bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultramafic mantle xenoliths in the Late Cenozoic volcanic rocks of the Antarctic Peninsula and Jones Mountains, West Antarctica
Authors: Leat Philip T. , Ross Aidan J. , Gibson Sally A.
Published: February 2021

Abundant mantle-derived ultramafic xenoliths occur in Cenozoic (7.7–1.5 Ma) mafic alkaline volcanic rocks along the former active margin of West Antarctica, that extends from the northern Antarctic Peninsula to Jones Mountains. The xenoliths are restricted to post-subduction volcanic rocks that were emplaced in fore-arc or back-arc positions relative to the Mesozoic–Cenozoic Antarctic Peninsula volcanic arc. The xenoliths are spinel-bearing, include harzburgites, lherzolites, wehrlites and pyroxenites, and provide the only direct evidence of the composition of the lithospheric mantle underlying most of the margin. The harzburgites may be residues of melt extraction from the upper mantle (in a mid-ocean ridge type setting), that accreted to form oceanic lithosphere, which was then subsequently tectonically emplaced along the active Gondwana margin. An exposed highly depleted dunite–serpentinite upper mantle complex on Gibbs Island, South Shetland Islands, supports this interpretation. In contrast, pyroxenites, wehrlites and lherzolites reflect percolation of mafic alkaline melts through the lithospheric mantle. Volatile and incompatible trace element compositions imply that these interacting melts were related to the post-subduction magmatism which hosts the xenoliths. The scattered distribution of such magmatism and the history of accretion suggest that the dominant composition of sub-Antarctic Peninsula lithospheric mantle is likely to be harzburgitic.
High NOV/CCN3 expression during high-fat diet pregnancy in mice affects GLUT3 expression and the mTOR pathway
Authors: Wang Hefei , Huang Binbin , Hou Anli , Xue Li , Wang Baobei , Chen Jie , Li Mengxia , Zhang Jian V.
Published: February 2021

NOV/CCN3 regulates glucose homeostasis in mice during pregnancy. NOV/CCN3 upregulates GLUT3 expression and affects the mTOR pathway in the GDM environment in vivo and in vitro.
Pancreatic β-cell heterogeneity in health and diabetes: classes, sources, and subtypes
Authors: Miranda Mario A. , Macias-Velasco Juan F. , Lawson Heather A.
Published: February 2021

Pancreatic β-cells perform glucose-stimulated insulin secretion, a process at the center of type 2 diabetes etiology. Efforts to understand how β-cells behave in healthy and stressful conditions have revealed a wide degree of morphological, functional, and transcriptional heterogeneity. Sources of heterogeneity include β-cell topography, developmental origin, maturation state, and stress response. Advances in sequencing and imaging technologies have led to the identification of β-cell subtypes, which play distinct roles in the islet niche. This review examines β-cell heterogeneity from morphological, functional, and transcriptional perspectives, and considers the relevance of topography, maturation, development, and stress response. It also discusses how these factors have been used to identify β-cell subtypes, and how heterogeneity is impacted by diabetes. We examine open questions in the field and discuss recent technological innovations that could advance understanding of β-cell heterogeneity in health and disease.
Dietary salt modifies the blood pressure response to renin-angiotensin inhibition in experimental chronic kidney disease
Authors: Bovée Dominique M. , Uijl Estrellita , Severs David , Rubio-Beltrán Eloisa , van Veghel Richard , Maassen van den Brink Antoinette , Joles Jaap A. , Zietse Robert , Cuevas Catherina A. , Danser A. H. Jan , Hoorn Ewout J.
Published: February 2021

Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.
Complexity Analysis of a Modified Predator-Prey System with Beddington–DeAngelis Functional Response and Allee-Like Effect on Predator
Authors: Wang Shuangte , Yu Hengguo
Published: February 2021

In this paper, complex dynamical behaviors of a predator-prey system with the Beddington–DeAngelis functional response and the Allee-like effect on predator were studied by qualitative analysis and numerical simulations. Theoretical derivations have given some sufficient and threshold conditions to guarantee the occurrence of transcritical, saddle-node, pitchfork, and nondegenerate Hopf bifurcations. Computer simulations have verified the feasibility and effectiveness of the theoretical results. In short, we hope that these works could provide a theoretical basis for future research of complexity in more predator-prey ecosystems.
A Novel Face Super-Resolution Method Based on Parallel Imaging and OpenVINO
Authors: Huang Zhijie , Zheng Wenbo , Yan Lan , Gou Chao
Published: February 2021

