bluuebunny/crossref_metadata_2025_split huggingface dataset:
Additional expression of T-cell engager in clinically tested oncolytic adeno-immunotherapy redirects tumor-infiltrated, irrelevant T cells against cancer cells to enhance antitumor immunity
Authors: Morita Daisuke , Rosewell Shaw Amanda , Biegert Greyson , Porter Caroline , Woods Mae , Vasileiou Spyridoula , Lim Bora , Suzuki Masataka 
Published: December 2024

BackgroundOncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested “Armed” OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose.MethodsTo address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients’ samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice.ResultsWe found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically “hot” and “cold” tumor models and also induced immunologic memory against rechallenged tumors.ConclusionsOur results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells.
METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer
Authors: Wu Ling , Bai Rui , Zhang Yujie , Chen Hao , Wu Jianghua , Chen Zetao , Wang Hui , Zhao Liang 
Published: December 2024

ObjectiveAlthough immune checkpoint blockade (ICB) therapy represents a bright spot in antitumor immunotherapy, its clinical benefits in colorectal cancer (CRC) are limited. Therefore, a new target for mediating CRC immunosuppression is urgently needed. Adenomatous polyposis coli (APC) mutations have been reported as early-stage characteristic events in CRC, but the role of truncated APC in the CRC immune microenvironment remains unclear and its clinical significance has yet to be explored.DesignAdenocarcinoma formation in the colon of the APCMin/+mouse model, which displays features associated with the translation of truncated APC proteins, was induced by azoxymethane/dextran sodium sulfate. Multiplexed immunohistochemical consecutive staining on single slides and flow cytometry were used to explore the activation of immune cells and the expression of the immune checkpoint V-domain immunoglobulin suppressor of T-cell activation (VISTA) in the CRC tissues of APCWTand APCMin/+mice. The construction of truncated APC vectors and an initial subserosal graft tumor mouse model was employed to mimic the tumor microenvironment (TME) during APC mutation. Methylated RNA immunoprecipitation-quantitative PCR assays were performed to investigate the N6-methyladenosine (m6A)-dependent transcriptional regulation of hypoxia-inducible factor-1 alpha (HIF1α) by methyltransferase-like protein 3 (METTL3). Mettl3fl/flvil1-cre+/−mice were used to demonstrate that targeting METTL3 is a mediator that mitigates the deleterious effects of the APC978∆-HIF1α axis on antitumor immunity. A chimeric VISTA humanized mouse model was used to evaluate the drug efficacy of the VISTA-targeted compound onvatilimab.ResultsWe showed that APC978∆, a truncated APC protein, mediated overexpression of METTL3, resulting in m6A methylation of HIF1α messenger RNA and high expression of HIF1α. Furthermore, HIF1α promotes the migration of myeloid-derived suppressor cells to the TME by binding to the promoters of MCP-1 and MIF. In addition, HIF1α enhances the expression of the immune checkpoint VISTA on CRC cells, weakening tumor immune monitoring.ConclusionsWe elucidate that an underappreciated function of truncated APC in CRC is its ability to drive an immunosuppressive program that boosts tumor progression. Our work could provide a new perspective for the clinical application of immunotherapy in patients with CRC resistant to ICB therapy.
Breakthrough cancer pain management: mixed-methods study of health care professionals
Authors: Crawford Gregory Brian , Lakhani Ali , Palmer L , Sebalj Menka , Rolan P 
Published: December 2024

ObjectivesKnowledge gaps in defining, diagnosing, educating health practitioners and treatment options hinder breakthrough cancer pain (BtCP) management. A systematic review revealed a lack of clarity on health professional derived definitions, management strategies and professional development for BtCP. The current study aimed to explore the perspectives of multidisciplinary health professionals by seeking to understand how they define, identify, treat and manage BtCP, barriers to management and professional development requirements.MethodsA mixed-methods approach involving a two-phase data collection process was employed. Health professionals initially completed an online survey capturing perspectives on BtCP, management strategies, barriers and education/professional development requirements. Survey participants expressing interest were then invited to complete a semistructured interview for an in-depth exploration of their perspectives. Descriptive statistics and frequencies summarised online survey data. Open-ended responses were themed, and categories created. Semistructured interview transcripts were inductively analysed for recurring or divergent themes.ResultsFifty-four participants completed the online survey and 11 of them participated in an interview. Findings confirmed the importance of patient communication and education in managing BtCP, emphasising the need for adequate resources and training. Interdisciplinary relationships were highlighted as important and contributing to effective BtCP management, supporting professional growth and confidence in prescribing pain management medication.ConclusionsThe study filled research gaps by involving diverse health professionals to explore BtCP identification, treatment, barriers and professional development need. Future research should emphasise interdisciplinary collaboration, invest in targeted resources, training and culturally appropriate communication to address barriers in patient interaction.
The onset of Magneto–Darcy–Rayleigh–Bénard convection under local thermal non-equilibrium with two-layer system
Authors: Sumithra R. , Venkatraman Shyamala , Aldeeb Horiya , Patil Nagaraj , Singh Shivender , Manjunatha N. , Punith Gowda R. J. 
Published: December 2024

