bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-11-30: Breast cancer follow-up. Patients expectations versus reality
Authors: Zaluska-Kusz Joanna , Litwiniuk Maria 
Published: March 2022

Abstract
Background: Breast cancer is the most common malignancy among women. The increased incidence and better treatment results lead to an increased number of breast cancer survivors. Polish and international guidelines clearly specify the rules for the tests performed in the follow-up. The only mandatory test is annual mammography. Our aim was to evaluate patients expectations and knowledge regarding follow-up visits. Methods: 188 patients after breast cancer radical treatment completed anonymous questionnaires about their knowledge and preferences of the follow-ups. Results: Median age of the respondents was 64. Median time from the breast cancer diagnosis was 6 years (2-34). 82% of the patients claimed that they were informed by the oncologist about the rules of follow-up visits, 78% knew recommendations about healthy lifestyle and diet. At the same time - 78% would prefer to have more tests done than it’s recommended (abdominal ultrasound - 58 patients (31%), CA 15-3 level- 27 patients (14%), chest x-ray- 18 patients (10%), PET scan - 5 patients (3%), other tests (bone scyntygraphy, brain scan, liver MRI) - 13 patients (7%). Many patients would like to have multiple tests done. When asked if they would prefer to have follow-up visits with their family doctor or in the oncological centre - 94% would prefer to be controlled in the cancer centre. Conclusions: There is a need to educate both oncologists, family doctors and patients, about the rules of follow-up in breast cancer. Patients feel safer if they have more tests done, even though the guidelines recommend only annual mammography. Patients prefer to be controlled in the cancer centres, where they were treated. Because the recommendations were made many years ago, it seems advisable to conduct new studies on possible modifications to these guidelines, due to tremendous advances in breast cancer treatment and the fact that breast cancer is now divided into a numer od biological subtypes. There is a strong need to perform studies to evaluate the role of liquid biopsy, ctDNA and PET-scan in breast cancer follow-up.
Citation Format: Joanna Zaluska-Kusz, Maria Litwiniuk. Breast cancer follow-up. Patients expectations versus reality [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 P4-11-30.
Abstract P5-01-10: A panel of murine mammary tumor cell lines to study immune responses to epitopes created by different mutagens including human APOBEC3 enzymes
Authors: Naumann Jordan , Carpenter Michael , Argyris Prokopios , Brown William , Harris Reuben 
Published: March 2022

Abstract
Background: Tumor mutation loads are a strong predictor of immunotherapy benefit. This is evidenced by studies on skin, lung, and colon cancer, where well-defined processes elicit high mutation burdens and checkpoint therapies often provoke strong anti-tumor immune responses. In comparison, only a small number of breast cancer patients have responded to checkpoint therapies such as anti-PD-L1 and anti-PD-1 monoclonal antibodies. Approximately one-fourth of primary breast cancer and one-third of metastatic tumors have a significant APOBEC mutation burden defined as C-to-T and C-to-G mutations in TCA or TCT trinucleotide motifs, and many tumors have &gt;10,000 of these APOBEC signature single base substitution mutations. However, to our knowledge, systematic immunotherapy studies focusing on this unique, hypermutated subset of breast cancers have yet to be done. Methods: To address the potential relationship between different checkpoint therapies and APOBEC mutation burden, we created a panel of &gt;30 mammary tumor cell lines derived from fully immune-proficient C57BL/6 animals. At least 6 of these cell lines are immortalized, readily engineered using standard molecular biology procedures, and capable of re-engraftment and tumor formation in immune proficient C57BL/6 animals. Two lines were engineered to inducibly express human APOBEC3A, subjected to 1- to 20-rounds of sublethal mutagenesis, and tested systematically for checkpoint therapy responsiveness. Results: Two cell lines were engineered to inducibly express APOBEC3A or a catalytic mutant (E72A). Clones were characterized for inducible APOBEC3A expression and associated DNA damage responses. After varying rounds of mutagenesis, clones were engrafted into the subcutaneous flank or mammary fat pad of C57BL/6 animals. Immunohistochemical and flow cytometry analysis revealed a robust intratumoral CD8 T cell population including a subset with PD-1 expression. Additionally, engrafted tumor cells expressed high levels PD-L1. Experiments are ongoing and immunotherapy responses will be presented. Conclusions: We have isolated a panel of C57BL/6 mammary tumor-derived cell lines and demonstrated re-engraftment into immunocompetent animals. These cell lines constitute a platform for studying the relationship between different mutagens including APOBEC and immunotherapy responses.
Citation Format: Jordan Naumann, Michael Carpenter, Prokopios Argyris, William Brown, Reuben Harris. A panel of murine mammary tumor cell lines to study immune responses to epitopes created by different mutagens including human APOBEC3 enzymes [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 P5-01-10.
Abstract P5-09-02: Tetrameric and monomeric gain-of-function mutant p53 interacts with chromatin
Authors: Annor George Kwakye 
Published: March 2022

