries, as desired by the patient.
Supporting victim-survivors during investigations of health practitioner misconduct: early learnings from a trauma-informed service
Authors: Evans Jacinta , Piech Katherine , Saar Eva , Anderson Sarah
Published: July 2024

Objective

In 2021, the Australian Health Practitioner Regulation Agency established a support service to provide additional assistance to victim-survivors involved in complaints related to sexual boundary violations. This study evaluates the first stages of service delivery to understand participants’ experiences with the service, gauge the service’s reception, and improve support provided in future.

Design

Programme data was analysed descriptively to understand uptake and participant engagement since inception. Semistructured interviews with a purposive convenience sample of participants who had recently completed service engagement were conducted over 6 months and analysed using reflexive thematic analysis. Findings were triangulated to judge the effectiveness of the support provided by the service and highlight learning and development opportunities.

Results

During the study period, 275 participants were referred to the programme and 175 (64%) of those referred had engaged with the service. At the time of analysis, less than a quarter (21%) had refused support or disengaged following referral. Participants reported appreciation of and satisfaction with the support they received from the service and strongly reiterated the need for support in this context. Flexibility and quality communication as part of the service model was associated with participants feeling supported through three main themes: safety and connection, guidance and process navigation and representation and advocacy.

Conclusion

Good uptake of the service and positive feedback from participants suggests that the programme has been a valuable and well-received initiative. Exploration of engagement trends as well as a more nuanced analysis of the benefits of support provided would augment these findings.
Leadership development programmes in healthcare research: a systematic review, meta-analysis and meta-aggregation
Authors: Kingsley-Smith Harry , Farrier Christian E , Foran Daniel , Kotze Koot , Mahtani Kamal , Short Sarah , Scott Anna Mae , Lyons Oscar
Published: July 2024

Background

Academic institutions benefit from researchers adopting leadership positions and, subsequently, leadership development programmes are of increasing importance. Despite this, no evaluation of the evidence basis for leadership development programmes for healthcare researchers has been conducted. In this study, the authors reviewed leadership development programmes for healthcare researchers and aimed to identify their impact and the factors which influenced this impact.

Methods

The authors searched MEDLINE, EMBASE, CINAHL and PsycINFO between January 2000 and January 2023 for evaluations of leadership development programmes with healthcare researchers. The authors synthesised results through exploratory meta-analysis and meta-aggregation and used the Medical Education Research Study Quality Instrument (MERSQI) and Joanna Briggs Institute (JBI) Checklist for Qualitative Studies to identify higher-reliability studies.

Results

48 studies met inclusion criteria, of which approximately half (22) met the criteria for higher reliability. The median critical appraisal score was 10.5/18 for the MERSQI and 3.5/10 for the JBI. Common causes of low study quality appraisal related to study design, data analysis and reporting. Evaluations principally consisted of questionnaires measuring self-assessed outcomes. Interventions were primarily focused on junior academics. Overall, 163/168 categorised programme outcomes were positive. Coaching, experiential learning/project work and mentoring were associated with increased organisational outcomes.

Conclusion

Educational methods appeared to be more important for organisational outcomes than specific educational content. To facilitate organisational outcomes, educational methods should include coaching, project work and mentoring. Programmes delivered by external faculty were less likely to be associated with organisational outcomes than those with internal or mixed faculty, but this needs further investigation. Finally, improving evaluation design will allow educators and evaluators to more effectively understand factors which are reliably associated with organisational outcomes of leadership development.
Building towards organisational resilience and complexity leadership: a case study of impacts and changes in a Dutch blood establishment during COVID-19
Authors: Langi Sasongko Praiseldy K , Janssen Mart , de Bruijne Martine
Published: July 2024

Objectives

This study examined how one large blood-related establishment coped and adapted during the first 1.5 years of the pandemic by evaluating the impacts and changes on its resources, communication, collaborations, and monitoring and feedback. Furthermore, we explored whether elements of complexity leadership emerged during this time.

