bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-05-01: Metabolite profiling and RNA-seq identifies novel metabolomic-genomic biomarker and therapeutic options for rapidly proliferating breast cancers
Authors: Glodowski Cherise R , Liao Chengheng , Fan Cheng , Liu Juan , Mott Kevin R , Kaushik Akash , Vu Hieu , Locasale Jason W , McBrayer Samuel K , DeBerardinis Ralph J , Perou Charles M , Zhang Qing 
Published: March 2022

Abstract
Metabolic dysregulation is one of the distinctive features of breast cancer, yet remains under-characterized in different subtypes of breast cancer. In this study, we performed full metabolome profiling and RNA-seq gene expression analyses on patient samples comprised of Triple Negative Breast Cancer (TNBC) and Estrogen Receptor (ER) positive breast cancers, as well as TNBC patient-derived xenografts (PDX). We identified two major metabolic groups using hierarchical clustering analysis of global metabolite levels: a Nucleotide/Carbohydrate-Enriched group and a Lipid/Fatty Acid-Enriched group. The Nucleotide/Carbohydrate-Enriched group is populated by the majority of TNBCs and all TNBC PDX samples, and shows high levels of energy consumption and nucleotide biosynthesis related metabolites, while the Lipid/Fatty Acid-Enriched group contained all ER+ cancers (and normal breast tissues) and showed high levels of lipids and fatty acids. Using these two metabolite-defined groups, we compared metabolic signatures to RNA-seq expression data and identified gene expression signatures that correlated with each metabolic group. This novel integrated signature identified classic proliferation-associated genes as highly expressed in the Nucleotide/Carbohydrate-Enriched metabolomics group. We next sought to therapeutically target the Nucleotide/Carbohydrate-Enriched group through targeting of nucleotide metabolism using a pyrimidine biosynthesis inhibitor (DHODH inhibitor, Brequinar), and/or a glutaminase inhibitor (CB-839), and observed tumor volume reductions and improved survival times using the TNBC PDX models. Notably,. when the DHODH inhibitor Brequinar was tested on four different immune-competent TNBC mouse models, it showed significant single agent activity, and in 3/4 cases had better activity than carboplatin/paclitaxel combination, and with less toxicity. Our study reveals a new molecularly targeted therapy for rapidly proliferating TNBCs, guided by a novel set of metabolic-genomic biomarkers, which might be translated quickly as DHODH inhibitors are already FDA approved for use in other diseases.
Citation Format: Cherise R Glodowski, Chengheng Liao, Cheng Fan, Juan Liu, Kevin R Mott, Akash Kaushik, Hieu Vu, Jason W Locasale, Samuel K McBrayer, Ralph J DeBerardinis, Charles M Perou, Qing Zhang. Metabolite profiling and RNA-seq identifies novel metabolomic-genomic biomarker and therapeutic options for rapidly proliferating breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-01.
Abstract P5-08-07: The complete estrogen receptor antagonist OP-1250 can combine with HER2 inhibition to inhibit estrogen receptor-driven cellular proliferation and shrink xenograft tumors in ER+/HER2+ breast cancer models
Authors: Parisian Alison D , Hodges-Gallagher Leslie , Sun Richard , Barratt Susanna , Palanisamy Gopinath S , Lawrence Julia , Klein Pamela , Myles David C , Harmon Cyrus L , Kushner Peter J 
Published: March 2022

