bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethnic Disparities in Early-Onset Gastric Cancer Persist across Rural–Urban Geographies
Authors: Narasimman Manasa , Pruitt Sandi L. , Murphy Caitlin C. , Singal Amit G. , Tavakkoli Anna 
Published: June 2023

Abstract

Background:
The incidence of noncardia gastric cancer is increasing in adults ages less than 50 years old. Early-onset gastric cancer (EOGC) is characterized by ethnic disparities occurring more in Hispanic persons than non-Hispanic persons. It is unknown whether rural–urban disparities exist in EOGC and if this intersects with ethnic disparities.

Methods:
We utilized the Surveillance Epidemiology and End Results 17 Census Tract-level Socioeconomic Status and Rurality Database from 2006 to 2018 to calculate incidence rates and incidence rate ratios of EOGC among Hispanic and non-Hispanic persons by census tract rural–urban location, age, gender, persistent poverty, and stage of disease. We used the Tiwari Method to estimate incidence rate ratios with 95% confidence intervals (CI).

Results:
Hispanic persons had higher incidence rates of EOGC compared with non-Hispanic persons in both rural [incident rate ratios (IRR), 2.12; 95% confidence interval (CI), 1.64–2.73] and urban census tracts (IRR, 2.03; 95% CI, 1.91–2.16). Similar findings were seen when comparing Hispanic to non-Hispanic persons in rural and urban census tracts by age, stage of disease, and persistent poverty.

Conclusions:
Higher incidence rates of EOGC among Hispanic persons persist across rural–urban locations. Further research is needed to understand the etiology of this elevated risk in young Hispanics and interventions that may help to modify their outcome.

Impact:
While other cancers have ethnic disparities which may differ by rural–urban location, the ethnic disparity in EOGC among Hispanic and non-Hispanic persons does not differ by rural–urban residence.
A Carbonic Anhydrase IX/SLC1A5 Axis Regulates Glutamine Metabolism Dependent Ferroptosis in Hypoxic Tumor Cells
Authors: Venkateswaran Geetha , McDonald Paul C. , Chafe Shawn C. , Brown Wells S. , Gerbec Zachary J. , Awrey Shannon J. , Parker Seth J. , Dedhar Shoukat 
Published: June 2023

Abstract
The ability of tumor cells to alter their metabolism to support survival and growth presents a challenge to effectively treat cancers. Carbonic anhydrase IX (CAIX) is a hypoxia-induced, metabolic enzyme that plays a crucial role in pH regulation in tumor cells. Recently, through a synthetic lethal screen, we identified CAIX to play an important role in redox homeostasis. In this study, we show that CAIX interacts with the glutamine (Gln) transporter, solute carrier family 1 member 5 (SLC1A5), and coordinately functions to maintain redox homeostasis through the glutathione/glutathione peroxidase 4 (GSH/GPX4) axis. Inhibition of CAIX increases Gln uptake by SLC1A5 and concomitantly increases GSH levels. The combined inhibition of CAIX activity and Gln metabolism or the GSH/GPX4 axis results in an increase in lipid peroxidation and induces ferroptosis, both in vitro and in vivo. Thus, this study demonstrates cotargeting of CAIX and Gln metabolism as a potential strategy to induce ferroptosis in tumor cells.
MTX-13, a Novel PTK7-Directed Antibody–Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao 
Published: June 2023

