bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for Caribbean plate subduction in southern Costa Rica
Authors: Bourke James R. , Levin Vadim , Arroyo Ivonne G. , Linkimer Lepolt
Published: March 2023

Nestled between the Cocos, Nazca, Caribbean, and South American plates, the Panama microplate represents an area of rapidly evolving tectonics throughout the past ~10 m.y. Past and current studies have observed a notable amount of seismicity throughout this region, in particular the Caribbean coast of Costa Rica, which experienced a Mw 7.7 earthquake in 1991 CE. We investigated the crust and upper mantle structure of this region using the receiver function methodology and report two results: (1) first-order lateral constraints on the position of the Panama microplate boundary near the intersection between the Central Costa Rica Deformed Belt (onshore) and North Panama Deformed Belt (offshore), and (2) an impedance contrast south and east of these belts, supporting that the Caribbean plate currently subducts beneath the Panama microplate. Observed local seismicity is a consequence of the recently (ca. 14 Ma) initiated Caribbean plate subduction beneath the overlying Panama microplate. Our results are also consistent with a doubly convergent subduction margin dominating southern Costa Rica tectonics, uplifting the Talamanca Cordillera, and causing the cessation of southern Costa Rica volcanism over the past ~10 m.y.
Non-integrability of strings in $$AdS_{6}\times S^{2}\times \Sigma $$ background and its 5D holographic duals
Authors: Alencar G. , Tahim M. O.
Published: March 2023

In this manuscript we study Liouvillian non-integrability of strings in $$AdS_{6}\times S^{2}\times \Sigma $$

A
d

S
6

×

S
2

×
Σ

background. We consider soliton strings and look for simple solutions in order to reduce the equations to only one linear second order differential equation called Normal Variation Equation (NVE). We study truncations in $$\eta $$
η
and $$\sigma $$
σ
variables showing their applicability or not to catch (non) integrability of models. With this technique we are able to study many recent cases considered in the literature: the abelian and non-abelian T-duals, the (p, q)-5-brane system, the T$$_{N}$$

N

, $$+_{MN}$$

+

MN

theories and the $${\tilde{T}}_{N,P}$$

T
~

N
,
P

and $$+_{P,N}$$

+

P
,
N

quivers. We show that all of them are not integrable. Finally, we consider the general case at the boundary $$\sigma =\sigma _0$$

σ
=

σ
0

for large $$\sigma _0$$

σ
0

and show that we can get general conclusions about integrability. For example, beyond the above quivers, we show generically that long quivers are not integrable. In order to establish the results, we numerically study the string dynamical system seeking by chaotic behaviour. Such a characteristic gives one more piece of evidence for non-integrability of the background studied.
International Geodiversity Day: from grassroots geoscience campaign to UNESCO recognition
Authors: Zwoliński Zbigniew , Brilha José , Gray Murray , Matthews Jack
Published: March 2023

The paper documents the process of proclaiming International Geodiversity Day as a grassroots initiative of the Earth science community for the benefit of our present civilization and for future generations. The huge support that this initiative has gained among scientists around the world has contributed to the rapid circulation of documents necessary to establish an international day at the UNESCO Forum. The paper presents the timeline of this process of proclaiming International Geodiversity Day, its implications and the course of the first celebrations in 2022.
The Mutare–Fingeren dyke swarm: the enigma of the Kalahari Craton's exit from supercontinent Rodinia
Authors: Gumsley Ashley P. , de Kock Michiel , Ernst Richard , Gumsley Anna , Hanson Richard , Kamo Sandra , Knoper Michael , Lewandowski Marek , Luks Bartłomiej , Mamuse Antony , Söderlund Ulf
Published: March 2023

The Rodinia supercontinent broke apart during the Neoproterozoic. Rodinia break-up is associated with widespread intraplate magmatism on many cratons, including the
c.
720–719 Ma Franklin large igneous province (LIP) of Laurentia. Coeval magmatism has also been identified recently in Siberia and South China. This extensive magmatism terminates ∼1 myr before the onset of the Sturtian Snowball Earth. However, LIP-scale magmatism and global glaciation are probably related. U–Pb isotope dilution–thermal ionization mass spectrometry (ID-TIMS) baddeleyite dating herein identifies remnants of a new
c.
724–712 Ma LIP on the eastern Kalahari Craton in southern Africa and East Antarctica: the combined Mutare–Fingeren Dyke Swarm. This dyke swarm occurs in northeastern Zimbabwe (Mutare Dyke Swarm) and western Dronning Maud Land (Fingeren Dyke Swarm). It has incompatible element-enriched mid-ocean ridge basalt-like geochemistry, suggesting an asthenospheric mantle source for the LIP. The Mutare–Fingeren LIP probably formed during rifting. This rifting would have occurred almost ∼100 myr earlier than previous estimates in eastern Kalahari. The placement of Kalahari against southeastern Laurentia in Rodinia is also questioned. Proposed alternatives, invoking linking terranes between Kalahari and southwestern Laurentia or close to northwestern Laurentia, also present challenges with no discernible resolution. Nevertheless, LIP-scale magmatism being responsible for the Sturtian Snowball Earth significantly increases.
Each at its Own Pace: Third-Party Dependency and Centralization Around the World
Authors: Kumar Rashna , Asif Sana , Lee Elise , Bustamante Fabian E.
Published: March 2023