Face image super-resolution refers to recovering a high-resolution face image from a low-resolution one. In recent years, due to the breakthrough progress of deep representation learning for super-resolution, the study of face super-resolution has become one of the hot topics in the field of super-resolution. However, the performance of these deep learning-based approaches highly relies on the scale of training samples and is limited in efficiency in real-time applications. To address these issues, in this work, we introduce a novel method based on the parallel imaging theory and OpenVINO. In particular, inspired by the methodology of learning-by-synthesis in parallel imaging, we propose to learn from the combination of virtual and real face images. In addition, we introduce a center loss function borrowed from the deep model to enhance the robustness of our model and propose to apply OpenVINO to speed up the inference. To the best of our knowledge, it is the first time to tackle the problem of face super-resolution based on parallel imaging methodology and OpenVINO. Extensive experimental results and comparisons on the publicly available LFW, WebCaricature, and FERET datasets demonstrate the effectiveness and efficiency of the proposed method.
JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
Authors: Paschalis Alec , Welti Jonathan , Neeb Antje J. , Yuan Wei , Figueiredo Ines , Pereira Rita , Ferreira Ana , Riisnaes Ruth , Rodrigues Daniel Nava , Jiménez-Vacas Juan M. , Kim Soojin , Uo Takuma , Micco Patrizio Di , Tumber Anthony , Islam Md. Saiful , Moesser Marc A. , Abboud Martine , Kawamura Akane , Gurel Bora , Christova Rossitza , Gil Veronica S. , Buroni Lorenzo , Crespo Mateus , Miranda Susana , Lambros Maryou B. , Carreira Suzanne , Tunariu Nina , Alimonti Andrea , Al-Lazikani Bissan , Schofield Christopher J. , Plymate Stephen R. , Sharp Adam , de Bono Johann S.
Published: February 2021

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease.

Significance:

This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.
MEK Inhibition Remodels the Immune Landscape of Mutant KRAS Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors
Authors: Yang Bin , Li Xi , Fu Yu , Guo Ensong , Ye Youqiong , Li Fuxia , Liu Si , Xiao Rourou , Liu Chen , Lu Funian , Huang Jia , Qin Tianyu , Han Leng , Peng Guang , Mills Gordon B. , Sun Chaoyang , Chen Gang
Published: February 2021

Mutant KRAS tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that KRAS mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti–PD-L1 antibodies. In mutant KRAS tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8+ T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti–PD-L1 resulted in marked tumor inhibition in immunocompetent mutant KRAS tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti–PD-L1 combination in clinical trials of mutant KRAS tumors.

Significance:

This study provides key insights into the potential for using MEKi combined with PARPi and anti–PD-L1 for the treatment of all mutant KRAS tumors.
Time-Dependent Effects of Oral Contraceptive Use on Breast, Ovarian, and Endometrial Cancers
Authors: Karlsson Torgny , Johansson Therese , Höglund Julia , Ek Weronica E. , Johansson Åsa
Published: February 2021

Oral contraceptive use has been suggested to influence the risk of breast, ovarian, and endometrial cancer. The purpose of this study is to clarify the time-dependent effects between long-term oral contraceptive use and cancer risk. We performed an observational study in 256,661 women from UK Biobank, born between 1939 and 1970. Information on cancer diagnoses were collected from self-reported data and from national registers until March 2019. Cumulative risk of cancer over the timespan of the study, as measured by the OR, and instantaneous risk, as measured by the HR, were assessed using Logistic and Cox regression analyses, respectively. The odds were lower among ever users, compared with never users, for ovarian cancer [OR = 0.72; 95% confidence interval (CI), 0.65–0.81] and endometrial cancer (OR = 0.68; 95% CI, 0.62–0.75), an association that was stronger with longer use (P < 0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age (OR = 1.10; 95% CI, 1.03–1.17), but not for the full timespan. We only found a higher HR for breast cancer in former users immediately (≤2 years) after discontinued oral contraceptive use (HR = 1.55; 95% CI, 1.06–2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives. Given the body of evidence presented in our study, we argue that oral contraceptives can dramatically reduce women's risk of ovarian and endometrial cancer, whereas their effect on lifetime risk of breast cancer is limited.