Abstract
The human epidermal growth factor receptor 2 (HER2, also known as ERBB2) oncogene is overexpressed in approximately 25% of breast cancer tumors and is associated with a high rate of brain metastasis. Patients with brain metastases have a poor prognosis and limited treatment options available. Since about half of HER2+ tumors are also hormone receptor positive, and cross talk has been shown to occur between these two signaling pathways, it is plausible that these tumors could benefit from the addition of hormonal therapy on top of HER2 inhibition. OP-1250 is a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), and has been shown to effectively inhibit estrogen receptor positive (ER+) breast cancer growth in both cell-based assays and xenograft studies. OP-1250 has favorable pharmacokinetic properties and demonstrated brain penetrance in non-clinical models. While extensively characterized in ER+/HER2- breast cancer models, OP-1250 had not previously been tested in a HER2+ context. Here we report OP-1250 inhibited estrogen receptor-driven proliferation and effectively degraded the estrogen receptor in multiple ER+/HER2+ cell lines. OP-1250 combined effectively with HER2 inhibitors tucatinib and trastuzumab, demonstrating that inhibition of both HER2 and estrogen receptor signaling was more effective in inhibiting breast cancer cell proliferation than inhibiting either pathway alone. The addition of OP-1250 to a HER2 inhibitor also resulted in greater tumor shrinkage in multiple ER+/HER2+ xenograft models. Our data suggests a potential clinical benefit in the addition of OP-1250 on top of HER2 inhibition for the treatment of ER+/HER2+ breast cancer and provides strong rationale for a clinical study evaluating the combination of OP-1250 and HER2 targeted agents, which is planned for 2022.
Citation Format: Alison D Parisian, Leslie Hodges-Gallagher, Richard Sun, Susanna Barratt, Gopinath S Palanisamy, Julia Lawrence, Pamela Klein, David C Myles, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 can combine with HER2 inhibition to inhibit estrogen receptor-driven cellular proliferation and shrink xenograft tumors in ER+/HER2+ breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-07.
Abstract P5-08-15: Overcoming mTOR inhibitor resistance by targeting the lysosomal deregulation
Authors: Zhang Shengzhe , Lee Sung Ho , Nie Litong , Jung Youn-Sang , Jun Sohee , Zhang Jie , Lien Esther M , Chen Junjie , Park Jae-Il 
Published: March 2022

Abstract
Increasing evidence suggests that the deregulated lysosomes contribute to tumorigenesis and therapeutic resistance. However, its underlying mechanisms remain elusive. Here, we identify transmembrane protein 9 (TMEM9) as a regulator involved in lysosomal metabolism and mammary tumorigenesis. The TMEM9 gene is markedly amplified in breast cancer, correlated with its transcriptional upregulation. We uncovered that Tmem9 knock-out inhibited mammary tumorigenesis in genetically engineered mouse models. Consistently, TMEM9 depletion suppressed the proliferation of breast cancer cells highly expressing TMEM9. Conversely, the ectopic expression of TMEM9 in TMEM9 low breast cancer cells promoted cell proliferation. The lysosome purification and proteomics approach showed that TMEM9 physically and functionally interacts with LAMTOR4, a subunit of the Ragulator complex, to hyperactivate mTOR signaling in breast cancer. Moreover, the combination of TMEM9-v-ATPase inhibitors with mTOR inhibitors exhibited the synergistic growth inhibition of breast cancer cells in vitro and in vivo. Our results reveal that the TMEM9-v-ATPase axis is not only a biomarker for resistance to mTOR inhibition therapy but also a molecular target overcoming mTOR inhibitor resistance.
Citation Format: Shengzhe Zhang, Sung Ho Lee, Litong Nie, Youn-Sang Jung, Sohee Jun, Jie Zhang, Esther M Lien, Junjie Chen, Jae-Il Park. Overcoming mTOR inhibitor resistance by targeting the lysosomal deregulation [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-15.
Abstract PD4-07: Targeting latent residual HER2+ breast cancer brain metastatic cells
Authors: Marquez-Palencia Mauricio , Malladi Srinivas 
Published: March 2022