We describe the results of a large-scale study of third-party dependencies around the world based on regional top-500 popular websites accessed from vantage points in 50 countries, together covering all inhabited continents. This broad perspective shows that dependencies on a third-party DNS, CDN or CA provider vary widely around the world, ranging from 19% to as much as 76% of websites, across all countries. The critical dependencies of websites -- where the site depends on a single third-party provider -- are equally spread ranging from 5% to 60% (CDN in Costa Rica and DNS in China, respectively). Interestingly, despite this high variability, our results suggest a highly concentrated market of third-party providers: three providers across all countries serve an average of 92% and Google, by itself, serves an average of 70% of the surveyed websites. Even more concerning, these differences persist a year later with increasing dependencies, particularly for DNS and CDNs. We briefly explore various factors that may help explain the differences and similarities in degrees of third-party dependency across countries, including economic conditions, Internet development, economic trading partners, categories, home countries, and traffic skewness of the country's top-500 sites.
The SeaLiT Ontology – An Extension of CIDOC-CRM for the Modeling and Integration of Maritime History Information
Authors: Fafalios Pavlos , Kritsotaki Athina , Doerr Martin
Published: March 2023

We describe the construction and use of the SeaLiT Ontology, an extension of the ISO standard CIDOC-CRM for the modelling and integration of maritime history information. The ontology has been developed gradually, following a bottom-up approach that required the analysis of large amounts of real primary data (archival material) as well as knowledge and validation by domain experts (maritime historians). We present the specification of the ontology, RDFS and OWL implementations, as well as knowledge graphs that make use of this data model for integrating information originating from a large and diverse set of archival documents, such as crew lists, sailors registers, naval ship registers, and payrolls. We also describe an application that operates over these knowledge graphs and which supports historians in exploring and quantitatively analysing the integrated data through a user-friendly interface. Finally, we discuss aspects related to the use, evolution, and sustainability of the ontology.
Molecular Detection of Virulence Factors in Salmonella serovars Isolated from Poultry and Human Samples
Authors: Lozano-Villegas Kelly Johanna , Herrera-Sánchez María Paula , Beltrán-Martínez Mónica Alexandra , Cárdenas-Moscoso Stefany , Rondón-Barragán Iang Schroniltgen
Published: March 2023

Salmonellosis is a common infectious disease in humans caused by Salmonella spp., which in recent years has shown an increase in its incidence, with products of avian origin being a common source of transmission. To present a successful infective cycle, there are molecular mechanisms such as virulence factors that provide characteristics that facilitate survival, colonization, and damage to the host. According to this, the study aims to characterize the virulence factors of Salmonella spp. strains isolated from broilers (n = 39) and humans (n = 10). The presence of 24 virulence genes was evaluated using end‐point PCR. All the strains of Salmonella spp. isolated from broiler chickens revealed presence of 7/24 (29, 16%) virulence genes (lpfA, csgA, sitC, sipB, sopB, sopE, and sivH). Regarding the strains isolated from cases of gastroenteritis in humans, all strains contained (14/24, 58, 33%) virulence genes (lpfA, csgA, pagC, msgA, spiA, sitC, iroN, sipB, orgA, hilA, sopB, sifA, avrA, and sivH). In summary, the presence of virulence genes in different strains of Salmonella isolated from broilers and humans could be described as bacteria with potential pathogenicity due to the type and number of virulence genes detected. These findings are beneficial for the pathogenic monitoring of Salmonella in Colombia.
Disparate Intent-to-Treat Outcomes for Pediatric Liver Transplantation Based on Indication
Authors: Lang Anna , Goff Cameron , Montgomery Ashley , Lynn Jake , Kamepalli Spoorthi , Goss John , Rana Abbas
Published: March 2023

