tbuckley/cabot-search huggingface dataset:
Opto-acoustic synergistic irradiation for vaporization of natural melanin-cored nanodroplets at safe energy levels and efficient sono-chemo-photothermal cancer therapy
Authors: Yaxin Hu, Shan Xue, Ting Long, Peizhao Lyu, Xinyu Zhang, Jingqin Chen, Siping Chen, Chengbo Liu, Xin Chen
Journal: Theranostics (2020)

Rationale: Insufficient penetration and accumulation of theranostic payloads in solid tumors greatly challenge the clinical translation of cancer nanomedicines. To address this challenge, we synthesized natural melanin-cored and doxorubicin-loaded perfluoropentane nanodroplets with good biocompatibility and self-assembling ability. Methods: We used an opto-acoustic synergistic irradiation (OASI) method that was effective at lower energy levels than ultrasound- or laser-only irradiation to safely vaporize the nanodroplets and to cavitate the generated microbubbles for mechanically enhancing intratumoral delivery. The delivered melanin and doxorubicin inside the tumors mediated secondary chemo-photothermal therapy under laser irradiation to fully kill cancer cells. Results:In vivo animal experiments demonstrated direct mechanical disruption of tumor structures (H&E staining), enhanced intratumoral penetration of melanin (photoacoustic imaging), and efficient intratumoral accumulation of doxorubicin (fluorescent imaging). Anti-tumor experiments demonstrated that the nanodroplets combined with OASI treatment and subsequent laser irradiation could efficiently eliminate melanoma tumors. Conclusion: Melanin-cored and doxorubicin-loaded perfluoropentane nanodroplets hold great promise for translational sono-chemo-photothermal cancer therapy.
Efficacy and safety of TOBI Podhaler in <i>Pseudomonas aeruginosa-</i>infected bronchiectasis patients: iBEST study
Authors: Michael R. Loebinger, Eva Polverino, James D. Chalmers, Harm A.W.M. Tiddens, Herman Goossens, Michael Tunney, Felix C. Ringshausen, Adam T. Hill, Rashidkhan Pathan, Gerhild Angyalosi, Francesco Blasi, Stuart J. Elborn, Charles S. Haworth
Journal: European Respiratory Journal (2020)

The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa sputum density in patients with bronchiectasis. This is a phase II, double-blind, randomised study in bronchiectasis patients aged ≥18 years with chronic P. aeruginosa infection. Patients were randomised 1:1:1 to either cohort A: three capsules of TIP once daily (84 mg); cohort B: five capsules once daily (140 mg) or cohort C: four capsules twice daily (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively and were followed up for 8 weeks. Overall, 107 patients were randomised to cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the P. aeruginosa sputum density from baseline to day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous TIP and 42.9% on cyclical TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of bronchiectasis was the most frequent (37.4%) adverse event. Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to adverse events. Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the P. aeruginosa sputum density in patients with bronchiectasis and chronic P. aeruginosa infection.
Abstract 1489: Exosomes are key players in nicotine-induced angiogenesis
Authors: Shubhangi Singh, Sirin Saranyutanon, Mohammad Aslam Khan, Sanjeev Kumar Srivastava, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2020)

Abstract Nicotine, an addictive component of cigarette smoke and tobacco, have been shown to promote cancer pathogenesis. Angiogenesis is an important hallmark of cancer that sustains the supply of nutrients and oxygen to the fast proliferating cancer cells through the formation of new blood vessels. The goal of present study was to examine the direct and indirect effect of nicotine on endothelial cell growth, their migration and invasion, and capillary forming ability. We treated the human umbilical vein endothelial cells with two doses of nicotine within physiological range of smokers (200nM and 400nM) and examined the effect on their growth. In parallel, we treated the prostate cancer cells with similar doses of nicotine or vehicle for 8 h and subsequently replaced the media. After next 48 h, conditioned media (CM) was collected from vehicle- (Veh-CM) and nicotine- (Nic-CM) treated prostate cancer cells and used for the treatment of endothelial cells. The growth of endothelial cells increased by ~19 % and ~22 % upon direct treatment of nicotine at 200nM and 400nM doses, respectively. However, a far greater increase was recorded (~128% and ~ 146%, respectively), when endothelial cells were treated with the conditioned media derived from nicotine-treated cancer cells at 200nM and 400nM doses. In next of experiments, we fractionated Veh-CM and Nic-CM (200nM dose) into soluble and exosomal fractions and examined their effect on endothelial cells. We observed that exosomal fraction was more potent (~89%) in inducing endothelial cell growth as compared to the soluble fraction (~46%). In addition, we also observed significant greater increase in motility, invasion and capillary-forming ability of endothelial cells that were pre-treated with Nic-Exo as compared to those treated with Veh-Exo. Studies are currently ongoing to examine the comparative efficacy of nicotine-treated soluble and exosomal factions in potentiating motility, invasion and capillary formation and define the underlying molecular mechanism(s). Our findings thus support a novel pathogenic role of nicotine in cancer where exosomes act as key players in promoting angiogenesis. Citation Format: Shubhangi Singh, Sirin Saranyutanon, Mohammad Aslam Khan, Sanjeev Kumar Srivastava, Seema Singh, Ajay P. Singh. Exosomes are key players in nicotine-induced angiogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1489.
Abstract 971: Effects of tumor cryo-ablation on cGAS-STING pathway and antitumor immunity in syngeneic murine rhabdomyosarcoma
Authors: Mohammad Abdulaziz Alshebremi, Jay T. Myers, Daniel T. Kingsley, Alex Y. Huang
Journal: Cancer Research (2020)

