bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer
Authors: Dorff Tanya , Horvath Lisa G. , Autio Karen , Bernard-Tessier Alice , Rettig Matthew B. , Machiels Jean-Pascal , Bilen Mehmet A. , Lolkema Martijn P. , Adra Nabil , Rottey Sylvie , Greil Richard , Matsubara Nobuaki , Tan Daniel S.W. , Wong Alvin , Uemura Hiroji , Lemech Charlotte , Meran Johannes , Yu Youfei , Minocha Mukul , McComb Mason , Penny Hweixian Leong , Gupta Vinita , Hu Xuguang , Jurida Gabor , Kouros-Mehr Hosein , Janát-Amsbury Margit M. , Eggert Tobias , Tran Ben 
Published: February 2024

Abstract

Purpose:
Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods:
Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed.

Results:
In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0–4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0–5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion.

Conclusions:
Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.
Abstract A017: Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
Authors: Veerla Srinivas , Hohmann Lennart , Nacer Deborah F. , Vallon-Christersson Johan , Staaf Johan 
Published: February 2024

Abstract
PAM50 gene expression subtypes represent a cornerstone in molecular classification of breast cancer and are included in risk prediction models to guide therapy. We aimed to illustrate the impact of included genes and biological processes on subtyping while considering a tumor’s underlying clinical subgroup defined by ER, PR and HER2 status. To do this we used a population-representative and clinically annotated primary breast tumor cohort of 6233 samples profiled by RNA sequencing and applied a perturbation strategy of excluding co-expressed genes (gene sets). We demonstrate how PAM50 nearest centroid classification depends on biological processes present across, but also within, ER/PR/HER2 subgroups and PAM50 subtypes themselves. Our analysis highlights several key aspects of PAM50 classification. Firstly, we observed a tight connection between a tumor’s nearest and second nearest PAM50 centroid. Additionally, we show that second-best subtype is associated with overall survival in ER-positive, HER2-negative, and node negative disease. We also note that ERBB2 has little impact on PAM50 classification in HER2-positive disease regardless of ER-status, and that the Basal subtype is highly stable in contrast to the Normal subtype. Improved consciousness of the commonly used PAM50 subtyping scheme will aid in our understanding and interpretation of breast tumors that have seemingly conflicting PAM50 classification when compared to clinical biomarkers. Finally, our study adds further support in challenging the common misconception that PAM50 subtypes are distinct classes by illustrating that PAM50 subtypes in tumors represent a continuum that may have clinical implications.
Citation Format: Srinivas Veerla, Lennart Hohmann, Deborah F. Nacer, Johan Vallon-Christersson, Johan Staaf. Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A017.
Abstract A062: Somatic engineering of rat models to recapitulate human breast cancer evolution and heterogeneity
Authors: Lutz Catrin , Song Ji-Ying , Messal Hendrik A , Badoux Madelon , Eijkman Timo , de Klein Bim , Wesseling Jelle , Jonkers Jos 
Published: February 2024

Abstract
Estrogen receptor (ER) positive breast cancer accounts for over 75% of all presenting clinical cases. In addition, almost all Ductal Carcinoma in situ (DCIS) lesions, now accounting for about 25% of all newly diagnosed ‘breast cancers’, are ER-dependent. Despite the high occurrence, the molecular underpinnings regulating DCIS initiation and progression to invasive disease remain elusive. This gap in knowledge is primarily due to the dearth of suitable preclinical models that accurately emulate breast cancer heterogeneity. To overcome this impediment, we developed a platform of somatic models by engineering the rat mammary gland and manipulating the genes most frequently mutated in hormone-dependent (pre-)breast cancer. This has successfully led to the generation of ER-positive disease models that provide a nuanced understanding of ER functionality and the complex mechanisms of ER signaling, which we show to be dependent on the cancer genotype. This has potential implications for the formulation of innovative endocrine therapy treatment regimens. Our models have generated an array of tumor types, including ductal and lobular carcinomas, manifesting both in situ and invasive phenotypes, faithfully recapitulating human breast disease and the evolution of tumorigenesis. Intriguingly, our results indicate how different oncogenic mutations modulate not only the architectural and histopathological characteristics of cancer but also the immune microenvironment, thereby generating possibilities for future therapeutic testing. Our research augments the range of available ER-positive in situ and invasive breast cancer models, benefitting the stratification of indolent from aggressive disease and facilitating the exploration of novel treatment strategies for this pervasive breast cancer subtype.
Citation Format: Catrin Lutz, Ji-Ying Song, Hendrik A Messal, Madelon Badoux, Timo Eijkman, Bim de Klein, Jelle Wesseling, Jos Jonkers. Somatic engineering of rat models to recapitulate human breast cancer evolution and heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A062.
Abstract A077: Investigating the relationship of socioeconomic status on the molecular biology of ER+ breast cancer
Authors: DeWitt Jerry T 
Published: February 2024