Significance:

These results enable women and physicians to make more informed decisions considering oral contraceptive use, thus constituting an important step toward personalized medicine.
Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes
Authors: Lee Minjung , Li Jianfang , Li Jia , Fang Shaohai , Zhang Joanna , Vo Anh Tran Tram , Han Wei , Zeng Hongxiang , Isgandarova Sevinj , Martinez-Moczygemba Margarita , Zhou Yubin , Sun Deqiang , Huang Yun
Published: February 2021

Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth.

Significance:

This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.
Spatiotemporal Heterogeneity across Metastases and Organ-Specific Response Informs Drug Efficacy and Patient Survival in Colorectal Cancer
Authors: Zhou Jiawei , Li Quefeng , Cao Yanguang
Published: February 2021

The sum of target lesions is routinely used to evaluate patient objective responses to treatment in the RECIST criteria, but it fails to address response heterogeneity across metastases. This study argues that spatiotemporal heterogeneity across metastases and organ-specific response is informative for drug efficacy and patient survival. We analyzed the longitudinal data of 11,404 metastatic lesions in 2,802 colorectal cancer patients from five phase III clinical trials. Initially, a metric Gower distance was applied to quantify response heterogeneity across metastases. Next, the spatiotemporal response heterogeneity across anatomic sites, therapies, and KRAS mutation status was assessed and examined for its association with drug efficacy and long-term patient survival. The response of metastatic lesions broadly differed across anatomic sites and therapies. About 60% of patients had at least one lesion respond contrarily from total tumor size. High interlesion heterogeneity was associated with shorter progression-free survival and overall survival. Targeted therapies (bevacizumab or panitumumab) combined with standard chemotherapy reduced interlesion heterogeneity and elicited more favorable effects from liver lesions (P < 0.001) than chemotherapy alone. Moreover, the favorable responses in liver metastases (> 30% shrinkage) were associated with extended patient overall survival (P < 0.001), in contrast to lesions in the lungs and lymph nodes. Altogether, the spatiotemporal response heterogeneity across metastases informed drug efficacy and patient survival, which could improve the current methods for treatment evaluation and patient prognosis.

Significance:

These findings support the modification of RECIST criteria to include individual lesion response to improve assessments of drug efficacy.
G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma
Authors: Kelly Gregory M. , Al-Ejeh Fares , McCuaig Robert , Casciello Francesco , Ahmad Kamal Nabilah , Ferguson Blake , Pritchard Antonia L. , Ali Sayed , Silva Ines P. , Wilmott James S. , Long Georgina V. , Scolyer Richard A. , Rao Sudha , Hayward Nicholas K. , Gannon Frank , Lee Jason S.
Published: February 2021

Purpose:

G9a histone methyltransferase exerts oncogenic effects in several tumor types and its inhibition promotes anticancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether LC3B, a G9a target gene, can predict treatment response.

Experimental Design:

Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model.

Results:

Patients with melanoma who responded to checkpoint inhibitor blockade were associated with not only a higher level of tumor LC3B but also a higher proportion of cells expressing LC3B. A higher expression of MAP1LC3B or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade, suggesting LC3B as a potential predictive biomarker. We demonstrate that G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death.

Conclusions:

Checkpoint inhibitor blockade response is limited to a subset of the patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.
Abstract PS18-16: The complete estrogen receptor antagonist OP-1250 shrinks tumors in xenograft models and has favorable preclinical pharmacokinetic attributes
Authors: Hodges-Gallagher Leslie , Sun Richard , Myles David C , Klein Pamela M , Zujewski Jo Anne , Harmon Cyrus L , Kushner Peter J
Published: February 2021

Antiestrogens are widely used to treat ER+, HER2- breast cancer however these may produce estrogen-like agonist effects in a cell and gene-specific manner. Furthermore, this partial agonism has been implicated in the development of tumor resistance. In contrast, a complete ER antagonist lacks agonist activity in all tissues. Given the high risk of recurrence in ER+ patients treated with endocrine therapies, we hypothesize that drugs that completely antagonize ER-mediated signaling will have a clinical advantage in treating resistant tumors, particularly in tumors for which the ER has acquired mutations conferring estrogen-independent growth.

