bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A52: PD-1High CAR T cells exhibit superior homing, retention, and function in solid tumors
Authors: Sailer Cooper , Hong Yeonsun , Reagan Patrick , Kim Minsoo 
Published: December 2022

Abstract
Chimeric antigen receptor (CAR)-T cell has emerged a promising treatment option for several cancers, with six FDA-approved therapies for hematologic malignancies. However, patients with solid tumors largely fail to respond to CAR T cell therapy due to T cell exhaustion, associated with impaired CAR T cell functions and strong immunosuppressive microenvironment at the tumor site. There are currently no FDA-approved CAR T cell therapies for solid tumors, which make up the vast majority of cancer cases. Here, we found that both murine and human CAR T cells manufactured ex vivo displayed phenotypic signs of terminal exhaustion and developed heterogeneous expression levels of PD-1 (i.e. PD1high and PD1low CAR T cells). Surprisingly, PD1high CAR T cells outperformed PD1low CAR T cells in multiple T cell function and anti-cancer activity assays both in vitro and in vivo, where PD1high CAR T cells exhibited heightened target tumor-cell killing and engagement, and also increased homing and retention within tumors. We show that the increased retention of PD1high cells in the tumor is independent of the PD1/PD-L1 signaling axis. The superior anti-cancer function of PD1high CAR T cells was closely associated with the elevated production of interferon gamma (IFNg) in PD1high cells. We further revealed that IFNg secreted from PD1high CAR T cells played an important role in actively regulating the tumor microenvironment by inducing ICAM-1 expression. In conclusion, our data identifies PD1high CAR T cell as a subset of clinically manufactured CAR T cells with improved anti-cancer functions. Our data supports the emerging notion that CAR T cells may interact differently between solid and liquid cancers, and suggests a unique T cell phenotype may be required to maximize solid tumor adoptive cell transfer therapies.
Citation Format: Cooper Sailer, Yeonsun Hong, Patrick Reagan, Minsoo Kim. PD-1High CAR T cells exhibit superior homing, retention, and function in solid tumors [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A52.
Abstract A67: CD40 agonism inhibits tumor growth in murine hormone receptor positive breast cancer via CD8 T cells
Authors: Zhang Jennifer , Lanchoney Olivia , Joshi Nikhil , Markosyan Nune , Vonderheide Robert 
Published: December 2022

Abstract
Breast cancer is the second most common malignancy affecting women and accounts for 15% of cancer-related mortality globally. Over 70% of breast cancers are hormone receptor (HR) positive (estrogen receptor and/or progesterone receptor positive) and human epidermal growth factor receptor 2 negative (HER2-). HR+HER2- breast cancers are poorly responsive to chemotherapy and recurrence and mortality remain high for patients with locally advanced disease. Thus, more therapeutic strategies are needed. Dendritic cell (DC) activation is an important pathway for T cell priming and subsequent improvements in immunosurveillance. In this study, we determined the ability of DC-targeted therapy with agonistic CD40 antibody to restore anti-tumor immunologic function in a murine orthotopic HR+HER2- breast cancer model. The Brpkp110 cell line was injected orthotopically into the abdominal mammary glands of 8 to 10-week-old C57BL/6 mice. Tumor-bearing mice treated with agonistic CD40 antibody (FGK4.5, 100 ug intraperitoneal) demonstrated decreased tumor growth and increased intratumoral CD8 T cells at 2 weeks. Both intratumoral DCs and tumor-associated macrophages in mice treated with agonistic CD40 were found to upregulate PD-L1 and CD40. CD8 T cell depletion abrogated the anti-tumor effect of agonistic CD40. Our data suggest that agonistic CD40 therapy may be a viable strategy for tumor inhibition and activation of anti-tumor immunity in HR+HER2- breast cancer.
Citation Format: Jennifer Zhang, Olivia Lanchoney, Nikhil Joshi, Nune Markosyan, Robert Vonderheide. CD40 agonism inhibits tumor growth in murine hormone receptor positive breast cancer via CD8 T cells [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A67.
Abstract B58: B cells modulate T cell infiltration in a preclinical model of HPV+ oropharyngeal cancer
Authors: Dorta-Estremera Stephanie M , Ortíz Jorge R Galán , del Valle Kamila A Andino , Rosario Abelardo A Perez , Rivera Jennifer Díaz , Castañón Daniel 
Published: December 2022

