bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA01: Longitudinal landscape analysis of the neoantigen-specific T-cell responses in patients with melanoma with or without response to PD1 blockade
Authors: Puig Saus Cristina 
Published: February 2025

Abstract
T-cell responses induced by immune checkpoint blockade therapy target, among others, neoantigens derived from non-synonymous mutations. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T-cell responses in patients over their treatment course. In this educational session, we will discuss a recently developed technology that allows the capture of low-frequency neoantigen-specific T cells and its application to characterize the neoantigen-specific T-cell responses in the blood and tumor from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. This approach uses personalized libraries of neoantigen-HLA capture reagents to single-cell isolate the T cells and clone their T-cell receptors. Our results show that multiple T cells with different TCR sequences (T-cell clonotypes) recognized a limited number of mutations in samples from seven patients with long-lasting clinical responses. These TCR clonotypes were recurrently detected over time in the blood and tumor. Samples from four patients with no response to anti-PD-1 also demonstrated neoantigen-specific T-cell responses in the blood and tumor to a restricted number of mutations with lower TCR polyclonality and were not recurrently detected in sequential samples. Reconstitution of the neoantigen-specific TCRs in donor T cells using non-viral CRISPR-Cas9 gene editing demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Our results show that effective anti-PD-1 immunotherapy is associated with a polyclonal CD8+ T-cell response in the tumor and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.
Citation Format: Cristina Puig Saus. Longitudinal landscape analysis of the neoantigen-specific T-cell responses in patients with melanoma with or without response to PD1 blockade [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA01.
Abstract IA04: New developments in drugging the adenosine pathway
Authors: Jaen Juan C 
Published: February 2025

Abstract
Adenosine is a pleiotropic immunosuppressive substance, produced mainly by the enzymes CD39 and CD73, from extracellular immunogenic ATP. Thus, CD73-rich tumors may experience decreased anti-tumor immune activity when treated with immunogenic chemotherapies (e.g., platinum-based drugs), relative to what might be possible in the absence of adenosine. From a therapeutic perspective, potential drugs that aim to interfere with the production or signaling of adenosine need to be potent and selective enough, under physiological conditions, to overcome the large amount of adenosine present in selected tumors. Recent results from several clinical studies are strongly supportive of the anti-cancer potential stemming from inhibition of the adenosine axis, when drug properties, tumor selection/setting, and combination backbones are taken into account. This presentation will briefly highlight key design elements for two such drugs, etrumadenant (a dual blocker of A2a and A2b adenosine receptors) and quemliclustat (a CD73 inhibitor), as well as recent clinical results with these agents in advanced colorectal cancer (CRC; ARC-9) and pancreatic cancer (PDAC; ARC-8), respectively. We will also describe how drug-related changes in markers of adenosine activity, as well as baseline levels of those markers, are associated with clinical outcomes in these trials.
Citation Format: Juan C Jaen. New developments in drugging the adenosine pathway [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA04.
Abstract IA05: KRAS inhibitors and modulation of inflammation and immunity
Authors: Vonderheide Robert H 
Published: February 2025

Abstract
The desire to target mutant KRAS therapeutically is now being realized with more and more broadly applicable and allele-specific molecular inhibitors entering clnical trials and gaining FDA approval. Tumor KRAS signaling plays a major role in orchestrating tumor immunosuppression leaving mutant KRAS inhibitors with the potential for immune modulation that could be synergistic with immuno oncology strategies. Here, data will be presented regarding the immune mechanisms and T cell dependency of KRAS inhibitors and their ability to work in concert with checkpoint blockade and CD40 activation for durable tumor regresssions.
Citation Format: Robert H Vonderheide. KRAS inhibitors and modulation of inflammation and immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA05.
Abstract IA07: Engineered cytokine-antibody fusion proteins for targeted stimulation of anti-cancer immunity
Authors: Spangler Jamie B 
Published: February 2025