We previously identified OP-1250 in our laboratory as a complete antagonist and degrader of wild type and mutant ERalpha in breast and uterus cells. Here we explore the pharmacokinetic properties of orally administered OP-1250 and its ability to shrink breast tumors from xenograft models expressing both wild type and mutant estrogen receptors. Orally administered OP-1250 produced high and stable levels in multiple species, suggesting that once daily dosing may be sufficient to produce excellent drug exposure in patients. OP-1250 shrank ER+ tumors in multiple patient-derived tumor xenografts in mice at daily doses of 3 mg/kg, including in tumors expressing the Y537S allele of ERalpha that confers estrogen-independent growth and tumor resistance. Furthermore, OP-1250 accumulated within tumor specimens, indicating excellent target penetration was achieved with low daily doses.

These preclinical studies indicate that OP-1250 has the potential to be a best-in-class antiestrogen due to its ability to complete antagonize ER, potent efficacy in shrinking tumors, and robust drug exposure. A Phase 1/2 dose escalation and expansion study in patients with ER+, HER2- metastatic or advanced BC previously treated with an endocrine therapy will be initiated this year.

Citation Format: Leslie Hodges-Gallagher, Richard Sun, David C Myles, Pamela M Klein, Jo Anne Zujewski, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 shrinks tumors in xenograft models and has favorable preclinical pharmacokinetic attributes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-16.
Abstract PS6-40: Clinical risk criteria and recurrence index for distant recurrence for patients with early stage luminal breast cancer
Authors: Cheng Skye Hung-Chun , Liu Liang-Chih , Tseng Ling-Ming , Chang Chuan-Hsun , Huang Chiun-Sheng , Liang Ji-An , Hsu Yu-Chen , Hsieh Chia-Ming , Wei Jun-Ru
Published: February 2021

Background:Clinical risk criteria (CRC) has been used in two well-known gene-expression trials (TAILORX and MINDACT) to predict the risk of distant recurrence (DR). The definition of clinical low-risk patients was (1) node-negative associated with (grade 1 with tumor ≤3cm, grade 2 with tumor≤2cm, or grade 3 with tumor ≤1cm) and N1 with grade 1 and tumor ≤2cm. Recurrence Index for distant recurrence (RI-DR) is a clinical-genomic model, based on genomic profiling derived from Asian women. The primary purpose of this study is to access the clinical utility of RI-DR and CRC in Asian breast cancer patients.

Methods:A total of 208 patients (N0 70.2%, N1 29.8%) with luminal-like breast cancer were enrolled in a retrospective study across Taiwan medical centers. Kaplan-Meier method was used to calculate the survival rates and the log rank test was applied for the survival difference between two or more independent groups. The primary endpoint was the recurrence-free interval (RFI).

Results:With a median follow-up of 49.05 [IQR 29.72-71.96], the 5-year RFI was significantly poorer in the high-risk group than the low-risk group (87.2% [95% CI, 80.0-95.0] versus 95.2% [89.75-100] by the RI-DR, p = 0.011; and 86.9% [79.8-94.6] versus 97.0% [92.9-100] by the clinical risk, p = 0.03). Combined the CRC and RI-DR together, clinical high (CH) and RI-DR high (RH)had the poorest 5-year RFI (85.2%, [76.6-94.8]); clinical low (CL) and RI-DR low (RL) had the best 5-year RFI (98.0% [94.08, 100]). Among CL-risk patients, RL group has a trend towards less recurrence than RH group (1/66 [1.51%] versus 2/19 [10.52%], p= 0.15). Similar trend was observed in CH-risk patients (RL: 2/41 (4.88%) versus RH: 12/82 [14.63%], p = 0.17) (Table 1).

