bluuebunny/crossref_metadata_2025_split huggingface dataset:
Barriers and facilitators of digital interventions use to reduce loneliness among older adults: a protocol for a qualitative systematic review
Authors: Zhang Hongyu , Välimäki Maritta , Li Xiaoyang , Nan Jiahui , Wu Shuang , Zeng Xianmei , Duan Yunzhu , Feng Hui 
Published: December 2022

IntroductionDigital interventions are considered as a potential solution to loneliness in older adults. However, this type of intervention has had limited acceptance among older adults (aged ≥60 years). To ensure the use of digital interventions in older adults, possible barriers and facilitating factors should be better understood from the user’s perspective. We aim to systematically examine the barriers and facilitators to the implementation of digital interventions designed to reduce loneliness in older adults by identifying, evaluating and synthesising qualitative studies.Methods and analysisA comprehensive search of qualitative studies for barriers and facilitators for use of digital interventions will be conducted in the following databases: PubMed, MEDLINE, CINAHL, Embase, Scopus, Cochrane Library and Web of Science. Studies reported in English will be considered for this review. Grey literature will not be included. Two reviewers (HZ and XL) will independently screen the literatures, and any differences will be solved by turning to the third reviewer (JN). The Joanna Briggs Institute (JBI) Qualitative Research Critical Appraisal Checklist will be used by two reviewers to independently assess the validity of the methods used. Relevant data about the populations, context, culture, geographical location, study methods and barriers and facilitators to the implementation of digital interventions will be extracted using the JBI standardised data extraction tool. JBI meta-aggregation methods will be implemented to synthesise the data, which will generate themes and categories based on the data. The final synthesis will establish confidence levels using the JBI ConQual approach.Ethics and disseminationThe protocol does not require ethical approval. The data are based on published scientific databases. The results will be disseminated through journal articles and scientific conference presentations (if feasible).PROSPERO registration numberCRD42022328609.
Everolimus for Estrogen Receptor–negative Breast Cancer Prevention: A Journey Begun?
Authors: Nye Lauren , Khan Seema A. 
Published: December 2022

Tamoxifen, the prototypic medication for breast cancer prevention, was approved for this purpose by the FDA in 1998. Other drugs have been proven to be effective in the ensuing decades. But the two major limitations of these have become clear over time: a lack of protection against hormone receptor–negative breast cancer, and a profile of safety and tolerability that is unacceptable to the majority of women at increased breast cancer risk. Recent preclinical data on targeting of the key oncogenic pathway of PI3K/AKT/mTOR signaling with drugs such as rapamycin and everolimus are provocative. Their efficacy signal should be pursued with further research, but their safety and tolerability profiles remain a concern.See related article by Mazumdar et al., p. 791
Abstract B003: Reprogramming of fibrotic macrophages to control DCIS progression
Authors: Hayward Mary-Kate , Timblin Greg A. , Northey Jason J. , Stashko Connor , Ironside Alastair J. , Hwang E. Shelley , Weaver Valerie M. 
Published: December 2022

Abstract
Women with aggressive DCIS are at high risk of progression to invasive breast cancer. Invasive disease is accompanied by extensive collagen remodeling and crosslinking that contributes to tissue fibrosis and stiffness. Fibrotic breast tumors are associated with an immune desert or immune excluded tumor microenvironment (TME) that functions to promote tumor progression. In particular, tumor-associated macrophages (TAMs) promote tumor invasion and metastasis and, drive immune suppression allowing tumors to evade intrinsic anti-tumor immune responses. Here, we show that collagen remodeling and crosslinking and tissue stiffness associate with DCIS progression and recurrence to invasion in patient tissues. The fibrotic and stiff TME promotes DCIS progression in a mouse model in part by inducing a suppressive TAM phenotype characterized by epigenetic and metabolic reprogramming that accompanies an impaired pro-inflammatory gene signature, as seen in tolerant macrophages. TAMs can be polarized by toll-like receptor (TLR) agonists to eliminate tumor cells by producing pro-inflammatory cytokines or by stimulating cytotoxic T cells, though these are poor cancer therapies alone. Thus, we hypothesized to improve the TLR agonists anti-tumor effects, we can reprogram the metabolic pathways associated with macrophage tolerance, and these together may control DCIS progression in fibrotic and stiff TMEs. We show that fibrotic TAMs can be reprogrammed with monophosphoryl lipid A (MPLA) and coenzyme A (CoA) to kill tumor cells. MPLA + CoA injected into the mammary fat pad reduces high risk features of DCIS in this breast cancer mouse model. We show that CoA supplementation alters macrophage metabolism by supporting acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription. MPLA + CoA reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages and activates cytotoxic T cells through macrophage-secreted cytokines. This treatment approach for engaging an anti-tumor immune response represents an alternative treatment to that of current invasive surgery options for women with high-risk DCIS.
Citation Format: Mary-Kate Hayward, Greg A. Timblin, Jason J. Northey, Connor Stashko, Alastair J. Ironside, E. Shelley Hwang, Valerie M. Weaver. Reprogramming of fibrotic macrophages to control DCIS progression [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B003.
Abstract B009: A SOX9-B7x axis safeguards dedifferentiated tumor cells from immunosurveillance to enable DCIS progression
Authors: Liu Yu , John Peter , Christin John R , Oktay Maja , Zang XingXing , Guo Wenjun 
Published: December 2022