Design

Duchek’s organisational resilience framework was primarily used. We followed a three-step sequential approach: (1) a document analysis of over 150 intranet, internet and internal reports; (2) 31 semistructured interviews with employees and (3) four feedback sessions.

Setting

Sanquin is known as the Dutch national blood bank and a large multidivisional expertise organisation in the Netherlands.

Results

Sanquin coped well. Respondents accepted the crisis and catalysed many collaborations to implement solutions, which were communicated to the public. There were many positive aspects related to internal collaborations, yet challenges remained related to its historical siloed structure and culture. Sanquin adapted partially. Many respondents experienced the organisation becoming more connected and flexible during the pandemic. However, Sanquin was not permanently changed due to significant leadership changes and organisational restructuring occurring simultaneously. Respondents reflected on lessons learnt, including the need for continual collaboration and improvements in Sanquin’s culture. An important driver in the successful coping was management’s enabling attitude and the adaptations occurring within and through the collaborative groups.

Conclusions

Sanquin improved its organisational resilience by exhibiting elements of adaptive spaces, enabling leadership and (temporary) emergence from complexity leadership. This illuminates how the organisation could continue benefiting from complexity leadership for non-crises and for future uncertainties.
A Comprehensive Study on m-Polar Picture Fuzzy Graphs and Its Application
Authors: Khatun Jasminara , Amanathulla Sk , Pal Madhumangal
Published: July 2024

In real-life problems, information collected from multiple agents often exhibits “multipolar information,” which cannot be accurately modeled by existing graph models. This paper introduces the [Formula: see text]-polar picture fuzzy graph (mPPFG) as a more efficient model for such problems. The mPPFG offers a precise, flexible and comparable system compared to other graph models. The paper defines the mPPFG model and introduces new terms and properties such as order, degree, weighted arithmetic average (WAA) order, WAA degree, complement, homomorphism, isomorphism, eccentricity, radius, diameter and more. It also explores the concepts of [Formula: see text]-polar antipodal picture fuzzy graphs, eccentric mPPFG, self-centered mPPFG and self-median mPPFG, highlighting their definitions and properties. The [Formula: see text]-polar antipodal picture fuzzy graph represents a graph where each vertex is associated with an [Formula: see text]-polar antipodal picture fuzzy set. The eccentric mPPFG focuses on highly eccentric vertices, while the self-centered mPPFG considers central vertices. The self-median mPPFG represents median vertices in the graph. The study of these graph types and their isomorphism properties contributes to a deeper understanding of the structural variations within mPPFGs. Furthermore, the paper proposes an application of the mPPFG model in evaluating the performance of ministers in India during their tenure. An algorithm is also developed for computing the performance of ministers.
How Today's Recommender Systems Use Machine Learning to Cater to Your Every Whim
Authors: Kugler Logan
Published: July 2024

Modern recommender systems use sophisticated engineering to suggest the thing you will want to buy, read, watch, or hear next online.
Longitudinal Study of Mobile Telepresence Robots in Older Adults’ Homes: Uses, Social Connection, and Comfort with Technology
Authors: Rheman Jennifer M. , Baggett Rune P. , Simecek Martin , Fraune Marlena R. , Tsui Katherine M.
Published: July 2024

Mobile telepresence robots can help reduce loneliness by facilitating people to visit each other and have more social presence than visiting via video or audio calls. However, using new technology can be challenging for many older adults. In this article, we examine how older adults use and want to use mobile telepresence robots, how these robots affect their social connection, and how they can be improved for older adults’ use. We placed a mobile telepresence robot in the home of older adult primary participants (
N
= 7; age 60

\(+\)

) for 7 months and facilitated monthly activities between them and a secondary participant (
N
= 8; age 18

\(+\)

) of their choice. Participants used the robots as they liked between monthly activities. We collected diary entries and monthly interviews from primary participants and a final interview from secondary participants. Results indicate that older adults found many creative uses for the robots, including conversations, board games, and hide “n” seek. Several participants felt more socially connected with others and a few had improved their comfort with technology because of their use of the robot. They also suggested design recommendations and updates for the robots related to size, mobility, and more, which can help practitioners improve robots for older adults’ use.
Zero-Configuration Alarms: Towards Reducing Distracting Smartphone Interactions while Driving
Authors: Pargal Sugandh , Dalmia Neha , Borse Harsh , Mitra Bivas , Chakraborty Sandip
Published: July 2024