Conclusions:The present study provides robust evidences that clinical-risk criteria and RI-DR testing could partition patients into good and poor prognosis in early-stage luminal breast cancer. RI-DR has a trend to identify low- and high-risk patients if clinical risk criteria have been applied in clinical practice.

Analyses of Clinical Risk Criteria and Recurrence Index TogetherNo. of PatientsNo. of Events5-year RFI % (95% CI)Log rank, P valueClinical-Clinical-HighRI-DR high821285.20 [76.55, 94.81]0.17RI-DR low41291.30 [80.15, 100]Clinical-LowRI-DR high19294.12 [83.57, 100]0.15RI-DR low66197.96 [94.08, 100]

Citation Format: Skye Hung-Chun Cheng, Liang-Chih Liu, Ling-Ming Tseng, Chuan-Hsun Chang, Chiun-Sheng Huang, Ji-An Liang, Yu-Chen Hsu, Chia-Ming Hsieh, Jun-Ru Wei. Clinical risk criteria and recurrence index for distant recurrence for patients with early stage luminal breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-40.
Abstract PS6-49: Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden
Authors: Katsuta Eriko , Yan Li , Opyrchal Mateusz , Kalinski Pawel , Takabe Kazuaki
Published: February 2021

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. While high tumor mutation burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. Triple-negative breast cancer (TNBC) has a higher TMB and accumulates more CTLs compared to other breast cancer subtypes. CTLs are identified by CD8 surface marker, which is encoded by CD8A gene. Granzyme B (GZMB) is a serine protease that is secreted by activated CTLs to induce apoptosis of the target cells. Chemokines, such as CXCL10 and CCL5 are key to the selective attraction of activated CTLs into tumors, as shown in multiple cancers. However, it remains unknown whether tumor infiltrating functional CTLs levels correlate with improved patient survival and are independent of TMB. In order to investigate it, we developed Functional Hotness Score (FHS) combining gene expressions of markers and attractants of activated CTL. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on gene expression levels of CTL and chemokine markers in bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: CD8, GZMB and CXCL10 combination resulted in the best prediction of the breas cancer patient prognosis. Thus, we established FHS based on the expression levels of these three genes. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the metastatic breast cancers. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival in hormone receptor (HR)-negative, especially TNBC, but not in HR-positive breast cancer. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time. Conclusions: TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robust when combined with TMB in TNBCs.

Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-49.
Abstract PS8-38: Development of random forest classifier method to predict breast cancer mortality among early stage breast cancer patients
Authors: Chandler Arwen
Published: February 2021

Background: Among women diagnosed with early stage breast cancer, breast cancer mortality was conditional on the onset of distant recurrence. Gene expression profiling (GEP) tests (e.g., Oncotype Dx) have been commonly used to determine the risk level of distant recurrence, but its predictive ability is often questioned. The objective of this study aims to explore the potential of random forest machine learning to predict the risk of breast cancer mortality.Method: 63,104 patients with node-negative early stage breast cancer in the SEER-GHI dataset were randomly sampled into two groups, for the purpose of training and testing the model where each group consisted of 67% and 33% of all patients, respectively. The patient characteristics and tumor features in the study included age, tumor size, grade, chemotherapy use, Oncotype DX test recurrence score, and more. Further feature selection in the construction of the predictive model was conducted via the Boruta algorithm. As the dataset is highly imbalanced with only a very small percentage of samples being fatal, Synthetic Minority Over-Sampling Technique (SMOTE) was employed to address this issue. A cross-validated grid search finds the best combination of hyper-parameters to improve the model’s performance.Results: The mean and standard deviation of follow-up duration in the cohort of patients were 32.4 and 14.3 months, respectively. Of 37,043 patients, there were 158 breast cancer deaths. Within up to a 59-month follow-up period, the breast cancer specific mortality rate was 0.43%. Based on the limited available data, the outcome of the random forest classifier method in predicting breast cancer mortality shows sensitivity 0.712, specificity 0.773, overall accuracy 0.773, and AUC (area under ROC curve) 0.742.

Conclusion: The use of the random forest ML algorithm to predict breast cancer mortality is promising when the hyper-parameters are fine-tuned. However, the model's positive predictive value is highly associated with sufficient data sources.