Background. The impact of indication for pediatric liver transplantation on waitlist and post-transplant mortality outcomes is well known, but the impact on intent-to-treat outcomes has not been investigated. Intent-to-treat survival analysis is important in this study because it is more comprehensive, combining the transplant outcomes of waitlist mortality, post-transplant mortality, and transplant rate into a single metric to elucidate any disparities in outcomes based on indication. Methods. Cox regression was used to analyze factors impacting survival in 8,002 children listed for liver transplant in the UNOS database between 2006 and 2016. The Kaplan–Meier method and log-rank test were used to assess differences in waitlist, post-transplant, and intent-to-treat mortality among the top 5 indications of biliary atresia, acute hepatic necrosis, metabolic disorders, hepatoblastoma, and autoimmune cirrhosis. Results. When compared to the reference group of biliary atresia, multivariate analyses showed that every indication was associated with inferior intent-to-treat outcomes except for metabolic disorders. Hepatoblastoma (hazard ratio (HR): 3.73), autoimmune cirrhosis (HR: 1.86), and AHN (HR: 1.77) were associated with significantly increased intent-to-treat mortality. Hepatoblastoma was also associated with increased post-transplant mortality (HR: 3.77) and was the only indication significantly associated with increased waitlist mortality (HR: 6.43). Conclusion. Significant disparity exists across all indications with respect to an increased intent-to-treat mortality, along with an increased post-transplant and waitlist mortality, when compared to the biliary atresia reference group. If further studies validate these findings, a reexamination of the equitable distribution of allografts for transplant may be warranted as well as a focus on disparities in survival after transplant.
Surveillance and Phylogenetic Characterisation of Avian Influenza Viruses Isolated from Wild Waterfowl in Zambia in 2015, 2020, and 2021
Authors: Kalonda Annie , Saasa Ngonda , Kajihara Masahiro , Nao Naganori , Moonga Ladislav , Ndebe Joseph , Mori-Kajihara Akina , Mukubesa Andrew Nalishuwa , Samutela Mulemba , Munjita Samuel , Sakoda Yoshihiro , Sawa Hirofumi , Takada Ayato , Simulundu Edgar
Published: March 2023

In recent years, the southern African region has experienced repeated incursions of highly pathogenic avian influenza viruses (HPAIVs), with wild migratory birds being implicated in the spread. To understand the profile of avian influenza viruses (AIVs) circulating in Zambia, we surveyed wild waterfowl for AIVs and phylogenetically characterised the isolates detected in 2015, 2020, and 2021. A total of 2,851 faecal samples of wild waterfowl were collected from Lochinvar National Park in the Southern Province of Zambia. During the study period, 85 (3.0%) low pathogenicity AIVs belonging to various subtypes were isolated, with H2N9, H8N4, and H10N8 being reported for the first time in avian species in Africa. The majority of the isolates were detected from glossy ibis (order Pelecaniformes) making it the first report of AIV from these birds in Zambia. Phylogenetic analysis of all eight gene segments of the 30 full genomes obtained in this study revealed that all the isolates belonged to the Eurasian lineage with their closest relatives being viruses isolated from wild and/or domestic birds in Bangladesh, Belgium, Egypt, Georgia, Mongolia, the Netherlands, and South Africa. Additionally, the Zambian viruses were grouped into distinct clusters based on the year of isolation. While no notifiable AIVs of the H5 or H7 subtypes were detected in wild birds in Zambia, viral internal protein genes of some viruses were closely related to H7 low pathogenicity AIVs. This study shows that periodically, a considerable diversity of AIV subtypes are introduced into the Zambian ecosystem by wild migratory waterfowl. The findings highlight the importance of continuous surveillance and monitoring of AIVs in wild waterfowl, including birds traditionally not considered to be major AIV reservoirs, for a better understanding of the eco-epidemiology and evolutionary dynamics of AIVs in Africa.
Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus
Authors: Han Xinai , Zhang Xiaoming , Song Rui , Li Shiqi , Zou Shujing , Tan Quanguang , Liu Tianyang , Luo Shugeng , Wu Zhe , Jie Hongyu , Wang Jinhong
Published: March 2023

Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.
Experimental Study and Numerical Simulation Analysis on Reinforcement of Mortise-Tenon Joints with Flat Steel Strips
Authors: Gan Shurong , Pan Wen , Su Hexian , Jin Yucheng , Zhu Chuanwei , Yu Shibin
Published: March 2023