The rising ubiquity of smartphones for navigation and driver mode, among others, has increased their use significantly among drivers; however, there are growing numbers of road fatalities being reported due to distractions from the phone while driving. In contrast to the existing solutions that use a camera or other communication media on the car or need external setups, this article proposes a solution called
ZeCA
, where the smartphone itself can identify in real time with zero pre-configurations whether its user is driving while engaging in a high-distraction interaction with the phone.
ZeCA
runs as a smartphone background service and generates audio-visual alerts when the phone can distract the driver. A thorough evaluation and usability study of
ZeCA
with 50 different models of vehicles driven by 70 drivers over five countries indicates that the proposed solution can infer distracting smartphone interactions with greater than 80% accuracy and a 70% reduction in smartphone usage during driving.
Spiking-NeRF: Spiking Neural Network for Energy-Efficient Neural Rendering
Authors: Li Ziwen , Ma Yu , Zhou Jindong , Zhou Pingqiang
Published: July 2024

Artificial Neural Networks (ANNs) have achieved remarkable performance in many artificial intelligence tasks. As the application scenarios become more sophisticated, the computation and energy consumption of ANNs are also constantly increasing, which poses a challenge for deploying ANNs on energy-constrained devices. Spiking Neural Networks (SNNs) provide a promising solution to build energy-efficiency neural networks. However, the current training methods of SNNs cannot output values as precise as ANNs. This limits the applications of SNNs to relatively simple image classification tasks. In this article, we extend the application of SNNs to neural rendering tasks and propose an energy-efficient spiking neural rendering model, called Spiking-NeRF (Spiking Neural Radiance Fields). We first analyze the ANN-to-SNN conversion theory and propose an output scheme for SNNs to obtain the precise scene property values. Then we customize the parameter normalization method for the special network architecture of neural rendering. Furthermore, we present an early termination strategy (ETS) based on the discrete nature of spikes to reduce energy consumption. We evaluate the performance of Spiking-NeRF on both realistic and synthetic scenes. Experimental results show that Spiking-NeRF can achieve comparable rendering performance to ANN-based NeRF with up to

\(2.27\times\)

energy reduction.
Unveiling Electrochemical Properties of Silicon for Stable Cycling Performance of Silicon Anode Materials
Authors: Zhang Sheng S.
Published: July 2024

Research on silicon (Si) as an anode material for Li-ion batteries has spanned two decades; however, certain electrochemical properties of Si remain unclear. Specifically, the cyclic voltammogram (CV) pattern of Li/Si cells varies from case to case, influenced not only by the material but also by the experimental conditions. In this work, slow cyclic voltammetry is employed to investigate Li/Si cells, resulting in three distinct CV patterns. It is further observed that the CV pattern, particularly during the delithiation, is contingent on the state-of-lithiation (SOL) during lithiation and correlates with the capacity fade of Li/Si cells in subsequent cycles. Additionally, it is revealed that the primary mechanism for capacity fade differs between nano-sized silicon (Si-NP) and micro-sized silicon (Si-MP). In brief, capacity fade in Li/Si-NP cells predominantly arises from parasitic reactions between the highly lithiated Li-Si alloy and electrolyte solvents, exacerbated by the large specific surface area of Si-NP materials, whereas capacity fade in Li/Si-MP cells is primarily attributed to the Li electrode rather than the Si-MP electrode due to the restricted lithiation of Si-MP materials. Finally, this work concludes that limiting the SOL of Li/Si cells offers a straightforward and effective pathway to achieving stable cycling performance.
Carbohydrate storage in cells: a laboratory activity for the assessment of glycogen stores in biological tissues
Authors: Brito-da-Silva Guilherme , Manzanares Gustavo , Beltrame Barone Beatriz , Silva dos Santos Vanessa , Sturion Fillipini Sabrina , G. Gandra Paulo
Published: July 2024