Abstract
Protein tyrosine kinase 7 (PTK7) is a Wnt signaling pathway protein implicated in cancer development and metastasis. When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody–drug conjugate (ADC), h6M24-vc0101 (PF-06647020/cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial. To improve patient response and to expand responding tumor types, we designed MTX-13, a PTK7-targeting ADC consisting of a novel antibody (Ab13) conjugated to eight molecules of topoisomerase I inhibitor exatecan through T1000, a novel self-immolative moiety. MTX-13 exhibited PTK7-specific cell binding, efficient internalization, and exatecan release to cause cytotoxic activity through DNA damage and apoptosis induction, and a strong bystander killing. MTX-13 displayed potent antitumor activities on cell line–derived xenograft and patient-derived xenograft models from a wide range of solid tumors, significantly outperforming h6M24-vc0101. PTK7 was shown to be an actionable target in small cell lung cancer for which MTX-13 showed complete and durable responses. With a consistent overexpression of PTK7 in squamous cell carcinomas derived from diverse anatomic sites, strong potency of MTX-13 in this group of heterogenous tumors suggested a common treatment strategy. Finally, MTX-13 inhibited tumor growth and metastasis in an orthotopic colon cancer xenograft model. MTX-13 displayed a favorable pharmacokinetic and safety profile in monkeys with the highest non-severely toxic dose (HNSTD) of ≥30 mg/kg, significantly higher than 3–5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with the potential to expand the responding patient population beyond that of current PTK7-targeting ADCs.
Enhancing CAR T-cell Therapy Using Fab-Based Constitutively Heterodimeric Cytokine Receptors
Authors: Righi Matteo , Gannon Isaac , Robson Matthew , Srivastava Saket , Kokalaki Evangelia , Grothier Thomas , Nannini Francesco , Allen Christopher , Bai Yuchen V. , Sillibourne James , Cordoba Shaun , Thomas Simon , Pule Martin 
Published: June 2023

Abstract
Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T-cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilizing nonnative dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilizing the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimicked the cytokine receptor heterodimerization, with transcriptomic signatures like those obtained by activation of the native IL2 receptor. Moreover, we found that this dimerization structure was agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs coexpressed with a clinically relevant solid tumor–specific GD2-specific chimeric antigen receptor (CAR). Based on this characterization, we suggest that the coexpression of either the common β-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T-cell expansion, engraftment, and efficacy. Our results demonstrate how Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T-cell therapies, as well as therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T-cell therapies.
Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer
Authors: Mehra Siddharth , Garrido Vanessa T. , Dosch Austin R. , Lamichhane Purushottam , Srinivasan Supriya , Singh Samara P. , Zhou Zhiqun , De Castro Silva Iago , Joshi Chandrashekar , Ban Yuguang , Datta Jashodeep , Gilboa Eli , Merchant Nipun B. , Nagathihalli Nagaraj S. 
Published: June 2023

Pancreatic ductal adenocarcinoma (PDAC) is a significant contributor to cancer-related morbidity and mortality, and it is known for its resistance to conventional treatment regimens, including chemotherapy and immune checkpoint blockade (ICB)-based therapies. We have previously shown that Urolithin A (Uro A), a gut microbial metabolite derived from pomegranates, can target and inhibit KRAS-dependent PI3K/AKT/mTOR signaling pathways to overcome therapeutic resistance and improve survival in PDAC. However, the effect of Uro A on the tumor immune microenvironment and its ability to enhance ICB efficacy has not been explored. This study demonstrates that Uro A treatment reduces stromal fibrosis and reinvigorates the adaptive T-cell immune response to overcome resistance to PD-1 blockade in a genetically engineered mouse model (GEMM) of PDAC. Flow cytometric–based analysis of Uro A-treated mouse tumors revealed a significant attenuation of immunosuppressive tumor-associated M2-like macrophages with a concurrent increase in the infiltration of CD4+ and CD8+ T cells with memory-like phenotype along with reduced expression of the exhaustion-associated protein, PD-1. Importantly, the combination of Uro A treatment with anti-PD-1 immunotherapy promoted enhancement of the antitumor response with increased infiltration of CD4+ Th1 cells, ultimately resulting in a remarkable improvement in overall survival in GEMM of PDAC. Overall, our findings provide preclinical evidence for the potential of Uro A as a novel therapeutic agent to increase sensitivity to immunotherapy in PDAC and warrant further mechanistic exploration in preclinical and clinical studies.