Abstract
In 80% of triple-negative breast cancers (TNBC) the TP53 gene is mutated, with a high occurrence of missense changed in the DNA binding domain. These mutations lead to loss of wild-type p53 (wtp53) function and some also create mutant p53 (mtp53) proteins with novel gain-of-function (GOF) tumor-promoting capabilities. We previously reported that mtp53 R273H interacts with replication-associated proteins including MCM2-7 and poly ADP-ribose polymerase (PARP1). Moreover, mtp53 is found on actively replicating nascent DNA. What remains unclear is which domains of mtp53 R273H are responsible for the protein’s chromatin-based replication activities. In this study, we tested whether the oligomerization state of mtp53 plays a role in oncogenic GOF activities. We destabilized tetramer formation by using site-directed mutagenesis to introduce oligomerization domain (OD) point mutations A347D, R337C, or L344P. The site-directed mutagenesis constructs were transiently transfected into p53-/- mammalian cell lines to evaluate the altered functions. The oligomerization state of mtp53 was assessed via glutaraldehyde crosslinking and western blot analyses. Western blot and qPCR analyses were used to test how OD mutations in plasmids expressing either wtp53 or R273H mtp53 regulated the targets p21, CDC7 and RRM2. We used chromatin fractionation and western blot analyses to compare the chromatin association of the R273H mtp53 (with variable OD mutants), PARP1, and MCM2 to assess how destabilizing tetramer formation influenced chromatin interactions. Compared to the tetrameric versions of wildtype (wt) and mutant (mt) p53, the wtp53-A347D and R273H-A347D were predominantly dimers, while wtp53-R337C, wtp53-L344P, mtp53 R273H-R337C, and mtp53R273H-L344P were predominantly monomers. When wtp53 tetramerization was blocked so was its ability to activate the cyclin-dependent kinase p21/waf. Interestingly, all oligomerization forms of mtp53 localized to the chromatin suggesting GOF does not require tetramer formation for all functions. Strikingly, all oligomerization mutants of R273H mtp53, compared to the tetrameric mtp53, had a stronger interaction with MCM2. When we examined the mtp53 GOF transcriptional target we found that only tetrameric mtp53 R273H activated the target gene RRM2. Our findings suggest that destabilizing tetramer formation reduced certain mtp53 R273H GOF oncogenic activities while activating others. These changes of functions require examination in the context of triple-negative breast cancers.
Citation Format: George Kwakye Annor. Tetrameric and monomeric gain-of-function mutant p53 interacts with chromatin [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 P5-09-02.
Abstract PD9-11: Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses’ health study
Authors: Stover Daniel G. , Damicis Adrienne , Heng Yujing J. , Collier Katharine A. , Adams Elizabeth J. , Kensler Kevin H. , Baker Gabrielle M. , Wesolowski Robert , Sardesai Sagar , Gatti-Mays Margaret , Ramaswamy Bhuvaneswari , Eliassen A. Heather , Hankinson Susan E. , Tabung Fred K. , Tamimi Rulla M. , Asad Sarah 
Published: March 2022

Abstract
Purpose: Immune infiltration is associated with better treatment response and outcomes in breast cancer, yet data regarding the role of modifiable patient factors in immune infiltration are limited. Patients and Methods: This population-based, prospective observational study evaluated 882 Nurses’ Health Study (NHS) and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor immunohistochemistry (IHC) for four canonical immune cell markers: CD8, CD4, CD20, CD163. In this training cohort, 105 published immune cell-specific gene expression signatures were calculated, then lasso regression was used to derive four immune cell-specific scores based on association with IHC. In the remaining 620 patient testing cohort, we evaluated association of each immune-cell specific score as outcomes, with body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score as predictors, using multivariable-adjusted linear regression. Results: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC (Spearman’s rho range 0.42-0.54; all p&lt;0.001). BMI change since age 18 was positively associated with CD4+ (β=0.16; SE=0.06; p=0.009), and CD163+ scores (β=0.14; SE=0.07; p=0.04) in multivariable analyses. Neither physical activity nor EDIP were significantly associated with any immune cell-specific expression score in multivariable analyses. Conclusions: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.
Citation Format: Daniel G. Stover, Adrienne Damicis, Yujing J. Heng, Katharine A. Collier, Elizabeth J. Adams, Kevin H. Kensler, Gabrielle M. Baker, Robert Wesolowski, Sagar Sardesai, Margaret Gatti-Mays, Bhuvaneswari Ramaswamy, A. Heather Eliassen, Susan E. Hankinson, Fred K. Tabung, Rulla M. Tamimi, Sarah Asad. Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses’ health study [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 PD9-11.
Abstract TF1-2: ER+ word salad decoded: SERD, SERM, SERCA, CERAN, PROTAC
Authors: Jhaveri K 
Published: March 2022