Abstract
Accumulating evidence has demonstrated a central role of dedifferentiation in carcinogenesis. In basal-like breast cancer mouse models, upregulation of SOX9 drives dedifferentiation of luminal progenitors to cells with luminal-basal hybrid features resembling embryonic multipotent mammary stem cells. Additionally, genetic inactivation of SOX9 inhibits dedifferentiation and blocks the progression of in situ tumors to malignant carcinoma. Whether the host immune system can recognize these dedifferentiated cells and how they eventually evade immunosurveillance are unclear. Here, we showed that SOX9 was necessary for limiting infiltrating T lymphocytes to protect dedifferentiated cells from immune surveillance in premalignant lesions of basal-like breast cancer. SOX9 deletion in spontaneous BLBC tumor models caused massive T lymphocyte infiltration and elimination of dedifferentiated cells. Antibody-mediated T cell depletion rescued the accumulation of dedifferentiated tumor cells in SOX9-deficient DCIS and its progression to invasive tumors. Mechanistically, through both stimulation of the STAT3 pathway and direct transcriptional activation, SOX9 upregulated the expression of the immune checkpoint B7x, which mediated the action of SOX9 in immunosuppression. In advanced tumors, B7x blockade reactivated antitumor immunity and effectively inhibited tumor growth. Furthermore, B7x depletion overcame the resistance to anti-PD-L1 immunotherapy. Collectively, these findings uncovered a dedifferentiation-associated immune evasion mechanism and demonstrated the therapeutic potential of targeting the SOX9-B7x pathway to eradicate dedifferentiated tumor cells for intercepting breast cancer progression.
Citation Format: Yu Liu, Peter John, John R Christin, Maja Oktay, XingXing Zang, Wenjun Guo. A SOX9-B7x axis safeguards dedifferentiated tumor cells from immunosurveillance to enable DCIS progression [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B009.
Abstract B018: Physical tumor microenvironment biomarkers to predict DCIS progression, upstaging, and early metastasis
Authors: Damaghi Mehdi , Raza Zainab , Farman Rana Adil , Bai JiDong , Saltz Joel , Niell Bethany L. 
Published: December 2022

Abstract
Ductal carcinoma in situ (DCIS) is defined as a neoplastic proliferation of epithelial cells confined to the mammary ductal-lobular system. Although metastasis can occur at the very early stages of DCIS, the majority of metastatic breast cancers are believed to arise through a years-long process of somatic evolution within the physical constraints of milk ducts, characterized by the accumulation of heritable genetic and epigenetic changes. While these genetic alterations during breast carcinogenesis have been extensively studied without any outcome that can be used as a clinical biomarker, less attention has been paid to the microenvironmental conditions that select for these genotypes. We have demonstrated that evolving pre-cancerous hyperplastic breast cells are selected under physical tumor microenvironment conditions such as hypoxia, acidosis, and starvation. We have also shown that these harsh conditions select cells with more aggressive phenotypes. We have developed several markers for the adapted cells under these harsh conditions such as LAMP2b for acidosis or CA9 for hypoxia. We, therefore, hypothesize that the expression of physical microenvironment adaptation proteins (PMA) can differentiate indolent from aggressive DCIS and that this can be used for decision support. DCIS can be detected by screening mammography followed by a percutaneous Biopsy for pathologic confirmation, which may be followed by surgery +/- adjuvant therapy.
Citation Format: Mehdi Damaghi, Zainab Raza, Rana Adil Farman, JiDong Bai, Joel Saltz, Bethany L. Niell. Physical tumor microenvironment biomarkers to predict DCIS progression, upstaging, and early metastasis [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B018.
Abstract IA010: Patient-derived and genetically engineered models of Ductal Carcinoma in Situ
Authors: Jonkers Jos 
Published: December 2022

