bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B035: Reciprocal macrophage - T cell interactions regulate anti-tumor immunity
Authors: Sudhakaran Meenakshi , Lombardi Sofia , Ayma Sophie , Krummel Matthew F. , Kersten Kelly
Published: November 2024

Cancer immunotherapy (including immune checkpoint blockade (ICB)) has shown great promise in the treatment of some solid cancers, but responses in breast cancer patients are limited. While breast cancer is generally considered poorly immunogenic, the abundance of CD8+ T cells correlates with clinical response. CD8+ T cells are critical mediators of anti-tumor immunity and the main target for ICB. However, the onset of terminal functional T cell exhaustion poses a major challenge. Although T cell exhaustion has been linked to persistent antigen exposure, it remains unclear how the immune composition of the breast tumor microenvironment (TME) contributes to this dysfunctional T cell state. Breast cancers are heavily infiltrated with tumor-associated macrophages (TAMs) and their abundance correlates with T cell exhaustion and poor prognosis. Previously, we discovered a spatiotemporal co-dependency between exhausted T cells (TEX) and TAMs in mouse models of melanoma and breast cancer. We showed that TEX actively recruit monocytes to the TME and shape their differentiation trajectory into TAMs. Reciprocally, these TAMs ‘capture’ T cells in long-lived synaptic interactions that contribute to functional T cell exhaustion. Our current work is focused on studying the TEX-derived chemokines that regulate these TAM – T cell interactions in the breast TME with the ultimate goal to alleviate immune evasion and improve responsiveness of breast cancer to immunotherapy.

Citation Format: Meenakshi Sudhakaran, Sofia Lombardi, Sophie Ayma, Matthew F. Krummel, Kelly Kersten. Reciprocal macrophage - T cell interactions regulate anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B035.
Abstract B042: The impact of opioids on the pancreatic tumor immune microenvironment
Authors: Maraszek Kathryn , Feigin Michael
Published: November 2024

Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 12.8%. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids. Opioids, which signal through the G protein-coupled receptor (GPCR) mu-opioid receptor (MOR), have peripheral effects outside of their analgesic function. Importantly, several studies have correlated opioids with worsened survival of patients receiving immunotherapy. However, the mechanism behind this is unknown. Immunotherapy is largely ineffective in pancreatic cancer, due in part to the tumor microenvironment (TME) characterized by dense, desmoplastic stroma, with cancer-associated fibroblasts (CAFs) comprising up to 90% of the tumor volume. CAFs play a large role in immunosuppression and therapy resistance, such as through promoting infiltration of immunosuppressive cells, resulting in reduced presence of antitumor immune cells and impaired immunotherapy efficacy. While the role of CAFs in promoting immunosuppression in the tumor microenvironment is well characterized, the effect of opioids on this phenomenon is unknown. We now provide evidence that MOR directly regulates CAF function. Specifically, knockdown of MOR in CAFs reduces gene expression of alpha-smooth muscle actin (aSMA) and leukemia inhibitory factor. MOR knockdown in CAFs also decreases protein expression of aSMA and type 1a collagen. We hypothesize that opioids promote MOR-dependent CAF activation and secretion of pro-inflammatory cytokines, resulting in a more immunosuppressive TME, and thus impaired immunotherapy response. The long-term goal of this work is to determine the role of opioids on CAFs in the pancreatic TME, as well as the role of MOR in promoting immunosuppression and the resulting value of MOR as a target to improve immunotherapy efficacy. This research is clinically significant because it could uncover a novel mechanism driving immunosuppression caused by a medication commonly prescribed to almost all pancreatic cancer patients.

Citation Format: Kathryn Maraszek, Michael Feigin. The impact of opioids on the pancreatic tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B042.
Abstract C031: Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the tumor microenvironment
Authors: Choi Brandon , Zhou Yuyuan , Kim Seungil , Mumenthaler Shannon M.
Published: November 2024

