bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of custom-made foot orthoses in patients with systemic lupus erythaematosus: protocol for a randomised controlled trial
Authors: Reina-Bueno María , Vázquez-Bautista María del Carmen , Palomo-Toucedo Inmaculada C , Domínguez-Maldonado Gabriel , Castillo-López José Manuel , Ramos-Ortega Javier , Munuera-Martínez Pedro V 
Published: March 2021

IntroductionSystemic lupus erythaematosus (SLE) is a chronic autoimmune disease of heterogeneous involvement. The disease may affect feet with a high prevalence of symptoms such as, for example, pain, forefoot and rearfoot deformities, and biomechanics dysfunctions. Custom-made foot orthoses (CMFO) have been previously reported to be effective in patients with other rheumatic diseases. However, as far as the authors know, there exist no studies about their effectiveness in SLE. This study aims at determining the effect of CMFO versus placebo flat cushioning insoles on pain, foot functionality, fatigue and quality of life in patients with SLE.Methods and analysisA randomised controlled trial would compare the effects of (1) CMFO and group B, which received a placebo, flat cushioning insoles, for 3 months. The main outcome measures are foot pain, foot functionality and foot-related disability. The secondary outcome measures are fatigue and quality of life.Ethics and disseminationThe study has been approved by the Portal de Ética de la Investigación Biomédica de Andalucía ethical committee 1494-N-19. The results will be disseminated regardless of the magnitude or direction of effect.Trial registartion numberClinicaltrials.gov identifierNCT04098055.
Psychoeducational and rehabilitative intervention to manage cancer cachexia (PRICC) for patients and their caregivers: protocol for a single-arm feasibility trial
Authors: Buonaccorso Loredana , Bertocchi Elisabetta , Autelitano Cristina , Allisen Accogli Monia , Denti Monica , Fugazzaro Stefania , Martucci Gianfranco , Costi Stefania , Tanzi Silvia 
Published: March 2021

IntroductionHalf of all patients with cancer experience cachexia, with the prevalence rising above 80% in the last weeks of life. Cancer cachexia (CC) is a complex relational experience that involves the patient–family dyad. There are no studies on the association between the psychoeducational component and the rehabilitative component of dyads for supporting more functional relationships in the management of CC.The primary objective of this study is to evaluate the feasibility of a psychoeducational intervention combined with a rehabilitative intervention on dyads.The secondary objective is to improve the quality of life (QoL) and acceptability of the intervention.Methods and analysisThis mixed-methods study with a nonpharmacological interventional prospective includes 30 consecutive cancer patients with cachexia and refractory cachexia and their caregivers, assisted by the Specialised Palliative Care Team. The recruitment will last 1 year. The intervention involves two components: (1) psychoeducational intervention: 3 weekly face-to-face consultations between dyads and trained nurses to help the dyads cope with involuntary weight loss and strengthening dyadic coping resources and (2) rehabilitation intervention: 3 biweekly educational sessions between dyads and trained physiotherapists focused on self-management, goal-setting, physical activity with three home exercise sessions per week.The primary endpoint will be in adherence to the intervention, indicated by a level of completion greater than or equal to 50% in both components. The secondary endpoints will be QoL (Functional Assessment of Anorexia-Cachexia Therapy), caregiver burden (Zarit Burden), physical performance (Hand-Grip strength and 30 seconds sit-to-stand test), and the acceptability of the intervention (ad hoc semi-structured interviews with the dyads and the healthcare professionals).Ethics and disseminationThe study was approved by the Ethics Committee Area Vasta Emilia Nord, Azienda USL-IRCSS Reggio Emilia, Italy, number: 73/2019/SPER/IRCCSRE. The authors will provide the dissemination of the results through publication in international scientific journals.Trial registration numberNCT04153019.
Abstract IA009: Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis
Authors: Kang Yibin 
Published: March 2021