Citation Format: Arwen Chandler. Development of random forest classifier method to predict breast cancer mortality among early stage breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-38.
A Selectable Biomarker in Hair Follicle Cycles – Cathepsins: A Preliminary Study in Murine
Authors: Bai Jingzhu , Gong Zijian , Xu Qingfang , Chen Haiyan , Chen Qiaoping , Fang Ruihua , Zheng Yue , Lai Wei
Published: February 2021

Background/Objective: Hair cycle is regulated by many biological factors. Cathepsins are involved in various physiological processes in human skin. Here, we investigated the cathepsin expression and distribution changes in follicular growth cycles for better understanding the hair cycles and to explore new intervention measures. Methods: The 24 mice (C57BL/6, female, 7-week old) were selected and removed the back hair via rosin/paraffin method. At Day 8, Day 20, and Day 25, biopsy on post-plucking area was done. Immunohistochemical staining, Western blot, and Q-PCR were used to test the cathepsin B/D/L/E. Results: In anagen, cathepsins (B, D, L, and E) were distributed in the hair follicle matrix, inner hair root sheath, and hair. In catagen, cathepsins were mainly observed in un-apoptosis inner root sheath and outer root sheath. Expression of cathepsins B-mRNA and L-mRNA was decreased from anagen and catagen to telogen. Cathepsin D-mRNA was increased in catagen and then decreased in telogen. Cathepsin E-mRNA was decreased in catagen and slightly increased in telogen. Conclusions: The distribution and expression of cathepsins B, D, L, and E in hair follicle changed with hair growth process which indicated that cathepsins might act as selectable biomarkers of hair cycle in different stages.
Epicardial Surface Area of Infarction
Authors: Smulders Martijn W. , Van Assche Lowie M.R. , Bekkers Sebastiaan C.A.M. , Nijveldt Robin , Beijnink Casper W.H. , Kim Han W. , Hayes Brenda , Parker Michele A. , Kaolawanich Yodying , Judd Robert M. , Kim Raymond J.
Published: February 2021

Background:

Microvascular obstruction (MO) is a pathophysiologic complication of acute myocardial infarction that portends poor prognosis; however, it is transient and disappears with infarct healing. Much remains unknown regarding its pathophysiology and whether there are predictors of MO that could function as stable surrogates. We tested for clinical and cardiovascular magnetic resonance predictors of MO to gain insight into its pathophysiology and to find a stable surrogate.

Methods:

Three hundred two consecutive patients from 2 centers underwent cardiovascular magnetic resonance within 2 weeks of first acute myocardial infarction. Three measures of infarct morphology: infarct size, transmurality, and a new index—the epicardial surface area (EpiSA) of full-thickness infarction—were quantified on delayed-enhancement cardiovascular magnetic resonance.

Results:

Considering all clinical characteristics, only measures of infarct morphology were independent predictors of MO. EpiSA was the strongest predictor of MO and provided incremental predictive value beyond that of infarct size and transmurality (
P
<0.0001). In patients with 3-month follow-up cardiovascular magnetic resonance (n=81), EpiSA extent remained stable while MO disappeared, and EpiSA was a predictor of adverse ventricular remodeling. After 20 months of follow-up, 11 died and 1 had heart transplantation. Patients with an EpiSA larger than the median value (≥6%) had worse outcome than those with less than the median value (adverse events: 6.4% versus 1.9%,
P
=0.045).

Conclusions:

The EpiSA of infarction is a novel index of infarct morphology which accurately predicts MO during the first 2 weeks of MI, but unlike MO, does not disappear with infarct healing. This index has potential as a stable surrogate of the presence of acute MO and may be useful as a predictor of adverse remodeling and outcome which is less dependent on the time window of patient assessment.
Sex-Related Differences in Cardiac Channelopathies
Authors: Asatryan Babken , Yee Lauren , Ben-Haim Yael , Dobner Stephan , Servatius Helge , Roten Laurent , Tanner Hildegard , Crotti Lia , Skinner Jonathan R. , Remme Carol Ann , Chevalier Philippe , Medeiros-Domingo Argelia , Behr Elijah R. , Reichlin Tobias , Odening Katja E. , Krahn Andrew D.
Published: February 2021

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.
Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing
Authors: Tijsen Anke J. , Cócera Ortega Lucía , Reckman Yolan J. , Zhang Xiaolei , van der Made Ingeborg , Aufiero Simona , Li Jiuru , Kamps Selina C. , van den Bout Anouk , Devalla Harsha D. , van Spaendonck-Zwarts Karin Y. , Engelhardt Stefan , Gepstein Lior , Ware James S. , Pinto Yigal M.
Published: February 2021

Background:

TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the
TTN
transcript are the most frequent cause of hereditary heart failure. We showed before that
TTN
produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20.