Cancer-associated fibroblasts (CAFs) are a prominent component of the tumor microenvironment (TME) and are known for their role in supporting tumor growth and progression through interactions with cancer cells and other stromal elements. Liver metastatic CAFs (lmCAFs), in particular, play an important role in establishing the secondary niche that facilitates tumor metastasis. Reprogramming the stroma, particularly targeting the pro-tumorigenic functions of lmCAFs, has emerged as a promising therapeutic intervention to disrupt the supportive environment tumors rely on for progression. An initial drug screen of FDA-approved oncology therapies was conducted on patient-derived colorectal cancer (CRC) CAFs and tumor organoids (PDTOs) to identify compounds that may be re-purposed as stroma targeting agents. All-trans retinoic acid (ATRA) was shown to specifically inhibit the proliferation of CAFs without affecting CRC-PDTOs. ATRA is an active metabolite of Vitamin A that exerts its canonical biological effects by binding to nuclear retinoic acid receptors (RAR). The differential RAR expression in multiple CAFs and PDTOs was confirmed with bulk RNA sequencing, with higher expression found in the CAF lines. Subsequent analysis included the qPCR assessment of glycolysis enzyme levels, CAF activation markers, and ATRA signaling in lmCAFs following treatment with ATRA for 5 days. Protein expression of key components of the TGF-b signaling pathway, including SMAD 2/3, Akt, and b-catenin, were also analyzed. Treatment of lmCAFs with ATRA induced expression of RARb and ALDH1A1, biomarkers associated with ATRA signaling pathways. In one patient-derived CAF line, ATRA treatment exhibited a decrease in CAF activation markers (e.g. aSMA) and glycolytic enzymes (e.g. lactate dehydrogenase). On the other hand, another CAF line showed increased fibroblast activation and a shift away from metabolic dependency on glycolysis upon ATRA treatment. Additionally, ATRA targeted TGF-b signaling through the pSMAD 2/3 and Akt pathways, highlighting the multifaceted impact on CAF function and heterogeneity. ATRA effectively reprograms some CAFs by inhibiting their proliferation and altering key signaling pathways, thereby disrupting the pro-tumorigenic environment of the TME. The results of this study suggest that ATRA holds potential as a therapeutic strategy to target and reprogram the CAFs within the permissive stromal components essential for tumor progression.

Citation Format: Brandon Choi, Yuyuan Zhou, Seungil Kim, Shannon M. Mumenthaler. Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C031.
Abstract C033: Identifying and targeting prostate cancer therapy resistance mechanisms driven by the tumor microenvironment
Authors: Heng Chu Tony Lok , Bankhead Armand , Coleman Ilsa , Frank Sander , Nelson Peter S. , Arman Tarana
Published: November 2024

Background: Prostate cancer is a prevalent malignancy in men, with treatment resistance posing a significant challenge to successful cure. Acquired Resistance to Therapy (ART) arises from two main components: (1) Tumor Microenvironment (TME) and (2) mutations or epigenetic changes at gene level within the tumor cells themselves. While most cancer therapies target the intrinsic biology of cancer cells, growing evidence indicates that these treatments can also harm the stromal cells within TME, potentially driving ART. The biology of ART may vary based on the types of treatments, cell types, and organ locations. Thus, this study aims to dissect ART components driven by TME-mediated cellular processes in a comprehensive manner. Hypothesis: We propose that cancer therapies induce stress responses in non-cancerous cells within the TME. These stress responses involve the secretion of cytokines, mediators, and growth factors, which we term Stress Response Secretory Programs (SRSPs). We further hypothesize that targeting SRSPs could overcome ART that helps to improve treatment specificity and efficacy. Materials and Methods: We employed comprehensive single-cell profiling of common metastatic sites included liver, prostate, lung, bone, lymph node and spleen in preclinical models to identify secreted proteins and dysregulated pathways caused by genotoxic therapies. In vitro, we evaluated treatment resistance in murine prostate epithelial cell lines (Myc-CAP) by exposing them to conditioned media (CM) from irradiated murine fibroblasts (F4M2), using cell growth assays. Results: Single-cell RNA sequencing of organ samples revealed significant expressions of SRSPs and increased inflammatory responses in liver and prostate fibroblasts as well as other stromal cells treated with carboplatin. In vitro, CM from irradiated F4M2 cells enhanced cell proliferation and survival of Myc-CAP cells in response to docetaxel treatment. Conclusion: Our findings highlight the crucial role of SRSPs in mediating ART through interactions within the TME, which alter tumor cell phenotypes. Targeting these SRSPs holds potential for overcoming treatment resistance and improving therapeutic outcomes, underscoring the need to consider TME complexity in cancer treatment strategies.

Citation Format: Tony Lok Heng Chu, Armand Bankhead, Ilsa Coleman, Sander Frank, Peter S. Nelson, Tarana Arman. Identifying and targeting prostate cancer therapy resistance mechanisms driven by the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C033.
Abstract C036: Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses
Authors: Fan Jiawei , Qi Sumeng , Shih Ie-Ming , Wang Tian-Li
Published: November 2024