Significance:
Immunotherapeutic agents are ineffective against pancreatic cancer, mainly due to the immunosuppressive tumor microenvironment and stromal desmoplasia. Our current study demonstrates the therapeutic utility of a novel gut microbial metabolite, Uro A, to remodel the stromal-immune microenvironment and improve overall survival with anti-PD-1 therapy in pancreatic cancer.
Sequential Chromogenic IHC: Spatial Analysis of Lymph Nodes Identifies Contact Interactions between Plasmacytoid Dendritic Cells and Plasmablasts
Authors: Claudio Natalie , Nguyen My-Tien , Wanner Adrian , Pucci Ferdinando 
Published: June 2023

Recent clinical observations have emphasized the critical role that the spatial organization of immune cells in lymphoid structures plays in the success of cancer immunotherapy and patient survival. However, implementing sequential chromogenic IHC (scIHC) to analyze multiple biomarkers on a single tissue section has been limited because of a lack of a standardized, rigorous guide to the development of customized biomarker panels and a need for user-friendly analysis pipelines that can extract meaningful data. In this context, we provide a comprehensive guide for the development of novel biomarker panels for scIHC, using practical examples and illustrations to highlight the most common complications that can arise during the setup of a new biomarker panel, and provide detailed instructions on how to prevent and detect cross-reactivity between secondary reagents and carryover between detection antibodies. We also developed a novel analysis pipeline based on non-rigid tissue deformation correction, Cellpose-inspired automated cell segmentation, and computational network masking of low-quality data. We applied this biomarker panel and pipeline to study regional lymph nodes from patients with head and neck cancer, identifying novel contact interactions between plasmablasts and plasmacytoid dendritic cells in vivo. Given that Toll-like receptors, which are highly expressed in plasmacytoid dendritic cells, play a key role in vaccine efficacy, the significance of this cell–cell interaction decisively warrants further studies. In summary, this work provides a streamlined approach to the development of customized biomarker panels for scIHC that will ultimately improve our understanding of immune responses in cancer.

Significance:
We present a comprehensive guide for developing customized biomarker panels to investigate cell–cell interactions in the context of immune responses in cancer. This approach revealed novel contact interactions between plasmablasts and plasmacytoid dendritic cells in lymph nodes from patients with head and neck cancer.
Assessing Students’ Learning: Revisiting Challenges of Secondary Mathematics Teachers in Bicol Region, Philippines
Authors: Sionicio Joan Belen , Besmonte Al Banico 
Published: June 2023

The COVID-19 pandemic led to a sudden paradigm shift in education worldwide. To ensure that education would be undisrupted, many countries, including the Philippines, shifted from the usual face-to-face classes to distance learning modalities such as modular, online and blended. With these rapid changes, mathematics teachers were confronted with a lot of uncertainties. To investigate the challenges they encountered in assessing their students’ learning during the remote setting, this study used a descriptive research design. Data were gathered through online questionnaires in Google form and informal interviews among 268 secondary mathematics teachers from the different divisions in Bicol Region, Philippines. Thematic analysis was utilized in the analysis of qualitative data. Results show challenges in terms of the quality of outputs, materials and resources, students’ performance and feedback mechanism. On a positive note, they regarded the pandemic as an opportunity for professional advancement and pedagogical flexibility.
The COVID-19 pandemic led to a sudden paradigm shift in education worldwide. To ensure that education would be undisrupted, many countries, including the Philippines, shifted from the usual face-to-face classes to distance learning modalities such as modular, online and blended. With these rapid changes, mathematics teachers were confronted with a lot of uncertainties. To investigate the challenges they encountered in assessing their students’ learning during the remote setting, this study used a descriptive research design. Data were gathered through online questionnaires in Google form and informal interviews among 268 secondary mathematics teachers from the different divisions in Bicol Region, Philippines. Thematic analysis was utilized in the analysis of qualitative data. Results show challenges in terms of the quality of outputs, materials and resources, students’ performance and feedback mechanism. On a positive note, they regarded the pandemic as an opportunity for professional advancement and pedagogical flexibility.
Intravenous Drug Use‐Associated Endocarditis Leads to Increased Intracranial Hemorrhage and Neurological Comorbidities
Authors: Hoang Alex N. , Shah Varun , Granger Jessica , III David Dornbos , Youssef Patrick P. , Powers Ciaran J. , Tanweer Omar , McCullough Louise D. , Nimjee Shahid M. 
Published: June 2023

