tbuckley/cabot-search huggingface dataset:
Abstract 3906: PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice
Authors: Madeline Lee, Jie Xiang, Tian Gan, Yuelei Shen, Chaoshe Guo
Journal: Cancer Research (2019)

Abstract Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses the early stages of T cell activation. In preclinical studies, blockade of CTLA-4 led to an increase in T-cell proliferation. Anti-CTLA-4 monoclonal antibodies (mAbs) have been shown to be an effective approach for tumor immunotherapy. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) characterization of these antibodies is essential for designing first-in human trials. PK prediction is especially challenging for monoclonal antibodies attributed to target-mediated drug disposition (TMDD). We generated a humanized B-hCTLA-4 mouse model, in which exon 2 of the murine CTLA-4 gene was replaced with its human counterpart. In homozygous mice, only human protein expression can be detected, while mouse CTLA-4 was knocked out. Using B-hCTLA-4 mice, we developed a mAb PK/PD model to characterize the anti-tumor effects of hCTLA-4 antibodies. MC38 cancer cells were inoculated into both C57BL/6 wild type and humanized CTLA-4 animals. After administering different antibody concentrations (ranging from 3.0, 1.0, 0.3, 0.1mg/kg), serum samples from each animal were taken at specific time points for PK/PD analysis. An NCA approach was used to determine serum concentrations of mAb in mice. The levels of 13 cytokines (IL-23, IL-1α, IFN-r, TNF-a, IL-6 etc.) were quantified using LEGENDplex bead-based immunoassays. The PK half-life was 50~100h and the cytokine concentration ranged from 0-2000pg/ml depending on the dose used. The Tumor Growth Inhibition (TGI) value was also evaluated as a PD effect in the MC38/B-hCTLA-4 model. The TGI value reached nearly 100% when the dose was above 0.3mg/kg. The PK/PD assays showed that the anti hCTLA-4 mAb tested has a dose-dependent tumor inhibition effect in hCTLA-4 mice. Results from TMDD model data showed that the humanized mice reached QuasiSteady State faster than wild type mice, indicating that the humanized mice are an appropriate TMDD model. In conclusion, humanized B-hCTLA-4 mice are a promising PK/PD model for CTLA-4 mAb preclinical trials. Citation Format: Madeline Lee, Jie Xiang, Tian Gan, Yuelei Shen, Chaoshe Guo. PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3906.
Lysosomal exocytosis: a mechanism for hyperthermia-induced HSP70 release from prostate cancer cells
Authors: Salamatu S. Mambula, Stuart K. Calderwood
Journal: Cancer Research (2006)

3878  Heat shock proteins were first characterized as molecular chaperones, however, recent studies have shown that they can be actively released from intact cells and participate in host immunity, for example, tumor immunity. HSP70 does not possess a secretory signal sequence yet other investigators as well as our studies demonstrate that HSP70 is actively secreted to the extracellular millieu. We observed HSP70 release from prostate cancer cells PC3 and LNCaP following heat shock at 400C, fever range hyperthermia and 430C, at a temperature which leads to maximal induction of HSP70. We also provide evidence for a regulated non-classical method of exocytosis that is similar to IL1-β exocytosis. Our data revealed that the leaderless protein HSP70 appears to be released from prostate carcinoma cells through an active mechanism that is independent of the rate of HSP70 synthesis and does not seem to involve cell death. The factors required for HSP70 release resemble those involved in IL-1β secretion, and we report here on the dramatic inhibitory effect of glibenclamide, potent inhibitors of ABC activity, on HSP70 secretion in prostate cancer cells. We also provide biochemical evidence that hyperthermia treated prostate cancer cells release HSP70 contained in lysosomal compartments thus increase in pH of the acidic lysosomal compartments inhibits HSP70 release. In conclusion, we have demonstrated a new mechanism of hyperthermia induced HSP70 release that occurs via lysosomes and regulated by ABC transport.
Sixty seconds on . . . gloves off
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Only if you mean fighting infection. Nurses at Great Ormond Street Hospital have started the “Gloves are off” campaign to encourage healthcare professionals to reduce their use of non-sterile gloves and instead wash their hands more regularly.