Abstract
Immunotherapies have revolutionized the cancer treatment landscape by empowering activation of the patient’s own immune system to fight disease. One of the first immunotherapies to receive FDA approval for cancer treatment was interleukin-2 (IL-2), a multi-functional cytokine that potently stimulates immune cell growth and activity. IL-2 has shown tremendous potential as an anti-cancer therapeutic and elicits complete and durable responses in 5-10% of treated patients. However, clinical use of IL-2 has been limited by severe toxicities, counterproductive activation of regulatory T cells (Tregs), and the cytokine’s vanishingly short serum half-life (&lt;5 min). Complexation of IL-2 with certain anti-IL-2 antibodies has been shown to selectively bias cytokine activity towards immune effector cells (i.e., effector T cells and natural killer [NK] cells) while concurrently extending its serum half-life, leading to potent antitumor activity in mice in the absence of adverse effects. Unfortunately, clinical development of a mixed cytokine/antibody complex is impeded by logistical hurdles such as dosing optimization, as well as concerns regarding complex stability. We overcame these challenges by engineering a single-agent IL-2/antibody fusion protein (termed an immunocytokine) that selectively stimulates immune effector cells. We demonstrated the efficacy of our immunocytokine in biasing the immune response in cellular and animal models. We achieved successful tumor targeting of our molecule through fusion to an extracellular matrix-binding protein domain and showed that the resulting immunocytokine induced robust antitumor activity without inducing toxicity in multiple mouse tumor models, both alone and in combination with immune checkpoint blockade. Overall, our strategy offers insight into the design and development of translationally promising IL-2 therapies with versatility to treat a range of cancer types.
Citation Format: Jamie B Spangler. Engineered cytokine-antibody fusion proteins for targeted stimulation of anti-cancer immunity [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA07.
Abstract PR004: Cancer cell intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis
Authors: Ou Peiqi , Eres Ittai , Zhao Junjie , Oh Jaehak , Han Chia-Jung , Li Chi-Ming , Rankin Andrew , Noubade Rajkumar , Yu Xin 
Published: February 2025

Abstract
The immunosuppressive tumor microenvironment (TME) plays a critical role in the therapeutic resistance to checkpoint inhibitors. However, precise factors that shape the immune contexture of the TME remain elusive. Here, we report that the Single-Stranded DNA Binding Protein 4 (SSBP4), a previously uncharacterized protein with no known function, suppresses intratumoral T cell activation by promoting excessive cholesteryl ester production from tumor cells. Overexpression of SSBP4 in tumor cells decreased T cell infiltration in the TME and accelerated tumor growth in a murine syngeneic tumor model. Conversely, genetic ablation of SSBP4 in tumor cells enhanced T cell infiltration, their activation and stunted tumor growth in a CD8+ T cell dependent manner. Furthermore, abrogation of SSBP4 dramatically enhanced the efficacy of anti-programmed cell death-1 (anti-PD-1) treatment. Mechanistically, SSBP4 expression promoted a concerted upregulation of cholesterol synthesis genes, leading to increased production of cholesteryl esters in tumor cells. In vitro studies showed that the cholesteryl esters released by SSBP4-expressing tumor cells directly suppressed CD8+ T cell activation and inhibited the expression of granzyme B and perforin. Together, we identify SSBP4 as a cancer cell intrinsic regulator of cholesterol biosynthesis that critically contributes to tumor immune evasion.
Citation Format: Peiqi Ou, Ittai Eres, Junjie Zhao, Jaehak Oh, Chia-Jung Han, Chi-Ming Li, Andrew Rankin, Rajkumar Noubade, Xin Yu. Cancer cell intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr PR004.
Abstract PR010: Genome-wide CRISPR screens in CD8+ T cells identify cullin-RING E3 ubiquitin ligase complex as a negative regulator of long-term effector function
Authors: Saco Justin , Karin Daniel , Al Deen Nataly Naser , Campbell Katie , Patten Justin , Fan Yichen , Medina Egmidio , Ribas Antoni 
Published: February 2025