Background
The United States is experiencing a rapidly increasing rate of opioid drug abuse. Intravenous drug use (IVDU)‐related endocarditis can lead to significant neurological complications with high morbidity and mortality. When patient care necessitates anticoagulation, the standards for radiographic screening and the risk for intracranial hemorrhage are not clearly elucidated.

Methods
We conducted a retrospective cohort study involving patients treated for infective endocarditis at a single institution from 2014 to 2018. Patients were grouped based in history of IVDU and their demographics and clinical predictors for intracranial hemorrhage were analyzed.

Results

A total of 351 patients met inclusion criteria for this study, of whom 170 patients (48%) had a history of IVDU‐associated endocarditis. IVDU was associated with an increased prevalence of intracranial hemorrhage (25.9% versus 13.9%;
P
=0.005), including intraparenchymal hemorrhage (12.4% versus 5.1%;
P
=0.012), subarachnoid hemorrhage (17.6 versus 4.4%;
P
=0.001), and cerebral microbleeds (14.1% versus 7.2%;
P
=0.022). IVDU was also associated with an increased incidence of infectious intracranial aneurysm (10.6% versus 1.8%;
P
=0.001) and brain abscesses (4.7% versus 1.1%;
P
=0.025). Multivariate analysis showed that the presence of intracranial septic emboli (odds ratio [OR], 18.47 [8.4–40.250];
P
=0.001) and infectious intracranial aneurysm (OR, 12.38 [3.24–47.28];
P
=0.001) as significant predictive factors for intracranial hemorrhage after presenting with endocarditis.

Conclusion
The opioid epidemic has increased the incidence of infective endocarditis and resultant neurovascular complications. IVDU‐associated endocarditis is associated with increased hemorrhagic stroke and more frequent neurodiagnostic imaging.
Clinicians’ views on cognitive assessment with Aboriginal Australians
Authors: Hindman Emily , Hassmén Peter , Orchard Abbey , Radford Kylie , Delbaere Kim , Garvey Gail 
Published: June 2023

Background: A shortage of standardised cognitive assessment tools for use with Aboriginal Australians is evident. Clinicians also miss the range of guidelines necessary to inform test selection and interpretation for all Aboriginal clients. This mixed methods study examines clinicians’ confidence, views and current practices when conducting cognitive assessments with Aboriginal Australian clients. Methods: Clinicians were asked about factors that influence their likelihood of using standardised testing in Aboriginal vs non-Indigenous Australian people. Twenty-one health professionals with experience conducting cognitive assessments with Aboriginal and non-Aboriginal Australians participated. Clinicians were presented with a series of different scenarios per the client’s level of education and language of origin via an online survey. Clinicians rated their likelihood and confidence using standardised cognitive assessment for each scenario. Open-ended questions captured clinicians’ views and information about their current clinical practices. Results: Clients’ age, education and language of origin influence the likelihood of clinicians’ use of standardised cognitive assessment measures with Aboriginal people. Overall, clinicians reported feeling only slightly more confident working with non-Indigenous clients than Aboriginal clients. Qualitative data indicate a lack of consistency regarding test selection. Conclusion: Clinicians expressed concerns about the validity of available cognitive assessment tools for use with Aboriginal Australians and the absence of evidence to assist decision-making. Cited barriers included language, educational attainment and cultural factors.
Grounding Identity and Mission in Catholic Universities: A Relational Approach
Authors: Gourlay Thomas V. 
Published: June 2023