The investigation focuses on the consequences of various thermal distributions examined in the context of Magneto–Darcy–Rayleigh–Bénard (MDRB) convection onset under local thermal non-equilibrium (LTNE). The system under consideration consists of a two-layer configuration, with an incompressible fluid and horizontally positioned adiabatic peripheries. An analytical solution to the resultant problem is accomplished using the regular perturbation method. Concerning the six thermal distributions, we examine variables such as the ratio of heat expansion in the solid phase, the ratio of heat diffusivities in the solid phase, and the inter-phase heat diffusivity ratio, which exhibits a propensity towards LTNE. Furthermore, we investigate the consequences of modifying the values of constraints, namely, the ratio of heat expansion in the fluid phase, the ratio of heat diffusivities in the fluid phase, the porous parameter, the heat ratio, and the Chandrasekhar number. The empirical observations indicate that the model (iii) exhibits a significantly higher degree of instability when compared to other distributions. Conversely, model (v) demonstrates a notable level of stability. Moreover, it is intriguing that the system governed by the model (vi) exhibits higher stability than the model (iv) thermal distribution within the context of a composite system.
Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer
Authors: Fusagawa Minami , Tokita Serina , Murata Kenji , Mariya Tasuku , Umemoto Mina , Sugita Shintaro , Matsuo Kazuhiko , Hirohashi Yoshihiko , Saito Tsuyoshi , Kanaseki Takayuki , Torigoe Toshihiko 
Published: December 2024

Abstract
Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in antitumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II–positive (HLA-II+) endometrial cancer with an inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte responses. We then experimentally demonstrated that neoantigen-specific CD4+ tumor-infiltrating lymphocytes lyse target cells in an HLA-II–dependent manner. Single-cell transcriptomic analysis of the TME coupled with T-cell receptor sequencing revealed the presence of CD4+ T-cell clusters characterized by CXCL13 expression. The CXCL13+ clusters contained two subclusters with distinct cytotoxic gene expression patterns. The identified neoantigen-specific CD4+ T cells were found exclusively in one of the CXCL13+ subclusters characterized by granzyme B and CCL5 expression. These results demonstrate the involvement of tumor-reactive CD4+ T cells with cytotoxic function in immune surveillance of endometrial cancer and reveal their transcriptomic signature.
Differential Expression Analyses on Human Aortic Tissue Reveal Novel Genes and Pathways Associated With Abdominal Aortic Aneurysm Onset and Progression
Authors: Temprano‐Sagrera Gerard , Peypoch Olga , Soto Begoña , Dilmé Jaume , Calsina Juscafresa Laura , Davtian David , de la Rosa Estadella Mireia , Nieto Lluís , Brown Andrew , Escudero José Román , Viñuela Ana , Camacho Mercedes , Sabater‐Lleal Maria 
Published: December 2024

Background
Abdominal aortic aneurysms (AAAs) are focal dilatations of the abdominal aorta that expand progressively, increasing their risk of rupture. Rupture of an AAA is associated with high mortality rates, but the mechanisms underlying the initiation, expansion, and rupture of AAAs are not yet fully understood. We aimed to characterize the pathophysiology of AAAs and identify new genes associated with AAA initiation and progression.

Methods and Results

This study used RNA sequencing data on 140 samples, becoming the largest RNA sequencing data set for differential expression studies of AAAs. We performed differential expression analyses and analyses of differential splicing between dilated and nondilated aortic tissue samples, and between AAAs of different diameters. We identified 3002 differentially expressed genes between AAAs and controls that were independent of ischemic time, 1425 of which were new. Additionally, 8 genes (
EXTL3
,
ZFR
,
DUSP8
,
DISP1
,
USP33
,
VPS37C
,
ZNF784
,
RFX1
) were differentially expressed between AAAs of varying diameters and between AAAs and control samples. Finally, 7 genes (
SPP1
,
FHL1
,
GNAS
,
MORF4L2
,
HMGN1
,
ARL1
,
RNASE4
) with differential splicing patterns were also differentially expressed genes between AAAs and controls, suggesting that splicing differences in these genes may contribute to the observed expression changes and disease development.