Research has shown that non-sterile gloves are associated with an increased risk of cross contamination and transmission of healthcare associated infections, because …
Abstract 5020: Therapeutic potential of an immune modulatory CCL22-based vaccine
Authors: Inés Lecoq, Katharina L. Kopp, Rikke Christensen, Ayako W. Pedersen, Evelina Martinenaite, Mai-Britt Zocca, Mads H. Andersen
Journal: Cancer Research (2019)

Abstract CCL22 is a macrophage-derived chemokine that exerts immunosuppressive functions by the recruitment of regulatory T cells (Tregs) through the CCL22/CCR4 axis. It is expressed by cells in the tumor microenvironment (TME) in many different cancer tissues including breast, lung, and pancreatic cancer and is thought to promote the suppression of anti-cancer immunity. Recently, we described that CCL22-specific T-cells from cancer patients can kill CCL22-expressing tumor cells, and activation of CCL22-specific T cells may directly influence the CCL22 concentration in the TME, suggesting that CCL22 may be an interesting target for an immune modulatory vaccine. Thus, in the present study we have targeted CCL22-expressing cells by activation of CCL22-specific effector T cells by peptide vaccination in tumor models. We present here that CCL22-targeting peptide vaccination leads to expansion of predominantly CD8+, IFNγ-secreting CCL22-specific T cells in both BALB/c and C57BL/6 mice. Furthermore, CCL22 vaccination results in delayed tumor growth and enhanced survival in tumor harboring hosts in CT26 and Pan02 models. Preliminary assessment of gene expression in the tumors reveals that CCL22 vaccination leads to a reduction of CCL22 expression, alongside other immune suppressive molecules, such as IDO1 in the TME. Characterization of vaccine-mediated changes of cellular composition of the TME is currently ongoing. In conclusion, our findings provide a rationale for a novel cancer immunotherapy to target the immune suppressive TME. Citation Format: Inés Lecoq, Katharina L. Kopp, Rikke Christensen, Ayako W. Pedersen, Evelina Martinenaite, Mai-Britt Zocca, Mads H. Andersen. Therapeutic potential of an immune modulatory CCL22-based vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5020.
Abstract 3744: Repurposing the neuroprotective agent dimethyl fumarate against white matter damage and cognitive decline after radiotherapy
Authors: Alexandra Taraboletti, Albert J. Fornace
Journal: Cancer Research (2019)

Abstract Radiation therapy (RT) is a critical tool for the treatment of metastatic brain tumors, most commonly glioblastoma multiforme (GBM), however, patients can have significant cognitive impairment due to the exposure to ionizing radiation. Up to 50%-90% of adult patients that survive these brain tumors will develop radiation-induced cognitive dysfunction within 3-6 months. Brain injury from IR is characterized by white matter damage from the loss of myelin-producing oligodendrocyte cells, subsequent demyelination, and vascular inflammation. While neuro-oncology outcomes are often concerned with survival, strategies to ameliorate and understand radiation-induced demyelination after IR treatment are needed to preserve and improve patient quality of life (QOL). Here we investigate the ability of dimethyl fumarate (DMF), an established neuroprotective agent, to amend damage and demyelination caused by RT in oligodendrocyte cells versus glioma cells. Our in vitro study confirms that DMF acts opposingly in each cell type at lower doses (10 nM), but proves toxic in both the tumor and normal model at high concentrations (100 µM). DMF also increased survival rates in oligodendrocytes after radiation. Using metabolomics, we also noted that oligodendrocyte cells upregulated TCA cycle intermediates in response to DMF treatment with RT. This work provides a basis for in vivo dosing and timing strategies using DMF to cause cessation of ROS-driven oligodendrocyte loss and inflammation after RT. Ultimately, DMF is a promising therapy that could be used to ameliorate radiation-induced demyelination, promoting patient QOL. Citation Format: Alexandra Taraboletti, Albert J. Fornace. Repurposing the neuroprotective agent dimethyl fumarate against white matter damage and cognitive decline after radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3744.
Abstract 4548: The chemokine receptor CCR1 is involved in microglia stimulated glioblastoma invasion
Authors: Salvatore J. Coniglio, Poornema Ramasundaram, Neshama Fournier, Danielle S. Hamilton, Gregory Marshall, Keia Smith, Diana Habib, James R. Merritt
Journal: Cancer Research (2019)