Since at least the 1960s, responding to changes both in the world and in the Church the project of Catholic university education in the United States and elsewhere has undergone a significant alteration in structure, and subsequently of its own sense of identity, purpose, and mission. Concerns about the integrity of Catholic universities both as Catholic and as university abound and have done for some time. Providing a brief review of some of the existing literature, this paper argues that the contemporary discussion regarding identity and mission for Catholic colleges and universities suffers from a decidedly modern inability to the address first order questions. This failure to properly treat questions pertaining to metaphysics render Catholic institutions of higher learning locked within the superficial plane in terms of how they address their own sense of identity and mission. In response to this, this paper argues that there exists within the Catholic tradition adequate metaphysical richness that can and should more faithfully ground the essence of the Catholic college or university. Drawing on the metaphysical work of such figures as David L. Schindler and others, the author argues that a relational ontology, characterized by an understanding of the metaphysics of gift can not only save the project of Catholic university education but is in fact central to its mission.
The role of risperidone in the treatment of children and adolescents with anorexia nervosa
Authors: Pruccoli Jacopo , Bergonzini Luca , Pettenuzzo Ilaria , Parmeggiani Antonia 
Published: June 2023

Background: Current Diagnostic and Statistical Manual of Mental Disorders (DSM)-5-based research provides limited data on the use of risperidone on children and adolescents with anorexia nervosa (AN) mainly in small-sample/case report studies. Aim: To report the use of risperidone in a group of children and adolescents with feeding and eating disorders, specifically with AN. Methods: Observational, naturalistic study. Psychopathology was assessed with Eating Disorders Inventory-3, Beck’s Depression Inventory-II, and Symptom Checklist-90-R. Data were reported for the whole sample, for patients treated with risperidone, and finally compared between patients with AN treated with risperidone and those receiving no atypical antipsychotics. Potential differences in admission–discharge changes in body mass index (BMI) and psychopathology were assessed with analyses of covariance corrected for baseline measures. Kaplan–Meier analyses were conducted to assess retention rates of risperidone (at 3 months and 1 year) and rates of rehospitalization on 1-year follow-up. Results: The study enrolled 120 patients with AN (42 treated with risperidone). Risperidone was used for 116.7 (±122.8) days (total exposure = 3979 days) and well-tolerated (nausea, asthenia in one case). No significantly different admission–discharge improvements for BMI or psychopathology were documented for patients treated with risperidone. Risperidone showed a 3-month retention rate of 50.0% (1 year: 9.5%) and was discontinued mainly for the resolution of target symptoms. Cumulative freedom from rehospitalization at 12 months was comparable for treated and untreated patients (hazard ratio = 1.088; Log-rank p = 0.908). Conclusions: This study reports real-life evidence of the use of risperidone in AN children and adolescents in the widest described sample so far. Longitudinal research should assess long-term prognostic factors and tolerability.
Perceived Neighborhood Characteristics and Later-Life Pain Outcomes: Evidence From the Health and Retirement Study
Authors: Yang Yulin , Sims Kendra D. , Lane Nancy E. , Duchowny Kate A. , Torres Jacqueline M. 
Published: June 2023

Objectives: This study examines whether perceived neighborhood characteristics relate to pain outcomes among middle-aged and older adults. Methods: Data were from the Health and Retirement Study (2006–2014; n = 18,814). Perceived neighborhood characteristics were physical disorder, social cohesion, safety, and social ties. We fitted adjusted generalized estimating equation models to evaluate prevalence, incidence, and recovery of moderate-to-severe limiting pain 2 years later. Results: The mean age of our sample was 65.3 years; 54.6% were female and 24.2% reported moderate-to-severe limiting pain at baseline. Positive neighborhood characteristics were associated with low prevalence (e.g., prevalence ratio [PR]: .71 for disorder) and reduced incidence (e.g., PR: .63 for disorder) of moderate-to-severe limiting pain. Positive neighborhood characteristics were associated with a high recovery rate from moderate-to-severe limiting pain (e.g., PR = 1.15 for safety), though the 95% CIs for disorder and cohesion crossed the null. Discussion: Neighborhood characteristics may be important determinants in predicting pain in later life.