bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying low-risk chest pain in the emergency department without troponin testing: a validation study of the HE-MACS and HEAR risk scores
Authors: Todd Fraser , Duff James , Carlton Edward 
Published: November 2021

IntroductionPatients presenting to EDs with chest pain of possible cardiac origin represent a substantial and challenging cohort to risk stratify. Scores such as HE-MACS (History and Electrocardiogram-only Manchester Acute Coronary Syndromes decision aid) and HEAR (History, ECG, Age, Risk factors) have been developed to stratify risk without the need for troponin testing. Validation of these scores remains limited.MethodsWe performed a post hoc analysis of the Limit of Detection and ECG discharge strategy randomised-controlled trial dataset (n=629; June 2018 to March 2019; 8 UK hospitals) to calculate HEAR and HE-MACS scores. A <4% risk of major adverse cardiac events (MACE) at 30 days using HE-MACS and a score of <2 calculated using HEAR defined ‘very low risk’ patients suitable for discharge. The primary outcome of MACE at 30 days was used to assess diagnostic accuracy.ResultsMACE within 30 days occurred in 42/629 (7%) of the cohort. HE-MACS and HEAR scores identified 85/629 and 181/629 patients as ‘very low risk’, with MACE occurring in 0/85 and 1/181 patients, respectively. The sensitivities of each score for ruling out MACE were 100% (95% CI: 91.6% to 100%) for HE-MACS and 97.6% (95% CI: 87.7% to 99.9%) for HEAR. Presenting symptoms within these scores were poorly predictive, with only diaphoresis reaching statistical significance (OR: 4.99 (2.33 to 10.67)). Conventional cardiovascular risk factors and clinician suspicion were related to the presence of MACE at 30 days.ConclusionHEAR and HE-MACS show potential as rule out tools for acute myocardial infarction without the need for troponin testing. However, prospective studies are required to further validate these scores.
25 Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer
Authors: Kim Leeseul , Chae Young Kwang , Lee Dong-Uk 
Published: November 2021

BackgroundPredicting immune-related adverse events (irAEs) in early stage is being emphasized even more. Host response to disease is reflected in serum proteome level and that allows serum proteome level as a new marker to explore response to immunotherapy. With the help of a serum-based proteomics test, Primary Immune Response (PIR), we are accessing the correlations between developing irAEs and immunotherapy in non-small cell lung cancer (NSCLC) patients.MethodsData of 48 consented NSCLC patients with baseline PIR test done within one week prior to the start of immunotherapy were collected. Samples were grouped into either sensitive or intermediate/resistant (not sensitive) by PIR classification. We analyzed the durations from the immunotherapy initiation to the first episode of irAE. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.ResultsAmong the 48 NSCLC patients, 19 patients (39%) experienced one or more irAEs with the majority classified as either grade 1 (n=7, 36%) or grade 2 (n=10, 52%). PIR-sensitive group showed no difference in irAE free period compared to PIR-not sensitive (p=0.92, HR=0.95, 95% CI=00.3212 to 2.834). The median ‘Time to first irAE’ were undefined and 24 in PIR-sensitive and PIR-not sensitive, respectively.ConclusionsOur results demonstrated PIR-sensitive patients are not likely to tolerate immunotherapy longer without developing irAEs.
31 Serum LAG-3 is associated with improved patient prognosis in high grade serous ovarian cancer
Authors: James Nicole , Eurich Katrin , Lips Erin , Cruz Payton De La , Woodman Morgan , Ribeiro Jennifer 
Published: November 2021