To study the aseismic performance after the reinforcement of the mortise-tenon joints of folk houses with traditional Chuan-Dou style wood structure and their steel plate, test specimens of joints—two for Tou mortise-tenon joints, two for Ban mortise-tenon joints, and two for dovetail mortise-tenon joints—were fabricated out of hemlock, and steel plates were utilized to reinforce one of the joint specimens of each type on the middle part of the mortise-tenon joint. By carrying out pseudo-static tests on the joints and building ABAQUS numerical model; the position where the mortise-tenon joints were to be reinforced by the steel plates was optimized for a comparative analysis into the test results on reinforced and unreinforced mortise-tenon joints and the numerically simulated bending moment-turning angle hysteresis curve, skeleton curve, energy-dissipating capacity, and rigidity degeneration curves. The results showed the following: the pulling-out phenomenon of tenons was severe, and the aseismic performance of Tou tenons was superior to Ban tenons and dovetail tenons; reinforcing the middle part of mortise-tenon joints with steel plates could effectively reduce the pulling-out amount of joints and promote the aseismic performance of mortise-tenon joints but have an insignificant promotive effect for the bearing capacity of Tou mortise-tenon joints; the aseismic performance was improved significantly after the flat steel strip reinforced position was moved to the upper and lower ends of mortise-tenon joints, with the ultimate bearing capacities being 1.5∼2.4 times that on the middle part of flat steel strip reinforced joints.
Solid-Liquid Phase Equilibria of the Quaternary System NaCl + NH4Cl + NaHCO3 + NH4HCO3 + H2O at 283.15 and 313.15 K
Authors: Gu Shuangshuang , Li Haoran , Sun Kangrui , Guo Yafei , Deng Tianlong , Meng Lingzong
Published: March 2023

The solid-liquid phase equilibria for the quaternary system (NaCl + NH4Cl + NaHCO3 + NH4HCO3 + H2O) at 283.15 and 313.15 K were studied with the isothermal solution method. There are four crystallization regions corresponding to NaCl, NH4Cl, NaHCO3, and NH4HCO3, five univariant solubility curves, and two invariant points saturated with the three coexisting minerals in the phase diagrams at the two temperatures. A comparison of the phase diagrams at 283.15 and 313.15 K shows that the areas of regions for NaCl, NaHCO3, and NH4Cl increase obviously. In contrast, the area of NH4HCO3 region decreases significantly as the temperature rises. The density and refractive index in the quaternary system change regularly with the concentration changing. The calculated densities and refractive indices in the quaternary system at the two temperatures with the empirical equations agree well with the experimental values.
Electroacupuncture Zusanli (ST36) Relieves Somatic Pain in Colitis Rats by Inhibiting Dorsal Root Ganglion Sympathetic-Sensory Coupling and Neurogenic Inflammation
Authors: Wang Yi-li , Zhu Hai-yan , Lv Xi-qian , Ren Xing-ying , Peng Ying-chun , Qu Jin-yu , Shen Xue-fang , Sun Ran , Xiao Meng-lu , Zhang Hong , Chen Zhao-hui , Cong Peng
Published: March 2023

Referred somatic pain triggered by hyperalgesia is common in patients with inflammatory bowel disease (IBD). It was reported that sprouting of sympathetic nerve fibers into the dorsal root ganglion (DGR) and neurogenic inflammation were related to neuropathic pain, the excitability of neurons, and afferents. The purpose of the study was to explore the potential and mechanism of electroacupuncture (EA) at Zusanli (ST36) for the intervention of colon inflammation and hyperalgesia. Sprague-Dawley (SD) was randomly divided into four groups, including control, model, EA, and sham-EA. Our results showed EA treatment significantly attenuated dextran sulfate sodium- (DSS-) induced colorectal lesions and inflammatory cytokine secretion, such as TNF-α, IL-1β, PGE2, and IL-6. EA also inhibited mechanical and thermal pain hypersensitivities of colitis rats. Importantly, EA effectively abrogated the promotion effect of DSS on ipsilateral lumbar 6 (L6) DRG sympathetic-sensory coupling, manifested as the sprouting of tyrosine hydroxylase- (TH-) positive sympathetic fibers into sensory neurons and colocalization of and calcitonin gene-related peptide (CGRP). Furthermore, EA at Zusanli (ST36) activated neurogenic inflammation, characterized by decreased expression of substance P (SP), hyaluronic acid (HA), bradykinin (BK), and prostacyclin (PGI2) in colitis rat skin tissues corresponding to the L6 DRG. Mechanically, EA treatment reduced the activation of the TRPV1/CGRP, ERK, and TLR4 signaling pathways in L6 DRG of colitis rats. Taken together, we presumed that EA treatment improved colon inflammation and hyperalgesia, potentially by suppressing the sprouting of sympathetic nerve fibers into the L6 DGR and neurogenic inflammation via deactivating the TRPV1/CGRP, ERK, and TLR4 signaling pathways.
Targeting CAFs to Improve Anti-PD-1 Checkpoint Immunotherapy
Authors: Tauriello Daniele V.F.
Published: March 2023

The tumor microenvironment is a complex ecosystem that drives cancer progression and restrains immunity. Although immune checkpoint inhibitors have shown strong potential in a subset of patients, a better understanding of suppressive mechanisms may inspire ways to improve immunotherapeutic efficacy. A new study in this issue of Cancer Research focuses on targeting cancer-associated fibroblasts in preclinical models of gastric tumors. Aiming to rebalance anticancer immunity and enhance treatment responses to checkpoint-blocking antibodies, this work also addresses the potential for multitarget tyrosine kinase inhibitors in treating gastrointestinal cancer.