Abstract Glioblastoma Multiforme (GBM) is the most aggressive form of adult brain tumor with a median survival time of twelve months. GBM is highly resistant to conventional therapy which includes surgical resection of the tumor, radiation treatment and chemotherapy. GBM cells are highly motile and invasive resulting in infiltrative tumors with poorly defined borders. GBM tumors are heavily infiltrated with microglia cells which are known to stimulate GBM cell invasion. Our laboratory has previously demonstrated that microglia strongly stimulates GBM invasion both in-vitro and in orthotopic animal models. This interaction was found to be dependent on CSF-1R which is expressed on all tumor infiltrating macrophages/microglia. Blockade of the CSF-1R using compounds such as pexidartinib (PLX3397) can inhibit microglia/macrophage-stimulated GBM invasion in-vitro and in vivo. A variety of chemokines are upregulated in the GBM tumor microenvironment and facilitate “cross-talk” between microglia and GBM cells eliciting a chemotactic response. We have demonstrated that the chemotactic ligand, CCL3, is similarly upregulated in GBM tumors. We postulated that inhibition of CCL3 associated receptors such as C-C receptor 1 (CCR1) might also inhibit GBM invasion, thus, a CCR1 antagonist could prove efficacious for blockade of microglia-induced glioblastoma invasion in vitro. Many potent CCR1 antagonists have been described in the literature. We chose four of these compounds with two distinct structural cores, all with reported IC50’s of less than 200 nM for inhibition of CCR1 binding versus CCL3. We examined the ability of these antagonists to block microglia-stimulated glioblastoma invasion using an in-vitro coculture invasion assay. Using quantitative PCR arrays, we also show that expression of chemokines and chemokine receptor genes is greatly altered in GBM conditioned media-treated microglia. Understanding the pattern of tumor-associated macrophage/microglia chemokine secretion in GBM may present additional targets for chemotherapeutic intervention and enhance immunotherapy. Citation Format: Salvatore J. Coniglio, Poornema Ramasundaram, Neshama Fournier, Danielle S. Hamilton, Gregory Marshall, Keia Smith, Diana Habib, James R. Merritt. The chemokine receptor CCR1 is involved in microglia stimulated glioblastoma invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4548.
Abstract 5136: Adapting long read sequencing technologies for targeted and single cell applications
Authors: Shruti Iyer, Sara Goodwin, W. Richard McCombie
Journal: Cancer Research (2019)

Abstract Structural variations (SV), a hallmark of genomic instability in cancer, include insertions, deletions, duplications, inversions, or translocations that can either activate oncogenes or inactivate tumor suppressor genes. These variants contribute to the complexity of the cancer genome but have not been successfully resolved yet. While short-read sequencing has aided cancer genomics, it has performed poorly in SV detection, with false positive and false negative rates of 50% or more. Long-read sequencing generates reads that are &amp;gt;10 kb long and has helped identify thousands of genomic features pertinent to cancer that were previously missed by short-read sequencing. Long reads can span SV with a single continuous read, giving a clearer idea of the variation, its position, and size. Currently, long-read sequencing methods are greatly limited by the DNA preparation step, with fragment lengths and yield often compromised by standard extraction methods. The potential to generate reads at the megabase level relies greatly on library preps using large amounts (several μg) of DNA input, which prevents its application to samples like patient tumors that are often limited in DNA. Our overarching goal is to develop a targeted approach that generates large contiguous reads from moderate to low input DNA masses. To this end, we use different extraction, amplification, fragmentation, and enrichment strategies to efficiently target and resolve complex regions of the genome that are often associated with disease conditions. Development of a targeted long-read sequencing strategy using low DNA input would give us the potential to explore the landscape of genetic variation across several individuals and heterogeneous cell populations. We are currently employing and adapting CRISPR-based targeting techniques to enrich for specific regions of the genome from intact cells and/or high-molecular-weight DNA. Citation Format: Shruti Iyer, Sara Goodwin, W. Richard McCombie. Adapting long read sequencing technologies for targeted and single cell applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5136.
Abstract 930: On-target resistance to mutant selective EGFR inhibitors develops in an allele-specific manner dependent on the original EGFR activating mutation
Authors: Yunkai Zhang, Benjamin P. Brown, David Westover, Yingjun Yan, Huan Qiao, Vincent Huang, Zhenfang Du, Jarrod A. Smith, Jeffrey S. Ross, Vincent A. Miller, Siraj Ali, Lyudmila Bazhenova, Alexa B. Schrock, Jens Meiler, Christine M. Lovly
Journal: Cancer Research (2019)

