tbuckley/cabot-search huggingface dataset:
Abstract 2728: Modulation of NFkappaB signaling influences tumor associated macrophage phenotypes in murine models of breast cancer
Authors: Kennady K. Bullock, Dominique Parker, Evan B. Glass, Alyssa Hoover, Alyssa Merkel, Richard Maynard, Andrew Wilson, Todd Giorgio, Julie A. Rhoades, Fiona E. Yull
Journal: Cancer Research (2021)

Abstract Tumor associated macrophages (TAMs) often exist in high densities in breast tumors and are associated with adverse clinical outcomes. TAM repolarization as a strategy to shift the breast cancer microenvironment from immunosuppressive to immunostimulatory is an active area of research. The canonical and non-canonical NfkappaB (NFkB) signaling pathways represent potential points of intervention to influence TAM phenotypes. We have found that upregulation of the canonical NFkB signaling pathway specifically in macrophages can be used to repolarize TAMs toward an M1, anti-tumor phenotype. Using our doxycycline inducible mouse model termed IKFM, we are exploring the effects of macrophage specific upregulation of NFkB signaling on different stages of tumor growth and metastasis. In studies using the IKFM mouse model, we found that doxycycline-induced NFkB activation in macrophages in established orthotopic mammary tumors has therapeutic effects on tumor outcomes. Compared to control mice, we found that IKFM mice have reduced tumor burden in the lung, indicating prevention of metastasis. Ongoing studies are focused on understanding how macrophage specific activation of NFkB influences the metastatic niches of lung and bone; two of the most common sites of breast cancer metastasis. To move our findings towards clinical translation, we have developed an M2-macrophage targeted nanoparticle that activates NFkB signaling by delivering an siRNA against IkappaBalpha, an inhibitor of the pathway. The M2 targeted nanoparticle is currently being tested in murine models of breast cancer metastasis to both lung and bone to translate our findings from the IKFM mouse model to a pharmacological manipulation. Citation Format: Kennady K. Bullock, Dominique Parker, Evan B. Glass, Alyssa Hoover, Alyssa Merkel, Richard Maynard, Andrew Wilson, Todd Giorgio, Julie A. Rhoades, Fiona E. Yull. Modulation of NFkappaB signaling influences tumor associated macrophage phenotypes in murine models of breast 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 2728.
Abstract 1318: Mechanochemical dynamic therapy for focal cancer treatment
Authors: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore
Journal: Cancer Research (2021)

Abstract This study proposes a new cancer drug delivery modality that allows for spatiotemporal control over activation of the therapeutic. Current standard cancer therapies of surgery, chemotherapy, and radiation therapy have their limitations, such as invasiveness and systemic toxicities. Developing a new modality that is localized and triggerable is becoming increasingly advantageous. Currently, photodynamic therapy (PDT) has been shown to be clinically effective but is limited by poor tissue penetration of light. Sonodynamic therapy (SDT) bypasses this pitfall with increased tissue penetration depth of ultrasound. However, PDT has limitations as it relies on the potentially damaging ultrasound cavitation effect and requires sonosensitizers or nanoparticles that have issues with bioavailability, biostability, and biosafety. In this study, we propose a novel ultrasound-based cancer treatment modality called mechanochemical dynamic therapy (MDT). In MDT, high intensity focused ultrasound (HIFU) delivers mechanical forces to force-responsive moieties of azo mechanophores that are embedded into biocompatible polyethylene glycol (PEG) hydrogel polymers. Upon focal sonication with HIFU, these mechanophores generate highly reactive free radicals (FRs) that are converted to reactive oxygen species (ROSs). The sonicated gels are then placed into in vitro cultures, allowing for the diffusion of ROSs into the cells to induce oxidative cytotoxicity and eventually cell death. Cell proliferation is monitored at 24-hour intervals, and by 72 hours, the sonicated gels produced cell killing effects comparable to lethal doses of H2O2 in both in vitro mouse melanoma (B16F10) and breast cancer (E0771) models. Sonication of control hydrogels that did not contain mechanophores showed minimal cytotoxicity. This study shows the potential of MDT as a drug delivery platform that overcomes the limitations of PDT and SDT and has the potential to be applied synergistically with other current cancer treatments. This is the first demonstration of using HIFU-activated mechanophores to non-invasively deliver cancer therapies with spatiotemporal control. Citation Format: Gun Kim, Qiong Wu, James L. Chu, Emily J. Smith, Michael L. Oelze, King C. Li, Jeffrey S. Moore. Mechanochemical dynamic therapy for focal cancer treatment [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 1318.
Abstract 487: Genomic difference of CD4 CD8 double-positive T cells versus conventional CD4 T cells and CD8 T cells in responders undergoing immunotherapy in advanced HCC
Authors: Vox Ting, Carmen Chak-Lui Wong, Yok Lam Kwong, Thomas Chung Cheung Yau
Journal: Cancer Research (2021)

