bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO5-25-02: Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes
Authors: Norek Karen , Kennard Jacob , Fuh Kenneth , Shepherd Robert , Rinker Kristina , Kharenko Olesya 
Published: May 2024

Abstract
The tumour microenvironment (TME) includes physical forces from interstitial fluid flow and cell-cell interactions that modulate cancer development and progression through activation of multiple oncogenic pathways leading to tumor growth and metastatic spreading. We previously reported on the role of physical forces on epithelial to mesenchymal transition (EMT) and S100 gene family expression and cell to cell adhesion properties with implications to normal breast development and cancer. Signals from the tumor exit the local tumor environment through interstitial fluid transport and cell migration where they can be found in the blood stream. We developed a whole blood RNA gene expression biomarker panel coupled with proprietary software capable of identifying the presence of an active breast cancer signature at early stages of disease with clinical study results previously reported. Here we report on results from transcriptomic and function studies with cell interaction models. Cancer cells can influence immune cells through direct contact or via secreted molecules causing the immune cells to undergo functional changes. To investigate mechanisms involved in the induction of these alterations in a model system, we performed co-culture studies with human monocytic cells and breast cancer cells. Interaction of human monocytic cells with the breast cancer cells caused significant changes in both behavior and transcriptomes. Moreover, using RNAseq and pathway analysis we demonstrated that the changes induced through the exposure to the more aggressive triple negative (TNBC) phenotype were distinct from the alterations triggered upon contact with an ER+ breast cancer cell line. We also show that cancer-immune crosstalk triggers EMT as well as activation of multiple oncogenic pathways associated with cell migration and invasion, cell chemotaxis and cell-to-cell interactions. As the interplay between cancer and immune cells plays an important role in cancer progression, these findings provide important insight into key mechanisms controlling these outcomes.
Citation Format: Karen Norek, Jacob Kennard, Kenneth Fuh, Robert Shepherd, Kristina Rinker, Olesya Kharenko. Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-02.
Abstract PO5-27-05: Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative breast cancer
Authors: Liu Francine , Zhai Andrew , Yoluk Ozge , Broom Aron , Stone Tracy , Butterfoss Glenn , Popa Serban , Li Tianyu , Siow Lucas , Ing Christopher , White David 
Published: May 2024

Abstract
Sortilin (SORT1) is a member of the vacuolar protein sorting 10 protein (Vps10p) family that functions as a receptor regulating peptide and protein trafficking between the plasma membrane, lysosomes, and trans-golgi network. As a cell surface receptor, SORT1 is able to mediate efficient endocytosis of extracellular ligands to the lysosomal compartment. Numerous reports have identified enriched SORT1 expression in a variety of tumor types, including triple-negative breast cancer (TNBC), a subtype of breast cancer associated with aggressive clinical behavior and poor disease outcomes. We sought to exploit SORT1-dependent internalization of peptides as a platform for rapid and specific chemotherapy delivery into TNBC cells. Using ProteinStudio (our proprietary computation-enabled design capabilities), we generated high-affinity SORT1 targeting peptides that exhibit efficient receptor dependent internalization and lysosomal localization. Alternative computational approaches such as AlphaFold2 failed to recapitulate the peptide design. Peptide drug conjugates (PDCs) were generated via a linkage strategy that combines our designed peptides to the antimitotic agent monomethyl auristatin E (MMAE). Our PDC molecules exhibit potent tumor regression in a MDA-MB-231 TNBC cell derived xenograft model, thereby highlighting the potential of SORT1-engaging PDCs as an efficacious targeted chemotherapeutic delivery strategy.
Citation Format: Francine Liu, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Li, Lucas Siow, Christopher Ing, David White. Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-27-05.
Abstract SoA3-01: SERMs versus SERDs for targeting ESR1 mutations
Authors: Greene G. 
Published: May 2024