Abstract
Black women in the US have worse health care options, poorer educational opportunities, and decreased income quality which collectively contribute to an overall lower socioeconomic status (SES) compared to White women. Furthermore, although the incidence of estrogen receptor positive (ER+) breast cancer is similar for Black and White women in the US, Black patients have significantly worse outcomes. The field has traditionally focused on systemic factors such as SES to explain outcome disparities. Consequently, differences in the molecular biology between tumors from Black and White women remains a gap in knowledge in the field. Recent studies have found that Black cancer patients have a unique gene expression profile that may modulate treatment response. For instance, ER+ breast tumors in Black women have distinct signatures of defective DNA damage repair (DDR) that associate with more aggressive tumor growth. However, how SES contributes to these differences in molecular biology and whether these differences alter treatment response remain unknown. One challenge to addressing these questions is that existing datasets significantly underrepresent Black women and are not sufficiently annotated to understand the complex interplay between molecular biology and factors of SES. Here, we present analysis of RNA expression datasets from 60 ER+ patient tumors (38 Black, 22 White), with corresponding SES and patient outcome annotations. Altogether, these data begin to define the complex interplay between factors of SES and changes in gene expression in addition to patient outcomes for women with ER+ breast cancer.
Citation Format: Jerry T DeWitt. Investigating the relationship of socioeconomic status on the molecular biology of ER+ breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A077.
Abstract B019: The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma
Authors: Basanta David , Bishop Ryan , Miller Anna , Lynch Conor C. , Froid Matthew , Silva Ariosto S. , Shain Kenneth H. 
Published: February 2024

Abstract
Multiple myeloma (MM) is an osteolytic plasma cell malignancy that, despite being responsive to therapies such as proteasome inhibitors, frequently relapses. Understanding the mechanism and the niches where resistant disease evolves remains of major clinical importance. Cancer cell intrinsic mechanisms and bone ecosystem factors are known contributors to the evolution of resistant MM but the exact contribution of each is difficult to define with current in vitro and in vivo models. Using a novel bmathematical model that incorporates key cellular species of the bone ecosystem that control normal bone remodeling and, in MM, yields a protective environment we studied how, under therapy, the bone ecosystem contributes to the evolutionary dynamics of resistant MM under control and proteasome inhibitor treatment. Our results show that Environmentally-Mediated Drug Resistance (EMDR) might not be sufficient to explain resistant disease. But our results highlight the importance of EMDR in facilitating the emergence of resistance, and more importantly facilitating the survival of tolerant cells, allowing the tumor multiple routes for resistant disease. Our results also provide evidence that intervention with therapies targetting the bone ecosystem would significantly improve the ability of treatment to increase the time to progression for patients with multiple myeloma and, potentially, other diseases where EMDR plays a role.
Citation Format: David Basanta, Ryan Bishop, Anna Miller, Conor C. Lynch, Matthew Froid, Ariosto S. Silva, Kenneth H. Shain. The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B019.
Abstract B039: SAMPLER: Unsupervised representations of whole slide images for tumor phenotype prediction
Authors: Mukashyaka Patience , Sheridan Todd B. , Foroughi pour Ali , Chuang Jeffrey H. 
Published: February 2024