Methods:

We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes.

Results:

Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as
MEF2A
and
CASQ2
. Strikingly, loss of cTTN1 also caused abnormal splicing of
TTN
itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20.

Conclusions:

We demonstrate that circRNAs formed from the
TTN
transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the
TTN
transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
Cardiac Remodeling During Pregnancy With Metabolic Syndrome
Authors: Yang Yijun , Kurian Justin , Schena Giana , Johnson Jaslyn , Kubo Hajime , Travers Joshua G. , Kang Chunya , Lucchese Anna Maria , Eaton Deborah M. , Lv Maoting , Li Na , Leynes Lorianna G. , Yu Daohai , Yang Fengzhen , McKinsey Timothy A. , Kishore Raj , Khan Mohsin , Mohsin Sadia , Houser Steven R.
Published: February 2021

Background:

The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders.

Methods:

The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet–feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)–induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat).

Results:

Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery.

Conclusions:

These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.
Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids
Authors: Luther James M. , Wei Dawei S. , Ghoshal Kakali , Peng Dungeng , Adler Gail K. , Turcu Adina F. , Nian Hui , Yu Chang , Solorzano Carmen C. , Pozzi Ambra , Brown Nancy J.
Published: February 2021

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism (
P
=0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=−0.52,
P
=0.026), 14,15-EET (
ρ
=−0.56,
P
=0.015), and 11,12-EET (
ρ
=−0.48,
P
=0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase (
Ephx2
) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.
Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes
Authors: Wright Clinton B. , Auchus Alexander P. , Lerner Alan , Ambrosius Walter T. , Ay Hakan , Bates Jeffrey T. , Chen Jing , Meschia James F. , Pancholi Suchita , Papademetriou Vasilios , Rastogi Anjay , Sweeney Mary , Willard James J. , Yee Jerry , Oparil Suzanne ,   for the SPRINT Research Group
Published: February 2021

In the SPRINT (Systolic Blood Pressure Intervention Trial), the number of strokes did not differ significantly by treatment group. However, stroke subtypes have heterogeneous causes that could respond differently to intensive blood pressure control. SPRINT participants (N=9361) were randomized to target systolic blood pressures of <120 mm Hg (intensive treatment) compared with <140 mm Hg (standard treatment). We compared incident hemorrhage, cardiac embolism, large- and small-vessel infarctions across treatment arms. Participants randomized to the intensive arm had mean systolic blood pressures of 121.4 mm Hg in the intensive arm (N=4678) and 136.2 mm Hg in the standard arm (N=4683) at one year. Sixty-nine strokes occurred in the intensive arm and 78 in the standard arm when SPRINT was stopped. The breakdown of stroke subtypes across treatment arms included hemorrhagic (intensive treatment, n=6, standard treatment, n=7) and ischemic stroke subtypes (large artery atherosclerosis: intensive treatment n=11, standard treatment, n=13; cardiac embolism: intensive treatment n=11, standard treatment n=15; small artery occlusion: intensive treatment n=8, standard treatment n=8; other ischemic stroke: intensive treatment n=3, standard treatment n=1). Fewer strokes occurred among participants without prior cardiovascular disease in the intensive (n=43) than the standard arm (n=61), but the difference did not reach predefined statistical significance level of 0.05 (
P
=0.09). The interaction between baseline cardiovascular risk factor status and treatment arm on stroke risk did not reach significance (
P
=0.05). Similar numbers of stroke subtypes occurred in the intensive BP control and standard control arms of SPRINT.
Association Between Hospital Resuscitation Champion and Survival for In‐Hospital Cardiac Arrest
Authors: Chan Jesse L. , Lehrich Jessica , Nallamothu Brahmajee K. , Tang Yuanyuan , Kennedy Mary , Trumpower Brad , Chan Paul S. ,   for the American Heart Association's Get With the Guidelines‐Resuscitation Investigators
Published: February 2021

Background

Although many hospitals have resuscitation champions, it is unknown if hospitals with very active physician or nonphysician champions have higher survival rates for in‐hospital cardiac arrest (IHCA).