Conclusions
This study identifies new genes and splicing patterns associated with AAAs and validates previous relevant pathways on AAAs. These findings contribute to the understanding of the complex mechanisms underlying AAAs and may provide potential targets to limit AAA progression and mortality risk.
Neural signatures of word learning during adult-child interactions
Authors: Mosteller Sara , Wijeakumar Sobanawartiny , Wass Sam 
Published: December 2024

Abstract
Early language acquisition relies on the successful communication of specific word meanings when speaking or encoding labels. Here, we tested for evidence of this communication within the parallel functional neural activation that occurred for adults and children as unfamiliar objects were labelled by the caregiver. Measuring event-related hemodynamic responses with functional near-infrared spectroscopy (fNIRS) simultaneously recorded from both individuals, we compared cortical responses that were time-locked to spontaneous instances of object labelling during openly structured interactions. Most notably, children’s responses differed between words learned and not learned in the right posterior temporal cortex, with relatively greater positive activation when children were not learning. The findings bear relevance to investigations of coordination between speakers and listeners during word-learning interactions
Perinatal development of structural thalamocortical connectivity
Authors: Oldham Stuart , Mansour L. Sina , Ball Gareth 
Published: December 2024

Abstract
Thalamocortical connections are crucial for relaying sensory information in the brain and facilitate essential functions including motor skills, emotion, and cognition. Emerging evidence suggests that thalamocortical connections are organised along spatial gradients that may reflect their sequential formation during early brain development. However, this has not been extensively characterised in humans. To examine early thalamocortical development, we analysed diffusion MRI data from 345 infants, scanned between 29 and 45 weeks gestational age. Using diffusion tractography, we mapped thalamocortical connectivity in each neonate and used Principal Component Analysis to extract shared spatial patterns of connectivity. We identified a primary axis of connectivity that varied along an anterior/medial to posterior/lateral gradient within the thalamus, with corresponding projections to cortical areas varying along a rostral-caudal direction. The primary patterns of thalamocortical connectivity were present at 30 weeks’ gestational age and gradually refined during gestation. This refinement was largely driven by the maturation of connections between the thalamus and cortical association areas. Differences in thalamocortical connectivity between preterm and term neonates were only weakly related to primary thalamocortical gradients, suggesting a relative preservation of these features following premature birth. Overall, our results indicate that the organisation of structural thalamocortical connections is highly conserved across individuals, develops early in gestation, and gradually matures with age.
The Implementation of Integrated Youth Services in Canada: Planning and Costing of a Pan-Canadian Model: La mise en œuvre des services intégrés pour les jeunes au Canada : planification et établissement des coûts d’un modèle pancanadien
Authors: Henderson Jo L. , de Oliveira Claire , Mathias Steve 
Published: December 2024

Objective The implementation of Integrated Youth Services (IYS) can help ensure that youth are adequately supported. The objective of this analysis was to provide a model for the planning and costing of IYS throughout Canada over a 15-year period. Methods To estimate resource allocation for IYS, we determined the number of hubs and hub staffing requirements by service level and jurisdiction, backbone support and infrastructure requirements by jurisdiction. A needs-based analytic framework for planning was employed to estimate the number of hubs required. The optimal mix of hub staffing requirements was determined based on prior literature. The costs of running each hub were estimated using publicly available data and internal documents from existing IYS agencies. Finally, the cost of setting up IYS hubs, IYS virtual care and respective backbone support throughout Canada was estimated and projected over 15 years and the cost-savings of IYS were calculated. Results At maturity, it was estimated that 399 hubs—188 small, 43 medium, 168 large—across Canada would be required to address youth mental health and substance use needs. The cost of implementing IYS initiatives across Canada would vary between $4,349,126 (for less populous jurisdictions) and $248,950,524 (for more populous jurisdictions), for a total annual cost of $676,633,388 (excluding costs of infrastructure). It was estimated that the implementation of IYS hubs would lead to cost-savings of $2.1 billion annually and have the potential to be cost-effective. Conclusion The implementation of IYS hubs can provide good value for money, in the form of high client satisfaction, earlier supports with improved youth outcomes and decreased health care costs. Future work should address gaps in data availability on mental health and substance use-related needs of youth with neurodevelopmental disorders, youth experiencing homelessness, youth in congregate living and foster care, and Indigenous youth.
Comparing Cisgender and Trans-spectrum Postsecondary Student Alcohol and Substance Use: Results From the Arkansas Collegiate Substance Use Assessment
Authors: Williams Adam , Slagle Derek R. , Blankenberger Robert J. , Slagle Brittany M. , Wuerzer Thomas 
Published: December 2024