Abstract
The benefit of adoptive cell transfer (ACT) therapies with T cells engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) is limited by T cell dysfunction upon repetitive antigen exposure. We integrated a pooled genome-wide CRISPR knockout screen with in vitro repetitive antigen exposure and phenotypic selection to identify gene knockouts that improved the ability of NY-ESO-1 TCR transgenic T cells to repeatedly kill the antigen- and HLA-matched melanoma cell line M407. In two replicate screens, knocking out of the genes CUL5, RNF7 or ARIH2, which are required for proper cullin 5-RING ligase complex (CRL5) assembly, significantly improved long-term tumor cell killing ability of T cells past five rechallenges (one-way ANOVA p&lt;0.0001). Mechanistically, we discovered that CRL5 interacts with SOCS-box containing proteins to regulate TCR stimulation and cytokine signaling through ubiquitination and proteasomal degradation. Ablation of CRL5 in T cells leads to an increase in polyfunctionality with augmented production and release of cytokines and cytolytic molecules across multiple rounds of killing when compared to control T cells (IFNg/TNFa producing T cells; Challenge 1: 18% versus 10%, Stimulation 3: 6% versus 3%, unpaired t-test p&lt;0.0001). We demonstrated through both CRISPR knockout, and pharmacological inhibition of CRL5 using the neddylation inhibitor MLN4924, the negative regulatory mechanism of CRL5 in CD8+ T cells. These results highlight the previously unrecognized regulation of T cell function through E3 ligase-mediated proteasomal degradation, and that CRL5 may be a target to endow lasting effector function to antigen-specific T cells for cancer immunotherapies.
Citation Format: Justin Saco, Daniel Karin, Nataly Naser Al Deen, Katie Campbell, Justin Patten, Yichen Fan, Egmidio Medina, Antoni Ribas. Genome-wide CRISPR screens in CD8+ T cells identify cullin-RING E3 ubiquitin ligase complex as a negative regulator of long-term effector function [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr PR010.
Preoperative Oral Antibiotics Preparation is Associated With Improved 30-day Outcomes in Elective Colectomy for Ulcerative Colitis
Authors: Li Renxi , Kartiko Susan 
Published: February 2025

Background Ulcerative colitis (UC) is characterized by colonic involvement, where the 10-year risk of colectomy remains high at about 20%. The use of preoperative oral antibiotic preparation (OAP) in colectomy remains a subject of debate and there was limited evidence for UC patients. This study aimed to retrospectively investigate the relationship between OAP and 30-day outcomes following elective colectomy in UC patients using a multi-institutional national dataset. Methods Patients with UC as the primary indication for colectomy were selected from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2013 to 2022. Thirty-day postoperative outcomes were compared by multivariable logistic regression, where demographics, baseline characteristics, preoperative preparation, and operative approaches were adjusted. Results Among 6075 patients who underwent elective colectomy for UC, 3193 (52.56%) of them received preoperative OAP. Patients with OAP had lower cardiac complications (aOR = 0.358, 95 CI = 0.137-0.932, P = 0.04), pulmonary complications (aOR = 0.686, 95 CI = 0.494-0.952, P = 0.02), bleeding requiring transfusion (aOR = 0.738, 95 CI = 0.601-0.906, P < 0.01), wound complications (aOR = 0.626, 95 CI = 0.527-0.743, P < 0.01), prolonged postoperative nothing by mouth (NPO) or nasogastric tube (NGT) use (aOR = 0.781, 95 CI = 0.678-0.901, P < 0.01), and 30-day readmission (aOR = 0.811, 95 CI = 0.676-0.972, P = 0.02). Moreover, patients with OAP had shorter length of stay ( P < 0.01). Conclusion The use of OAP in elective UC colectomy was shown to have additional benefits beyond surgical site infections. Further large-scale randomized trials may be needed to determine the cause and effect of these observations.
Interprofessional collaboration: Measuring occupational therapists and teachers’ perceptions of collaborative practice in inclusive Australian primary schools
Authors: Jeremy Jill , Hinitt Joanne , Spandagou Ilektra 
Published: February 2025