Abstract
Programmed Death-1 (PD-1) blockade has been FDA approved to treat head and neck squamous cell carcinoma (HNSCC), however, less than 30% of patients respond. Among the different immune cells present within tumors, B cells also infiltrate HPV+ HNSCC and different B cell subsets may exert opposite functions in tumor development. Therefore, fine regulation of anti-tumor and tumor-promoting B cell subsets is necessary to promote an effective anti-tumor response and therefore prevent tumor progression. However, the role of B cells during PD-1 blockade in HPV+ oropharyngeal cancer needs to be better defined. By using the preclinical mouse model for HPV+ oropharyngeal cancer (named mEER), we have determined that tongue-implanted tumors are sensitive to anti-PD-1, where around 50% of the mice clear the tumors, whereas flank-implanted tumors are completely resistant to these treatments. By using this in vivo model, we characterized B cells within tumors and during anti-PD-1 therapy by flow cytometry and determined whether B cell deficiency (µMt) affected tumor growth. We determined that tongue-implanted tumors (sensitive) contained high infiltration of CD8+ T cells and low infiltration of B cells whereas flank-implanted tumors contained (resistant) high frequency of B cells compared to T cells. Interestingly, when we compared tongue tumor-bearing mice treated with anti-PD-1, we observed that tumors that responded to the therapy contained more T cells and B cells than the ones that did not respond. B cell-deficient mice showed a slower tumor growth rate and longer survival compared to wild-type (WT) mice, however, treatment with PD-1 blockade did not affect tumor growth when comparing WT vs. µMt. B cell deficiency increased CD8+ T cell infiltration however, PD-1 blockade also increased regulatory T cells. Our data suggest that B cells modulate T cell infiltration and therefore affect tumor development. Also, PD-1 blockade affects different regulatory immune cell types, therefore, affecting its efficacy. Identification of B cell subsets and their functions within tumors may better predict responsiveness to PD-1 blockade in HPV+ HNSCC patients.
Citation Format: Stephanie M Dorta-Estremera, Jorge R Galán Ortíz, Kamila A Andino del Valle, Abelardo A Perez Rosario, Jennifer Díaz Rivera, Daniel Castañón. B cells modulate T cell infiltration in a preclinical model of HPV+ oropharyngeal cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B58.
Abstract B66: Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2
Authors: Lotz-Jenne Carina , Cren Sylvaine , Joesch Christoph , Ackerknecht Sabine , Brandes Jennifer , Moebs Claire , Hartl Dominik , Hartrampf Felix , Guerry Philippe , Pothier Julien , Chavanton-Arpel Alexia 
Published: December 2022

Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the oxidation of L-Tryptophan (TRP) leading to the formation of immunosuppressive kynurenine (KYN) pathway metabolites. According to TCGA, a substantial fraction of different tumor types express both IDO1 and TDO2. In 82 tumor samples (GBM, hepatocellular carcinoma, NSCLC, and ovarian cancer) analyzed for IDO1/TDO2 RNA expression (RNA sequencing) and TRP metabolite content (LC-MS/MS), we found TDO2 highly expressed in hepatocellular carcinoma and to lower levels in NSCLC and ovarian cancer. IDO1 was found to be expressed in NSCLC and ovarian cancer but at higher levels and its expression was correlating with KYN levels. Immunosuppressive properties of KYN and downstream metabolites are mediated through T cell apoptosis and regulatory T cell (Treg) induction. In our hands, KYN at concentrations ≥ 50uM was shown to be immunosuppressive, notably inducing T cell apoptosis. According to our and published data, such high KYN concentrations (≥ 50uM) can be found in a subset of human tumors. As outlined, both IDO1 and TDO2 can contribute to high KYN levels in tumors. Hence, dual IDO1/TDO2 inhibition should be superior in decreasing tumor KYN levels and levering immunosuppression as compared to IDO1 selective inhibition. In this regard, we have generated potent dual IDO1/TDO2 inhibitors inhibiting IDO1 and TDO2 enzyme activity in cellular assays in vitro. To proof the concept of superiority in vivo, we established a dual IDO1/TDO2 expressing human tumor model (LOVO+IFNg) in the mouse and showed that the oral administration of a dual IDO1/TDO2 inhibitor as compared to an IDO1 selective inhibitor showed enhanced KYN/TRP modulation in the tumor. Lead compounds with favorable drug-like properties are currently investigated for pre-clinical development.
Citation Format: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel. Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2 [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B66.
Abstract IA20: Checkpoint blockade–induced dermatitis and colitis are dominated by tissue-resident memory T cells and Th1/Tc1 cytokines
Authors: Reschke Robin , Shapiro Jason W , Yu Jovian , Rouhani Sherin J , Olson Daniel J , Zha Yuanyuan , Gajewski Thomas F 
Published: December 2022

Abstract
Immune checkpoint blockade is therapeutically successful for many patients across multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Herein, we report our analysis of tissues from patients with irAE dermatitis using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization (RISH). Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue-resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared with healthy skin controls. Spatial transcriptomics allowed us to focus on areas containing TRM cells to discern functional phenotype and revealed expression of Th1-associated genes in irAEs, compared with Th17-asociated genes in psoriasis. Expression of PD-1, CTLA-4, LAG-3, and other inhibitory receptors was observed in irAE cases. RISH technology combined with IF confirmed expression of IFNγ, CXCL9, CXCL10, and TNFα in irAE dermatitis, as well as IFNγ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared with healthy colon.
Citation Format: Robin Reschke, Jason W Shapiro, Jovian Yu, Sherin J Rouhani, Daniel J Olson, Yuanyuan Zha, Thomas F Gajewski. Checkpoint blockade–induced dermatitis and colitis are dominated by tissue-resident memory T cells and Th1/Tc1 cytokines [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA20.
Safety and Efficacy of Sacubitril/Valsartan in Patients With a Failing Systemic Right Ventricle: A Prospective Single-Center Study
Authors: Fusco Flavia , Scognamiglio Giancarlo , Merola Assunta , Iannuzzi Angela , Palma Michela , Grimaldi Nicola , Sarubbi Berardo 
Published: December 2022

Background:
Sacubitril/valsartan was demonstrated to reduce hospitalization rate and mortality in patients with heart failure with reduced ejection fraction. Data on the effects of sacubitril/valsartan in patients with a systemic right ventricle are still lacking.

Methods:
Patients with transposition of the great arteries following Senning/Mustard procedure or congenitally corrected transposition of the great arteries with impaired systemic right ventricle systolic function were prospectively included. Primary end points included sacubitril/valsartan safety and efficacy. Primary efficacy end points were NT-proBNP (N-terminal pro-B-type natriuretic peptide) and systolic function improvement. Secondary end points included New York Heart Association class, 6-minute walking distance, and quality of life change.

Results:

Fifty patients (38±12 years, 60% male, 35% congenitally corrected transposition of the great arteries) were included and followed for 1 year. No major adverse events occurred. Two (4%) patients ceased treatment due to hypotension and 1 (2%) developed a nephrotic syndrome. The target dose was reached in 20 (42%) patients. NT-proBNP values decreased significantly immediately after treatment initiation, while returned to baseline at 1 year. Echocardiography showed progressive fractional area change increase (29.2±5.8 versus 34.9±5.1%;
P
<0.001), and right ventricle global longitudinal strain (−13.9 [−15.1, −11.8] versus −15.3 [−17.2, −13.4]%;
P
<0.001) and free-wall global longitudinal strain (−14.3 [−17.3, −12.3] versus −17.2 [−19.3, −15.8]%;
P
<0.001) raise, whereas tricuspid regurgitation severity improved only in transposition of the great arteries patients (
P
=0.006). Moreover, 3-dimensional echocardiography demonstrated right ventricle volumes reduction (end-diastolic volume: 181±63 versus 156±50 mL;
P
=0.002; end-systolic volume: 117±48 versus 89±33 mL;
P
<0.001), and significantly increased systemic right ventricle ejection fraction (35.6±8.1 versus 41.5±7.5%;
P
<0.001). Clinical improvement was suggested by New York Heart Association class change (
P
<0.001), increased 6-minute walking distance (425 [333, 480] versus 500 [443, 560] m;
P
<0.001) as well as improved quality of life at 1-year follow-up. Beneficial effects were observed irrespective of the underlying anatomy and were more pronounced in those on target dose.