BackgroundHigh grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy with a five-year survival rate of only 39 percent.1 Despite the fact that ovarian tumors are considered immunologic, HGSOC patients respond poorly to PD-1 based immunotherapy. Hence, the need to identify novel prognostic and therapeutic immunologic factors is crucial. Our previous investigation uncovered intratumoral levels of immune co-inhibitory receptor LAG-3 as a marker of improved HGSOC patient survival. For this current study we sought to evaluate the prognostic utility of serum-based LAG-3, as well as determine how these circulating levels change in response to HGSOC standard of care therapy.MethodsThis study was approved by the Women and Infants Institutional Review Board; approval number 1057626. HGSOC serum samples were obtained from the Department of Special Testing and the Program in Women’s Oncology Gynecologic Tissue Bank at Women and Infants Hospital. A total of 43 HGSOC treatment naïve serum samples were tested for serum LAG-3 and in 20 of these patients, samples from on- and post- frontline platinum-based chemotherapy were also analyzed. A commercially available ELISA kit was employed to detect serum LAG-3.ResultsThere was no statistically significant change in pre-, on-, and post- serum LAG-3 levels following frontline chemotherapy, however median levels of LAG-3 decreased once patients initiated therapy and remained stable post-treatment. Spearman Rank Correlation analysis revealed a significant relationship between progression-free survival (PFS) and pre-treatment serum LAG-3 levels (r=0.36, p=0.017). Furthermore, it was found that patients with a PFS of 6 months or less exhibited a significantly (p=0.0031) lower mean rank of pre-treatment serum LAG-3 levels, compared to patients with a PFS of 18 months or longer. Finally, Kaplan Meier curve analysis revealed a statistically significant association between longer patient PFS and higher pre-treatment LAG-3 concentrations, when stratified by both median(HR=0.4916, log-rank p=0.022) and quartile LAG-3 serum levels (HR=0.2679, log-rank p=0.0031).ConclusionsThis study demonstrates for the first time that circulating immune checkpoint receptors have prognostic capabilities in ovarian cancer. Our findings suggest that LAG-3 is a marker for improved patient PFS. Future directions include an expansion of this original cohort in order to validate and further assess the clinical prognostic utility of serum LAG-3 in HGSOC.ReferenceSurvival Rates for Ovarian Cancer, American Cancer Society, [https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html]
35 Chemokine-driven spatial organization of immune cell microaggregates marks oropharyngeal squamous cell carcinomas containing tumor-specific T cells
Authors: Abdulrahman Ziena , Santegoets Saskia , Sturm Gregor , Charoentong Pornpimol , Ijsselsteijn Marieke , Somarakis Antonios , Höllt Thomas , Finotello Francesca , Trajanoski Zlatko , Egmond Sylvia van , Mustafa Dana , Welters Marij , Miranda Noel de , Burg Sjoerd van der 
Published: November 2021

BackgroundOropharyngeal squamous cell carcinoma (OPSCC) is the most prevalent type of head and neck cancer. The survival of patients with OPSCC is tightly linked to the intratumoral presence of tumor-specific CD4+ and CD8+ T cells. Yet, immunotherapy is currently far from effective in OPSCC partly due to our limited understanding of its immune microenvironment.MethodsHere a multi-modal, high-dimensional approach was used to dissect the immune landscape in a unique cohort of pre-therapy OPSCC patient samples (n=20) in which intratumoral tumor-specific T cells were either detected (immune response positive, IR+) or not (IR-). This included imaging mass cytometry (Hyperion) for high-dimensional phenotyping, spatial localization and interaction analyses of the cells in the tumor mircoenvironment with our newly developed imaging processing pipeline employing machine learning, Nanostring PanCancer IO360 panel analysis of immune signaling pathways, and combined single-cell gene expression profiling and T cell receptor sequencing (scRNAseq) to characterize the transcriptional states of clonally expanded tumor-infiltrating T cells.ResultsImmune cell infiltration in IR+ tumors is stronger and highly coordinated, with a distinct spatial phenotypic signature characterized by microaggregates of tumor-resident (CD103+) CD8+ and CD4+ T cells and dendritic cells within the tumor cell beds, which retained after permutation based correction for differences in cell frequencies. Furthermore, the increased expression of CXCL12 and LTB produced by CD4+ T cells, both involved in the spatial organization of immune cell infiltration, and the clonal expansion of CD8+ T cells producing the DC-attracting chemokines CCL4 or XCL1 in IR+ OPSCC, indicate that tumor-reactive T cells act as a positive feedback loop in the formation of these aggregates. The impact of these chemokines on local immunity and clinical outcome was confirmed in an independent TCGA OPSCC cohort. In contrast, the IR- OPSCC signature comprised spatial interactions between lymphocytes and different subpopulations of immunosuppressive myeloid cells.ConclusionsOur study reveals that the chemokine-driven spatial immune signature of OPSCC has strong potential as a prognostic and predictive biomarker. While the immune signature of IR+ OPSCC suggests potential benefit from neoadjuvant immunotherapeutic approaches to limit the side effects of current radio(chemo)therapy, that of IR- OPSCC calls for strategies focused on stimulating T cells and counteracting immune suppressive mechanisms.
42 The role of tissue stiffness in predicting the immunotherapy response in hepatocellular carcinoma
Authors: Yavuz Betul Gok , Hasanov Elshad , Xiao Lianchun , Mohamed Yehia , Lee Sunyoung , Rashid Asif , Kaseb Ahmed , Qayyum Aliya 
Published: November 2021