Introduction: Globally occupational therapists are collaborating with teachers to support the inclusion of students with disabilities in mainstream schools. To begin to understand how collaboration promotes inclusion, this study aimed to measure occupational therapists and teachers perceived collaborative practice. Method: A quantitative cross-sectional analysis of occupational therapists and teachers in mainstream primary schools in three Australian states was conducted via an anonymous online survey. Eligible participants were recruited via self-selection and snowballing, resulting in a nonprobability sample of 108 occupational therapists and 33 primary teachers. The Teacher – Therapist Collaboration Index, an instrument based on an existing conceptual framework and associated tool was developed to measure perceived collaborative practice. Results: Occupational therapist and teacher profiles were similar. Both professions report above average collaborative practice, although teachers rated themselves more collaborative on two components. Ratings did not significantly differ by profession, demographic, or background. Personal, professional and systems influences positively correlated with collaboration ratings, with systems having the strongest relationship. Conclusion: Systems changes may be necessary to improve collaboration. Therapists could use the framework and measurement instrument as tools to plan, execute and evaluate their collaborative practice.
Adverse Reactions by Radiopharmaceuticals: Retrospective Analysis of the Portuguese National Pharmacovigilance System
Authors: Martins Sara , Jesus Ângelo , Andrade Ricardo , Rocha Mariana , Martín-Suarez Ana 
Published: February 2025

Background: Radiopharmaceuticals are essential in the field of nuclear medicine, but like any other medicinal product, radiopharmaceuticals can potentially cause adverse reactions in patients. Objective: To describe the adverse reactions to radiopharmaceuticals reported to the Portuguese National Pharmacovigilance System (SNF). Methods: We performed a retrospective, observational study by examining individual case safety reports (ICSRs) provided by the SNF related to all radiopharmaceuticals commercially available in Portugal from 2010 to 2023. Results: The SNF received a total of 84 ICSRs. These reports resulted in a total of 224 adverse drug reactions (ADR), which involved a total of 15 different radiopharmaceuticals. The mean age of patients was 61.9 years old. Twenty-one different system organ classes (SOCs) were identified, with the most prevalent situations being “Gastrointestinal Disorders” (18.3%; n = 41) followed by “General disorders and administration site conditions” (16.5%; n = 37), “Skin and subcutaneous tissue disorders” (11.2%; n = 25) and “Blood and lymphatic system disorders” (10.3%; n = 23). Fifty-seven reports (67.85%) showed at least 1 serious ADR. Most notified radiopharmaceuticals were, respectively, radium—223 (n = 36, 41.4%), lutetium-177 oxotreotide (n = 12, 13.8%) and iodide—131 (n = 9, 10.3%). Conclusion and Relevance: Although the number of notifications is limited, these findings provide valuable insights into the types and frequencies of adverse reactions associated with radiopharmaceuticals used in Portugal between 2010 and 2023. The data highlight the importance of continued pharmacovigilance efforts to monitor the safety of these specialized medical products and inform clinical decision-making.
Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Nervous System Disorders: A Systematic Review and Meta-Analysis
Authors: Xu Bo , Yang Mingxia , Li Shaoqian , Kang Bo , Zhou Jiecan 
Published: February 2025