Abstract
Estrogen receptor (ER) plays an important role in gene transcription and the proliferation of ER positive (ER+) breast cancers. Selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and fulvestrant, a selective estrogen receptor degrader (SERD) are currently approved therapeutic approaches for ER positive breast cancers. While these treatment strategies are highly effective, de novo and secondary resistance remains a challenge. Despite resistance mechanisms including due to mutations in the ligand binding domain of the ERα gene (ESR1 mutations), ER+ breast cancers continue to rely on receptor activity for growth signaling, underscoring the need for more effective treatments. To overcome the limitations of the existing endocrine therapies, there has been a quest to develop more potent and selective ER antagonists by altering aspects of drug binding or induction of proteolytic degradation of the receptor through different mechanisms. These orally bioavailable agents offer the potential for low toxicity and improved activity and are in various phases of clinical development either as monotherapy or in combination with targeted therapies.
Citation Format: K Jhaveri. ER+ word salad decoded: SERD, SERM, SERCA, CERAN, PROTAC [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 TF1-2.
Abstract TF2-2: Heterogeneity in treatment outcomes for HER2+ breast cancer - Clinical management strategies
Authors: Tolaney S 
Published: March 2022

Abstract
HER2-positive breast cancers are complex tumors that are clinically and biologically heterogeneous. Even within HER2+ breast cancer, there are different molecular subtypes, mutational profiles, levels of HER2 protein, and immune infiltration. Additionally, HER2 may not be expressed homogeneously among all the cancer cells in the same tumor, some tumors may have low HER2 expression, while other tumors evolve during treatment. These molecular differences help explain why patients do not benefit to the same extent to HER2-directed therapies. We will review data regarding outcomes for tumors with known tumor heterogeneity, hormone receptor positivity, HER2-low positivity, and cases where brain metastases may be present. We will discuss optimal clinical management in the modern era with multiple HER2-directed therapies, including next-generation antibody-drug conjugates. Future strategies to tailor therapy to the individual patient will need to not just factor in anatomic tumor burden, but also key molecular features.
Citation Format: S Tolaney. Heterogeneity in treatment outcomes for HER2+ breast cancer - Clinical management strategies [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 TF2-2.
Abstract TF2-3: Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted?
Authors: Prat A 
Published: March 2022

Abstract
HER2+ breast cancer is clinically and biologically heterogenous. In the last 10 years, translational research in this disease has deciphered many biological features, which are associated with clinical outcomes both in early and metastatic disease. Among them, RNA-based gene expression has identified 4 main molecular subtypes (HER2-enriched, Basal-like, Luminal A and Luminal B), and HER2-enriched tumors within HER2+ breast cancer show high HER2 activation and response to anti-HER2 therapy. At the same time, ERBB2 mRNA levels by itself have also been linked to a higher response to anti-HER2 therapy, including T-DM1. Whether these 2 biological features will predict response to novel anti-HER2 therapies such as DS8201a is currently unknown. One important aspect is that levels of the target (i.e., HER2/ERBB2) and the activation of the downstream signaling pathway (i.e., HER2-enriched) are related but different at the same time. In other words, higher levels of ERBB2 mRNA are associated with a HER2-enriched phenotype; however, a substantial proportion of HER2+ tumors with low levels of ERBB2 are also HER2-enriched. Thus, they should not be considered the same, and this could have clinical implications. Similarly, hormone receptor negative HER2+ breast cancer has higher levels of ERBB2 and higher proportion of HER2-enriched disease than hormone receptor-positive. The high sensitivity of hormone receptor-negative and HER2-enriched disease to anti-HER2 therapy has been demonstrated in the neoadjuvant setting as well as studies looking at on-treatment biology after short-course of anti-HER2 treatment. Indeed, in advanced HER2+ breast cancer, the major gains in overall survival with new anti-HER2-based therapies are seen in hormone receptor-negative disease. Finally, tumor microenvironment plays a critical role. Indeed, tumor-infiltrating lymphocytes and immune gene expression signatures are associated with treatment response and better survival outcome. Whether this immune-related variables predict response to antiPD1/PDL1 is currently unknown, although translational studies do suggest that there might be a link. To conclude, the biological heterogeneity that exists within HER2+ disease is now well-known, and these variables, together with clinical-pathological features, should allow the design of new biomarkers to help answer critical clinical questions.
Citation Format: A Prat. Molecular heterogeneity in HER2+ breast cancer - can outcomes be predicted? [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 TF2-3.
Adjuvant PD-1 Blockade in Resected Melanoma: Is Preventing Recurrence Enough?
Authors: Smithy James W. , Shoushtari Alexander N. 
Published: March 2022