Abstract
TGF-β signaling is a well established pathway driving different steps of bone metastasis progression. Wnt signaling plays a dichotomous role in bone metastasis, with recent studies showing that inhibition of Wnt signaling by DKK1 is critical for avoidance of immune clearance of dormant bone micrometastasis and activation of osteoclast activity during osteolytic outgrowth. On the other hand, engagement of bone vascular E-selectin by disseminated tumor cells (DTCs) promotes metastatic colonization in bone by activating Wnt signaling to enhance tumor initiating activity of DTCs. These findings imply a complex interplay between TGF-b and Wnt signaling in different stages of bone metastasis development that allows efficient colonization, dormancy and outgrowth of secondary tumors in bone. What mediates the dynamic transition of TGF-β and Wnt signaling states during metastasis is currently unknown. Here we present data describing a novel phase-separated organelle organized by bone metastasis promoting protein Dact1 which mediates the crosstalk of TGF-β and Wnt signaling. We found that Dact1 is induced by TGF-β signaling and forms dynamically regulated biomolecular condensates that suppress Wnt signaling. A high level of Dact1 expression is associated with an elevated risk of bone metastasis in breast cancer patients and Dact1 is necessary for bone metastasis in mouse models of breast and prostate cancers.
Citation Format: Yibin Kang. Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA009.
Abstract IA011: Conventional dendritic cells as regulators of therapeutic response in pancreas cancer
Authors: DeNardo David G. 
Published: March 2021

Abstract
In these studies, we utilized spontaneous models of pancreatic and lung cancer to examine how neo-antigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) resulted in exacerbation of the inflammatory and fibrotic tumor microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early- stage PDAC leads to disease restraint, while restoration of cDC function thru treatment with both CD40 agonists and FLT3L in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.
Citation Format: David G. DeNardo. Conventional dendritic cells as regulators of therapeutic response in pancreas cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA011.
Abstract IA018: Linking obesity-associated inflammation with cancer metastasis
Authors: McDowell Sheri A. , Luo Robin , Spicer Jonathan D. , Dannenberg Andrew J. , Walsh Logan A. , Quail Daniela F. 
Published: March 2021

Abstract
Obesity is associated with increased incidence and mortality of multiple tumor types, and competes with smoking tobacco as the leading preventable risk factor for all cancer-related deaths. In breast cancer, epidemiological studies have shown that obesity is linked to enhanced metastasis to lung and liver. However, it is not known how to improve cancer outcomes in the obese patient population as the mechanistic link between obesity and cancer progression is currently lacking. Using genetic and diet-induced obesity mouse models, it was previously shown that obesity promotes pulmonary metastasis of breast cancer by inducing lung neutrophilia via a IL5–GM-CSF signaling axis. We have now determined that neutrophils are reprogrammed by obesity within the lung to produce elevated levels of reactive oxygen species (ROS) and release neutrophil extracellular traps (NETs). This in turn weakens endothelial barrier integrity, leading to enhanced microvascular permeability and tumor cell extravasation into the lung parenchyma. This effect can be reversed by targeting ROS via pharmacological or genetic approaches, or by preventing NETosis using PAD4 inhibitors. To confirm the translational relevance of our findings, we performed imaging mass cytometry on lung metastasis samples from cancer patients, and observed a significant correlation between body mass index and NETosis, neutrophil oxidative burst, and ROS status. Given the high prevalence of obesity on an international scale, our data provide insight into mechanisms of cancer progression for a significant proportion of the adult population, including (potentially) those who are metabolically obese but normal weight.
Citation Format: Sheri A. McDowell, Robin Luo, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh, Daniela F. Quail. Linking obesity-associated inflammation with cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA018.
Abstract IA026: Activating a collaborative innate-adaptive immune response to control metastasis
Authors: Egeblad Mikala 
Published: March 2021

Abstract
Tumor-associated macrophages (TAMs) promote metastasis and inhibit cytotoxic T cells. Yet, macrophages can be polarized to kill cancer cells. Macrophage polarization could therefore be a strategy for controlling cancer. We have found that monophosphoryl lipid A (MPLA, a derivative of lipopolysaccharide [LPS]) with IFNγ can polarize macrophages isolated from metastatic pleural effusions of breast cancer patients to kill cancer cells in vitro. Injecting tumors with MPLA+IFNγ reduced primary tumor growth, greatly suppressed metastasis, and enhanced the response to chemotherapy in breast and ovarian cancer mouse models. Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. Mechanistically, the combined MPLA+IFNγ treatment stimulated type I interferon signaling, reprogramed TAMs (CD206+) to tumoricidal macrophages (iNOS+), and activated cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). MPLA and IFNγ are already used individually in clinical practice and together represent a previously unexplored approach to engage a systemic anti-tumor immune response.
Citation Format: Mikala Egeblad. Activating a collaborative innate-adaptive immune response to control metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA026.
Abstract LT005: Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy
Authors: Siolas Despina , Vucic Emily , Kurz Emma , Hajdu Cristina , Bar-Sagi Dafna 
Published: March 2021