Abstract
Estrogen receptor positive (ER+) breast cancers are effectively treated with adjuvant endocrine therapies, with or without the addition of CDK4/6 inhibitors. However, many patients develop resistance and progress to ER+ metastatic disease (MBC). Acquired mutations in ESR1, which encodes estrogen receptor alpha (ERa), contribute to 20-40% of endocrine therapy resistant MBC. An emerging, unanswered and controversial question is the best choice of ER-targeted therapy for ET-resistant mutant ER+ MBC, recognizing that for most patients, a balance between compliance, effectiveness and quality of life are competing issues. To partially address some of these issues, we have tested and compared a relatively nontoxic SERM, lasofoxifene, to a complete estrogen receptor antagonist (CERAN), OP1250, in a mutant ERa (MCF-7 Y537S ERa) MBC endocrine therapy resistant xenograft tumor model (MIND = Mammary intraductal) to examine the efficacy of both drugs in a metastatic context in which a frequently observed, aggressive mutant ERa is expressed. As single agents, both Lasofoxifene and OP1250 inhibited primary tumor growth as well as metastasis to the lung, liver, brain and bone, with greater effect at higher doses of each drug, and both were substantially more effective than fulvestrant, the current gold standard for treating progressive disease. When combined with palbociclib, an additional decrease in metastasis was observed, compared to lasofoxifene, OP1250 or palbociclib as single agents. In total, these results demonstrate that lasofoxifene, a SERM, is as effective as OP-1250, a complete ER antagonist and SERD in a xenograft MIND model of mutant ER+ metastatic breast cancer. The potential use of lasofoxifene or OP1250, both alone and in combination with CDK4/6 inhibitors, to reduce tumor growth and metastasis in patients with ET-resistant metastatic breast cancer, is being tested in clinical trials to determine whether either drug is a preferred therapy versus current standard of care for mutant ER+ MCB.
Citation Format: G. Greene. SERMs versus SERDs for targeting ESR1 mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SoA3-01.
Abstract Wrk2-04: Virtual screening of ultra-large chemical spaces for novel chemotype discovery
Authors: Irwin J. 
Published: May 2024

Abstract
Recently, 'tangible' virtual libraries have made billions of molecules readily available. Prioritizing these molecules for synthesis and testing demands computational approaches, such as docking. We will present recent results in which protein structure is interrogated using molecular docking, resulting in new high-affinity compounds that exhibit new biology in animal models. Singh I, Seth A, Billesbølle CB, Braz J, Rodriguiz RM, Roy K, Bekele B, Craik V, Huang XP, Boytsov D, Pogorelov VM, Lak P, O'Donnell H, Sandtner W, Irwin JJ, Roth BL, Basbaum AI, Wetsel WC, Manglik A, Shoichet BK, Rudnick G. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell. 2023 May 11;186(10):2160-2175.e17. doi: 10.1016/j.cell.2023.04.010. Epub 2023 May 2. PMID: 37137306; PMCID: PMC10306110. Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 Sep 30. PMID: 36173843; PMCID: PMC10360211. Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. 2022 Oct;610(7932):582-591. doi: 10.1038/s41586-022-05258-z. Epub 2022 Sep 28. PMID: 36171289; PMCID: PMC9996387.
Citation Format: J. Irwin. Virtual screening of ultra-large chemical spaces for novel chemotype discovery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr Wrk2-04.
T-Cell Expression of CXCL13 is Associated with Immunotherapy Response in a Sex-Dependent Manner in Patients with Lung Cancer
Authors: Brennan Michelle , DeBruin David , Nwokolo Chinye , Hunt Katey S. , Piening Alexander , Donlin Maureen J. , Ferris Stephen T. , Teague Ryan M. , DiPaolo Richard J. , Alspach Elise 
Published: May 2024