Carbohydrates are one of the primary energy sources utilized by our cells. Liver and skeletal muscle glycogen, which are the main carbohydrate reserves in the body, play a central role in energy metabolism, especially during periods of fasting and exercise. In this laboratory activity, students measure glycogen levels in tissues to gain insights into how carbohydrates are stored in our cells and understand the role and limitations of liver and muscle carbohydrate stores.
TRPV1 and mast cell involvement in repeated variate stress-induced urinary bladder dysfunction in adult female mice
Authors: Sidwell Amanda B. , Girard Beatrice M. , Campbell Susan E. , Vizzard Margaret A.
Published: July 2024

Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.
Biomechanical costs influence decisions made during ongoing actions
Authors: Canaveral Cesar Augusto , Lata William , Green Andrea M. , Cisek Paul
Published: July 2024

In this study, we aim to shed light on how biomechanical factors influence decisions made during ongoing actions. Previous work suggested that decisions made during actions disregard biomechanical costs, in contrast to decisions made before movement. Our results challenge that proposal and suggest instead that the effect of biomechanical factors is dependent on the types of actions being compared (e.g., continuous tracking vs. point-to-point reaching). These findings contribute to our understanding of the dynamic interplay between biomechanical considerations and action choices during ongoing interactions with the environment.
Cable Force Measurement of Cable‐Stayed Bridge Based on Microwave Radar Test Technology
Authors: Che Gongjian , Jia Ruixin , Liu Kaiquan , Zhu Shangqing , Hu Jianxin
Published: July 2024

In recent years, the safety of cables of cable‐stayed bridges has attracted extensive attention, and the rise of radar technology has provided new possibilities for the performance testing of cable‐stayed bridges. In this regard, this paper introduces the principle of microwave radar measurement technology and uses the microwave cable force measuring instrument to perform noncontact microwave radar cable force measurement on a total of 72 stay cables in Shifeng Bridge and San‐Jiadian Bridge compared with the measurement results of the cloud smart collector. The results show that the fundamental frequency deviation rate of 71 cables is within 3%, and the cable force deviation rate of 67 cables is within 5%. This shows that the microwave radar cable force measurement method has a high degree of reliability and accuracy; meanwhile, it is also found that the forces on the left and right sides of the two bridges are in a symmetrical state, and the structure is in good condition; the signal characteristics are obvious, and the simultaneous measurement of multiple cables can be realized, and it is not limited by weather, site, and the length of the stay cable and has strong practical value.
Primary Conjunctival Basal Cell Carcinoma Mimicking an Ocular Surface Squamous Neoplasia in a Young Adult Filipino: A Case Report and Literature Review
Authors: Mangahas Lorenz Jacob , Reyes Rowena Wea , Siazon Richmond
Published: July 2024

Objective: To describe the morphological and histopathological features of primary conjunctival basal cell carcinoma (BCC) in a young adult Filipino.

Introduction: Malignant conjunctival tumors arise from different cells, the most common of which are squamous cell carcinomas (SCCs), (including ocular surface squamous neoplasia [OSSN]), melanomas, and lymphomas. Primary conjunctival BCC is rare and can mimic the clinical features of OSSN. Only seven reported cases were published. Most cases are in the 6th–8th decades of life, and we report the first case in a young adult male.

Case Summary: A 37/M, HIV‐seronegative, presenting with a 3‐year history of enlarging fleshy, pedunculated mass on the right eye measuring 8.5 mm × 8.0 mm at the superonasal limbus encroaching on the cornea, with prominent feeder vessels. Whitish‐to‐grayish plaques were observed on the surface of the lesions. Wide excision of the mass using the no‐touch technique was performed under local anesthesia. Four cycles of mitomycin C (0.02%) were administered as chemoadjuvant therapy. Histopathology showed basaloid cells with peripheral palisading, most consistent with BCC. Immunohistochemistry was positive for Bcl‐2 and CD10 markers and negative for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), confirming conjunctival BCC. Eight weeks postoperatively, fibrovascular tissue proliferation was noted at the excision site. Anterior segment‐optical coherence tomography (AS‐OCT) revealed a thickened hyperreflective band that was continuous with the epithelium, indicating possible recurrence. Resection with rush frozen section revealed fibrotic tissue that was negative for tumor cells. The bare sclera was covered with conjunctival autograft. There was no recurrence of the lesion after 16 months of follow‐up.