Abstract
KRASG12D mutations in tumor cells can modify the immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), though the effects of secondary genetic alterations have been unexplored. After oncogenic KRAS, TP53 is the most frequently mutated gene in PDAC, however the immune effects of neomorphic TP53 mutations have not been defined. We sought to evaluate the non-cell-autonomous role of mutant p53 in modulating the immune microenvironment of pancreatic cancer by comparing the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) genetically engineered to express the Trp53R172H gain-of-function mutation to their p53 wildtype control. We found orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC had a distinct immune profile in comparison to KrasG12D/+;Trp53+/+ tumors, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy.
Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor-intrinsic gain of function p53R172H mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment that promotes resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT005.
Abstract LT010: Pleiotrophin drives pro-metastatic immune niche within breast tumor microenvironment
Authors: Ganguly Debolina , Sorrelle Noah , Dominguez Adrian , Toombs Jason , Schmidt Marcel , Mora Fa Valdes , Ortega David Gallego , Wellstein Anton , Brekken Rolf A. 
Published: March 2021

Abstract
Background: Pleiotrophin (PTN), a heparin binding cytokine important during embryonic development, is expressed at elevated levels in several cancers, including breast cancer. High PTN expression in serum and tumor tissues of breast cancer patients correlates with worse outcome. Previous studies indicate PTN contributes to angiogenesis, hematopoiesis, and inflammation; however, the function of PTN in breast cancer progression and metastasis has not been elucidated.
Methods: The effect of anti-PTN therapy (mAb; 3B10) on breast tumor progression and pulmonary metastasis was evaluated in four preclinical models of breast cancer: 4T1, E0771, Met-1, MMTV-PyMT. In addition, the effect of global loss of PTN using Ptn-deficient mice was evaluated in two murine models of breast cancer. Tissues from these experiments were analyzed by RNAseq and histology for changes in angiogenesis, hematopoiesis, immune cell infiltration, and cytokine/chemokine expression.
Findings: TCGA data shows high PTN expression correlates with poor survival of Stage IV breast cancer patients. Furthermore, our data indicate that: a) blocking PTN pharmacologically or genetically results in a significant reduction of lung metastasis in multiple preclinical mouse models of breast cancer, b) scRNAseq and dual FISH-IHC (fluorescence in-situ hybridization and immunohistochemistry) demonstrates that endothelial cells and select population of tumor cells express PTN in the tumor microenvironment (TME), c) inhibition of PTN results in a decrease in overall inflammation with a particular decrease in neutrophil populations at primary and secondary tumor sites, d) in a genetically engineered mouse model (GEMM) of breast cancer, MMTV-PyMT, PTN expression is enriched at the metastatic site.
Conclusion: Our data suggests that PTN is important in driving a pro-metastatic immune niche within the TME that promotes tumor cell escape from the primary tumor and survival of metastatic cancer cells in secondary sites. Additionally, our studies highlight that inhibition of PTN has potential to reduce metastatic burden in breast cancer and suggest that future studies testing the combination of PTN inhibition with standard chemotherapy or immune therapy are warranted.
Citation Format: Debolina Ganguly, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Marcel Schmidt, Fa Valdes Mora, David Gallego Ortega, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives pro-metastatic immune niche within breast tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT010.
Abstract LT016: Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance
Authors: Tello-Lafoz Maria , Srpan Katja , Hu Jing , Romin Yevgeniy , Calò Annalisa , Hsu Katharine C. , Massagué Joan , Huse Morgan , Emrah Er Ekrem 
Published: March 2021