Abstract
Emerging evidence in preclinical models demonstrates that antitumor immunity is not equivalent between males and females. However, more investigation in patients and across a wider range of cancer types is needed to fully understand sex as a variable in tumor immune responses. We investigated differences in T-cell responses between male and female patients with lung cancer by performing sex-based analysis of single cell transcriptomic datasets. We found that the transcript encoding CXC motif chemokine ligand 13 (CXCL13), which has recently been shown to correlate with T-cell tumor specificity, is expressed at greater levels in T cells isolated from female compared with male patients. Furthermore, increased CXCL13 expression was associated with response to PD1–targeting immunotherapy in female but not male patients. These findings suggest that there are sex-based differences in T-cell function required for response to anti–PD1 therapy in lung cancer that may need to be considered during patient treatment decisions.
See related Spotlight by Cruz-Hinojoza and Stromnes, p. 952
Comparative Epigenetic Profiling Reveals Distinct Features of Mucosal Melanomas Associated with Immune Cell Infiltration and Their Clinical Implications
Authors: Dai Jie , Jia Jia , Zhang Fanshuang , Liu Kaihua , Xi Yanfeng , Yuan Pei , Mao Lili , Bai Xue , Wei Xiaoting , Wang Bingning , Li Jiangtao , Xu Yang , Liu Ting , Chang Shuang , Shao Yang , Guo Jun , Ying Jianming , Si Lu 
Published: May 2024

Abstract

Mucosal melanoma exhibits limited responsiveness to anti-PD-1 therapy. However, a subgroup of mucosal melanomas, particularly those situated at specific anatomic sites like primary malignant melanoma of the esophagus (PMME), display remarkable sensitivity to anti-PD-1 treatment. The underlying mechanisms driving this superior response and the DNA methylation patterns in mucosal melanoma have not been thoroughly investigated. We collected tumor samples from 50 patients with mucosal melanoma, including 31 PMME and 19 non-esophageal mucosal melanoma (NEMM). Targeted bisulfite sequencing was conducted to characterize the DNA methylation landscape of mucosal melanoma and explore the epigenetic profiling differences between PMME and NEMM. Bulk RNA sequencing and multiplex immunofluorescence staining were performed to confirm the impact of methylation on gene expression and immune microenvironment. Our analysis revealed distinct epigenetic signatures that distinguish mucosal melanomas of different origins. Notably, PMME exhibited distinct epigenetic profiling characterized by a global hypermethylation alteration compared with NEMM. The prognostic model based on the methylation scores of a 7-DMR panel could effectively predict the overall survival of patients with PMME and potentially serve as a prognostic factor. PMME displayed a substantial enrichment of immune-activating cells in contrast to NEMM. Furthermore, we observed hypermethylation of the TERT promoter in PMME, which correlated with heightened CD8+ T-cell infiltration, and patients with hypermethylated TERT were likely to have improved responses to immunotherapy. Our results indicated that PMME shows a distinct methylation landscape compared with NEMM, and the epigenetic status of TERT might be used to estimate prognosis and direct anti-PD-1 treatment for mucosal melanoma.

Significance:
This study investigated the intricate epigenetic factor of mucosal melanomas contributed to the differential immune checkpoint inhibitor response, and found that PMME exhibited a global hypermethylation pattern and lower gene expression in comparison to NEMM. TERT hypermethylation may contribute to the favorable responses observed in patients with mucosal melanoma undergoing immunotherapy.
Service Quality, Patient Satisfaction, and Improvement Indicators
Authors: Mabini Jr. Silvestre P. , Narsico Lalaine O. , Narsico Peter G. 
Published: May 2024