Abstract
Approximately fifty percent of breast cancer patients with brain metastasis are positive for human epidermal growth factor receptor 2 (HER2+). Systemically effective cytotoxic drugs, and HER2 targeted therapies are ineffective on brain metastases. Current understanding of HER2 brain metastatic disease is limited as biopsying brain metastatic lesions and detecting micro-metastasis from asymptomatic patients with residual disease remains a challenge. Therefore, to isolate disseminated tumor cells that stay latent in the brain, while retaining their metastasis-initiating capabilities, we performed a phenotypic screen in mouse employing human breast cancer cell lines. Using this approach, we isolated isogenic latent residual cells (Lat) and metachronous brain metastatic outbreaks (M-BM). Phenotypically stable latent cells display stem cell-like characteristics, downregulate immune activating sensors and survive in equilibrium with innate immune surveillance, while M-BM escape and metastasize. Brain-tropic Lat and M-BM cells are resistant to HER2 targeted therapies - lapatinib, neratinib and tucatinib. Transcriptomic analysis identified AXL, a receptor tyrosine kinase from the TAM receptor family, to be highly enriched in brain-tropic Lat and M-BM. Moreover, AXL is over expressed in metachronous brain metastasis samples compared to matched primary tumors from HER2+ breast cancer patients. AXL activation and overexpression has been associated with chemoresitance mechanisms, dormancy maintenance, invasion, tumor angiogenesis, immune regulation, metastasis and poor prognosis in cancer patients. Therefore, we hypothesized AXL promotes residual/latent breast cancer survival and brain metastatic relapse in HER2+ breast cancer. shRNA depletion of AXL in Lat and M-BM resulted in reduced oncosphere formation, an assay used to measure tumor or metastasis initiating capacity. Brain metastatic incidence was significantly attenuated in mice bearing AXL depleted M-BM compared to their controls. Bemcentinib, an AXL inhibitor currently in clinical trials for non-small cell lung cancer, triple negative breast cancer, pancreatic cancer and melanoma, alone or in combination with lapatinib, neratinib or tucatinib, reduced oncosphere formation in HER2 therapy resistant Lat and M-BM cells. Ongoing experiments are designed to assess the impact of bemcentinib on brain metastasis in vivo and to mechanistically define how AXL promotes survival of latent residual and brain metastatic HER2+ breast cancer cells.
Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. Targeting latent residual HER2+ breast cancer brain metastatic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-07.
Abstract PD5-10: Consequent job loss, return to work and multidimensional well-being after breast cancer treatment in working-age black and white women
Authors: Emerson Marc A , Reeve Bryce B , Gilkey Melissa B. , Elmore Shekinah N , Bradley Cathy J , Troester Melissa A 
Published: March 2022

Abstract
Background: Few studies have assessed relationships between job loss due to breast cancer and well-being. These relationships may vary by race, work type, and functional difficulties.Methods: In the Carolina Breast Cancer Study, 1,646 women with primary breast cancer who worked prior to diagnosis were longitudinally evaluated for post-diagnosis job loss and well-being using the Functional Assessment of Cancer Therapy General (FACT-G) measure. Women were classified as having ‘sustained work’ (working at baseline and 25 months); ‘returned to work’ (not working at baseline, working at 25 months); ‘consequent job loss’ (working at baseline, not working at 25 months); or ‘persistent non-employment’ (not working at either timepoint). Analysis of covariance was used to evaluate associations between work status and well-being (physical, functional, social, emotional).Results: Women who had sustained work or returned to work had higher FACT-G scores than women with consequent job loss and persistent non-employment in all well-being domains (p&lt;.05). Consequent job loss and persistent non-employment were associated with higher frequency of service/laborer job types, lower education and income, later stage at diagnosis, longer treatment duration, non-private insurance, and greater disability. Consequent job loss was more common among Black than White women (adjusted odds ratio [aOR]=3.44; 95% confidence interval [CI] 2.37-4.99). Black versus White women with job loss reported lower well-being in all domains (p&lt;.05) and greater disability (mean score 42.8 vs. 29.3) and work-related difficulties (aORs=10.3, 95% CI 5.9-18.2 vs. 5.7, 95% CI 2.9-11.2).Conclusions: Work status is an indicator of multidimensional well-being after breast cancer.
Citation Format: Marc A Emerson, Bryce B Reeve, Melissa B. Gilkey, Shekinah N Elmore, Cathy J Bradley, Melissa A Troester. Consequent job loss, return to work and multidimensional well-being after breast cancer treatment in working-age black and white women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-10.
Effects of Magnesium Citrate, Magnesium Oxide, and Magnesium Sulfate Supplementation on Arterial Stiffness: A Randomized, Double‐Blind, Placebo‐Controlled Intervention Trial
Authors: Schutten Joëlle C. , Joris Peter J. , Groendijk Iris , Eelderink Coby , Groothof Dion , van der Veen Yvonne , Westerhuis Ralf , Goorman Frans , Danel Richard M. , de Borst Martin H. , Bakker Stephan J. L. 
Published: March 2022

Background
Magnesium supplements may have beneficial effects on arterial stiffness. Yet, to our knowledge, no head‐to‐head comparison between various magnesium formulations in terms of effects on arterial stiffness has been performed. We assessed the effects of magnesium citrate supplementation on arterial stiffness and blood pressure and explored whether other formulations of magnesium have similar effects.