Conclusion: Primary BCC of the conjunctiva is rarely encountered, especially in young individuals, mimicking squamous neoplasia both in morphology and histopathology. Therefore, this should be considered in the differential diagnosis of OSSN. Immunostaining is crucial in differentiating between the two conditions and confirming the diagnosis. In most cases, wide surgical excision is sufficient. In addition, adjuvant therapies may be beneficial in preventing tumor recurrence.
Environmental and Anthropogenic Predictors Influence the Diversity of Nonflying Mammals in a Native Savanna Landscape of Northern South America
Authors: Mosquera-Guerra Federico , Moreno-Niño Nathalia , Barreto Sebastian , González-Delgado Tania Marisol , Armenteras-Pascual Dolors
Published: July 2024

The native savannas of eastern Colombia cover about six percent of the Neotropical savannas. Within these 17 million hectares, the current composition of nonflying mammals evidenced colonization from Andean, Guyanese, and Amazonian speciation centers and endemism processes. Scientific knowledge of the mammal species in native savanna ecosystems in Colombia remains limited. We assessed (a) the species alpha and beta diversity of mammal assemblages and trophic guilds, (b) the influence of environmental predictors on mammal species diversity, and (c) the conservation status of species at both international and national levels. Our sampling included 213 camera trap stations with a total of 25.560 camera trap days. We reported 31 species from 19 families and 10 orders. The mammals best represented by the average relative abundance index (RAI) were Tayassu pecari (RAI = 0.83, n = 2.936) and Cuniculus paca (RAI = 0.33, n = 1.491), and the omnivore group was the most diverse trophic guild. The best‐fitting generalized additive model for location, scale, and shape (GAMLSS) (GAIC = 1305.3) indicated that the diversity of the mammal species detected at camera trap stations was influenced by environmental predictors, including (a) distance to the burned area (burned = p > 3.6 × 10−9) and (b) distance to human infrastructure (built‐up = p > 5.05 × 10−7). Sixteen percent of the mammal species reported are classified as threatened by the International Union for Conservation of Nature (IUCN), while 22% are listed as threatened by Colombia. In addition, 58% fall into the categories of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). We discussed the high plains native savannas as a diversity hotspot for Neotropical mammals. However, this important mammal’s habitat is currently under threat due to human infrastructure and the increasing frequency and intensity of forest fires.
Hypoxic Memory Mediates Prolonged Tumor-Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression
Authors: Iriondo Oihana , Mecenas Desirea , Li Yilin , Chin Christopher R. , Thomas Amal , Moriarty Aidan , Marker Rebecca , Wang Yiru J. , Hendrick Haley , Amzaleg Yonatan , Ortiz Veronica , MacKay Matthew , Dickerson Amber , Lee Grace , Harotoonian Sevana , Benayoun Bérénice A. , Smith Andrew , Mason Christopher E. , Roussos Torres Evanthia T. , Klotz Remi , Yu Min
Published: July 2024

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a “hypoxic memory” phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade.

Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis.

See related commentary by Purdy and Ford, p. 3125
Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors
Authors: Xian Shiyun , Chen Xiaona , Ren Sihang , Chen Xiaolong , Wang Hangxiang
Published: July 2024

Therapeutic strategies that induce inflammatory responses in immunologically “cold” tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the stimulator of interferon gene (STING) pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment. The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic tumor microenvironment, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune-stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.