See related article by Akiyama et al., p. 753
Reversal of Lactate and PD-1–mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer
Authors: Chaudagar Kiranj , Hieromnimon Hanna M. , Khurana Rimpi , Labadie Brian , Hirz Taghreed , Mei Shenglin , Hasan Raisa , Shafran Jordan , Kelley Anne , Apostolov Eva , Al-Eryani Ghamdan , Harvey Kate , Rameshbabu Srikrishnan , Loyd Mayme , Bynoe Kaela , Drovetsky Catherine , Solanki Ani , Markiewicz Erica , Zamora Marta , Fan Xiaobing , Schürer Stephan , Swarbrick Alex , Sykes David B. , Patnaik Akash
Published: March 2023

Purpose:

Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC.

Experimental Design:

Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150–200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti–PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic, and proteomic profiling, or ex vivo co-culture studies. Single-cell RNA sequencing on human mCRPC samples was performed using 10X Genomics platform.

Results:

Coclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1–expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination–induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.

Conclusions:

Immunometabolic strategies that reverse lactate and PD-1–mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.
Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem
Authors: Siddhartha Rohit , Garg Minal
Published: March 2023

Studying the complex mechanisms of tumorigenesis and examining the interactions of neoplastic cells within tumor ecosystem are critical to explore the possibility of effective cancer treatment modalities. Dynamic tumor ecosystem is constantly evolving and is composed of tumor cells, extracellular matrix (ECM), secreted factors, and stromal cancer-associated fibroblasts (CAF), pericytes, endothelial cells (EC), adipocytes, and immune cells. ECM remodeling by synthesis, contraction, and/or proteolytic degradation of ECM components and release of matrix-sequestered growth factors create a microenvironment that promotes EC proliferation, migration, and angiogenesis. Stromal CAFs release multiple angiogenic cues (angiogenic growth factors, cytokines, and proteolytic enzymes) which interact with ECM proteins, thus contribute to enhance proangiogenic/promigratory properties and support aggressive tumor growth.

Targeting angiogenesis brings about vascular changes including reduced adherence junction proteins, basement membrane and pericyte coverage, and increased leakiness. This facilitates ECM remodeling, metastatic colonization and chemoresistance. Owing to significant role of denser and stiffer ECM in inducing chemoresistance, direct or indirect targeting of ECM components is being reported as major axis of anticancer treatment. Exploring the agents targeting angiogenesis and ECM in a context specific manner may lead to reduced tumor burden by promoting conventional therapeutic effectiveness and overcoming the hurdles of therapy resistance.
Abstract ED1-2: How to incorporate PROs into clinical care
Authors: Fayanju Oluwadamilola (Lola)
Published: March 2023

Patient-reported outcomes (PROs) are self-reported assessments of health status that come from the patient’s perspective. Communicated without interpretation by a physician, PROs can enhance shared-decision making. When administered in multi-lingual, level-appropriate, and culturally aware formats, PROs can be used to address the individual and collective health status of potentially vulnerable groups including children, older adults, those with disabilities, and those from racial/ethnic minority backgrounds thereby providing an opportunity not only to address the needs of individuals but also identify potential disparities across groups. In her talk, Dr. Fayanju will provide strategies to facilitate incorporation of PROs into routine patient care and describe the benefits and potential challenges associated with doing so.

Citation Format: Oluwadamilola (Lola) Fayanju. How to incorporate PROs into clinical care [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED1-2.
Abstract ED3-3A: Mechanisms of resistance
Authors: Ellisen Leif
Published: March 2023