Abstract Even with current improvement in cancer therapy, tumor immunosuppressive microenvironment and metastatic tumors are important factors which have shown to be a challenge for cancer treatment. Thus, targeting the tumor microenvironment (TME) locally are required to modify the activation of innate immunity, which can provoke subsequent global adaptive anti-tumor immunity. Tumor cryo-ablation, a medical procedure that utilizes ultra-cold temperatures to destroy in situ local tumor tissues, has the capability to induce the release of immune danger signals that activate antigen-presenting cells to initiate the anti-tumor immunity. To understand the mechanism of immune activation by cryo-ablation, we performed comprehensive analyses on the effects of tumor cryo-ablation on mononuclear phagocytic lineage cells and the antitumor immunity. Here, we show that cryo-ablation of syngeneic Rhabdomyosarcoma (RMS) tumor, an aggressive sarcoma affecting children and young adults, was able to induce both the regression of tumor and the upregulation of the critical immune cytokines and chemokines profile. Moreover, cryo-ablation of RMS tumor initiates cGAS-STING signaling activation and type I interferon production in dendritic cells, which are consequential in pro-inflammatory TME. We also report that antitumor effects of cryo-ablation was more inhibitive, but not completely abrogated, in STING-deficient mice comparing with wild-type mice, demonstrating that both host-derived and tumor-intrinsic cGAS-STING signaling plays an important role in antitumor effects of tumor cryo-ablation. Ongoing experiments will address the efficacy of RMS tumor cryo-ablation on systemic anti-tumor immune activation leading to an abscopal effect on tumor regression at metastatic tumor. Taken together, our results demonstrate that tumor cryo-ablation affects antitumor immunity and cGAS-STING signaling in RMS tumor, and this approach may help guide future immunotherapy to improve cancer treatment outcomes. Citation Format: Mohammad Abdulaziz Alshebremi, Jay T. Myers, Daniel T. Kingsley, Alex Y. Huang. Effects of tumor cryo-ablation on cGAS-STING pathway and antitumor immunity in syngeneic murine rhabdomyosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 971.
Abstract 1761: Examination of therapeutic potential of epigenetic modulation by dual HDAC-LSD1 inhibition in murine models of triple negative breast cancer (TNBC)
Authors: Shanta M. Messerli, Mariah M. Hoffman, Jessica S. Zylla, Etienne Gnimpieba, Keith W. Miskimins
Journal: Cancer Research (2020)