Conclusions:
Our data showed that sacubitril/valsartan is well tolerated and is associated with systemic right ventricle remodeling and improved systolic function as well as improved clinical status, supporting its use in this complex population.
Sex Disparities in Failure to Rescue After Cardiac Surgery in California and New York
Authors: Alabbadi Sundos , Rowe Georgina , Gill George , Vouyouka Ageliki , Chikwe Joanna , Egorova Natalia 
Published: December 2022

Background:
Women have a higher risk of mortality than men after cardiac surgery independent of other risk factors. The reason for this may not be limited to patient-specific variables. Failure to rescue (FTR) patients from death after a postoperative complication is a nationally endorsed quality care metric. We aimed to identify whether sex disparities exist in the quality of care after cardiac surgery using FTR rates.

Methods:
A retrospective analysis of 30 973 men (70.4%) and 13 033 women (29.6%) aged over 18 years undergoing coronary artery bypass graft or valve surgery in New York (2016–2019) and California (2016–2018) who experienced at least one serious postoperative complication. The primary outcome was the FTR. Multivariable logistic regression was used to identify predictors of death after complication. Propensity matching was used to adjust for baseline differences between sexes and yielded 12 657 pairs.

Results:

Female patients that experienced complications were older (mean age 67.8 versus 66.7,
P
<0.001), more frail (median frailty score 0.1 versus 0.07,
P
<0.001), and had more comorbidities (median Charlson score 2.5 versus 2.3,
P
<0.001) than male patients. The overall FTR rate was 5.7% (2524), men were less likely to die after a complication than women (4.8% versus 8%,
P
<0.001). Independent predictors of FTR included female sex (relative risk [RR]: 1.46 [CI, 1.30–1.62]), area-level poverty rate >20% (RR, 1.21 [CI, 1.01–1.59]), higher frailty (RR, 2.83 [CI, 1.35–5.93]), undergoing concomitant coronary artery bypass graft and valve surgeries (RR, 1.69 [CI, 1.49–1.9]), and higher number of postoperative complications (RR, 16.28 [CI, 14–18.89]). In the propensity-matched cohorts, the FTR rate remained significantly lower among men than women (6.0% versus 8.0%,
P
<0.001).

Conclusions:
Women are less likely to be rescued from death following postoperative complications, independent of socioeconomic and clinical characteristics. Further research is warranted to investigate the clinical practices contributing to this disparity in quality of care following cardiac surgery.
Information Theory–based Compositional Distributional Semantics
Authors: Amigo Enrique , Ariza-Casabona Alejandro , Fresno Victor , Marti M. Antonia 
Published: December 2022

Abstract
In the context of text representation, Compositional Distributional Semantics models aim to fuse the Distributional Hypothesis and the Principle of Compositionality. Text embedding is based on co-ocurrence distributions and the representations are in turn combined by compositional functions taking into account the text structure. However, the theoretical basis of compositional functions is still an open issue. In this article we define and study the notion of Information Theory–based Compositional Distributional Semantics (ICDS): (i) We first establish formal properties for embedding, composition, and similarity functions based on Shannon’s Information Theory; (ii) we analyze the existing approaches under this prism, checking whether or not they comply with the established desirable properties; (iii) we propose two parameterizable composition and similarity functions that generalize traditional approaches while fulfilling the formal properties; and finally (iv) we perform an empirical study on several textual similarity datasets that include sentences with a high and low lexical overlap, and on the similarity between words and their description. Our theoretical analysis and empirical results show that fulfilling formal properties affects positively the accuracy of text representation models in terms of correspondence (isometry) between the embedding and meaning spaces.
Anton van den Wyngaerde’s threefold project of the Panorama of Walcheren (c. 1547-1570)
Authors: Gregg Ryan E. 
Published: December 2022

