bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract

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.
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

Abstract
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.
Abnormal breathing pattern features in chronic refractory cough
Authors: Jeffery Jordan , Vertigan Anne E. , Bone Sarah , Gibson Peter G. 
Published: July 2024

BackgroundChronic refractory cough (CRC) is a challenging condition that responds to speech pathology intervention. Clinical observation suggests abnormal breathing patterns occur in CRC and may be indirectly addressed as part of behavioural treatment, yet breathing pattern changes in CRC are poorly understood. The aims of this study were to 1) describe breathing patterns in patients with CRC, 2) compare breathing pattern features between patients with CRC and inducible laryngeal obstruction (ILO), and 3) estimate the effect of breathing pattern features on clinical measures of laryngeal sensory and motor dysfunction.MethodsThis retrospective cross-sectional observational study included 634 patients with CRC or ILO. A file audit of speech pathology assessment data was undertaken. Analysis of self-reported laryngeal symptoms (viaquestionnaires) and clinical assessment of voice and breathing of those with CRC and ILO was conducted.ResultsMost participants with CRC (73%) demonstrated at least one abnormal breathing pattern feature. The most common feature was thoracic breathing (69%) followed by oral breathing (33%). The type and prevalence of abnormal breathing patterns were similar between CRC and ILO. Abnormal breathing patterns were associated with reduced maximum phonation time (MPT); however, there was no association between these features and Newcastle Laryngeal Hypersensitivity Questionnaire scores.ConclusionsAbnormal breathing features are common in patients with CRC and are not significantly different from those occurring in ILO. There is some association between abnormal breathing features and MPT, suggesting impairment of laryngeal motor function. Conversely, there is no association between abnormal breathing features and laryngeal hypersensitivity.
Severe COVID-19 multisystem inflammatory syndrome versus severe dengue in children from Indonesia: a cross-sectional study
Authors: Alam Anggraini , Andriyani Fina Meilyana , Peryoga Stanza Uga 
Published: July 2024

Abstract
Introduction
Severe multisystem inflammatory syndrome in children (MIS-C) and severe dengue are challenging to identify during the COVID-19 pandemic in dengue-endemic areas. Fever, multiorgan involvement, and shock characterize both severe MIS-C and severe dengue. Distinguishing between the two diseases is beneficial in initiating proper management.

Methods
Medical records of children < 18 years old who were hospitalized at Hasan Sadikin General Hospital’s PICU between December 2020 and July 2022 with severe MIS-C or severe dengue were recorded. Differences were assessed using comparative and descriptive analyses.

Results
Seventeen severe dengue patients and 4 severe MIS-C were included. The average age of severe MIS-C was 11.5 years (SD ± 2.9, 95% CI), and that of severe dengue patients was 6.2 years (SD ± 4.4, 95% CI) (p value = 0.034, 95%). Fever and abdominal pain were the most common symptoms in both groups (p = 0.471, 95% CI). Rash (p = 0.049) and nonpurulent conjunctivitis (p = 0.035) were two symptoms with significant differences. The highest platelet count (p-value = 0.006, 95% CI), AST (p-value = 0.026, 95% CI), and D-dimer level (p-value = 0.025, 95% CI) were significantly different between the two cohorts. Cardiac abnormalities were found in all (100%) severe MIS-C patients, but only one (5.9%) in severe dengue patients.

Conclusion
Age, rash, nonpurulent conjunctivitis, platelet count, AST and D-dimer level may distinguish severe MIS-C from severe dengue fever.
Expression genome-wide association study identifies key regulatory variants enriched with metabolic and immune functions in four porcine tissues
Authors: Farhangi Samin , Gòdia Marta , Derks Martijn F.L. , Harlizius Barbara , Dibbits Bert , González-Prendes Rayner , Crooijmans Richard P.M.A. , Madsen Ole , Groenen Martien A.M. 
Published: July 2024

Abstract
Background
Integration of high throughput DNA genotyping and RNA-sequencing data enables the discovery of genomic regions that regulate gene expression, known as expression quantitative trait loci (eQTL). In pigs, efforts to date have been mainly focused on purebred lines for traits with commercial relevance as such growth and meat quality. However, little is known on genetic variants and mechanisms associated with the robustness of an animal, thus its overall health status. Here, the liver, lung, spleen, and muscle transcriptomes of 100 three-way crossbred female finishers were studied, with the aim of identifying novel eQTL regulatory regions and transcription factors (TFs) associated with regulation of porcine metabolism and health-related traits.

Results
An expression genome-wide association study with 535,896 genotypes and the expression of 12,680 genes in liver, 13,310 genes in lung, 12,650 genes in spleen, and 12,595 genes in muscle resulted in 4,293, 10,630, 4,533, and 6,871 eQTL regions for each of these tissues, respectively. Although only a small fraction of the eQTLs were annotated as cis-eQTLs, these presented a higher number of polymorphisms per region and significantly stronger associations with their target gene compared to trans-eQTLs. Between 20 and 115 eQTL hotspots were identified across the four tissues. Interestingly, these were all enriched for immune-related biological processes. In spleen, two TFs were identified: ERF and ZNF45, with key roles in regulation of gene expression.

Conclusions
This study provides a comprehensive analysis with more than 26,000 eQTL regions identified that are now publicly available. The genomic regions and their variants were mostly associated with tissue-specific regulatory roles. However, some shared regions provide new insights into the complex regulation of genes and their interactions that are involved with important traits related to metabolism and immunity.