Abstract Intro: The number of undergoing clinical trials using more than one immune checkpoint inhibitor is rising rapidly. Previously, we have observed CD4 CD8 double-positive T cells (Figure 1) from checkpoint inhibitor responder in advanced HCC patient. To further investigate the genomic difference between CD4 CD8 double-positive T (DP T) cell and conventional CD4, CD8 T cells, we have applied GO, KEGG, and Reactone database to compare. Material and method: Two responders showed a partial response to PD-1/PD-L1 inhibitor treatment with advanced HCC were included. DP T cells were measured with Carl Zeiss Laser Scanning Microscopy (LSM) 780 (Zeiss) at Faculty Core Facility. Blood samples from responders were stained with an antibody cocktail containing CD3, CD4 and CD8 T cells. To visualise the labelling cells, CD3, CD4 and CD8 surface fluorescence was shown in yellow, violet and green dots respectively. Conventional CD4, CD8 T cells and DP T cells were further sorted using the same staining protocol before extraction. RNA extraction were immediately applied after cell sorting, where CD4 CD8 double-negative T (DN T) cells were also included. All patients were seen at the Department of Medical Oncology, Queen Mary Hospitals. Blood samples were collected after the treatment along with clinical routine blood test. Results: A total number of 3723 and 4653 genes respectively were differentially expressed in DP T cell versus CD8 T cell and DP T cell versus CD4 T cell in responder 1, whereas a total 11117 differential expressed genes were measured in DP T cell and DN T cell. In responder 2, a total number of 6439 genes were differentially expressed in DP T versus CD8 T cell, while a total number of 316 and 488 differential expressed genes were measured in DP T cell versus CD4 T cell and DP T cell versus DN T cell. GO, KEGG and Reactone database analysis indicated cytokine receptor, cell cytotoxicity and cell activation enrichment in DP T cell compared to conventional CD4 or CD8 T cell. Citation Format: Vox Ting, Carmen Chak-Lui Wong, Yok Lam Kwong, Thomas Chung Cheung Yau. Genomic difference of CD4 CD8 double-positive T cells versus conventional CD4 T cells and CD8 T cells in responders undergoing immunotherapy in advanced HCC [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 487.
High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: specific cell subtypes influence survival and determine molecular subtype classification
Authors: Siel Olbrecht, Pieter Busschaert, Junbin Qian, Adriaan Vanderstichele, Liselore Loverix, Toon Van Gorp, Els Van Nieuwenhuysen, Sileny Han, Annick Van den Broeck, An Coosemans, Anne-Sophie Van Rompuy, Diether Lambrechts, Ignace Vergote
Journal: Genome Medicine (2021)