Anton van den Wyngaerde’s (c. 1490-1571) Panorama of Walcheren in the Plantin-Moretus Museum in Antwerp depicts the mid-sixteenth-century island of Walcheren and the North Sea across ten meters of paper. Its length and extensive geographic coverage make it unique amongst the artist’s extant oeuvre. Primarily known for his depictions of Spanish and Netherlandish cities drawn for King Philip II, Van den Wyngaerde did paint a similar prospect in 1564 for the king’s El Pardo palace. The present panorama (also known as Zeelandia descriptio) owes its origins in part to that project.
Though often mined for illustrations of a c. 1550 Walcheren, the drawings themselves have not been studied since 1956, when Jules van Beylen proposed a series of unspecified dates for the entirety’s manufacture. The present study clarifies the timeline for the current Panorama’s generation over several decades. Through examination of the object, its depicted environments, and archival material, at least three discrete working periods and three distinct panoramic sections are proposed.
The artist initially travelled across the island sketching its locations sometime between 1547 and 1552. After arriving in Spain in 1562 at Philip II’s request, Van den Wyngaerde compiled his earlier sketches into an overall draft. The first third of the present Panorama belongs to this preparatory stage for a second project. He then produced a more finished, colored drawing from the draft, in which he updated and corrected visual information. The middle section remains from this second stage. The c. 1564 El Pardo painting likely replicated the colored presentation drawing. The third project, undertaken between c. 1567 and c. 1570, copied at least a portion of the painting if not the entire prospect, and remains extant in the right section. The remainders from these projects were then combined at an indeterminate time to form the Panorama as it exists today.
Some notes by Ernst Brinck (1582-1649) on painters, collectors and exceptional art
Authors: Abbing Michiel Roscam 
Published: December 2022

This article focuses on the Harderwijk regent Ernst Brinck (1582-1649) who owned an extensive cabinet of curiosities and a library full of valuable books. His exceptionally wide range of interests is also evident from surviving notebooks of his in the Harderwijk archives. The entries they contain show that Brinck visited other collectors and viewed their cabinets. It goes without saying that interesting information was exchanged during these encounters, which Brinck noted in his booklets. It can be found scattered there among all kinds of other topics.
Around 1645, Brinck classified some of these notes under the heading ‘De picturis eximiis, et [rebus] quae concernunt picturas’ (Of exceptional paintings and [all manner of things] that concern the art of painting) and ‘Van eenige treflicke Conststucken’ (Of several excellent works of art). Twenty-two previously unpublished anecdotal statements can be found in these categories. Examples include the average cost of the civic guard portraits in the Great Hall of the Arquebusiers Company (Doelenzaal) in Amsterdam (no. 6); the wealthy collector Pieter Spiering and his art books (no. 12): the obscene paintings of Torrentius (no. 7); Rubens’ earnings for the cycle of paintings on the life of Marie de’ Medici, queen of France, in Paris (no. 8); the Brazilian paintings commissioned by John Maurice of Nassau and painted by Jacob van Campen, which Brinck saw at the artist’s estate near Amersfoort (no. 5); and the wooden prayer nut, now in the Abegg-Stiftung, Switzerland (no. 19).
In one of the booklets, hidden among other notes, Brinck penned an entry on Rembrandt’s Hundred guilder print that would have fitted very well in his list on exceptional art, but is absent there. Brinck wrote that Rembrandt had sold a print with the subject ‘Let the children come to me’ (Matthew 19: 13-15) for a hundred guilders. The note establishes that Rembrandt himself sold the print for that amount, in 1648 or 1649.