Methods and Results
In this randomized trial, subjects who were overweight and slightly obese received either magnesium citrate, magnesium oxide, magnesium sulfate, or placebo for 24 weeks. The total daily dose of magnesium was 450 mg/d. The primary outcome was carotid‐to‐femoral pulse wave velocity, which is the gold standard method for measuring arterial stiffness. Secondary outcomes included blood pressure and plasma and urine magnesium. Overall, 164 participants (mean±SD age, 63.2±6.8 years; 104 [63.4%] women) were included. In the intention‐to‐treat analysis, neither magnesium citrate nor the other formulations had an effect on carotid‐to‐femoral pulse wave velocity or blood pressure at 24 weeks compared with placebo. Magnesium citrate increased plasma (+0.04 mmol/L; 95% CI, +0.02 to +0.06 mmol/L) and urine magnesium (+3.12 mmol/24 h; 95% CI, +2.23 to +4.01 mmol/24 h) compared with placebo. Effects on plasma magnesium were similar among the magnesium supplementation groups, but magnesium citrate led to a more pronounced increase in 24‐hour urinary magnesium excretion than magnesium oxide or magnesium sulfate. One serious adverse event was reported, which was considered unrelated to the study treatment.

Conclusions
Oral magnesium citrate supplementation for 24 weeks did not significantly change arterial stiffness or blood pressure. Magnesium oxide and magnesium sulfate had similar nonsignificant effects.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03632590.
Cardiac Structure and Function and Diabetes‐Related Risk of Death or Heart Failure in Older Adults
Authors: Inciardi Riccardo M. , Claggett Brian , Gupta Deepak K. , Cheng Susan , Liu Jiankang , Echouffo Tcheugui Justin B. , Ndumele Chiadi , Matsushita Kunihiro , Selvin Elizabeth , Solomon Scott D. , Shah Amil M. , Skali Hicham 
Published: March 2022

Background
Whether cardiac structure and function abnormalities associated with dysglycemia are sufficient to explain the increased risk of death or heart failure (HF) remains unclear.

Methods and Results

We analyzed 6059 participants (mean age, 75±5 years; 58% women; and 22% Black individuals) who attended the ARIC (Atherosclerosis Risk in Communities) study visit 5 examination (2011–2013). Participants were categorized as no diabetes, pre‐diabetes, and diabetes (on the basis of medical history and glycated hemoglobin values). We assessed whether diabetes modified the association between echocardiographic measures of cardiac structure and function and the composite of all‐cause death or HF hospitalization and then estimated the extent to which the increased risk of the composite outcome associated with diabetes was explained by cardiac structure and function. Diabetes was prevalent in 33.5% of the subjects. Death or HF occurred in 1111 (18%) at a rate of 3.6 per 100 person‐years. Both measures of cardiac structure and function and diabetes status were significantly associated with worse prognosis after accounting for clinical confounders. While diabetes was consistently associated with a higher risk of events, it did not significantly modify the association between cardiac abnormalities and the risk of death or HF, except for subjects with higher left atrial volume who showed higher relative risk of events (
P
for interaction <0.001). Measures of cardiac structure and function accounted for ≈16% of the increased risk of death or HF associated with diabetes. Similar results were observed analyzing subjects without prevalent heart disease.

Conclusions
In a biracial cohort of older adults, the increased risk of events associated with diabetes was partially explained by cardiac structure and function abnormalities.
Endothelial Transient Receptor Potential Canonical Channel Regulates Angiogenesis and Promotes Recovery After Myocardial Infarction
Authors: Wen Xin , Peng Yidi , Gao Mengru , Zhu Yuzhong , Zhu Yifei , Yu Fan , Zhou Tingting , Shao Jing , Feng Lei , Ma Xin 
Published: March 2022

Background
Transient receptor potential canonical (TRPC) channels play a role in angiogenesis. However, the involvement of TRPC1 in myocardial infarction (MI) remains unclear. The present study was aimed at investigating whether TRPC1 can improve the recovery of cardiac function via prompting angiogenesis following MI.