Abstract
Ductal Carcinoma in Situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer (IBC). DCIS is usually treated by surgery combined with radiotherapy, which can have a large impact on the life of patients. However, many of these DCIS lesions would never progress into IBC. To reduce the overtreatment of DCIS, but assure proper treatment for high-risk DCIS, it is crucial to understand the biology underlying DCIS. Therefore, we established patient-derived xenograft (PDX) mouse models of DCIS by intraductally injecting patient DCIS material into the mammary ducts of female immunocompromised mice. In addition, we used somatic engineering approaches to establish genetically engineered rat models of DCIS. Together, these preclinical in vivo model platforms enable us to (i) identify biomarkers able to distinguish high-risk from low-risk DCIS, (ii) functionally validate candidate DCIS genes, (iii) study the contribution of tumor cell-intrinsic and -extrinsic processes to DCIS progression, and (iv) study the response to targeted therapeutics.
Citation Format: Jos Jonkers. Patient-derived and genetically engineered models of Ductal Carcinoma in Situ [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA010.
Abstract IA012: Mammary epithelial architecture modulates field cancerization
Authors: Messal Hendrik , Scheele Colinda , Lips Esther , Lutz Catrin , Hutten Stefan , Kristel Petra , Vlahu Carmen , Jonkers Jos , Wesseling Jelle , van Rheenen Jacco 
Published: December 2022

Abstract
The architecture of the human breast undergoes extensive remodeling throughout puberty, the menstrual cycle, pregnancy and involution with a risk of accumulating genetic alterations and tissue changes. Cells that have acquired mutations in driver genes are found to be abundant in tissues of healthy individuals, but they rarely develop into tumors. Yet, the underlying protection mechanisms that prevent tumor formation are largely unknown. Here, we utilized tissue clearing and imaged 15 normal human breasts and DCIS resections with cellular resolution to unravel the 3D architecture of thousands of mammary ducts. Surprisingly, our analysis revealed that disease-free breasts carry a high burden of microscopic tissue lesions. Distinct trees from the same breast differ in the kind and frequency of lesions, which coevolve scattered along the ductal routes. Interestingly, combining tissue clearing of FFPE archival material with spatial CNV-seq reveals that in half of the cases disease-free ductal segments neighboring DCIS lesions contain molecular alterations. To resolve the mechanisms that restrain and permit mutation spread, we compare the clonal fate behavior of cells that acquire oncogenic mutations with those bearing neutral mutations in the mouse mammary gland epithelium. From the quantitative analysis of the clonal dynamics, we find that local tissue remodeling during the estrous cycle leads to the stochastic elimination of the majority of mutant clones, while massively accelerating the expansion of a minority of clones that, by chance, survive. Thereby, oncogenic mutations can be spread along entire ducts before signs of transformation become visible. Together this data provides quantitative understanding of the earliest stages of epithelial evolution preceding disease.
Citation Format: Hendrik Messal, Colinda Scheele, Esther Lips, Catrin Lutz, Stefan Hutten, Petra Kristel, Carmen Vlahu, Jos Jonkers, Jelle Wesseling, Jacco van Rheenen. Mammary epithelial architecture modulates field cancerization [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA012.
Abstract IA016: The DCIS: A biological challenge and clinical dilemma
Authors: Srivastava Sudhir 
Published: December 2022

Abstract
Currently, one of the most challenging problems in oncology is predicting more precisely whether lesions that are detected by sensitive screening tests are indolent (hence, not requiring extensive treatment) or progressive and potentially life-threatening. For example, the increase in breast cancer “incidence” observed over the last 20 years is largely attributable to increased detection of ductal carcinoma in situ (DCIS) and stage I disease by imaging. Despite the increase in early-stage disease, the rates of advanced stage disease have changed only minimally, and the rate of metastatic disease has been virtually unchanged. Conversely, all screening tests miss some life-threatening cancers, known as “interval cancers,” that are diagnosed between scheduled screening tests. Breast cancer best illustrates the problem of interval cancers. It is known that more-aggressive types of breast cancer are more likely to be missed by screening; the cancer grows so quickly it becomes symptomatic after a normal screening test. For example, interval-detected breast cancers are 1.8 to 2.6-fold more likely to be estrogen receptor (ER) negative compared to screen-detected tumors, are likely to be diagnosed at a more advanced stage and are faster growing on average than screen-detected cancers. Relatively little is known about the molecular and cellular differences between screen- detected lesions and interval tumors which might be used to distinguish among the two types of lesions and potentially point to more effective strategies and targets for intervention. The National Cancer Institute has established programs to identify cellular and molecular characteristics that distinguish progressive from non-progressive lesions. Recent progress in this direction will be discussed by the speaker.
Citation Format: Sudhir Srivastava. The DCIS: A biological challenge and clinical dilemma [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr IA016.
Abstract A007: Assessing immunoprevention efficacy of an agonist of CD137 pathway in a tobacco carcinogen-induced lung cancer preclinical model
Authors: Gulen Ayse Ece , Tarique Mohammad , Ulker Vahap , Agca Evrim , Shirwan Haval , Yolcu Esma S. 
Published: December 2022