Antibody Drug Conjugates (ADCs) are emerging as promising therapeutics for all subtypes of breast cancer. ADCs are composed of a monoclonal antibody directed against a tumor-expressed antibody, conjugated via a variety of linker chemistries to a cytotoxic or other tumor-active payload. Tumor-selective drug delivery via ADCs has the potential to substantially improve the therapeutic window and efficacy for a variety of therapeutic agents. Indeed, recent clinical data have demonstrated significant improvements in overall survival with the use of single-agent ADCs across the spectrum of advanced breast cancer. However, both de novo and acquired resistance to ADCs is common, and may involve a diverse array of potential mechanisms that reflect the complexity of ADC action. These include alteration or downregulation of the ADC target, deregulation of intracellular trafficking or endolysosomal processing of the internalized ADC, and a variety of payload-specific mechanisms of resistance such as induction of drug efflux or activation of cell survival pathways. Which mechanism(s) dominates in a given setting may depend on both ADC-specific and tumor-specific factors. For example, linker design is likely to have a major influence on potential ADC resistance: ADCs with a non-cleavable linker (e.g. trastuzumab emtansine) are dependent upon fusion with acidified lysosomes for degradation and payload release, and attenuated acidification has been demonstrated pre-clinically as a resistance mechanism. In contrast, ADCs with a cleavable peptide linker (e.g. trastuzumab deruxtecan) may not require lysosomal processing for payload release. Furthermore, highly genetically unstable tumors may simultaneously generate multiple types of resistance mechanisms. We recently demonstrated the emergence of distinct acquired resistance mutations to sacituzumab govitecan, involving the ADC antibody target (TROP2) and the payload target (topoisomerase 1), within different metastatic lesions of an individual patient. General strategies to overcome ADC resistance include the sequential use of multiple ADCs, and/or the up-front use of select combination therapies incorporating ADCs. Clearly, the success of these approaches will require a more thorough evaluation and understanding of resistance mechanisms as they occur in patients. Fortunately, the relative success of ADCs for breast cancer treatment to date is spurring the identification of new targets, approaches for linker design, and a wide diversity of payloads that will be instrumental for efforts to overcome resistance.

Citation Format: Leif Ellisen. Mechanisms of resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED3-3A.
Abstract ED6-1: Contralateral mastectomy in patients with germline mutations
Authors: Yao Katharine
Published: March 2023

The educational session titled "Contralateral mastectomy in patients with germline mutations" will cover contralateral mastectomy in affected gene carriers. The session will first cover trends in contralateral mastectomy in germline mutation carriers and the impact of genetic testing on contralateral mastectomy utilization. Second, the session will review guidelines on contralateral mastectomy for gene carriers. Literature on potential beneficial impacts of contralateral mastectomy for gene carriers will be reviewed. Impact to contralateral risk, survival outcomes and patient quality of life will be examined. Lastly, the session will review new surgical approaches for prophylactic mastectomy and protocols to reduce pain and enhance recovery after mastectomy.

Citation Format: Katharine Yao. Contralateral mastectomy in patients with germline mutations [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED6-1.
Abstract ED7-4: Beyond the lab: Clinical implications
Authors: Curtis Christina
Published: March 2023

During this talk, I will review the ever expanding repertoire of single cell and spatially resolved profiling techniques which enable the interrogation breast cancer pathlogy, immuno-biology and treatment response at unprecedented resolution. I will outline considerations for throughput, plex and resolution across different methods before providing several case studies in their application. As one example, I will outline the use of multi-omic single cell profiling and spatial proteomic profiling to characterize changes throughout the course of neoadjuvant Her2-targeted therapy and leading to the identification of candidate predictive biomarkers. I will go on to discuss translational and potential clinical applications of these techniques.

Citation Format: Christina Curtis. Beyond the lab: Clinical implications [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED7-4.
Abstract ED8-1: Overview of the current state of the art – what patients and oncologists need to know
Authors: Jimenez Rachel
Published: March 2023

While radiation therapy plays a significant role in the treatment of breast cancer for many patients, the nuances of modern day radiation therapy are often poorly understood by both patients and referring providers. Radiation therapy techniques to reduce toxicity and improve treatment accuracy have rapidly evolved in the past decade. This session will introduce non-radiation oncologists to recent innovations that allow increased personalization of treatment based on anatomical variations. Methods to improve patient positioning will be discussed. Frequently utilized dosimetric techniques for breast radiotherapy will be described and compared, including Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Radiation Therapy (IMRT), and 3D conformal planning. New methods for patient monitoring during treatment and the purpose of respiratory gating will be reviewed. Finally, the impact of surgical therapies on radiation planning and delivery will also be examined. Attendees should leave the session having a greater understanding of the current available options for radiotherapy and rationale for the choice of treatment technique.

Citation Format: Rachel Jimenez. Overview of the current state of the art – what patients and oncologists need to know [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED8-1.
Abstract GS1-06: Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial
Authors: O’Regan Ruth , Zhang Yi , Fleming Gini F. , Francis Prudence , Kammler Roswitha , Viale Giuseppe , Láng István , Ezquerra Meritxell Bellet , Bonnefoi Hervé R. , Loi Sherene , Colleoni Marco , Schnabel Catherine A. , Treuner Kai , Regan Meredith
Published: March 2023

Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. The benefit from the addition of OFS was most clinically meaningful for patients at higher clinico-pathologic risk of recurrence. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs T alone in the SOFT trial.

Methods: All available FFPE tumor samples from the SOFT trial (n=1718 of 3047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests.