As a critical component of innate and adaptive immunity, macrophages play an important role in shaping the tumor microenvironment (TME), which affects tumor initiation, progression, and response to treatment. Tumor-associated macrophages can display anti-tumor or pro-tumor activity, a cell fate attributed to macrophage polarization that depends on metabolomic regulation. Targeting macrophage metabolism could be a promising approach for cancer treatment by converting a pro-tumor TME into an anti-tumor TME. To examine in vivo mechanisms behind glutamine metabolism on macrophages, we treated immunocompetent murine ovarian cancer models with a clinical-grade glutamine prodrug, JHU083, and performed single-cell RNA sequencing (scRNAseq). In addition to the significant anti-tumor efficacy of JHU083, we found that JHU083 specifically suppressed the M2-like tumor macrophages while sparing M1-like macrophages. To better understand the molecular mechanism of how JHU083 causes macrophage polarization shift, we cultured an M1-like macrophage cell line with DON (6-Diazo-5-oxo-L-norleucine), the active component of JHU083, and performed bulk RNA sequencing. Using bulk RNAseq and scRNAseq transcriptome analyses on M1-like macrophages, glutamine inhibitor treatment significantly enhanced MHC class II genes, including CD74, H2-Aa, H2-Eb1, H2-Ea, H2-Ab1, and TNF family genes including Tnfsf12, and Tnfrsf14 which may promote T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Moreover, DON-treated bone marrow-derived M1 macrophages promoted CD4+ T cell expansion. On the other hand, DON treatment significantly suppressed bone marrow-derived M2 macrophages. In conclusion, our findings suggest that glutamine metabolism reprogramming can promote anti-tumor functions in tumor macrophages. Therefore, targeting glutamine metabolism to regulate macrophage function and polarization can be a promising direction for future cancer therapy.

Citation Format: Jiawei Fan, Sumeng Qi, Ie-Ming Shih, Tian-Li Wang. Pharmacological modulation of glutamine metabolism alters macrophage activity and tumor immune responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C036.
Abstract C052: Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents
Authors: Yang Yang
Published: November 2024

High-grade serous ovarian carcinoma (HGSOC) is a very aggressive form of ovarian cancer, contributing to most ovarian cancer deaths. Paclitaxel is one of the major components of the first line treatment for HGSOC, but the development of chemoresistance to paclitaxel leads to the frequent relapse of the disease and poor prognosis in HGSOC patients. However, the mechanism underlying the chemoresistance has not been well established nor have the strategies to overcome the resistance been developed, which was investigated in the present study using three representative HGSOC cell lines (i.e. Kuramochi, OVCAR4, and OVCAR3 cells) in vitro. The results from our study show that induction of senescence contributes to paclitaxel-induced chemoresistance in HGSOC cells. More importantly, we found that senescent HGSOC cells induced by paclitaxel became highly dependent on BCL-xL for survival and thus were very sensitive to BCL-xL targeting agents, particularly to DT2216 (a BCL-xL specific proteolysis targeting chimera or PROTAC) and 753b (a BCL-xL and BCL-2 dual PROTAC). Because these PROTACs are more potent against senescent HGSOC cells but less toxic to platelets than ABT263 (a BCL-xL and BCL-2 dual inhibitor), they have the potential to be developed as new senolytics to overcome HGSOC chemoresistance to paclitaxel without causing the on-target and dose-limiting thrombocytopenia associated with ABT263 treatment.

Citation Format: Yang Yang. Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C052.
Abstract IA016: Vascular control of metastasis
Authors: Augustin Hellmut G.
Published: November 2024

The molecular analysis of tumor vessel interactions during tumor progression and metastasis has primarily focused on the study of tumor cell-derived angiogenic and lymphangiogenic signals with the purpose to exploit such factors as therapeutic targets. Angiogenic factors activate endothelial cells in nearby blood and lymphatic capillaries to sprout towards the tumor. Tumor angiogenesis thereby not only nourishes the growing tumor, but access to the blood and lymphatic vasculatures enables cells from the primary tumor to enter the circulation to eventually form metastases at distant sites. The complex cellular interactions between tumor cells and endothelial cells have in this context mostly been studied from a tumor cell-centric perspective, i.e., the tumor cells send signals to which endothelial cells merely respond. Yet, the past decade has witnessed a fundamental change of paradigm with the discovery that the vascular endothelium does not just respond to exogenous cytokines but exerts active ’angiocrine’ gatekeeper roles controlling their microenvironment in an instructive manner. We have applied the concepts of angiocrine signaling towards the study of tumor progression and metastasis. Employing novel surgical preclinical metastasis models that better mimic tumor progression and the response to therapy as it occurs in humans, we have molecularly dissected vascular endothelial cells in progressing primary tumors as well as in the pre-metastatic and metastatic niches. These experiments were on the one hand aimed at establishing the systems map of endothelial transcriptomic changes during tumor progression and metastasis and on the other hand to identify and validate novel therapeutic targets. This presentation will review recent advances in the field of tumor microenvironment research and present novel angiocrine signaling mechanisms as promising targets of future mechanism-driven anti-metastatic therapy.