Abstract
Purpose: Lung cancer is the leading cause of cancer-related deaths worldwide. Cigarette smoking is the primary risk factor for lung cancer and is linked to 80-90% of lung cancer deaths according to the Centers for Disease Control (CDC). The most carcinogenic component of tobacco smoke is NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). SA-4-1BBL is a novel CD137 receptor agonist that has shown cancer immunoprevention efficacy in transplantable preclinical tumor models by invoking an innate immune surveillance mechanism involving CD4+ CD44+ T and NK cells. As a preclinical model for high-risk populations, we evaluated the immunoprevention efficacy of SA-4-1BBL in lung tumor formation induced by NNK. Experimental Procedures: A/J female mice were used as a preclinical model for lung cancer immunoprevention due to their susceptibility to tobacco-carcinogen-induced lung cancer. A/J mice were i.p. injected with NNK weekly for eight consecutive treatments. The mice were also treated s.c. with 100 µg SA-4-1BBL twice, two weeks apart on weeks 6 and 8 of NNK treatment. Animals were monitored for 21 weeks and euthanized to harvest the lung and lung-draining lymph nodes for histology (H&E staining and PCNA immunofluorescence staining). In separate groups, mice were treated with a depleting antibody to CD4 twice two weeks apart on weeks 6 and 8 of NNK treatment to investigate the role of CD4+ immune cells in cancer immunoprevention. Results: NNK treatment resulted in lung tumor formation as assessed by PCNA immunofluorescence staining in all saline-injected control mice by the 21-week experimental end-point. Treatment with SA-4-1BBL resulted in significantly fewer macroscopic and microscopic tumor numbers than the control group (p &lt; 0.01). Animals treated with SA-4-1BBL and subjected to CD4+ cell depletion showed similar numbers of macroscopic and microscopic lung tumors to the vehicle group. Conclusions: Prophylactic treatment with SA-4-1BBL significantly prevents NNK-induced lung tumor formation and CD4+ immune cells play a critical role in the observed immunoprevention efficacy of SA-4-1BBL. Supported by a grant from DOD LC190524 to Esma S. Yolcu.
Citation Format: Ayse Ece Gulen, Mohammad Tarique, Vahap Ulker, Evrim Agca, Haval Shirwan, Esma S. Yolcu. Assessing immunoprevention efficacy of an agonist of CD137 pathway in a tobacco carcinogen-induced lung cancer preclinical model [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A007.
Abstract A015: The β-blocker carvedilol prevents DMBA-induced mammary gland tumors
Authors: Sardar Pabitra K. , Shahid Ayaz , Yeung Steven , Andresen Bradley T. , Huang Ying 
Published: December 2022

Abstract
Breast cancer is the most diagnosed cancer globally and is the fifth leading cause of cancer related mortality worldwide. Chemoprevention is a promising method of reducing cancer mortality. However, there are no drugs that are used routinely as breast cancer preventative agents. Carvedilol (CAR), a beta-adrenergic receptor blocker, use in humans reduces breast cancer incidence; therefore, we hypothesized that carvedilol acts as a breast cancer preventative agent. Two protocols were used to evaluate the ability of carvedilol to prevent 15 mg 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. In protocol 1, two doses of carvedilol (2 and 10 mg/kg) were provided as a 7-day pretreatment and throughout the study. In protocol 2, 10 mg/kg tamoxifen and 10 mg/kg carvedilol were provided as a 7-day pretreatment and treatment was halted after six weeks. In all studies carvedilol and tamoxifen were administered in the drinking water, animals were palpated weekly beginning at week 5 to detect the presence and location of mammary tumors, tumors were measured via calipers, and the experiments terminated at week 13. In protocol 1, 10 mg/kg, but not 2 mg/kg carvedilol was effective in delaying the tumor occurrence (P = 0.0002); the first appearance of tumors and median tumor appearance were separated by 6 and 4 weeks, respectively, compared to rats receiving DMBA alone. However, the tumors that appeared, grew at similar rate as those in the DMBA group. In protocol 2, tamoxifen prevented all but 1 rat developing a tumor and was similar to the negative control; however, 10 mg/kg carvedilol was indistinguishable from the DMBA group. Although tamoxifen prevented DMBA-induced breast cancer, the rats drank significantly less water resulting in statistically lower body weight than all other groups. The rats also drank significantly less of the carvedilol-laced water, but not to a degree that affected their body weight. Therefore, continuous carvedilol treatment is essential to achieve the observed chemopreventive effects.
Our data demonstrates the chemopreventive activity of carvedilol in a rat model of mammary gland carcinogenesis. The results provide significant implications in breast cancer chemoprevention using carvedilol, which is a safe FDA-approved medicine.
Citation Format: Pabitra K. Sardar, Ayaz Shahid, Steven Yeung, Bradley T. Andresen, Ying Huang. The β-blocker carvedilol prevents DMBA-induced mammary gland tumors [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A015.