Abstract In-frame deletions within exon 19 (Ex19Del) and the Leu858Arg mutation within exon 21 (L858R) are the two most common oncogenic EGFR mutations found in non-small cell lung cancer (NSCLC). Currently, there is little data differentiating Ex19Del from L858R, and patients whose tumors harbor Ex19Del and L858R are approached similar in clinic when choosing EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, resistance mutations may emerge against all classes of EGFR TKIs, including osimertinib. Recently, G724S has been identified as a novel mutation which is selected in osimertinib resistant tumors. Interestingly, in a large genomic profile database of NSCLC patient samples we found that G724S co-occurs preferentially with Ex19Del (15/19 G724S cases) but not with L858R (0/19 G724S cases). We further combined in silico and in vitro investigations to demonstrate the mechanism of G724S mutation confers resistance to TKIs in an oncogenic variant-dependent manner. Our in silico investigations showed evidence of reduced stability of the osimertinib-bound G724S/Ex19Del complex but not the osimertinib-bound G724S/L858R complex. G724S/Ex19Del-transduced cells are resistant to osimertinib treatment in vitro, while G724S/L858R-transduced cells are sensitive to osimertinib treatment. These results suggest G724S/Ex19Del may emerge under selective pressure from EGFR TKIs, and the underlying oncogenic profile of EGFR can influence the development of drug resistance mutations. Our results have potential direct implications for the treatment of patients with EGFR-mutant NSCLC. Citation Format: Yunkai Zhang, Benjamin P. Brown, David Westover, Yingjun Yan, Huan Qiao, Vincent Huang, Zhenfang Du, Jarrod A. Smith, Jeffrey S. Ross, Vincent A. Miller, Siraj Ali, Lyudmila Bazhenova, Alexa B. Schrock, Jens Meiler, Christine M. Lovly. On-target resistance to mutant selective EGFR inhibitors develops in an allele-specific manner dependent on the original EGFR activating mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 930.
Abstract 20498: Transcriptome-Wide Analysis Reveals Differential Expression of Histone Genes Associated With Dysregulation of Immune System in High Versus Low Stress African Americans
Authors: Samson Gebreab, Pia Riestra, Rumana Khan, Ruihua Xu, Sharon Davis
Journal: Circulation (2017)

Background: African Americans experience higher rates of premature of morbidity and mortality from stress-related cardiovascular diseases compared to European Americans. Stress-related alterations ...
Defining lesional, perilesional and unaffected skin in hidradenitis suppurativa: proposed recommendations for clinical trials and translational research studies
Authors: J.W. Frew, K. Navrazhina, A.S. Byrd, A. Garg, J.R. Ingram, J.S. Kirby, M.A. Lowes, H. Naik, V. Piguet, E.P. Prens
Journal: British Journal of Dermatology (2019)

Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory skin condition for which the pathogenesis is not completely elucidated1. With the increase in HS‐related research comes the need to enhance reproducibility, quality and accuracy of scientific methods. Unlike other inflammatory dermatoses such as psoriasis or atopic dermatitis, HS lesions are morphologically diverse and include nodules, abscesses, tunnels and fibrosis in various permutations and combinations admixed in the same anatomical region1. This makes general definitions as ‘lesional’ and ‘non‐lesional’ insufficient for HS‐related investigations. A definition for non‐lesional skin is lacking.
Abstract 1151: Real-time visualization of brain metastasis <i>in vivo</i>
Authors: Takahiro Tsuji, Hiroaki Wake, Hiroaki Ozasa, Koichiro Haruwaka, Hitomi Ajimizu, Yuto Yasuda, Yuichi Sakamori, Takashi Nomizo, Young Hak Kim, Toyohiro Hirai
Journal: Cancer Research (2019)

Abstract Research into physiological phenomena has taken a leap forward by recent advanced optical bio imaging techniques. Traditionally, physiological phenomena including cell division, cell function, molecular transport and expression, and signal transduction were detected by biochemical methods. However, this information lacked high resolution spatial or temporal information. Using recent bio imaging techniques, both spatial and temporal information can be integrated across the molecular, cellular and systems levels that allow us to further investigate the hierarchical interaction of organ systems. Here, we have developed an in vivo imaging method to visualize brain metastasis of lung cancer which provides real-time information of their proliferation, metastasis and the immune reaction for cancer cells. CMT167 and LLC1 cell lines which expressed mCherry or Venus were established. The fluorescently labeled cell lines were administered into the brain via the carotid artery or direct injection to the CX3CR1-GFP mice, transgenic mice in which microglia was specifically labeled with GFP. The metastasis cancer and the immune reaction were visualized using 2-photon microscopy for 14 days. Interaction between cancer cells and microglia was observed. We identified heterogeneity of the interaction between microglia and cancer cells. Some microglia cells showed phagocytosis-like response to cancer. Other microglia touched, surrounded, and released cancer cells without phagocytotic response. These interactions between microglia and cancer cells could be observed by 3-6 hours continuous real-time in vivo imaging. Further study to address detailed mechanism for microglia reaction is in progress. This research has potential to provide the information of brain metastasis in vivo and to be a new solution to elucidate the process of immunity and niche. Citation Format: Takahiro Tsuji, Hiroaki Wake, Hiroaki Ozasa, Koichiro Haruwaka, Hitomi Ajimizu, Yuto Yasuda, Yuichi Sakamori, Takashi Nomizo, Young Hak Kim, Toyohiro Hirai. Real-time visualization of brain metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1151.
Fibroblast Growth Factor Receptor 3 Alterations and Response to PD-1/PD-L1 Blockade in Patients with Metastatic Urothelial Cancer
Authors: Li Wang, Yixuan Gong, Abdel Saci, Peter M. Szabo, Alberto Martini, Andrea Necchi, Arlene Siefker-Radtke, Sumanta Pal, Elizabeth R. Plimack, John P. Sfakianos, Nina Bhardwaj, Amir Horowitz, Adam M. Farkas, David Mulholland, Bruce S. Fischer, William K. Oh, Padmanee Sharma, Jun Zhu, Matthew D. Galsky
Journal: European Urology (2019)
Abstract 4296: Recent Changes in the Practice of Elective PCI for Stable Angina
Authors: Harold L Dauerman, Winthrop D Piper, Bina Ahmed, John F Robb, David Goldberg, Richard A Boss, William J Phillips, Frank Fedele, Thomas J Ryan, David Butzel, M. T Silver, David J Malenka
Journal: Circulation (2009)

BACKGROUND: On March 27, 2007 COURAGE was published, reporting comparable outcomes at 4.6 years for stable angina patients undergoing PCI versus optimal medical management. The influence of these r...
Abstract 16878: Metabolic Markers of Response in Cardiorespiratory Fitness After Exercise Training in High-Risk Individuals: A STRRIDE Sub-Study
Authors: S. K Smith, Damian M Craig, Lydia Kwee, Carol Haynes, James R Bain, Michael J Muehlbauer, Kim H Huffman, William E Kraus, Svati H Shah
Journal: Circulation (2017)

Introduction: The molecular pathways underlying the heterogeneous response to exercise in individuals at risk for cardiovascular disease remain unclear. Less is known about the molecular links to c...