Citation Format: Hellmut G. Augustin. Vascular control of metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA016.
Abstract IA025: Targeting the gut microbiome for cancer immunotherapy
Authors: Trinchieri Giorgio
Published: November 2024

Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The impaired response to immunotherapy in patients treated with antibiotics supports this role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analyzed the underlying mechanisms. Gut microbial communities (microbiotypes) with non-uniform geographic distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts Now, a better understanding of the taxonomy of the species involved and of their mechanisms of action has been achieved. Defined bacterial species have been shown to promote a response to immune checkpoint inhibitors through the production of different products or metabolites, although a suppressive effect of Gram(-) bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on patients’ microbiota composition can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, the interest in modulating the microbiota composition to improve patients’ responsiveness to therapy has been mounting. Our data of a fecal microbiota transfer clinical trial in anti-PD1 refractory melanoma patients has provided clinical proof of concept of the possibility to target the gut microbiota composition in cancer therapy. Also, both in clinical studies and in experimental animals, diets rich in fibers improve the response to immunotherapy by modifying the gut microbiome suggesting the possibility of dietary approaches to target the microbiota composition in cancer therapy. However, while many early clinical studies have analyzed the association of the microbiota composition with the response to anti-PD-1 in cancer patients, emerging evidence suggests that the association may be context dependent and different types of mono or combination immunotherapies may be differentially regulated by the microbiota, Thus, a more personalized approach depending original gut microbiota composition of the patients and the type of immunotherapy protocol selected may be necessary for optimal clinical results.

Citation Format: Giorgio Trinchieri. Targeting the gut microbiome for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA025.
Abstract PR001: An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-liver metastasis
Authors: Das Sunny , Donaher Joana Liu , Verhoeven Lisa , Mishra Ranjan , Reinhardt Ferenc , Gupta Sumeet , Li Zheqi , Polyak Kornelia , Weinberg Robert A.
Published: November 2024

While major advancements have been made in treatment of primary tumors in estrogen receptor-positive (ER+) breast cancer, reducing mortality from metastatic breast cancer (mBC) in treated patients who develop endocrine resistance to first line therapies remains an unmet clinical need. Wild-type ER activity or availability of its cognate ligand 17-beta estradiol (E2) are major factors in primary tumor progression, which are lost/reduced due to endocrine treatments, such as use of selective estrogen degraders (SERDs) and aromatase inhibitors (AIs), respectively. Over time, this leads to selection of rare cancer cells bearing point mutations in ESR1, the gene encoding ER-alpha, which become the dominant population at metastatic sites, and such mutations are now recognized as a frequent driver of endocrine resistance and metastasis, especially in patients with advanced ER+ breast cancer who have been heavily pre-treated with AIs. Analyses of clinical samples have shown a statistically significant association enrichment of ESR1 mutations in liver metastases, compared to the primary tumor. Other distant tissues commonly colonized by breast cancer cells, such as bones, lungs, or brain, although prevalent, do not display this strong association. While this might be due to ease of biopsy sampling in the liver compared to other sites, an alternate and intriguing hypothesis is that the liver offers a fertile soil for metastatic colonization by mutant ER-expressing cells, compared to other distant sites, such as lungs. Using a combination of pre-clinical models, we assessed if mutant ER could drive metastatic colonization at distant sites, such as the liver. We have uncovered a novel link between cancer cell-intrinsic immunomodulatory signaling pathways that are specifically upregulated in mutant ER-expressing breast cancer cells, which represents at least one major molecular mechanism underlying the observed liver tropism of mutant ER-associated, endocrine resistant ER+ breast cancer. We show that disseminated, mutant ER-expressing BC cells engage in crosstalk with the liver stromal and immune populations post-extravasation to further fuel metastatic outgrowth.

Citation Format: Sunny Das, Joana Liu Donaher, Lisa Verhoeven, Ranjan Mishra, Ferenc Reinhardt, Sumeet Gupta, Zheqi Li, Kornelia Polyak, Robert A. Weinberg. An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-liver metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR001.
Abstract PR003: Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses
Authors: Chhabra Yash , Weeraratna Ashani T.
Published: November 2024

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Dermal fibroblasts are known to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, visceral metastasis, and responses to therapy. We find that skin fibroblasts undergo age-mediated sex-differential changes in their proliferation, senescence, ROS production and stress response. We find that aged male fibroblasts drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging promotes sex- dimorphic BMP2 secretion exclusively by aged male fibroblasts, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provide an integrated view of how host factors such as advancing age and biological sex alter the tumor microenvironment and contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare.