Significance: STING-activating nanoadjuvants rationally engineered using an ionizable prodrug approach for systemic administration are well-tolerated and yield durable antitumor immune responses, providing a potential immunotherapeutic strategy to improve cancer treatment.
An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression
Authors: Shrestha Raunak , Chesner Lisa N. , Zhang Meng , Zhou Stanley , Foye Adam , Lundberg Arian , Weinstein Alana S. , Sjöström Martin , Zhu Xiaolin , Moreno-Rodriguez Thaidy , Li Haolong ,   SU2C/PCF West Coast Prostate Cancer Dream Team, Alumkal Joshi J. , Aggarwal Rahul , Small Eric J. , Lupien Mathieu , Quigley David A. , Feng Felix Y.
Published: July 2024

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR− neuroendocrine−), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC.

Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.
Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma
Authors: Lozano Ester , Mena Mari-Pau , Garrabou Glòria , Cardús Oriol , Díaz Tania , Moreno David F. , Mañé-Pujol Joan , Oliver-Caldés Aina , Battram Anthony , Tovar Natalia , Cibeira María-Teresa , Rodríguez-Lobato Luis-Gerardo , Bladé Joan , Fernández de Larrea Carlos , Rosiñol Laura
Published: July 2024

Purpose:

TIGIT blockade in our ex vivo model of bone marrow (BM) reduced the number of malignant plasma cells (PC) in only half of patients with multiple myeloma. Here, we wanted to investigate whether increased expression of TIGIT ligands may inhibit T-cell immune response promoting resistance to TIGIT blockade.

Experimental Design:

We first characterized the number and phenotype of BM macrophages in different stages of the disease by multiparameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival by performing experiments in the ex vivo BM model and analyzed changes in gene expression by using NanoString technology and real-time PCR.

Results:

The frequency of BM macrophages was significantly decreased in multiple myeloma, which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PC in ex vivo BM cells cultured onto the poliovirus receptor (PVR) and nectin-2 compared with control, suggesting that both ligands may support PC survival. In addition, the presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL2. Furthermore, exogenous IL2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules.

Conclusions:

IL2 induced TIGIT on T cells in the BM, in which increased PVR expression resulted in cytotoxic T-cell inhibition, promoting PC survival and resistance to TIGIT blockade.
Figure 5 from PTP4A2 Promotes Glioblastoma Progression and Macrophage Polarization under Microenvironmental Pressure
Authors: Chouleur Tiffanie , Emanuelli Andrea , Souleyreau Wilfried , Derieppe Marie-Alix , Leboucq Téo , Hardy Serge , Mathivet Thomas , Tremblay Michel L. , Bikfalvi Andreas
Published: July 2024

Phenotype of macrophages and microglia in P3 xenografts. A, Representative images of macrophages (CD45+ IBA1+ P2RY12−) and microglia (CD45+ IBA1+ P2RY12+) in the tumor core and in the contralateral brain of a control tumor. Red triangles indicate macrophages positive for both CD45 and IBA1 and negative for P2RY12. White triangles indicate microglia positive for CD45, IBA1, and P2RY12. B, Proportion of macrophages and microglia within the leukocyte population of the tumor core and contralateral brain of KO, Ctrl, and OE xenografts. C, Immunostaining of COX2 and IBA1 with representative images (left) and quantification (right). Kruskal–Wallis test followed by Dunn tests. White triangles indicate IBA1+ COX2+ cells, red triangles indicate IBA1− COX2+ cells, and green triangles indicate IBA1+ COX2− cells. n = 5–6 mice per group.
Figure 4 from PTP4A2 Promotes Glioblastoma Progression and Macrophage Polarization under Microenvironmental Pressure
Authors: Chouleur Tiffanie , Emanuelli Andrea , Souleyreau Wilfried , Derieppe Marie-Alix , Leboucq Téo , Hardy Serge , Mathivet Thomas , Tremblay Michel L. , Bikfalvi Andreas
Published: July 2024