Abstract
Metastatic dissemination of cancer cells to vital secondary organs pose a lifelong lethal threat unless they can successfully be eliminated by the immune system. Interestingly, despite their ability to evade immunity at primary organs, the vast majority of disseminated cancer cells are killed at secondary organs, suggesting that the process of dissemination renders cancer cells sensitive to immunity. Understanding how dissemination renders cancer cells sensitive to immunity would therefore provide exciting new opportunities to target metastases, but the relationship between dissemination and the immune response is not clear. In our effort to study this relationship, we manipulated cancer cells’ expression of myocardin related transcription factors A and B (MRTFA/B), which are central in regulation of actin cytoskeleton and are indispensable for metastatic invasion, dissemination and colonization. Surprisingly, despite MRTFA/B’s established roles in promoting metastasis, we found that MRTFA/B expression in cancer cells downregulated metastatic colonization in fully immuno-competent mouse models. MRTFA/B mediated decrease in colonization was completely reversed upon immune cell depletion suggesting that the immune cells exploit MRTFA/B expression in cancer cells for cytotoxicity. Among various cancer cell parameters involved in immune cell activation, T- and NK cell activation most prominently correlated with MRTFA/B driven mechanical compliance of cancer cells. Mechanical compliance, also known as stiffness, of antigen presenting cells and synthetic substrates are well-known to activate T- and NK cells through biophysical and mechano-chemical signal transduction. As such, perturbing cancer cells’ stiffness downregulated the immune response and cytotoxicity. Thus, we termed this process mechanosurveillance. Our work on mechanosurveillance will help us understand how disseminated cancer cells are targeted by immunity and how they evade it at secondary organs. Importantly the concept of mechanosurveillance will help guide the use of existing therapeutics that alter tissue stiffness and immune boosting therapies to combat metastases.
Citation Format: Maria Tello-Lafoz, Katja Srpan, Jing Hu, Yevgeniy Romin, Annalisa Calò, Katharine C. Hsu, Joan Massagué, Morgan Huse, Ekrem Emrah Er. Mechanosurveillance eliminates disseminated cancer cells by sensing their mechanical compliance [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT016.
Abstract PO001: Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer
Authors: Boral Debasish , Kenney Shelby R. , Liu Haowen N. , Marchetti Dario 
Published: March 2021

Abstract
Despite widespread knowledge that bone marrow-resident breast cancer cells (BMRCs) affect tumor progression, signaling mechanisms of BMRCs implicated in maintaining long-term dormancy have not been characterized. Further, there is no model of clinical dormancy that can comprehensively emulate the entire spectrum of heterogeneous clones of Circulating Tumor Cells (CTCs) present in cancer patients. To overcome these hurdles, we developed a new experimental model of clinical dormancy employing patient-isolated de novo CTCs and their injection in xenografts with subsequent tumor monitoring and CTC characterization (ex vivo CTCs). We hypothesized that significant distinctions exist between signaling pathways of bone marrow-homing vs metastasis-competent CTCs upon transplantation in xenografts. Comparative transcriptomic analyses of ex vivo vs de novo CTCs identified increased mTOR signaling – a critical pathway frequently dysregulated in breast cancer and implicated in cell survival and dormancy – with contrasting actions by its two complementary arms (mTORC2/mTORC1). Heightened mTORC2 downstream targets augmented quiescent CTCs (Ki67-/RBL2+ cells) in paired breast cancer tissues, along with high mTORC2 activity in solitary BMRCs and tissue-resident CTCs. Further, shRNA mediated knockdown of RICTOR, an essential component of mTORC2, augmented Ki67/PCNA biomarker expression and proliferation. Collectively, these findings suggest that the balance between mTORC1 vs mTORC2 signaling regulates CTC-associated mitotic and/or dormancy characteristics. Further elucidation of mTOR-mediated CTC dormancy will provide novel strategies for therapeutic interventions in patients having early-event metastatic seeding but yet to develop clinically-detectable overt metastasis.
Citation Format: Debasish Boral, Shelby R. Kenney, Haowen N. Liu, Dario Marchetti. Molecular interplay between bone marrow-resident cells (BMRCs) and CTCs in Breast Cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO001.