High-grade serous tubo-ovarian cancer (HGSTOC) is characterised by extensive inter- and intratumour heterogeneity, resulting in persistent therapeutic resistance and poor disease outcome. Molecular subtype classification based on bulk RNA sequencing facilitates a more accurate characterisation of this heterogeneity, but the lack of strong prognostic or predictive correlations with these subtypes currently hinders their clinical implementation. Stromal admixture profoundly affects the prognostic impact of the molecular subtypes, but the contribution of stromal cells to each subtype has poorly been characterised. Increasing the transcriptomic resolution of the molecular subtypes based on single-cell RNA sequencing (scRNA-seq) may provide insights in the prognostic and predictive relevance of these subtypes.We performed scRNA-seq of 18,403 cells unbiasedly collected from 7 treatment-naive HGSTOC tumours. For each phenotypic cluster of tumour or stromal cells, we identified specific transcriptomic markers. We explored which phenotypic clusters correlated with overall survival based on expression of these transcriptomic markers in microarray data of 1467 tumours. By evaluating molecular subtype signatures in single cells, we assessed to what extent a phenotypic cluster of tumour or stromal cells contributes to each molecular subtype.We identified 11 cancer and 32 stromal cell phenotypes in HGSTOC tumours. Of these, the relative frequency of myofibroblasts, TGF-β-driven cancer-associated fibroblasts, mesothelial cells and lymphatic endothelial cells predicted poor outcome, while plasma cells correlated with more favourable outcome. Moreover, we identified a clear cell-like transcriptomic signature in cancer cells, which correlated with worse overall survival in HGSTOC patients. Stromal cell phenotypes differed substantially between molecular subtypes. For instance, the mesenchymal, immunoreactive and differentiated signatures were characterised by specific fibroblast, immune cell and myofibroblast/mesothelial cell phenotypes, respectively. Cell phenotypes correlating with poor outcome were enriched in molecular subtypes associated with poor outcome.We used scRNA-seq to identify stromal cell phenotypes predicting overall survival in HGSTOC patients. These stromal features explain the association of the molecular subtypes with outcome but also the latter's weakness of clinical implementation. Stratifying patients based on marker genes specific for these phenotypes represents a promising approach to predict prognosis or response to therapy.
Exploring the Gap Between Excess Mortality and COVID-19 Deaths in 67 Countries
Authors: Francesco Sanmarchi, Davide Golinelli, Jacopo Lenzi, Francesco Esposito, Angelo Capodici, Chiara Reno, Dino Gibertoni
Journal: JAMA Network Open (2021)

ResultsMost of the 67 countries experienced an increase in mortality during 2020 (Table ).Among countries with increased mortality (ie, those located above 0 on the y-axis in the Figure ), a small number appeared under the identity line, showing lower-than-expected mortality after subtracting COVID-19 deaths.Countries located above the identity line can be visually classified into 2 groups: 1 with several Latin American and East European countries, which exhibit a large gap between EM and CCM (eg, Mexico, 212 excess deaths vs 96 COVID-19 deaths per 100 000 population); the other, more heterogeneous group showed a moderate EM beyond CCM (eg, Greece, 57 excess deaths vs 45 COVID-19 deaths per 100 000 population).Countries with negative EM also had very low CCM and
Analysis of primari non-function, delayed graft function and overall graft survival for expanded criteria donors’ kidneys
Authors: M.R. Peradejordi Font, A. Vilaseca Cabo, L. Peri Cusi, M. Musquera Felip, T. Ajami Fardoun, C. Mercader Barrull, A. Ruiz Arranz, D. Paredes Zapata, F. Diekmann, A. Alcaraz Asensio
Journal: European Urology (2021)
Clinical Strategy for the Diagnosis and Treatment of Immune Checkpoint Inhibitor–Associated Myocarditis
Authors: Lorenz H. Lehmann, Jennifer Cautela, Nicolas Palaskas, Alan H. Baik, Wouter C. Meijers, Yves Allenbach, Joachim Alexandre, Tienush Rassaf, Oliver J. Müller, Mandar Aras, Aarti H. Asnani, Anita Deswal, Michal Laufer-Perl, Franck Thuny, Mathieu Kerneis, Salim S. Hayek, Stéphane Ederhy, Joe-Elie Salem, Javid J. Moslehi
Journal: JAMA Cardiology (2021)

In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor-associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed.Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte-associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis.This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.
Concerns About Study on Fluoroquinolone Use and Risk of Development Of Aortic Aneurysm
Authors: Antonio V. Sterpetti
Journal: JAMA Surgery (2021)

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Abstract 1050: Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia
Authors: Xiaoyue Chen, Sean Caenepeel, Brian Belmontes, Patricia L. McElroy, Karen Rex, Tao Osgood, Paul Hughes
Journal: Cancer Research (2021)