The study delves into the intricate symbiotic relationship between service providers and customers, which becomes increasingly complex amid competitive landscapes. It counts on the service provider’s capability to deliver exceptional service that fosters a unique customer satisfaction that not only encourages repeat patronage but also prompts referrals to others. The study sought to determine the presence of a correlation between the quality of service delivered by medical staff and patients' satisfaction levels by using the SERVQUAL model with 22 slightly modified indicators spread across five service quality dimensions that include reliability, assurance, tangibles, empathy, and responsiveness. The research was conducted within the confines of a hospital in Cebu. 314 patisents consented to participate in the data collection process. A survey was conducted to gather data on service delivery and another was conducted for patient satisfaction. Multiple regression analysis and Dublin-Watson test were used to compute correlations and Analysis of Variance (ANOVA) was used to compute the significance of difference. The following items are the findings. The five dimensions of service quality are above average and the service quality rating in its entirety was 3.756. Patient satisfaction was above average with a rating of 3.131. All the service quality dimensions were statistically correlated with patient satisfaction. Service quality in its entirety was statically correlated with patient satisfaction. There was a significant difference between service quality in its entirety and patient satisfaction. Finally, the ratings suggest that improvements were needed in all service dimensions, and because of high patient expectations improvements are both necessary and urgent.
Evinacumab and Cardiovascular Outcome in Patients With Homozygous Familial Hypercholesterolemia
Authors: Béliard Sophie , Saheb Samir , Litzler-Renault Stéphanie , Vimont Alexandre , Valero René , Bruckert Éric , Farnier Michel , Gallo Antonio 
Published: May 2024

BACKGROUND:
Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome.

METHODS:
The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event–free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia.

RESULTS:

Twelve patients, 5 women and 7 men (12–57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L;
P
<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood
P
=0.0267).

CONCLUSIONS:
Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event–free survival of patients with HoFH.
Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis
Authors: Fan Xiaoxi , Han Jibo , Zhong Lingfeng , Zheng Wenyuan , Shao Ruiyin , Zhang Yucong , Shi Si , Lin Shuang , Huang Zhouqing , Huang Weijian , Cai Xueli , Ye Bozhi 
Published: May 2024

BACKGROUND:
Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release.

METHODS:

ApoE
−/−

and

Gsdmd
−/−

ApoE
−/−

mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis.

RESULTS:

First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and

Gsdmd
−/−

attenuates the atherosclerotic lesion area in high-fat diet–fed

ApoE
−/−

mice. We performed single-cell RNA sequencing of

ApoE
−/−

and

Gsdmd
−/−

ApoE
−/−

mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis.

CONCLUSIONS:
Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.
Testing the Sensitivity of a WRF-Based Great Lakes Regional Climate Model to Cumulus Parameterization and Spectral Nudging
Authors: Hutson Abby , Fujisaki-Manome Ayumi , Lofgren Brent 
Published: May 2024

Abstract
The Weather Research and Forecasting (WRF) Model is used to dynamically downscale ERA-Interim global reanalysis data to test its performance as a regional climate model (RCM) for the Great Lakes region (GLR). Four cumulus parameterizations and three spectral nudging techniques applied to moisture are evaluated based on 2-m temperature and precipitation accumulation in the Great Lakes drainage basin (GLDB). Results are compared to a control simulation without spectral nudging, and additional analysis is presented showing the contribution of each nudged variable to temperature, moisture, and precipitation. All but one of the RCM test simulations have a dry precipitation bias in the warm months, and the only simulation with a wet bias also has the least precipitation error. It is found that the inclusion of spectral nudging of temperature dramatically improves a cold-season cold bias, and while the nudging of moisture improves simulated annual and diurnal temperature ranges, its impact on precipitation is complicated.

Significance Statement
Global climate models are vital to understanding our changing climate. While many include a coarse representation of the Great Lakes, they lack the resolution to represent effects like lake effect precipitation, lake breeze, and surface air temperature modification. Therefore, using a regional climate model to downscale global data is imperative to correctly simulate the land–lake–atmosphere feedbacks that contribute to regional climate. Modeling precipitation is particularly important because it plays a direct role in the Great Lakes’ water cycle. The purpose of this study is to identify the configuration of the Weather Research and Forecasting Model that best simulates precipitation and temperature in the Great Lakes region by testing cumulus parameterizations and methods of nudging the regional model toward the global model.