Methods and Results
In vitro, coronary artery endothelial cells from floxed TRPC1 mice and endothelial cell‐specific TRPC1 channel knockout mice were cultured to access EC angiogenesis. Both EC tube formation and migration were significantly suppressed in mouse coronary artery endothelial cells from endothelial cell‐specific TRPC1 channel knockout mice. In vivo, coronary artery endothelial cells from floxed TRPC1 and endothelial cell‐specific TRPC1 channel knockout mice were subjected to MI, then echocardiography, triphenyltetrazolium chloride staining and immunofluorescence were performed to assess cardiac repair on day 28. Endothelial cell‐specific TRPC1 channel knockout mice had higher ejection fraction change, larger myocardial infarct size, and reduced capillary density in the infarct area compared with coronary artery endothelial cells from floxed TRPC1 mice. Furthermore, we found underlying regulation by HIF‐1α (hypoxic inducible factor‐1α) and MEK‐ERK (mitogen‐activated protein kinase/extracellular signal‐regulated kinase) that could be the mechanism for the angiogenetic action of TRPC1. Significantly, treatment with dimethyloxaloylglycine, an activator of HIF‐1α, induced cardiac improvement via the HIF‐1α‐TRPC1‐MEK/ERK pathway in MI mice.

Conclusions
Our study demonstrated TRPC1 improves cardiac function after MI by increasing angiogenesis via the upstream regulator HIF‐1α and downstream MEK/ERK, and dimethyloxaloylglycine treatment has protective effect on MI through the HIF‐1α‐TRPC1‐MEK/ERK pathway.
The Youth Ministry Wars and the Formation of Youthworks College
Authors: Lukabyo Ruth 
Published: March 2022

AbstractAnglican Youthworks College was established in 2000, as the first college in Australia with a specialist focus on youth and children’s ministry. In this article I will discuss the factors that led to the formation of the college in Sydney and the character of the theological training that it offered. I will examine how the college was established in the context of politics in the Diocese of Sydney and debates over the best way to do youth ministry (the “youth ministry wars”). Those involved in youth ministry were concerned about poor retention of young people in the church and as a result turned against what was called attractional ministry for (what was seen as) a more biblical and theological model. I will argue that the college used a distinctive method of youth ministry education which prioritised: the Bible, critical reflection on ministry and life, and the concept of temporary community for student formation. It reflected a concern to professionalise and think critically about spiritual formation amongst children as well as youth. I will finish with some observations that maybe helpful for youth and children’s ministry today.
Fictive Kinship, Participation and Belief
Authors: Marion John , Corney Tim 
Published: March 2022

Abstract
Belonging is connected to young people’s wellbeing, and understanding how youth workers perceive belonging can assist youth work practice. Belonging in youth work is promoted through fictive kinship, in the context of Christian faith-based youth work practice, it is also connected to how young people construct belief. This research was conducted as an instrumental case study to explore Christian faith-based youth workers’ biographies, experiences and perceptions of belonging, and relationship to their youth work practice. Themes emerging from the findings suggest that participants connected belonging to fictive kinship notions of ‘family’, and as a result sought to create a sense of family-like kinship relationships in their practice. Christian faith-based youth workers (cfbyw) also connected kinship and a sense of belonging to participation, including having a role, a voice, and a right to be part of a community, which can be seen in the setting as pointing to the potential presence of belonging. This article contributes to a conceptual understanding of faith-based work with young people and the implications for youth work practice through investigating the place of belonging in Christian faith-based youth work, its relationship to belief and the role of fictive kinship in youth work.
Spectroscopic Studies of BA Class Liquid Crystals in the 6–15 THz Range Using the Fourier Transform Infrared (FT-IR) Method
Authors: Lepodise Lucia M. , Horvat Josip 
Published: March 2022

Fourier transform infrared spectroscopy was performed for two structurally similar liquid crystals: 4-octyloxybenzoic acid and 4-decyloxybenzoic acid in 6–15 THz range. Density functional theory modeling at PBE0/def2-TZVPP level was used to assign the vibrational modes to each observed absorption peak. We observed six peaks that are common for both liquid crystals, assigned to the same vibrational modes and appearing at similar energies. Each of the samples also had additional peaks unique to itself. A strong absorption peak appears at about 280 cm–1 for both samples; however, it corresponds to different vibrational modes for the two samples. This work shows that the spectroscopy in this often-neglected frequency range can easily distinguish structurally similar compounds.