tbuckley/cabot-search huggingface dataset:
Abstract 2642: Using 3-Dimensional <i>in vitro</i> models to unravel the complexity of the metastatic microenvironment in high-grade serous ovarian cancer
Authors: Beatrice Malacrida, Robin Delaine-Smith, Sam Nichols, Eleni Maniati, Roanne L. Jones, Martin M. Knight, Oliver M. Pearce, Frances R. Balkwill
Journal: Cancer Research (2021)

Abstract Studying the complexity of the tumor microenvironment (TME) still represents a challenge in research. The intricate communication within the stroma - fibroblast, immune cells, endothelial cells and the extracellular matrix (ECM) - and the malignant cell compartment sustains every stage of cancer progression and resistance to cancer therapies, but it is difficult to model this using human cells. Using a multi-level deconstruction of human metastases as a template and validation, we developed multicellular models of high-grade serous ovarian cancer (HGSOC) with increased complexity. The different models - tri-, tetra- and penta-cultures - consist of different combinations of primary adipocytes, fibroblasts, mesothelial cells, HGSOC cells and myeloid cells that mimic the structure and the composition of a human omental metastatic tissue. In HGSOC biopsies, we previously identified a prognostic matrisome signature and a number of pathways correlating ECM deposition and disease progression. This knowledge combined with the versatile nature of our platforms has allowed us to identify the contributions of each cell type in supporting tumor progression and ECM remodeling. For instance, 14-day tri-culture of malignant cells, adipocytes and fibroblasts was sufficient to replicate the deposition of specific ECM proteins and the prognostic matrisome signature seen in human omental metastases. Moreover, we found that TGFβR and Hedgehog signaling pathways act together on the fibroblasts to stimulate ECM production. In addition, in the tetra-culture model, we identified platelets as promoters of early metastatic invasion by activating mesothelial cells. As the immune system plays an important role in HGSOC tumor microenvironment, we have now added myeloid cells to form a more complex penta-culture in which we can analyze the behavior and impact of myeloid cells. In conclusion, the multicellular models presented here could be a new resource to study new and established cancer therapies and provide a useful tool to better understand the molecular mechanisms that drive cancer progression. Citation Format: Beatrice Malacrida, Robin Delaine-Smith, Sam Nichols, Eleni Maniati, Roanne L. Jones, Martin M. Knight, Oliver M. Pearce, Frances R. Balkwill. Using 3-Dimensional in vitro models to unravel the complexity of the metastatic microenvironment in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2642.
Identifying the cause of breast and nipple pain during lactation
Authors: Lisa H Amir, Carmela Baeza, Jayne R Charlamb, Wendy Jones
Journal: BMJ (2021)

### What you need to know

A first time mother developed left nipple pain 24 hours after the birth. This persisted despite trying nipple shields and topical lanolin. On day 7 she developed mastitis in her left breast and was prescribed flucloxacillin, but the nipple and breast pain continued. Her friend suggested oral probiotics, to no effect. At the breastfeeding clinic (6 weeks postpartum) the left breast pain was excruciating and a burning pain had started in her right breast. She was also concerned about her baby’s slow weight gain. On examination, her nipples were sensitive to light touch and examination of the baby indicated torticollis. When observing a feed, good positioning and attachment was seen on the right but the infant’s torticollis made it difficult for him to attach on the left side and the mother quickly took him off her breast because it was too painful. The left nipple was flattened after the feed .

More than 70% of first time mothers report nipple and/or breast pain in the first week post partum.1 This is frequently nipple pain resulting from inadequate latching; however, multiple diagnoses should be considered.2

This article helps clinicians promptly identify and resolve the underlying cause(s) of pain so that premature cessation of breastfeeding can be avoided and the breastfeeding relationship becomes enjoyable for mother and baby. We explain the three elements of assessment—the mother’s health, the infant’s …
Abstract 677: Immune biomarkers of response to Ra223 dichloride and stereotactic body radiation therapy in patients with oligometastatic prostate cancers
Authors: Marice Alcantara, Tanya Dorff, Jessica Liu, Paul Frankel, Przemyslaw Twardowski, Savita Dandapani, Marcin Kortylewski
Journal: Cancer Research (2021)