Abstract Acute Myeloid Leukemia (AML) is the most common and aggressive acute leukemia in adults, with a 25% 5-year survival rate. FLT3 is the most frequently mutated gene in AML. About 25% of AML patients harbor FLT3 internal tandem duplication (ITD) mutations, and about 8 % of patients harbor FLT3 tyrosine kinase domain (TKD) mutations. Both FLT3-ITD and FLT3-TKD mutations constitutively activate the protein, which causes poor survival. Gilteritinib is a highly potent and selective oral FLT3 inhibitor recently approved by the FDA. Although gilteritinib showed strong single agent activity in AML patients with FLT3 mutations, the development of gilteritinib resistance limits the long-term efficacy of this treatment, indicating that combination therapy may be advantageous for AML patients with FLT3 mutations. FLT3 mutations are known to be anti-apoptotic. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic protein, expressed in a large percentage of the AML patient population, plays a critical role in AML cell survival and drug resistance. AMG 176 is a potent, selective and orally bioavailable MCL-1 inhibitor, which induces rapid commitment to apoptosis in AML. Here we demonstrated that AMG 176 and gilteritinib combination treatment synergistically targeted FLT3-ITD mutated AML. A strong synergistic effect (Combination index &amp;lt;0.2) was observed in two FLT3-ITD mutated AML cell lines treated with the AMG 176 plus gilteritinib combination. Increased Bcl-2-like protein 11 (BIM) expression and decreased BIM/MCL-1 interaction was observed under the combination treatment, coupled with a significant increase in apoptosis. In the MV4-11 AML xenograft model, mice treated with two cycles of AMG 176 (2 days on 5 days off) at 30 mg/kg or with 3 mg/kg gilteritinib daily showed 76% or 74% tumor growth inhibition respectively. A statistically significant increase in efficacy was observed in the combination treatment group, with 92.8% tumor regression, including 50% of mice being tumor free. No significant difference in body weight was found between groups. Our results show that AMG 176 plus gilteritinib treatment was effective and well tolerated in mouse models of AML, which supports further evaluation in a clinical setting. Citation Format: Xiaoyue Chen, Sean Caenepeel, Brian Belmontes, Patricia L. McElroy, Karen Rex, Tao Osgood, Paul Hughes. Efficacy of AMG 176 in combination with gilteritinib in preclinical models of acute myeloid leukemia [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 1050.
Next-generation cophylogeny: unravelling eco-evolutionary processes
Authors: Isabel Blasco-Costa, Alexander Hayward, Robert Poulin, Juan A. Balbuena
Journal: Trends in Ecology & Evolution (2021)

A fundamental question in evolutionary biology is how microevolutionary processes translate into species diversification. Cophylogeny provides an appropriate framework to address this for symbiotic associations, but historically has been primarily limited to unveiling patterns. We argue that it is essential to integrate advances from ecology and evolutionary biology into cophylogeny, to gain greater mechanistic insights and transform cophylogeny into a platform to advance understanding of interspecific interactions and diversification more widely. We discuss key directions, such as incorporating trait reconstruction and considering multiple scales of network organization, and highlight recent developments for implementation. A new quantitative framework is proposed to allow integration of relevant information, such as quantitative traits and assessment of the contribution of individual mechanisms to cophylogenetic patterns.
Somatic mutations provide important and unique insights into the biology of complex diseases
Authors: Sigurgeir Olafsson, Carl A. Anderson
Journal: Trends in Genetics (2021)

Somatic evolution of cells within the body is well known to lead to cancers. However, spread of somatic mutations within a tissue over time may also contribute to the pathogenesis of non-neoplastic diseases. Recent years have seen the publication of many studies aiming to characterize somatic evolution in healthy tissues. A logical next step is to extend such work to diseased conditions. As our understanding of the interplay between somatic mutations and non-neoplastic disease grows, opportunities for the joint study of germline and somatic variants will present themselves. Here, we present our thoughts on the utility of somatic mutations for understanding both the causes and consequences of common complex disease and the challenges that remain for the joint study of the soma and germline.
Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab
Authors: James L Alexander, Hajir Ibraheim, Bhavisha Sheth, Jessica Little, Muhammad Saheb Khan, Camellia Richards, Nikki Hunter, Dharmisha Chauhan, Raguprakash Ratnakumaran, Kathleen McHugh, David J Pinato, Paul Nathan, Julia Choy, Shanthini M Crusz, Andrew Furness, Samra Turajlic, Lisa Pickering, James Larkin, Julian P Teare, Sophie Papa, Ally Speight, Anand Sharma, Nick Powell
Journal: Journal for ImmunoTherapy of Cancer (2021)

Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.