BackgroundCurrently, there is no standard biomarker that predict immunotherapy response in hepatocellular carcinoma (HCC). Here, we aim to investigate the role of tissue stiffness measured by magnetic resonance elastography (MRE) in predicting neoadjuvant immunotherapy response in patients with resectable HCC.MethodsThis was a study of 15 patients with HCC treated with immune checkpoint blockade (ICB) therapy, nivolumab ± ipilimumab, followed by surgical resection. HCC MRE assessment was performed at baseline and after 6 weeks of therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). Baseline stiffness and changes in stiffness were compared with treatment response to ICB. Treatment response was defined as a tumor with more than 60% necrosis which was the major pathological response. Analysis was performed using descriptive statistics, Fisher’s exact test, and Wilcoxon rank sum test; p-value <0.05 was considered statistically significant.ResultsFifteen patients were evaluable for MRE assessment. The median age was 67 years. Etiology of liver disease was NASH (n=4), HCV (n=3), HBV (n=2) and unknown (n=6). Three out of 15 patients (20%) achieved a major pathological response (MPR). Median baseline HCC stiffness and change in stiffness were 4.6 kPa and –0.2 kPa, respectively. Among the 4 patients with stiffness increase, 3 (75%) of them achieved MPR and 1 (25%) did not achieve MPR. Among the patients without stiffness increase, none of them achieved MPR. Fisher’s exact test indicates that increase in stiffness was associated with a higher chance to achieve MPR than patients without stiffness increase (p=0.0088). Median baseline HCC stiffness for responders and non-responders was 6.8 (5.4, 9) kPa and 3.9 (2.2, 9.7) kPa, respectively (p=0.09). The median change in HCC stiffness for responders and non-responders was 1 (1, 1.4) kPa and -0.4 (-2.2, 0.7) kPa, respectively (p=0.02).ConclusionsPatients who achieved MPR inclined to have a higher baseline stiffness than patients who did not achieve MPR. Regarding the changes in stiffness between the two arms, patients with MPR group had a greater increase than that in the non-MPR group. In conclusion, baseline and change in MRE stiffness may be a useful biomarkers in predicting response to ICB therapy in HCC.Ethics ApprovalThis was an Institutional Review Board approved study (MDACC 2017–0972). All patients provided written informed consent.
69 Immunophenotyping of TCR and BCR clonotypes
Authors: Chenchik Alex , Makhanov Michael , Darst Russell , Liu Tianbing , Kobzik Lester 
Published: November 2021

BackgroundT-cell receptor (TCR) and B-cell receptor (BCR) repertoire profiling holds great potential for understanding disease mechanisms and for the development of new therapeutics in infectious diseases, autoimmunity and in immuno-oncology. However, this potential could be greatly improved by combining information about receptor clonotypes with immuno-phenotypes of T and B cells.MethodsTo facilitate these studies, we developed a novel technology for combined profiling of all human TCR and BCR variable regions and phenotypic characterization of immune cells in bulk and at the single-cell level in PBMC and immune cell fraction samples. The developed TCR/BCR Immunophenotyping method involves multiplex RT-PCR amplification and sequencing of CDR3 regions of TCR and BCR genes and a set of the most informative T- and B-cell phenotyping genes. Bioinformatics analysis of NGS data allows profiling of TCR/BCR clonotypes, and identification of major immune cell subtypes and their activation status.ResultsData will be presented showing how combined TCR/BCR clonotype analysis combined with targeted expression profiling of immune cells can be applied for large-scale discovery of novel cell typing and activation biomarkers in several immune-responsive model systems.ConclusionsPreliminary studies demonstrate the assay has unparalleled throughput, sensitivity, and improved cost-effectiveness for high-throughput immunity biomarker discovery applications.
211 SQZ™ eAPCs generated from PBMCs by delivery of multiple mRNAs encoding for antigens, costimulatory proteins, and engineered cytokines
Authors: Maloney Michael , Ozay Emrah Ilker , Merino Amy , Silva Andrea , Martin Amber , Manja Sanjana , Upadhyay Madhav , Trumpfheller Christine , Umana Pablo , Sharei Armon , Bernstein Howard , Loughhead Scott 
Published: November 2021