Purpose Examine self-reported substance use of cisgender and trans-spectrum students. Design Observational Study, cross-sectional design. Setting Arkansas post-secondary institutions. Subjects Active students enrolled in 2021, sample responses n = 3659. Measures 9 Demographics, 13 recent substance use outcomes, 1 weekly alcohol use outcome, and 1 COVID-related substance use outcome. Analysis Demographic and geospatial descriptives; t test/Cohen’s d effect size; X2 Test for Independence/Cramer’s V effect size; OLS Regression/Standardized Beta coefficients/Adjusted R2 effect sizes; level of significance = .05. Results Trans-spectrum students are 1.8% of the sampled responses (n = 3315) with geographical variation. Weekly alcohol consumption is greater with trans-spectrum (MD = 0.74, d = .102), along with frequency of recent use of marijuana (V = .113), cocaine (V = .097), sedatives (V = .098), hallucinogens (V = .127), designer drugs (V = .087), and meth (V = .151). Suicidal thoughts (V = .112) and attempted suicide (V = .118) are greater and COVID increased use of substances (29.3% for trans-spectrum v 13.7% for cisgender, V = .073). Gender (B = .099), family history (B = .092), and campus policies (B = .084) impact weekly alcohol consumption ( P < .001, R2 = .024). Discussion/Conclusions Trans-spectrum students report higher usage rates, suicidal thoughts, and COVID impacts on usage. Family history and campus policies also show impact on weekly alcohol use. Future postsecondary substance use assessments should include trans-spectrum demographic categories.
Changing human resource professionals from gatekeepers to enablers of disability employment: Lessons learned from disability-employment research
Authors: Bezyak Jill , Chan Fong , Tansey Timothy N. , Wu Jia-Rung , Iwanaga Kanako , Lee Deborah 
Published: December 2024

Background People with disabilities are one the most discriminated groups in the United States, and this discrimination negatively impacts the ability to find and maintain employment. While more companies are making it a priority to include people with disabilities in their workforces in order to diversify talent pools, many organizations still lack knowledge regarding the benefits of disability-employment and effective strategies for disability inclusion in the workplace. Objective There is a need to provide an integrative review of the disability inclusion literature for vocational rehabilitation professionals to expand employer engagement efforts by helping companies adopt strategies to hire and support people with disabilities in the workplace. Method A review of disability employment and disability inclusion publications was conducted. Findings from the research were compiled into a discussion of lessons learned for vocational rehabilitation professionals. Results The article shares the lessons learned from conducting disability-employment research with attention to the following domains: (1) stigmatizing attitudes of employers, (2) disability employment legislation, (3) characteristics of companies that promote disability-employment, (4) disability inclusion policies and practices, and (5) implicit bias and disability inclusion training for human resource (HR) professionals. Conclusion Providing employers and HR professionals with trainings on these domains will increase awareness of bias toward people with disabilities in the workplace and develop increasingly effective disability inclusion policies and practices for their organization.
Limb Symmetry Index in Collegiate Dancers Using the Modified Star Excursion Balance Test and Single Leg Hops
Authors: Wiese Kelley R. , Ambegaonkar Jatin P. , Hansen-Honeycutt Jena 
Published: December 2024

Introduction: Dance is physically demanding and often involves unilateral movements performed within a small base of support. Prior authors have reported that dancers use one leg preferentially over the other (ie, lower extremity asymmetry). Increased leg asymmetry—quantified using the Limb Symmetry Index (LSI), is associated with increased injury risk. Clinicians often use LSI to make return-to-performance decisions (eg, >85% performance on injured vs non-injured limb). However, limited research has examined leg symmetry in collegiate dancers. Purpose: To examine LSI in collegiate dancers using the modified star excursion balance test (mSEBT) and single-leg hop test (SLH). Methods: 120 healthy collegiate dancers (105 females, 15 males; 18.31 ± 0.80 years; 164.18 ± 7.12 cm; 61.18 ± 8.46 kg) performed the mSEBT (normalized to % leg-length: LL) in the anterior, posteromedial, and posterolateral directions and the SLH test (normalized to % body height: BH) across both legs using previously published guidelines. mSEBT scores were averaged for all three directions per leg. SLH scores were averaged per leg. LSI was calculated as (lower value/higher value) × 100 to obtain a percentage. Results: Mean mSEBT scores were 95.7 ± 14.2%LL (lower score) and 96.6 ± 14.3%LL (higher score). Dancers LSI for mSEBT was 99.1 ± 0.9%. Mean SLH scores were 82.8 ± 13.3%BH (lower score) and 86.4 ± 13.5%BH (higher score). Dancers LSI for SLH was 95.9 ± 3.5%. Conclusions: Dancers’ LSI% was greater than 90% for mSEBT and SLH, concurrent with the normal values of LSI > 90% in healthy, physically active adults. Dancers displayed lower leg symmetry. Practitioners can thus use the contralateral leg as a reference for return-to-performance decisions following injury in dancers. LSI should be integrated into a comprehensive screening process to identify large (>85%) asymmetries and guide training programs post-injury to assist educators and practitioners’ evidence-based return-to-performance decisions. Future researchers should examine LSI in other dance genres and across levels. Level of Evidence: 2C