Results: Tumor samples from 1687 (98%) patients (30.4% < 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5%% HER2-, 53.3% received prior chemotherapy) were successful in BCI testing and included in the final analysis. Patient characteristics in the translational cohort are representative of the parent SOFT trial. 42.4% of patients’ tumors had H/I-High status. Prognostic and predictive analyses are ongoing and will be presented at the meeting.

Citation Format: Ruth O’Regan, Yi Zhang, Gini F. Fleming, Prudence Francis, Roswitha Kammler, Giuseppe Viale, István Láng, Meritxell Bellet Ezquerra, Hervé R. Bonnefoi, Sherene Loi, Marco Colleoni, Catherine A. Schnabel, Kai Treuner, Meredith Regan. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-06.
Abstract GS5-12: Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study
Authors: Yadav Budhi Singh , Dahiya Divya , Gupta Manish
Published: March 2023

Background HRBC is a phase III randomized open label study of adjuvant radiotherapy in patients with breast cancer. In this study we compared a 3 weeks radiation schedule with 2 weeks. Materials and methods Patients with breast cancer, stage I-III, post mastectomy or after breast conservative surgery who needed adjuvant locoregional radiotherapy were randomized to 34Gy in 10 fractions over 2 weeks (study arm) or 35Gy in 15 fractions over 3 weeks to the chest wall and 40Gy/15#/3wks to breast and supraclavicular fossa (control arm). Boost dose when indicated was 8Gy/2# in both the arms. Patients were planned on simulator with 2 tangential fields to breast/chest wall and incident supraclavicular fossa field. Acute toxicity was assessed using a RTOG grading system. Assessment was carried out weekly during radiotherapy and at 4 weeks after treatment by the physician. Cosmetic outcome was assessed using Harvard/NSABP/RTOG scale. The toxicity between the two arms was compared using Fisher’s exact test. The trial was approved by institutional ethics committee. This trial is registered with ClinicalTrials.gov, number NCT04075058. Results This study included 1121 patients. Median follow up was 35 months (range 6-84 months). Mean age was 48 year (range 24-80 years). The patient characteristics were comparable between the two arms except for more mastectomies in the 3 week arm and more node positive patients in the 2 week arm. There were more oestrogen receptor positive tumors in the 3 week arm. Acute skin toxicities were comparable between the two arms. Grade 2 and 3 skin toxicity was 98(17%) and 82(15%); and 16(3%) and 10(2%) in the 3 week and 2 week arm (p=0.15), respectively. Cosmetic outcome was significantly better in 2 week arm 94% as compared to 90% in the 3 week arm (p=0.016). Conclusion The two radiation schedules were comparable in terms of acute skin toxicity. Cosmetic outcome was better in the 2 week schedule.

Citation Format: Budhi Singh Yadav, Divya Dahiya, Manish Gupta. Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-12.
Abstract P1-05-26: A blood-based lipid panel for personalized risk assessment of breast cancer
Authors: Fahrmann Johannes , Irajizad Ehsan , Vykoukal Jody , Barrera Angelica Gutierrez , Dennison Jennifer , Wu Ranran , Arun Banu K. , Brewster Abenaa , Hanash Samir
Published: March 2023

Background: The metabolic syndrome characterized in part by obesity, hyperinsulinemia, and insulin resistance is associated with increased risk of breast cancer. However there remains a need to establish a circulating biomarker metabolic profile indicative of increased risk of breast cancer. In the current study, we performed a comprehensive metabolomics screen to identify biomarkers indicative of increased risk of breast cancer. Methods: Unbiased metabolomics profiling was conducted on an initial Development Set of plasmas collected from 353 newly-diagnosed breast cancer cases and 141 controls. A deep learning neural network with 3 layers each containing 32 nodes based on 11 individual lipids corresponding to discrete lipid subclasses was built for risk prediction of breast cancer. The model was validated in an independent Test Set consisting of 79 breast cancer cases and 163 controls. Using a nested case:control matched design, we evaluated the performance of the model among body mass index (BMI) strata (≥ 30 or < 30kg/m2). Results: An 11-marker lipid biomarker panel encompassing lipid subclasses with known pro-inflammatory and tumor promoting roles yielded an AUC of 0.75 (95% CI: 0.70-0.79) for distinguishing breast cancer cases from controls in the Development Set. Predictive performance of the lipid panel was comparable when stratifying cases into hormone-receptor (HR) positive, HER2-positive/HR negative, and triple-negative breast cancer subtypes. The biomarker panel had an AUC of 0.74 (95% CI: 0.68-0.81) in the independent Test Set. The predictive performance of the panel was most pronounced among obese subjects (BMI ≥ 30) with an AUC of 0.81 (95% CI: 0.71-0.91) in the Test Set. Conclusions: The lipid-based biomarker panel has utility for identifying women with ‘metabolic obesity’ who are at increased risk of breast cancer and would benefit from tailored screening.