BackgroundAntigen-specific CD8+ T cells are critical components of mounting an effective immune response against tumors. Generation of antigen-specific T cells require interactions with multiple signals produced by antigen presenting cells (APCs). These signals are comprised of three components: (signal 1) the peptide-MHC complex binding to the T cell receptor, (signal 2) costimulatory molecules on the surface of APCs, and (signal 3) inflammatory cytokines binding to cognate receptors on T cells.MethodsTo engineer all major cell subsets of human peripheral blood mononuclear cells (PBMCs) to become enhanced APCs (eAPCs), we used Cell Squeeze® technology to deliver multiple mRNA encoding for non-self-antigens (signal 1), CD86 (signal 2), and/or membrane-bound cytokines (signal 3). The signal 3 molecules, membrane-bound IL-12 (mbIL-12) and membrane-bound IL-2 (mbIL-2), are chimeric proteins designed to increase the localized concentration of the cytokines and limit off-target effects. Flow cytometry and western blots were used to confirm the translation of each of the delivered mRNA. The increased capabilities of these enhanced APCs were assessed in vitro by culturing the APCs with antigen-specific T cells for multiple days before measuring the functionality of antigen-specific T cells via intracellular cytokine staining or ELISA.ResultsWe demonstrate that Cell Squeeze® processing of PBMCs with mRNA encoding for signals 1, 2, and 3 results in highly effective enhanced APCs in vitro. In a single squeeze process, efficient delivery and translation of up to five mRNA is observed in all major PBMC cell subsets including T cells, B cells, NK cells, and monocytes. Once translated, the chimeric mbIL-2 and mbIL-12 can bind to their cognate receptors and exhibit minimal shedding from the surface. We show that enhanced APCs can present antigenic peptides derived from mRNA encoding for a foreign antigen on MHC complexes in an HLA agnostic manner, which drives antigen-specific T cell responses. The addition of CD86, mbIL-2, and mbIL-12 further enhance the activation and potency of antigen-specific T cells, as measured by an increase in the secretion of inflammatory cytokines upon restimulation (i.e. IFNγ).ConclusionsCell squeezing of human PBMCs with mRNA encoding for signals 1, 2, and 3 has the potential to generate enhanced APCs that drive robust CD8+ T cell response against multiple targets across several disease areas. The versatility of the Cell Squeeze® technology potentially enables rapid exchange of mRNA to other antigens or T cell activation signals.
370 Time course of treatment-related adverse events (TRAEs) during dostarlimab therapy in the GARNET trial
Authors: Pothuri Bhavana , Berton Dominique , Moreno Victor , Oaknin Ana , Trigo Perez Jose Manuel , Curigliano Giuseppe , Ellard Susan , Pikiel Joanna , Banerjee Susana , Barretina-Ginesta Maria-Pilar , Miller Rowan , Tinker Anna , Jewell Andrea , Plummer Ruth , Joly Florence , Veneris Jennifer , Duan Tao , Andre Thierry 
Published: November 2021

BackgroundDostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the ligands PD-L1 and PD-L2. Dostarlimab is approved as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR; US) or dMMR/microsatellite-instability high (EU) recurrent or advanced endometrial cancer that has progressed progressing on or following prior treatment with a platinum-containing regimen. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in pts with solid tumors.MethodsPts with dMMR solid tumors, mismatch repair proficient endometrial cancer, and non-small cell lung cancer that progressed on or after prior therapy received 500 mg of dostarlimab IV every 3 weeks (Q3W) for 4 cycles, then 1000 mg IV every 6 weeks (Q6W) for up to 2 years or until disease progression or discontinuation. Here, we report TRAEs by cycle.ResultsA total of 515 pts were included. Of these pts, 60 (11.7%) experienced TRAEs leading to treatment interruption, and 25 (4.9%) experienced TRAEs leading to discontinuation. TRAEs of any grade with overall incidence of ≥10% of pts are shown (table 1). The majority of TRAEs occurred during cycles 1–3, with highest incidence during cycle 1. Grade 3 or 4 TRAEs were rare; those seen in ≥1% of pts are shown. Immune-related (ir) TRAEs of any grade with overall incidence of ≥2% of pts are shown. Most cases (96.9%) of irTRAEs occurred during cycles 1–8. The peak incidence of hypothyroidism occurred during cycle 4; in addition, frequency was increased during cycles 5–8, compared with cycles 1–4. No deaths were attributed to dostarlimab.Abstract 370 Table 1Time course of adverse events in the GARNET trialConclusionsNo new safety signals were detected with dostarlimab compared to other anti–PD-1 inhibitors. Most TRAEs were low grade. The majority of TRAEs and grade ≥3 TRAEs occurred in the first 3 cycles (first 12 weeks), but some cases occurred later, suggesting a need for ongoing monitoring. Few increases in the incidence of TRAEs were seen during cycle 5 following the transition to the 1000-mg Q6W dosing schedule; the TRAEs with increased incidence after the transition were fatigue and lipase increased. An increase in the frequency of the irTRAE hypothyroidism was seen after transitioning to the 1000-mg Q6W schedule.
Proximity of IQOS and JUUL points of sale to schools in Israel: a geospatial analysis
Authors: Elbaz Daniel , Bar Zeev Yael , Berg Carla J , Abroms Lorien C , Levine Hagai 
Published: November 2021