Abstract Prostate cancer is the second leading cause of death in men in the developed countries. Androgen deprivation therapy (ADT) is commonly used to treat prostate tumors at earlier stages due to hormone-dependence of cancer cells. However, the onset of androgen-resistance with tumor progression and the negative impact of ADT on the quality of life are significant challenges. To address these issues, we have initiated a novel clinical trial combining radium Ra223 dichloride with stereotactic body radiation treatment (SBRT) and short course of ADT in patients with oligometastatic, castration-sensitive prostate cancer (NCT03351735). Patients with one to four oligometastatic prostate cancer lesions have been receiving ADT for nine months, together with SBRT to all metastatic sites and six cycles of Ra223 to target micrometastatic bone lesions. Eight out of the planned 24 patients have already completed the full treatment course, with five patients currently on surveillance (not requiring any further treatment) and three patients receiving next cycle of therapy. As part of this investigator-initiated study, we have performed a comprehensive immune characterization of peripheral immune cells and serum immune biomarkers in all treated patients. Based on flow cytometric analysis, we found a significant decrease in the percentage of CD4+ T cells befoe and after SBRT (cycle 1) but no changes in the elevated levels of programmed cell death-1 (PD-1), a marker of T-cell exhaustion, on the circulating CD4+ and CD8+ T cells. In addition, we observed high levels of the activated STAT3 (pSTAT3) in myeloid-derived suppressor cells (MDSCs), together with its downstream target Arginase-I. Finally, IL-8 stood out as a cytokine strongly elevated in plasma of patients who received the complete Ra223 treatment but not directly after SBRT. Overall, these preliminary results suggest that this combinatorial radiotherapy patients with oligometastatic prostate cancers impacts immune cell activity but rather than leading to T cell activation it may promote tolerogenic activity of MDSCs. Citation Format: Marice Alcantara, Tanya Dorff, Jessica Liu, Paul Frankel, Przemyslaw Twardowski, Savita Dandapani, Marcin Kortylewski. Immune biomarkers of response to Ra223 dichloride and stereotactic body radiation therapy in patients with oligometastatic prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 677.
Analysis of the detection rate of target only vs. target plus standard biopsy in naïve patients based on radical prostatectomy specimens
Authors: E. Checcucci, S. De Cillis, D. Amparore, G. Volpi, F. Piramide, S. Granato, M. Sica, P. Alessio, A. Pecoraro, G. Cattaneo, D. Garrou, M. Manfredi, C. Fiori, E. Bollito, I. Stura, G. Migliaretti, F. Porpiglia
Journal: European Urology (2021)
Identifying a genomic region at Chromosome 11p.14.1 that is associated to FSH serum level in men with unexplained male infertility
Authors: M. Schubert, L. Pérez Lanuza, M. Wöste, M. Dugas, Y. Rassam, S. Heilmann-Heimbach, F. Tüttelmann, S. Kliesch, J. Gromoll
Journal: European Urology (2021)
Abstract 2384: Hypoxia-induced exosomal miR-376c-3p promotes metastatic potential of ovarian cancer cells
Authors: HyunA Jo, Wenyu Wang
Journal: Cancer Research (2021)

Abstract Background: Hypoxia significantly impacts cancer progressions, in various types of solid tumors including ovarian cancer. Exosomes (30-150nm) secreted from cells in the hypoxic tumor microenvironment play a critical role in cancer progression through transferring functional proteins, mRNAs, and miRNAs as mediators of intercellular communication. However, the underlying mechanisms how cancer exosomes induced by hypoxia regulate cancer progressions remain elusive. This study aims to assess the effect of exosomes secreted from hypoxic cancer cells on the metastatic ability of ovarian cancer cells. Methods: Two ovarian cancer cell lines, Kuramochi and SKOV-3, were used. Exosomes from cancer cells cultured under normoxic or hypoxic conditions (normoxic or hypoxic exosomes) were isolated using Exoquick-TC kit and identified by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. BCA assay was done to evaluate the concentration of exosomes. Normoxic or hypoxic exosomes were treated on ovarian cancer cells. Cell migration and invasion abilities were examined by wound healing assay and MatriGel invasion assay respectively. Furthermore, miRNA sequencing was performed to explore the miRNA profiling of hypoxic and normoxic exosomes. Results: The size of exosomes was ranging from 52nm to 121nm (mean diameter = 85nm). The quantity of hypoxic exosomes was significantly more than that of normoxic exosomes. Hypoxic exosomes increased the migration and invasion ability of kuramochi and SKOV-3 cells. In addition, hypoxic exosomes treatment on ovarian cancer cells up-regulated the expression of MMP-2 and Snail-1 at the protein level. MiRNA sequencing showed that miR-376c-3p was significantly upregulated in hypoxic exosomes in both ovarian cancer cell lines. Moreover, miR376c-3p enhanced migration and invasion ability of ovarian cancer cells, validated by miR376c-3p inhibitor and mimics. Conclusions: Taken together, our study suggests that miR376c-3p transferred by hypoxic exosomes could promote the metastatic potential of ovarian cancer cells by inducing MMP-2 and Snail-1. Citation Format: HyunA Jo, Wenyu Wang. Hypoxia-induced exosomal miR-376c-3p promotes metastatic potential of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2384.
HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection
Authors: Anju Bansal, Mika N. Gehre, Kai Qin, Sarah Sterrett, Ayub Ali, Ying Dang, Sojan Abraham, Margaret C. Costanzo, Leon A. Venegas, Jianming Tang, N. Manjunath, Mark A. Brockman, Otto O. Yang, June Kan-Mitchell, Paul A. Goepfert
Journal: Journal of Clinical Investigation (2021)

CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E-restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E-restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E-restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E-restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection.
Accurate differentiation of renal tumour pathological subtypes using a machine learning model of epigenetic markers
Authors: S. Rossi, I. Newsham, S. Pita, G. Park, R. Lach, A. Babbage, C. Smith, K. Brennan, T. Mitchell, A. Warren, O. Gevaert, J. Leppert, G.D. Stewart, C.E. Massie, S.A. Samarajiwa
Journal: European Urology (2021)
Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure
Authors: Francesca Leo, Tatsiana Suvorava, Sophia K. Heuser, Junjie Li, Anthea LoBue, Frederik Barbarino, Eugenia Piragine, Rebekka Schneckmann, Beate Hutzler, Miranda E. Good, Bernadette O. Fernandez, Lukas Vornholz, Stephen Rogers, Allan Doctor, Maria Grandoch, Johannes Stegbauer, Eddie Weitzberg, Martin Feelisch, Jon O. Lundberg, Brant E. Isakson, Malte Kelm, Miriam M. Cortese-Krott
Journal: Circulation (2021)

Current paradigms suggest that nitric oxide (NO) produced by endothelial cells (ECs) through endothelial nitric oxide synthase (eNOS) in the vessel wall is the primary regulator of blood flow and blood pressure. However, red blood cells (RBCs) also carry a catalytically active eNOS, but its role is controversial and remains undefined. This study aimed to elucidate the functional significance of RBC eNOS compared with EC eNOS for vascular hemodynamics and nitric oxide metabolism. We generated tissue-specific loss- and gain-of-function models for eNOS by using cell-specific Cre-induced gene inactivation or reactivation. We created 2 founder lines carrying a floxed eNOS (eNOSflox/flox) for Cre-inducible knockout (KO), and gene construct with an inactivated floxed/inverted exon (eNOSinv/inv) for a Cre-inducible knock-in (KI), which respectively allow targeted deletion or reactivation of eNOS in erythroid cells (RBC eNOS KO or RBC eNOS KI mice) or in ECs (EC eNOS KO or EC eNOS KI mice). Vascular function, hemodynamics, and nitric oxide metabolism were compared ex vivo and in vivo. The EC eNOS KOs exhibited significantly impaired aortic dilatory responses to acetylcholine, loss of flow-mediated dilation, and increased systolic and diastolic blood pressure. RBC eNOS KO mice showed no alterations in acetylcholine-mediated dilation or flow-mediated dilation but were hypertensive. Treatment with the nitric oxide synthase inhibitor Nγ-nitro-l-arginine methyl ester further increased blood pressure in RBC eNOS KOs, demonstrating that eNOS in both ECs and RBCs contributes to blood pressure regulation. Although both EC eNOS KOs and RBC eNOS KOs had lower plasma nitrite and nitrate concentrations, the levels of bound NO in RBCs were lower in RBC eNOS KOs than in EC eNOS KOs. Reactivation of eNOS in ECs or RBCs rescues the hypertensive phenotype of the eNOSinv/inv mice, whereas the levels of bound NO were restored only in RBC eNOS KI mice. These data reveal that eNOS in ECs and RBCs contribute independently to blood pressure homeostasis.
The therapeutic implications of immunosuppressive tumor aerobic glycolysis
Authors: Bradley I. Reinfeld, W. Kimryn Rathmell, Tae Kon Kim, Jeffrey C. Rathmell
Journal: Cellular and Molecular Immunology (2021)

Abstract In 2011, Hanahan and Weinberg added “Deregulating Cellular Energetics” and “Avoiding Immune Destruction” to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.
Compensatory Vascular Remodeling in Stage 5 Chronic Kidney Disease in Response to Chronic Inflammation: An Interplay between Platelets and Lymphocytes
Authors: Jack Bontekoe, Justin Lee, Vinod K Bansal, Debra Hoppensteadt, Paula D'Almeida Maia, Amanda Walborn, Jawed Fareed
Journal: Blood (2017)
Taking globally consistent health impact projections to the next level
Authors: Joacim Rocklöv, Veronika Huber, Kathryn Bowen, Richard Paul
Journal: The Lancet Planetary Health (2021)