Transcriptional modulation of proinflammatory markers in P3 xenografts. A, Gene expression of different markers expressed by the human tumor cells inside the mouse brain, normalized by luciferase expression. qPCR primers were specific to human genes. B, Gene expression of different markers expressed by the TME, arranged by typical cell types and phenotypes: total macrophages, proinflammatory, and protumoral. Expression was normalized by actin expression. qPCR primers were specific to mouse genes. Kruskal–Wallis test followed by Dunn tests for all the figures. n = 7–8 mice per group
FOXC1 and FOXC2 Ablation Causes Abnormal Valvular Endothelial Cell Junctions and Lymphatic Vessel Formation in Myxomatous Mitral Valve Degeneration
Authors: Tan Can , Ge Zhi-Dong , Kurup Shreya , Dyakiv Yaryna , Liu Ting , Muller William A. , Kume Tsutomu
Published: July 2024

BACKGROUND:

Mitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates that mutations of the human transcription factor
FOXC1
are associated with MV defects, including MV regurgitation. In this study, we sought to determine whether murine
Foxc1
and its closely related factor,
Foxc2
, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar ECM (extracellular matrix).

METHODS:

Adult mice carrying tamoxifen-inducible, vascular endothelial cell (EC), and lymphatic EC–specific, compound
Foxc1;Foxc2
mutations (ie, EC-
Foxc
-DKO and lymphatic EC-
Foxc
-DKO mice, respectively) were used to study the function of
Foxc1
and
Foxc2
in the maintenance of MVs. The EC and lymphatic EC mutations of
Foxc1/c2
were induced at 7 to 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of these mutant mice were assessed via whole-mount immunostaining, immunohistochemistry/RNAscope, Movat pentachrome/Masson Trichrome staining, and Evans blue injection.

RESULTS:

EC deletions of
Foxc1
and
Foxc2
in mice resulted in abnormally extended and thicker MVs by causing defects in the regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-
Foxc
-DKO mice. PROX1 (prospero homeobox protein 1), a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-
Foxc1/c2
mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded and dysfunctional in EC-
Foxc1/c2
mutant MVs. Lymphatic EC deletion of
Foxc1/c2
also resulted in similar structural/ECM abnormalities as seen in EC-
Foxc1/c2
mutant MVs.

CONCLUSIONS:

Our results indicate that
Foxc1
and
Foxc2
are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessel formation/function to prevent myxomatous MV degeneration.
Synergy Between NK Cells and Monocytes in Potentiating Cardiovascular Disease Risk in Severe COVID-19
Authors: Gunasena Manuja , Alles Mario , Wijewantha Yasasvi , Mulhern Will , Bowman Emily , Gabriel Janelle , Kettelhut Aaren , Kumar Amrendra , Weragalaarachchi Krishanthi , Kasturiratna Dhanuja , Horowitz Jeffrey C. , Scrape Scott , Pannu Sonal R. , Liu Shan-Lu , Vilgelm Anna , Wijeratne Saranga , Bednash Joseph S. , Demberg Thorsten , Funderburg Nicholas T. , Liyanage Namal P.M.
Published: July 2024

BACKGROUND:

Evidence suggests that COVID-19 predisposes to cardiovascular diseases (CVDs). While monocytes/macrophages play a central role in the immunopathogenesis of atherosclerosis, less is known about their immunopathogenic mechanisms that lead to CVDs during COVID-19. Natural killer (NK) cells, which play an intermediary role during pathologies like atherosclerosis, are dysregulated during COVID-19. Here, we sought to investigate altered immune cells and their associations with CVD risk during severe COVID-19.

METHODS:

We measured plasma biomarkers of CVDs and determined phenotypes of circulating immune subsets using spectral flow cytometry. We compared these between patients with severe COVID-19 (severe, n=31), those who recovered from severe COVID-19 (recovered, n=29), and SARS-CoV-2–uninfected controls (controls, n=17). In vivo observations were supported using in vitro assays to highlight possible mechanistic links between dysregulated immune subsets and biomarkers during and after COVID-19. We performed multidimensional analyses of published single-cell transcriptome data of monocytes and NK cells during severe COVID-19 to substantiate in vivo findings.