Citation Format: Yash Chhabra, Ashani T. Weeraratna. Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR003.
Abstract PR018: Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia
Authors: Tisty Thea D. , Pan Deng , Gascard Philippe , Caruso Joseph , Ferri Lorenzo , Chen-Tanyolac Chira
Published: November 2024

Chronic exposure to tobacco smoke triggers chronic inflammation, fostering a fibrotic microenvironment and promoting the focal replacement of columnar human bronchial epithelial cells (hBECs) with cells exhibiting squamous morphology, termed metaplasia. How squamous metaplasia progresses to squamous dysplasia and, ultimately, squamous lung carcinoma is under intense investigation. Using human bronchial tissues, we demonstrate that, both in vitro and in vivo, cellular stress associated with chronic inflammation (e.g., oxidative stress, DNA damage) enhances TGF-β signaling and creates a fibroblast state exhibiting upregulated HSP47 expression, driving increased collagen fiber alignment, elevated tissue stiffness, and subsequent activation of YAP-dependent mechanotransduction in adjacent hBECs. These Stress/Tension-producing Instructive Fibroblasts (STIFs) alone were sufficient to induce hBECs to squamous metaplasia, precursors to tumor formation. Furthermore, when tumor suppressor function was compromised in hBECs, STIFs induced dysplastic phenotypes. Mechanistically, STIFs act in a dominant manner modulating epithelial cell identity and malignant phenotypes via extracellular matrix (ECM)-dependent mechanotransduction. Inhibition of HSP47-dependent collagen processing effectively prevented fibroblast-induced squamous metaplasia and dysplasia and was capable of reversing fibroblast-induced metaplasia, restoring bronchial epithelial cell identity.

Citation Format: Thea D. Tisty, Deng Pan, Philippe Gascard, Joseph Caruso, Lorenzo Ferri, Chira Chen-Tanyolac. Inflammation-induced mechanotransduction is necessary and sufficient to create pre-cancerous squamous lung metaplasias and necessary to drive progression to dysplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR018.
Supplementary Table S2 from St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors
Authors: Matt Gavriel Y. , Sioson Edgar , Shelton Kyla , Wang Jian , Lu Congyu , Zaldivar Peraza Airen , Gangwani Karishma , Paul Robin , Reilly Colleen , Acić Aleksandar , Liu Qi , Sandor Stephanie R. , McLeod Clay , Patel Jaimin , Wang Fan , Im Cindy , Wang Zhaoming , Sapkota Yadav , Wilson Carmen L. , Bhakta Nickhill , Ness Kirsten K. , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Zhang Jinghui , Yasui Yutaka , Zhou Xin
Published: November 2024

Major data types on the portal
Supplementary Figure S7 from St. Jude Survivorship Portal: Sharing and Analyzing Large Clinical and Genomic Datasets from Pediatric Cancer Survivors
Authors: Matt Gavriel Y. , Sioson Edgar , Shelton Kyla , Wang Jian , Lu Congyu , Zaldivar Peraza Airen , Gangwani Karishma , Paul Robin , Reilly Colleen , Acić Aleksandar , Liu Qi , Sandor Stephanie R. , McLeod Clay , Patel Jaimin , Wang Fan , Im Cindy , Wang Zhaoming , Sapkota Yadav , Wilson Carmen L. , Bhakta Nickhill , Ness Kirsten K. , Armstrong Gregory T. , Hudson Melissa M. , Robison Leslie L. , Zhang Jinghui , Yasui Yutaka , Zhou Xin
Published: November 2024

User interface for genetic association analysis on the portal
Figure 3 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells
Authors: Schaaf Zachary A. , Ning Shu , Leslie Amy R. , Sharifi Masuda , Gao Richard Y. , Maine James P. , Lou Wei , Lombard Alan P. , Liu Chengfei , Yu Ai-Ming , Mitsiades Nicholas , Gao Allen C.
Published: November 2024

Mitochondrial live stain and ETC functional test demonstrate higher function in 2B-OlapR cells. A, Left, MitoTracker staining counterstained with nuclear-specific DAPI reveals higher amounts of relative mitochondrial mass in 2B-OlapR cells over C42B. 10× images shown, with 20× crops within. Right, TCF ratio of MitoTracker to DAPI displaying quantification of relative increased active mitochondria in the resistant cell subline. B, Left, ETCC1 kit assay results express a higher rate of ETCC1 activity in 2B-OlapR cells. Right, Reported rate of change in NAD+ associated absorbance between 300 and 2,000 seconds show significant increased ETCC1 rate in 2B-OlapR cells. ***, P≤0.001; ****, P≤0.0001.
Percursos de uma artista-mediadora: diálogos com a área da educação em contexto catarinense
Authors: Moura Sabrina de
Published: November 2024

This study proposes to share the journeys of an artist in Theatrical Mediation, which have been taking place since 2015 in the municipality of Blumenau. This investigation aims to dialogue with education, play with the possibilities of the simbolic field, and expand relationships with teachers-spectators. Reflections dialogue with authors such as Cecilia Almeida Salles, Maria Lúcia de Souza Barros Pupo, Flavio Desgranges, and Jacques Rancière. Procedures involve the reseacher’s role as an actress and teacher at Cia Carona de Teatro and as a mediator in two theoretical-practical projects and a Theater Festival, all involving teachers-spectators. This study highlights the mediation space as a living and unfinished organism which blurs the boundaries of production, reception, mediation, pedagogy, art, and life.
Artistas-Educadores-Gestores: a atuação do licenciado em artes na gestão de equipamentos culturais
Authors: Glória Catharina da Cunha , Lambert Marisa Martins
Published: November 2024