Methods and Results

We surveyed adult hospitals in Get With The Guidelines‐Resuscitation about resuscitation practices, including about their resuscitation champion. Hospitals were categorized as having a very active physician champion, a very active nonphysician champion, or other (no champion or not very active champion). For each hospital, we calculated risk‐standardized survival rates for IHCA during the period of 2016 to 2018 and categorized them into quintiles of risk‐standardized survival rates. The association between a hospital's resuscitation champion type and their quintile of survival was evaluated using multivariable hierarchical proportional odds logistic regression. Overall, 192 hospitals (total of 44 477 IHCAs) comprised the study cohort. Risk‐standardized survival rates for IHCA varied widely between hospitals (median: 24.7%; range: 9.2%–37.5%). Very active physician champions were present in 29 (15.1%) hospitals, 64 (33.3%) had very active nonphysician champions, and 99 (51.6%) did not have a very active champion. Compared with sites without a very active resuscitation champion, hospitals with a very active physician champion were 4 times more likely to be in a higher survival quintile, even after adjusting for resuscitation practices across hospital groups (adjusted odds ratio [OR], 3.90; 95% CI, 1.39–10.95). In contrast, there was no difference in survival between sites without very active champions and those with very active non‐physician champions (adjusted OR, 1.28; 95% CI, 0.62–2.65).

Conclusions

The background and engagement level of a resuscitation champion is a critical factor in a hospital's survival outcomes for IHCA.
Meta‐Analysis of Intensive Lipid‐Lowering Therapy in Patients With Polyvascular Disease
Authors: Alkhalil Mohammad , Kuzemczak Michał , Whitehead Nicholas , Kavvouras Charalampos , Džavík Vladimír
Published: February 2021

Background

Polyvascular atherosclerotic disease is associated with an increased risk of future cardiovascular events. Intensive lipid‐lowering therapy (ILT) may mitigate this risk. The aims of this study‐level meta‐analysis were to examine the effects of ILT in patients with polyvascular disease and whether baseline low‐density lipoprotein cholesterol (LDL‐C) may determine the level of benefit.

Methods and Results

Electronic databases were searched through January 2020 to identify randomized controlled trials of treatments targeting upregulation of LDL‐C receptors (ie, statins, ezetimibe, and PCSK9 [proprotein convertase subtilisin–kexin type 9] inhibitors). The primary end point was major adverse vascular events as defined by the included studies. A total of 94 362 patients (14 821 [18.6%] with polyvascular disease) from 7 studies were included. In patients with monovascular disease, ILT was associated with a 13% reduction in the primary end point (rate ratio [RR] 0.87; 95% CI, 0.81–0.93 [
P
=0.0002]) (absolute RR, 1.8%) compared with less ILT, while patients with polyvascular disease had 15% relative RR (0.85; 95% CI, 0.80–0.90 [
P
<0.00001]) (absolute RR, 6.5%) (
P
=0.66 for interaction). When factoring LDL‐C, unlike patients with monovascular disease, the relative benefits of ILT, compared with less ILT, in patients with polyvascular disease were comparable with LDL‐C >100 mg/dL (RR, 0.85; 95% CI, 0.80–0.90 [
P
<0.00001]) and LDL‐C <100 mg/dL (RR, 0.88; 95% CI, 0.81–0.96 [
P
=0.003]) (
P
=0.23 for interaction).

Conclusions

Patients with polyvascular disease experienced comparable benefits to those with monovascular disease in response to ILT. The benefits of ILT in patients with polyvascular disease were not dependent on baseline LDL‐C, challenging the approach of using LDL‐C as a prerequisite to commence ILT for this high‐risk subgroup.