RESULTS:

During severe COVID-19, we observed alterations in cardiometabolic biomarkers including oxidized–low-density lipoprotein, which showed decreased levels in severe and recovered groups. Severe patients exhibited dysregulated monocyte subsets, including increased frequencies of proinflammatory intermediate monocytes (also observed in the recovered) and decreased nonclassical monocytes. All identified NK-cell subsets in the severe COVID-19 group displayed increased expression of activation and tissue-resident markers, such as CD69 (cluster of differentiation 69). We observed significant correlations between altered immune subsets and plasma oxidized–low-density lipoprotein levels. In vitro assays revealed increased uptake of oxidized–low-density lipoprotein into monocyte-derived macrophages in the presence of NK cells activated by plasma of patients with severe COVID-19. Transcriptome analyses confirmed enriched proinflammatory responses and lipid dysregulation associated with epigenetic modifications in monocytes and NK cells during severe COVID-19.

CONCLUSIONS:

Our study provides new insights into the involvement of monocytes and NK cells in the increased CVD risk observed during and after COVID-19.
Serum Concentrations of Matrix Metalloproteinase‐1 and Procollagen Type I Carboxy Terminal Propeptide Discriminate Infarct‐Like Myocarditis and Non−ST‐Segment−Elevation Myocardial Infarction
Authors: Bacmeister Lucas , Cavus Ersin , Bohnen Sebastian , Tahir Enver , Wolf Hanna , Buellesbach Annette , Heidenreich Adrian , Haacke Virginia K. , Weber Susanne , Hilgendorf Ingo , Zeller Tanja , Ojeda Francisco , Radunski Ulf K. , Lund Gunnar K. , Adam Gerhard , Blankenberg Stefan , Westermann Dirk , Muellerleile Kai , Lindner Diana
Published: July 2024

Background

Biomarkers simplifying the diagnostic workup by discriminating between non–ST‐segment–elevation myocardial infarction (NSTEMI) and infarct‐like myocarditis are an unmet clinical need.

Methods and Results

A total of 105 subjects were categorized into groups as follows: ST‐segment−elevation myocardial infarction (n=36), NSTEMI (n=22), infarct‐like myocarditis (n=19), cardiomyopathy‐like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase‐1 (MMP‐1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non‐ST‐segment‐elevation, for example NSTEMI or infarct‐like myocarditis, categorized as the non−ST‐segment−elevation acute coronary syndrome−like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP‐1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non−ST‐segment−elevation acute coronary syndrome−like cohort, MMP‐1 concentrations discriminated infarct‐like myocarditis and NSTEMI with an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI, 0.89−1.00), whereas high‐sensitivity cardiac troponin T performed inferiorly (AUC, 0.74 [95% CI, 0.58−0.90];
P
=0.012). Application of an optimal MMP‐1 cutoff had 94.4% sensitivity (95% CI, 72.7%−99.9%) and 90.9% specificity (95% CI, 70.8%−98.9%) for the diagnosis of infarct‐like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68−0.97). As assessed by likelihood ratio tests, incorporating MMP‐1 or PICP with age and C‐reactive protein into composite prediction models enhanced their diagnostic performance.

Conclusions

MMP‐1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct‐like myocarditis in individuals with non−ST‐segment−elevation acute coronary syndrome‐like presentation, though further research is needed to validate their clinical applicability.
Phase 2 trial of the farnesyltransferase inhibitor tipifarnib for relapsed/refractory peripheral T-cell lymphoma
Authors: Witzig Thomas , Sokol Lubomir , Kim Won Seog , de la Cruz Vicente Fátima , Martín García-Sancho Alejandro , Advani Ranjana , Roncero Vidal Jose Maria , de Oña Navarrete Raquel , Marín-Niebla Ana , Rodriguez Izquierdo Antonia , Terol María José , Domingo-Domenech Eva , Saunders Andrew , Bendris Nawal , Mackey Julie , Leoni Mollie , Foss Francine
Published: July 2024

A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.