Abstract
Deep learning has revolutionized digital pathology, allowing for automatic analysis of hematoxylin and eosin (H&E) stained whole slide images (WSIs) for various tasks, such as the classification of cancers into clinical subtypes. In such analyses, WSIs are broken down into smaller images, hereafter called tiles, for efficient processing, with each tile encoded by a deep learning backbone. To reconstruct a slide level representation, a widely applied approach is to combine tile-level features using attention-based deep learning models for each downstream prediction task. These training strategies are (a) computationally intensive, (b) challenging to optimize, (c) sensitive to stain variations across datasets, and (d) require sufficiently large and labeled datasets for supervised training, which are not always available. We propose SAMpling of multiscale empirical distributions for LEarning Representations (SAMPLER), a fully statistical approach to generate WSI representations by encoding the empirical cumulative distribution function (CDF) of multiscale tile features. We evaluated this approach by training logistic regression classifiers from SAMPLER representations. SAMPLER-based classifiers were able to accurately separate subtypes of breast carcinoma (BRCA: AUC=0.911 ± 0.029), subtypes of non-small cell lung carcinoma (NSCLC: AUC=0.940±0.018), and subtypes of renal cell carcinoma (RCC: AUC=0.987±0.006) diagnostic slides of the cancer genome atlas (TCGA). Performance was similar to fully deep learning attention models but &gt;100 times faster. We further validated out models on external test sets. Histopathological review confirms that SAMPLER-identified high attention tiles contain tumor morphological features specific to the tumor type, while low attention tiles contain fibrous stroma, blood, or tissue folding artifacts. SAMPLER is a fast and accurate approach for analyzing WSIs, with greatly improved scalability over attention methods to benefit digital pathology analysis.
Citation Format: Patience Mukashyaka, Todd B. Sheridan, Ali Foroughi pour, Jeffrey H. Chuang. SAMPLER: Unsupervised representations of whole slide images for tumor phenotype prediction [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B039.
Estimation of Right Atrial Pressure by Ultrasound-Assessed Jugular Vein Distensibility in Patients With Heart Failure
Authors: Ammirati Enrico , Marchetti Davide , Colombo Giada , Pellicori Pierpaolo , Gentile Piero , D’Angelo Luciana , Masciocco Gabriella , Verde Alessandro , Macera Francesca , Brunelli Dario , Occhi Lucia , Musca Francesco , Perna Enrico , Bernasconi Davide P. , Moreo Antonella , Camici Paolo G. , Metra Marco , Oliva Fabrizio , Garascia Andrea 
Published: February 2024

BACKGROUND:
Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population.

METHODS:
We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup.

RESULTS:

A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64–0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73–0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg;
P
<0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank
P
=0.034).

CONCLUSIONS:
Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03874312.
Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction
Authors: Azzo Joe David , Dib Marie-Joe , Zagkos Loukas , Zhao Lei , Wang Zhaoqing , Chang Ching-Pin , Ebert Christina , Salman Oday , Gan Sushrima , Zamani Payman , Cohen Jordana B. , van Empel Vanessa , Richards A. Mark , Javaheri Ali , Mann Douglas L. , Rietzschel Ernst R. , Schafer Peter H. , Seiffert Dietmar A. , Gill Dipender , Burgess Stephen , Ramirez-Valle Francisco , Gordon David A. , Cappola Thomas P. , Chirinos Julio A. 
Published: February 2024

Background:
NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood.

Methods:
We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis.

Results:

NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; β
TOPCAT
=0.539;
P
<0.0001; β
PHFS
=0.516;
P
<0.0001) and ANGPT2 (angiopoietin 2; β
TOPCAT
=0.571;
P
<0.0001; β
PHFS
=0.459;
P
<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations.