This study approaches cultural management from the perspective of arts teaching graduates, considering the impact of teacher training on the development of artistic, socio-cultural, mediating, and community articulation actions. Methodological procedures were used, such as interviews, contextual approach experiences, and bibliographical analyses. The author’s personal reports on her experiences as an artist-educator-manager were also included, intertwining reflections on the notions of body, territory, citizenship and cultural democracy, which intersect the training of arts teaching graduates and the practice of cultural managers. The conclusion of this study emphasizes the potential of this professional, who creatively aligns artistic, educational, and administrative processes for a mediated and territorialized cultural management.
Mediação cultural nas artes cênicas: avanços e resistências
Authors: Bordeaux Marie-Christine , Santos Ricardo , Fernandes Renata
Published: November 2024

Os mais diversos públicos de arte estão a cada dia mais familiarizados com técnicas e modos de ter seu encontro mediado por diferentes experiências artísticas. No entanto, o desenvolvimento da mediação enquanto função profissional está desigualmente distribuído entre as diferentes áreas culturais. Seria esse desequilíbrio o sinal da incapacidade crônica de operar uma síntese entre a educação popular e a política artística e cultural? Ou seria o resultado de uma síntese impossível entre as práticas e os desafios das diferentes áreas das artes e da cultura? Uma análise das mediações no teatro e na dança, apresentada neste artigo, traz algumas respostas a essas questões, tornando evidente a natureza ao mesmo tempo ímpar e diversa da arte e dos objetos culturais, contrapondo-se a uma visão única e homogênea do papel da mediação cultural e da função dos agentes mediadores.
Mediação artística: ações entre a universidade e a escola
Authors: Ricci Nina Menezes
Published: November 2024

This study aims to understand how artistic mediation and audience development initiatives contribute to educate artists, particularly undergraduate ones. We draw from our experience with extension projects that establish connections between undergraduate students and students in basic education to assess the impacts of the developed actions on participants’ education. Conceptually, we rely on the studies of mediation and audience development by Flávio Desgranges, Maria Lucia Pupo, and Ingrid Koudela.
Refugee Education: Aligning Access, Learning & Opportunity
Authors: Dryden-Peterson Sarah
Published: November 2024

Access, learning, and opportunity are usually conceptualized in a sequential and linear way: with access to school comes learning and with learning comes opportunity. But for most refugee students-and for most marginalized students globally-this model simply does not hold. In settings where students’ mobility and their social, economic, and political rights have massive restrictions, access to school does not translate into learning, and learning does not translate into opportunities. Creating education that enables refugee young people to feel a sense of belonging and prepares them to help build more peaceful and equitable futures requires us to address these misalignments, which are rooted across the ecosystem, from macrolevel geopolitical arrangements to micro-level interactions in classrooms. I pose three questions as central in understanding these misalignments: Who is allowed to be where and for how long? Who is responsible for refugee education? And who can feel a sense of belonging? Answering these questions informs how we might work, through policy and practice, toward alignment.
Educational Equity in Schools in India: Perils & Possibilities
Authors: Joshee Reva
Published: November 2024

India is one of the most diverse nation-states in the world. After gaining independence from Britain in 1947, it adopted a constitution that was based on pluralism, secularism, and egalitarianism. This constitutional vision guided the national education policies until very recently. The current moment in all areas of public policy is being defined by the ruling party's agenda of Hindutva, or Hindu nationalism. In education, the hallmarks of this move have been a rewriting of history to glorify a mythohistoric version of the Hindu past and a call to engage with ancient Indian knowledge systems and traditions. Unfortunately, Hindu nationalism is creating growing rifts between the majority Hindu population and other groups, including Muslims, Christians, and Dalits (formerly known as “untouchables” or “outcastes”). The aim of this essay is to understand what is happening in Indian education and to consider ways to return to an engagement with the constitutional principles of pluralism, secularism, and egalitarianism.
Constructing Effective Civic Education for Noncitizen Students
Authors: Banks Angela M.
Published: November 2024