Citation Format: Johannes Fahrmann, Ehsan Irajizad, Jody Vykoukal, Angelica Gutierrez Barrera, Jennifer Dennison, Ranran Wu, Banu K. Arun, Abenaa Brewster, Samir Hanash. A blood-based lipid panel for personalized risk assessment of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-26.
Abstract P1-10-07: Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy
Authors: Kim Dowook , Kim Jin Ho , Kim In Ah , Chang Ji Hyun , Shin Kyung Hwan
Published: March 2023

Purpose: The role of post-mastectomy radiation therapy (PMRT) in breast cancer patients after neoadjuvant chemotherapy (NAC) is highly controversial. This study aimed to evaluate the impact of PMRT according to pathologic nodal status. Methods and Materials: We retrospectively reviewed 682 patients with clinical stage II-III breast cancer who underwent NAC and mastectomy from 2013 to 2017. Of total, 596 (87.4%) received PMRT and 86 (12.6%) did not. We investigated the relationship amongst locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), overall survival (OS), and various prognostic factors. Subgroup analyses to identify the patients who may benefit from PMRT were also performed. Results: The median follow-up duration was 67 months. In ypN+ patients (n = 368, 51.2%), PMRT showed significant benefit for LRRFS, DFS, and OS (all p < 0.001). Based on multivariate analysis, histologic grade (HG) III (hazard ratio [HR] = 3.67, p = 0.002), lymphovascular invasion (LVI) (HR = 2.38, p = 0.045), and ypN2-3 (HR = 2.37, p = 0.02) were identified as significant risk factors for poor LRRFS. In ypN1 patients with more than two factors among (i) luminal subtype (ii) HG I-II and (iii) absence of LVI, PMRT showed no significant difference in LRRFS (p = 0.18). In ypN0 patients (n = 351, 48.8%), PMRT was not significantly associated with LRRFS, DFS, and OS. However, PMRT showed better LRRFS in triple-negative breast cancer (TNBC) subtype (p = 0.04). Conclusion: PMRT had a high impact on treatment outcomes in patients with residual lymph nodes following NAC and mastectomy. Among the ypN0 patients, PMRT may be beneficial only in the TNBC subtype.

Citation Format: Dowook Kim, Jin Ho Kim, In Ah Kim, Ji Hyun Chang, Kyung Hwan Shin. Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-07.
Abstract P1-10-16: Cardiac conduction system exposure with modern radiotherapy techniques for breast cancer irradiation
Authors: Loap Pierre , Goudjil Farid , De Marzi Ludovic , Servois Vincent , Kirov Krassen , Fourquet Alain , Kirova Youlia M.
Published: March 2023

Introduction: Exposition of cardiac conduction system during breast radiotherapy has never been studied, despite increasing use of intensity modulated radiotherapy which expose larger volume to low dose bath. We evaluated conduction node exposure during breast irradiation with volumetric modulated arctherapy (VMAT) and estimated the potential dosimetric benefit with intensity modulated protontherapy (IMPT). Materials and methods: Atrioventricular (AVN) and sinoatrial (SAN) nodes were retrospectively delineated according to published guidelines on the simulation CT scans of twelve breast cancer patients having undergone conserving surgery and adjuvant locoregional VMAT. IMPT treatment was re-planned on the simulation CT scans for all breast cancer patients. Mean and maximum doses to the SAN and the AVN were retrieved and compared. Correlation coefficients were calculated between doses to the SAN or the AVN and to the whole heart. Results: Average mean doses to the SAN and to the AVN were 2.8 Gy and 2.3 Gy respectively for left-sided irradiation and 9.6 Gy and 3.6 Gy respectively for right-sided irradiation. Average maximum doses to the SAN and to the AVN were 3.5 Gy and 2.8 Gy respectively for left-sided irradiation and 13.1 Gy and 4.6 Gy respectively for right-sided irradiation. IMPT significantly reduces doses to conduction nodes. Correlations between doses to the SAN or the AVN and the whole heart were usually significant. Conclusion: SAN and AVN can be substantially exposed during breast VMAT, especially for right-sided irradiation. Cardiotoxicity studies evaluating conduction node exposure might define dose constraints and criteria for additional cardiac sparing techniques, such as respiratory techniques or proton therapy, which could be beneficial to patients with underlying rhythmic or conduction disorders.

Citation Format: Pierre Loap, Farid Goudjil, Ludovic De Marzi, Vincent Servois, Krassen Kirov, Alain Fourquet, Youlia M. Kirova. Cardiac conduction system exposure with modern radiotherapy techniques for breast cancer irradiation [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-16.