Conclusions:
Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.
Abstract TMP83: Macrophage Metabolic Reprograming to Face Ferroptosis After ICH
Authors: Bories Gael , DeLong Jonathan , Sansing Lauren H 
Published: February 2024

Intracerebral Hemorrhage (ICH) is a destructive neurovascular disease with no efficient treatment. Trapped Red Blood Cells (RBCs) in the brain lyse releasing toxic heme from hemoglobin. Heme, a lipophilic molecule with iron, triggers severe oxidative stress, particularly to lipid-rich cell plasma membranes (PM), causing cell death via ferroptosis. Macrophages are specialized in hematoma phagocytosis; their survival determines hematoma detoxification in the brain.
Using in vitro murine macrophage cultures treated with heme, we noted heme induced cell death (Fig 1A), along with heightened oxidized fatty acids (FAs), a marker of ferroptosis (Fig 1B). Heme-triggered cell death was countered by the ferroptosis inhibitors ferrostatin-1 (Fer-1), NAC, β-ME and Deferoxamine (DFO) (Fig 1C-F), which confirm that heme induces ferroptosis in macrophages.
Macrophages may shift metabolism to the Pentose Phosphate Pathway (PPP) in the presence of heme to promotes NADPH synthesis, vital for heme degradation and oxidation defense. Dehydroisoandrosterone (DHEA), a potent PPP inhibitor, worsened heme-induced ferroptosis (Fig 1 G&H). This underscores the PPP's vital role against heme-driven ferroptosis.
Ferroptosis involves PM oxidation and loss of integrity, causing cell death. Heme induced rapid extracellular ATP release (Fig I). Lysosomes contain abundant ATP, thus we hypothesized that ATP release triggers by heme is the result of PM repair by lysosomal exocytosis/endocytosis. Using metabolomics, we found that heme induced accumulation of membrane components like phospholipids, sphingolipids, and cholesterol (Fig J-L), all which require NADPH for synthesis. This suggests PPP aids NADPH production, aiding lysosomal synthesis for PM repair. Overall, the findings support a critical role for the PPP in macrophage resistance to ferroptosis in the presence of heme and suggest a possible new therapeutic target for macrophage survival after ICH.
Abstract TP247: Focused Approach to Tailor Native American Stroke Awareness Messaging in Montana
Authors: Guzman Joani , Brown Stefanie , Wintermeyer Jay , Burcham Heather 
Published: February 2024

Overall, African Americans, Hispanics, and Native Americans have higher stroke risks, stroke occurrence at an earlier age, and for some people of color possibly more severe strokes than non-Hispanic whites. Native Americans make up approximately 6.5% of the population of Montana—equating to around 78,000 people. A focused objective of the Mission: Lifeline Stroke Montana initiative was to specifically engage with Native Americans through public awareness campaigns to improve stroke outcomes in Montana.

Method:
In 2021 a survey was deployed to Native Americans in Montana to evaluate knowledge, awareness, and understanding of stroke risk factors, signs and symptoms, and what to do in the event of a stroke. Surveys were collected from eight tribal nations. The results of this survey guided message development to create a tailored public awareness campaign.

Results:
Analysis of the 398 surveys collected showed a representative sampling of respondents by age, gender, education, and geographic area. The key findings were:· Less than 38% of respondents reported having ever talked with a healthcare provider about their risk of stroke, with men being less likely than women to have discussed their stroke risk.· Nearly 94% of respondents said they knew high blood pressure was a risk factor for stroke but have not discussed their personal risk with a healthcare provider.· When asked what action they would take in the event of a possible stroke, over 75% of respondents said they would call 911. Less than half of the respondents indicated the best mode of transportation, in the event of a possible stroke, was an ambulance.

Conclusion:
Based on survey findings, specific engagement strategies were centered around two main messages:-Know the risk factors for stroke and talk with a healthcare provider about your risk.

-Stroke is a medical emergency that requires immediate attention. Call 9-1-1 at the first sign of stroke to access treatment through Montana’s Stroke System of Care.
A post-campaign survey will be deployed in the fall of 2023. This survey will aim to assess the effectiveness of these tailored campaign initiatives.