SignificanceExploring proximity and density of heated tobacco product (HTP) and electronic nicotine delivery system (ENDS) points of sale (POS) to schools is critical for understanding youth marketing exposure and informing policy and enforcement to protect youth. This study examined IQOS and JUUL POS (prominent HTPs and ENDS), specifically their proximity to and density around schools in Israel.MethodsUsing geospatial analysis and IQOS/JUUL website data, distance matrices were used to calculate distance from each school in Israel (grades 1–12) to the nearest POS and number of POS within 1 km, accounting for schools’ neighbourhood socioeconomic status (SES) ranking.ResultsAn average of 8.7 IQOS POS and 5.2 JUUL POS were within walking distance (1 km) from schools. Average distances from schools to nearest IQOS and JUUL POS were 954 m (median=365 m) and 1535 m (median=579 m), respectively. The percentages of schools with at least one IQOS or JUUL POS within 1 km were 86% and 74%, respectively. The average numbers of POS within 1 km of schools in low-SES, middle-SES, and high-SES neighbourhoods were 7.5, 9.9, and 7.6 for IQOS and 4.1, 5.9, and 5.5 for JUUL, respectively. Median distances from schools in low-SES, middle-SES, and high-SES neighbourhoods to nearest POS were 428 m, 325 m, and 403 m for IQOS and 1044 m, 483 m, and 525 m for JUUL.ConclusionsYouth experience high environmental exposure to IQOS and JUUL POS, particularly IQOS. POS were more densely located near schools in middle-SES neighbourhoods. Thus, regulating HTP and ENDS POS near schools and in certain neighbourhoods is key to reducing youth population impact in Israel and elsewhere.
The Norwegian Association for Heredity Research and the Organized International Eugenics Movement. Expertise, Authority, Transnational Networks and International Organization in Norwegian Genetics and Eugenics (1919–1934)
Authors: Kyllingstad Jon Røyne 
Published: November 2021

Abstract
The Norwegian Association for Heredity Research played a key role in the rise of genetics as a research field in Norway. The immediate background of its establishment in 1919 was the need for an organization that could clarify scientific issues regarding eugenics and coordinate Norwegian representation in the organized international eugenics movement. The Association never assumed this role. Instead, Norway was represented in the international eugenics movement by the so-called Norwegian Consultative Eugenics Commission, whose leader, Jon Alfred Mjøen, was dismissed as a pseudo-scientist by Norwegian geneticists. The paper explores the Association’s role in defining and delimiting scientific expert knowledge in the field of genetics and eugenics in Norway. It demonstrates how struggles about academic authority on the national arena were intertwined with struggles about representation and impact in the international eugenics movement and how transnational scientific networks where mobilized to legitimize and delegitimize notions about Nordic race supremacy, racial mixing and the politics of eugenic sterilizations.
In the Name of Human Adaptation: Japanese American “Hybrid Children” and Racial Anthropology in Postwar Japan
Authors: Hyun Jaehwan 
Published: November 2021

AbstractBy focusing on the emergence and integration of “hybrid children” (konketsuji) anthropology into the Human Adaptability section of the International Biological Program (HA-IBP) in Japan during the 1950s and 1970s, this paper presents how transnational dynamics and mechanisms played out in shaping and maintaining the racist aspects while simultaneously allowed them to be included in the HA-IBP framework. It argues that Japanese anthropologists operated a double play between their national and transnational spaces, that is, they attenuated racist aspects of their research in their international activities while authenticating race in their national work. This paper will conclude with reflections on the transnational nationalism of konketsuji anthropology.