Background: Adults with type 2 diabetes mellitus (T2DM) are at an increased risk for certain brain or psychiatric disorders, as are those with or without chronic kidney disease or heart failure. Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with these diseases is unclear. Objective: This systematic review and meta-analysis aimed to investigate the effects of SGLT2 inhibitors on nervous system disorders. Methods: We searched PubMed, ClinicalTrials.gov, and Web of Science for randomized, double-blind placebo-controlled trials of at least ≥24 weeks. We used Mantel–Haenszel statistical method, risk ratio (RR), and 95% confidence interval (CI) to dichotomous variables. Results: We included 52 publications/trials covering 111 376 participants (SGLT2 inhibitors 62 192; Placebo 49 184). Sodium-glucose cotransporter 2 inhibitors had no significant effect on ischaemic stroke (RR = 0.97; 95% CI = 0.87-1.09; P = 0.64), cerebrovascular accident (RR = 1.05; 95% CI = 0.91-1.22; P = 0.50), dementia (RR = 1.29; 95% CI = 0.78-2.12; P = 0.32), carotid artery occlusion/carotid artery stenosis (RR = 1.18; 95% CI: 0.92-1.53; P = 0.20), haemorrhagic stroke (RR = 0.84; 95% CI = 0.62-1.12; P = 0.23), and transient ischaemic attack (RR = 0.97; 95% CI = 0.82-1.15; P = 0.73) compared to placebo. No significant heterogeneity was observed. However, SGLT2 inhibitors showed slight effects to reduce the risk of Parkinson’s disease (major heart failure subgroup). Empagliflozin and dapagliflozin significantly increased the risk of syncope (RR = 1.65; 95% CI = 1.15-2.38; P < 0.01) and carotid artery occlusion/carotid artery stenosis (RR = 1.65; 95% CI = 1.04-2.61; P = 0.03), respectively. Conclusion and Relevance: No significant effect of SGLT2 inhibitors on nervous system disorders was observed. There was reduced risk for Parkinson’s Disease observed in some specific populations. In addition, the risks of empagliflozin and dapagliflozin concerning syncope and carotid artery occlusion/carotid artery stenosis are worth attention.
Non-Candida mycosis in Gulf Cooperation Council (GCC) countries: perspective of a low-incidence region
Authors: AlSaleh Abdullah , Shahid Mohammed 
Published: February 2025

Abstract

Background
Fungal pathogens are ubiquitous microorganisms that are implicated in a wide range of infections, affecting individuals with underlying health conditions and immune suppression therapy; however, immunocompetent individuals may also be at risk. Among these infections, many are caused by molds and yeasts other than Candida and are recognized in clinical practice, such as aspergillosis, mucormycosis, fusariosis, phaeohyphomycosis, and basidiobolomycosis, among others, each presents different clinical manifestations and requires clinical management specific to the site of involvement. Although pathogenic fungal contaminants and potential sources of mycosis in humans are plentiful in Gulf Cooperation Council (GCC) countries, epidemiological reports regarding mycosis in the region are scarce.

Aim
The aim of this review is to shed some light on the epidemiology of clinically associated molds and yeasts other than Candida and to survey all related case reports and epidemiological studies conducted in the GCC over the past 10 years.

Methods
A comprehensive search of the Medline (PubMed) and Scopus databases was conducted using the following keywords: Aspergillosis, Mycosis, Mucormycosis, Fusarium, Kuwait, Bahrain, Saudi Arabia, Qatar, Oman and the United Arab Emirates. A timeframe was set to include only articles that were published from 2014 to 2024.

Results
One hundred thirty-five of the 1563 articles examined fulfilled the purpose of this review. Most studies were in Saudi Arabia (45%), Qatar (18%) and Kuwait (16%). Mucormycosis, aspergillosis, phaeohyphomycosis and basidiobolomycosis were among the most commonly reported fungal infections in the GCC, with corresponding mortality rates of 53%, 37%, 69% and 24%, respectively. The average estimations of non-Candida fungal infections indicate a low regional incidence in comparison with global estimations.

Conclusion
Awareness and a high index of suspicion are warranted in successfully managing non-Candida mycosis. More specific immunological and molecular markers are needed for differential diagnosis to rule out fungal infections. Additionally, incorporating non-Candida mycosis-related antifungal resistance surveys in GCC national surveillance efforts should be enforced, especially when considering the increase in global mycosis rates.