Summary:
Grossmann and colleagues report the results of a large randomized trial demonstrating improved recurrence-free survival with adjuvant pembrolizumab in resected melanoma compared with adjuvant ipilimumab or IFNα2b. However, it remains unclear whether adjuvant immunotherapies extend overall survival as outcomes for patients with advanced melanoma continue to improve.
See related article by Grossmann et al., p. 644 (1).
SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells
Authors: Han Yuling , Zhu Jiajun , Yang Liuliu , Nilsson-Payant Benjamin E. , Hurtado Romulo , Lacko Lauretta A. , Sun Xiaolu , Gade Aravind R. , Higgins Christina A. , Sisso Whitney J. , Dong Xue , Wang Maple , Chen Zhengming , Ho David D. , Pitt Geoffrey S. , Schwartz Robert E. , tenOever Benjamin R. , Evans Todd , Chen Shuibing 
Published: March 2022

Background:
Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.

Methods:

We used both a hamster model and human ESC (hESC)–derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in
SHOX2:GFP;MYH6:mCherry
hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN–like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2–induced ferroptosis.

Results:
Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis.

Conclusions:
Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.
Prognostic Significance of Ventricular Arrhythmias in 13 444 Patients With Acute Coronary Syndrome: A Retrospective Cohort Study Based on Routine Clinical Data (NIHR Health Informatics Collaborative VA‐ACS Study)
Authors: Sau Arunashis , Kaura Amit , Ahmed Amar , Patel Kiran H. K. , Li Xinyang , Mulla Abdulrahim , Glampson Benjamin , Panoulas Vasileios , Davies Jim , Woods Kerrie , Gautama Sanjay , Shah Anoop D. , Elliott Paul , Hemingway Harry , Williams Bryan , Asselbergs Folkert W. , Melikian Narbeh , Peters Nicholas S. , Shah Ajay M. , Perera Divaka , Kharbanda Rajesh , Patel Riyaz S. , Channon Keith M. , Mayet Jamil , Ng Fu Siong 
Published: March 2022

Background
A minority of acute coronary syndrome (ACS) cases are associated with ventricular arrhythmias (VA) and/or cardiac arrest (CA). We investigated the effect of VA/CA at the time of ACS on long‐term outcomes.

Methods and Results
We analyzed routine clinical data from 5 National Health Service trusts in the United Kingdom, collected between 2010 and 2017 by the National Institute for Health Research Health Informatics Collaborative. A total of 13 444 patients with ACS, 376 (2.8%) of whom had concurrent VA, survived to hospital discharge and were followed up for a median of 3.42 years. Patients with VA or CA at index presentation had significantly increased risks of subsequent VA during follow‐up (VA group: adjusted hazard ratio [HR], 4.15 [95% CI, 2.42–7.09]; CA group: adjusted HR, 2.60 [95% CI, 1.23–5.48]). Patients who suffered a CA in the context of ACS and survived to discharge also had a 36% increase in long‐term mortality (adjusted HR, 1.36 [95% CI, 1.04–1.78]), although the concurrent diagnosis of VA alone during ACS did not affect all‐cause mortality (adjusted HR, 1.03 [95% CI, 0.80–1.33]).

Conclusions
Patients who develop VA or CA during ACS who survive to discharge have increased risks of subsequent VA, whereas those who have CA during ACS also have an increase in long‐term mortality. These individuals may represent a subgroup at greater risk of subsequent arrhythmic events as a result of intrinsically lower thresholds for developing VA.
Balancing State and Local Power over School Districts’ Finances
Authors: Bowman Kristine L. , Zuschlag Dirk F. 
Published: March 2022

Abstract
During and for many years after the 2008–10 Great Recession, financial crises in districts across the country triggered varying state involvement in those districts’ finances and governance, up to and including complete takeover. While these actions were most prominent in a handful of states, all states have laws that enable them to intervene in school districts’ finances. These laws shape important governance relationships as well as the allocation of educational resources, yet we know very little about them. Accordingly, this policy brief reports our identification of 449 state statutory provisions across the country, which together contain 1049 potential interventions; our analysis of those provisions included identifying patterns, trends, and potential interactions with other areas of education policy. At a national level and disaggregated by state, we present what potential state interventions into school district finances already exist, which is a necessary foundation to understand which interventions a district could be subject to in the near future, and how states can both contextualize their policy approaches and best address districts’ financial conduct and fiscal challenges going forward.