Primary and secondary education is essential because it not only provides students with critical literacy and numeracy skills, but also, for many students, it begins their civic education. The goals of civic education vary by country, but a consistent goal is to provide students with the knowledge and skills necessary to be productive members of society. Globally, approximately thirty-six million children are living outside of their country of nationality. With the growing number of migrant children, states are facing two challenges to effective civic education. The first is access to schools, and the second is creating a civic education curriculum that effectively prepares all students to participate in society in ways that align with democratic principles and goals. This essay focuses on unauthorized migrant children's access to public schools and argues for civic education to incorporate the exploration of membership boundaries so that students, citizen and noncitizen alike, can study unauthorized migrants' participation in society within the context of membership status. This exploration offers students the opportunity to consider how to better align unauthorized migrants' lived realities with their legal status-and to better realize democracy's promise.
Extricating Sexual Corruption from the Shadow of Anti-Corruption Law: The Imperative for a New Approach
Authors: Williams Sope
Published: November 2024

Sexual corruption is a gendered crime, in which especially women and girls are coerced into providing sexual acts in exchange for access to public services or public opportunities. It has not received sufficient legislative attention, is often partially and inadequately criminalised through a patchwork of laws that ignore the different dimensions of the offence, and its impact on women and girls. This paper examines the legal framework against sexual corruption in South Africa and in several other countries, examining the approaches taken to criminalize sexual corruption and the challenges inherent in these approaches. The paper suggests a new way of defining sexual corruption and proposes a framework for addressing sexual corruption through a dedicated sexual corruption offence and victim-centred reporting infrastructure.
A new species of giant gecko of the genus Rhacodactylus from New Caledonia (Squamata, Gekkota, Diplodactylidae)
Authors: KÖHLER GUNTHER , SAMEIT JOACHIM , SEIPP ROBERT , GEISS KATHARINA
Published: November 2024

We describe a new species of giant gecko, Rhacodactylus willihenkeli sp. nov. from New Caledonia. The new species is most similar in external appearance and molecular data (16S and ND2 sequences) with R. leachianus from which it differs in coloration as well as having a genetic distance of 5.0% in the 16S gene fragment and 8.5% in the ND2 fragment, respectively.
Hidden under darkened wings: the identity of Doryctobracon fluminensis (Lima, 1938) (Hymenoptera: Braconidae) and a new species of the genus from Brazil
Authors: MARINHO CLÁUDIA F. , SHIMBORI EDUARDO M. , ALVARENGA CLARICE D. , ZUCCHI ROBERTO A.
Published: November 2024

Doryctobracon fluminensis (Lima) is one of several species of braconid parasitoids of fruit flies occurring in Brazil. Nearly 60 years passed after the original description by Lima (1938) until the publication of new records of D. fluminensis in several Brazilian states. Species identifications in these records were generally based on the darkened (infumate) fore wings, which has become the main character used in identification keys for recognizing D. fluminensis. After examination of the holotype of D. fluminensis, and comparison with several Brazilian specimens, we concluded that infumate fore wing alone is insufficient for separating species in the genus, as other Doryctobracon species also possess this feature. Here, we describe a new species, Doryctobracon simulatus Marinho sp. nov., based on specimens previously identified as D. fluminensis; redescribe D. fluminensis (Lima); and redefine the limits of D. maculatus Marinho. The misidentification discovered in the only two voucher specimens available indicates that other records of D. fluminensis in Brazil may also be incorrect, although those identifications cannot be verified. Our results demonstrate the importance of preserving voucher specimens in collections for future studies. An updated key to the species of Doryctobracon attacking fruit-infesting tephritids in Brazil is presented.
Serum microRNA qPCR profiling and validation indicate upregulation of circulating miR-145-5p and miR-26a-5p in migraineurs
Authors: Kordacka Joanna , Gruszka Renata , Zakrzewska Magdalena
Published: November 2024

Background

In recent years, miRNAs found in biological fluids have gained interest as biomarkers of numerous conditions, including migraine. This study aimed to identify differences in the levels of circulating miRNAs in the serum of migraineurs as compared to healthy controls, as well as between patients with different types of migraine and during the ictal and nonictal phases of the condition.

Methods

The screening phase of the study included serum from 13 migraine patients and 13 sex and age matched controls. A panel of 179 miRNAs was analysed using locked nucleic acid SYBR based qPCR. Based on statistical analysis (U Mann-Whitney test) and data from existing literature, nine miRNAs were selected for validation by TaqMan qPCR in an independent cohort of 26 migraineurs and eleven healthy controls. For comparison between the study and control group, U Mann-Whitney test was performed. The differences between patients with chronic and episodic migraine, migraine with and without aura and in ictal and nonictal phases were analysed with Kruskal-Wallis test. The results were corrected for multiple comparisons using Benjamini-Hochberg method. In all analysis p value ≤ 0,05 was considered as significant.

Results

Two miRNAs, miR-145-5p and miR-26a-5p were significantly upregulated in serum of migraineurs compared to healthy controls. MiRNA-19a-3p was downregulated in patients currently experiencing migraine headache compared to those in the interictal period. No differences were found between patients with different migraine types.