<h2>Summary</h2> Despite intensive research activity within the area of climate change, substantial knowledge gaps still remain regarding the potential future impacts of climate change on human health. A key shortcoming in the scientific understanding of these impacts is the lack of studies that are conducted in a coordinated and consistent fashion, producing directly comparable outputs. This Viewpoint discusses and exemplifies a bottom-up initiative generating new research evidence in a more coordinated and consistent way compared with previous efforts. It describes one of the largest model comparisons of projected health impacts due to climate change, so far. Yet, the included studies constitute only a selection of health impacts in a variety of geographical locations, and are therefore not a comprehensive assessment of all possible impact pathways and potential consequences. The new findings of these studies shed light on the complex and multidirectional impacts of climate change on health, where impacts can be both adverse or beneficial. However, the adverse impacts dominate overall, especially in the scenarios with more greenhouse gas forcing. Overall, the future population at risk of disease and incidence rates are predicted to increase substantially, but in a highly location-specific and disease-specific fashion. Greenhouse gas emission mitigation can substantially reduce risk and resultant morbidity and mortality. The potential positive impact of adaptation has not been included in the models applied, and thus remains a major source of uncertainty. This bottom-up initiative lays out a research strategy that brings more meaningful research outputs and calls for greater coordination of research initiatives across the health community.
Abstract 2888: Reversible and dose-dependent suppression of motility of human breast cancer cells with ONC201 and/or TR57 in culture
Authors: Yana Evstratova, Margarita Kobyakova, Irina Odinokova, Alexander Stolyarov, Artyom Mishukov, Lee M. Graves, Ekhson Holmuhamedov
Journal: Cancer Research (2021)

Abstract The cytotoxicity and cytostatic effects of imipridone family drugs ONC201 and its analog TR57 (Madera, USA) in variety of cultured breast cancer cell line (estrogen dependent BT474) was manifested through induction of ISR (Integrated Stress Response), UPRER and UPRMT. The major consequences of drug treatment are inhibition of proliferation and mitochondrial structural and functional damage(s). Our preliminary data demonstrated that 24 h exposure of BT474 leads to dysregulation and suppression in mitochondrial Ca2+ uptake and Ca2+ capacity (Odinokova et al., 2021). In the present work, we extend our study to include the effect of these drugs on the rate of migration intact and treated cells in culture. Treatment of BT474 cells in culture for 24h resulted in decreased motility of cells from 17 ± 2 µm/h in the absence of the drugs to 5 ± 1 µm/h and to 3±1 µm/h in cells treated with 10µM of ONC201 or 50nM of TR57 (n=5). This suppression was fully reversible and removal of drugs for 120h resulted in time dependent restoration of the initial motility of BT474 cells, and TR57 caused larger inhibitory effect on motility as compared with ONC201. Buffering of extracellular Ca2+ with 5 mM EGTA or intracellular Ca2+ with 10 µM BAPTA, 30 min suppressed motility of cells (19 ± 2 µm/h vs 6 ± 1 µm/h). Gd3+, selective blocker of store operated Ca2+ entrance (SOCE) pathway at concentration of 10 µM suppressed the motility of BT474 cells, and rate of migration changed for from 16 ± 2 µm/h in control to 7± 2 µm/h, in Gd3+ treated cells. In line with our preliminary data, taken together these data indicate that ONC201 and/or TR57 induced dysfunction in mitochondrial Ca2+ homeostasis, which translates into the suppression of the migration of human breast cancer cells in culture. Support of Funding Information: Russian Science Foundation № 19-75-20145 Citation Format: Yana Evstratova, Margarita Kobyakova, Irina Odinokova, Alexander Stolyarov, Artyom Mishukov, Lee M. Graves, Ekhson Holmuhamedov. Reversible and dose-dependent suppression of motility of human breast cancer cells with ONC201 and/or TR57 in culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2888.
Abstract 1502: Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity
Authors: John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Kelly T. Kennewick, Lupita S. Lopez, Hee J. Lee, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman
Journal: Cancer Research (2021)

Abstract Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity. Citation Format: John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Kelly T. Kennewick, Lupita S. Lopez, Hee J. Lee, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman. Pre-conditioning modifies the tumor microenvironment to enhance solid tumor CAR T cell efficacy and endogenous immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1502.