Conclusion

The results of our study add to the growing body of evidence for dysregulation of the circulating miRNA profile by migraine. They are further supported by previous reports on differential expression of miR-145-5p, miR-26a-5p and miR-19a-3p in migraineurs. However, more research on larger populations is needed to validate these findings, as well as elucidate the role of circulating miRNAs in the condition. Moreover, to wholly explore the biomarker potential of miRNAs, migraine patients should not only be compared to healthy controls but also to populations with different headache disorders.

Graphical Abstract
Dose-related effect of acetylcholine on human gingival blood flow
Authors: Nagy Tamás László , Mikecs Barbara , Lohinai Zsolt M. , Vág János
Published: November 2024

Background

This study investigates the dose-response relationship of acetylcholine (ACh) on healthy human gingival blood flow (GBF). Understanding this dose-response relationship contributes to studying vasodilatory mechanisms in various pathological conditions.

Methods

The study involved 22 young healthy men (21 - 32 years) to investigate the dose-response relationship of ACh on GBF. Semi-circular wells were created on the labial surface of the upper right second incisor (FDI #12) and upper left first incisor (FDI #21), including the gingival sulcus, for the application of drugs. ACh-chloride solutions at 0.1, 1, and 10 mg/mL were administered to the gingival sulcus of tooth FDI #12 with a Hamilton syringe. Physiological saline was applied on the contralateral side to FDI #21 as a control. The GBF was measured non-invasively by the laser speckle contrast imaging method in four 1mm high adjacent regions: coronal, midway1, midway2, and apical, and was expressed in a laser speckle perfusion unit (LSPU). After the baseline blood flow recording, ACh doses were applied sequentially, with washout periods in between. Data were statistically analyzed using a linear mixed model.

Results

The GBF did not change on the saline site throughout the experiment. The GBF was significantly higher at the coronal region after all ACh doses (baseline: 218±31 LSPU, and 227±38 LSPU p < 0.05, 239±40 LSPU p < 0.001, 291±54 LSPU p < 0.001, respectively) compared to the saline. It was also elevated following 1 and 10 mg/mL at the midway1 (245±48 LSPU,
p < 0.05, 293±65 LSPU p < 0.001). At midway2 and apical, only the 10 mg/mL dose was effective (285±71 LSPU, p < 0.001; 302±82 LSPU, p < 0.001).

Conclusions

Our findings suggest a dose-dependent vasodilation to ACh, emphasizing its role in human gingival microcirculation. Only the 10 mg/mL ACh could evoke remote vasodilation 3 mm from the application. The described method could facilitate the investigation of endothelium-dependent vasodilation in disorders affecting microcirculation, such as periodontitis or diabetes.
Healthcare providers’ hospital breastfeeding practices during the COVID-19 endemic and associated factors in Thailand: a cross-sectional study
Authors: Lawin Nongyao , Nuampa Sasitara , Somsuk Chananchida , Srisawad Sutthisak , Raungrongmorakot Kasem , Ketsuwan Sukwadee
Published: November 2024

Background

During COVID-19, healthcare providers were limited in their ability to provide breastfeeding support while women encountered breastfeeding difficulties. Enhancing appropriate breastfeeding care practices among healthcare providers in hospitals may improve the safety of breastfeeding during an endemic. However, little is known about the breastfeeding care practices by healthcare providers and associated factors during the endemic impact.

Objective

To investigate the effect of the endemic on breastfeeding care practices by healthcare providers in hospitals and examine their associated factors in Thailand.

Methods

A descriptive comparative design was conducted through an online survey with 350 healthcare providers across five regions of Thailand between January and March 2022. The convenience sampling was used to recruit healthcare providers who had at least two years of experience supporting breastfeeding practices and were full-time working in the obstetric and pediatric departments of public tertiary hospitals. Analysis of variance and the independent t-test with relevant statistical corrections were utilized for comparisons of associated factors on breastfeeding care practices in healthcare providers.

Results

The mean breastfeeding care practices in hospitals during the COVID-19 endemic by healthcare providers was 39.17 (SD = 4.64, range 23 to 50). Four factors were statistically significant differences in breastfeeding care practices score, including work position (F = 7.03, df = 2.0, p = 0.001), types of COVID-19 vaccination (F = 6.95, df = 2, p = 0.001), education (F = 4.78, df = 2, p = 0.009), and monthly family income (F = 4.25, df = 3, p = 0.006), respectively. In addition, dose of COVID-19 vaccination and types of COVID-19 vaccination were significantly associated with individual breastfeeding support in hospitals (p < 0.05).

Conclusions

Healthcare providers’ breastfeeding care practices in hospitals during the COVID-19 endemic were mostly at a moderate level in the Thai context. Hospital policy for maternal and child health support should strongly recommend the effective and safe practice of breastfeeding to encourage mothers to continue their breastfeeding duration.