Abstract This study examines the effects of the epigenetic modulator 4SC-202, a dual histone deacetylase (HDAC) /lysine-specific histone demethylase 1A (LSD1) small molecule inhibitor, on tumor growth and metastasis in a mouse model of breast cancer. 4SC-202 differs from clinically available HDAC inhibitors such as Vorinostat (SAHA) by specifically targeting class I HDACs including HDAC1, HDAC2, and HDAC3 and the histone demethylase LSD1. The hypothesis to be examined is that epigenetic modulation via dual inhibition of HDAC1 and LSD1 improves disease control in breast cancer. In vitro data indicates that 4SC-202 is significantly cytotoxic and cytostatic to the highly metastatic murine Triple Negative Breast Cancer (TNBC) murine model 4T1 and the human TNBC cell line MDA-MB-231 and reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model which closely mimics human TNBC in terms of sites of metastasis, show increased necrosis in 4T1 tumors, reduced tumor burden in vivo as compared to Vorinostat treatment, and significantly reduced metastasis. Furthermore, multiple studies in different cell types indicate that the mechanism of action of 4SC-202 may involve effects on cancer stem cells, which are able to self-renew and form metastatic lesions. It has been shown that a marker of cancer stem cells (CSC's) in breast cancer is high aldehyde dehydrogenase (ALDH) activity and that ALDH high cells mediate metastasis. In the 4T1 syngeneic mouse model of breast cancer, inhibition of ALDH activity suppresses stem-like cell properties. Preliminary data suggests 4SC-202 substantially reduces the ALDH high 4T1 cancer stem population. Transcriptome bulk RNA -sequencing analysis from 4T1 tumors reveal changes in metastatic related pathways in 4SC-202 treated tumors, including significant changes to the expression levels of genes implicated in focal adhesion and ECM-receptor interaction pathways. Furthermore, 4SC-202 appears to alter expression of cytokines which serve as chemokines, potentially leading to increased expression of tumor infiltrating lymphocytes. In summary, treatment of a highly metastatic murine model of TNBC with 4SC-202 significantly reduces metastasis, and warrants further preclinical studies in conjunction with standard of care chemotherapy treatment. Citation Format: Shanta M. Messerli, Mariah M. Hoffman, Jessica S. Zylla, Etienne Gnimpieba, Keith W. Miskimins. Examination of therapeutic potential of epigenetic modulation by dual HDAC-LSD1 inhibition in murine models of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1761.
Abstract 4414: Single-cell analysis on the Cancer Genomics Cloud reveals changes in the transcriptome profiles of endothelial tumor cells over time - novel insights from a public dataset of a mouse model of melanoma
Authors: Nemanja Vucic, Manisha Ray, Dalibor Veljkovic, Stefan Cidilko, Brandi Davis-Dusenbery
Journal: Cancer Research (2020)

Abstract The Cancer Genomics Cloud (CGC) powered by Seven Bridges makes the analysis of large datasets accessible from any environment, which is critical as the volume of datasets continues to expand. This expansion of the size, complexity, and location of datasets has been prominent in the field of single-cell genomics, which can present challenges for data analysis. Here we combined the rich datasets available through the Human Cell Atlas (HCA) with the tools and computational resources available on the CGC to provide a path for any scientist to explore complex biological questions. To demonstrate these capabilities, we processed a single-cell dataset of immune and stromal cells isolated from the tumor and lymph nodes of a mouse model of melanoma using an optimized version of the SmartSeq2 pipeline recommended by the HCA. This dataset contains 13.3k paired-end sequencing files for 6.6k estimated cells, with a total size of 371.60 GB. The entire dataset was transferred from Human Cell Atlas Data Portal to the CGC, where it is accessible to all users. The goal of this study was to process a single-cell dataset on the tumor microenvironment with the SmartSeq2 pipeline and to investigate changes in transcriptome profiles of endothelial tumor cells over time. We used an alternative approach than authors in the original study, which aimed to analyze the immune and stromal cells (Davidson et al. bioRxiv 2018). To perform alignment and quantification of raw sequencing reads using the CGC execution environment, we created an implementation of the SmartSeq2 pipeline in Common Workflow Language. Quantification results were used to perform cell clustering, followed by a pseudotime analysis on the endothelial tumor cells. For the cell clustering and pseudotime analyses, we created interactive notebooks in the RMarkdown format that can be executed within the RStudio environment on the CGC. In summary, this work demonstrates the importance of developing reproducible workflows that can run on multiple environments as well as data sharing that can bring to light new insights from the existing data. Citation Format: Nemanja Vucic, Manisha Ray, Dalibor Veljkovic, Stefan Cidilko, Brandi Davis-Dusenbery. Single-cell analysis on the Cancer Genomics Cloud reveals changes in the transcriptome profiles of endothelial tumor cells over time - novel insights from a public dataset of a mouse model of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4414.
Gastric ischemia and portal vein thrombosis in a COVID-19-infected patient
Authors: See-Wei Low, Karen L. Swanson, Josiah D. McCain, Ayan Sen, Akira Kawashima, Shabana F. Pasha
Journal: Endoscopy (2020)

A 51-year-old man admitted with acute respiratory failure from a SARS-CoV-2 infection had large volume of bloody output via orogastric tube following initiation of heparin for a lower extremity deep vein thrombosis. Esophagogastroduodenoscopy revealed diffuse and severe mucosal ischemia involving the gastric fundus ([Fig. 1]), greater curvature, and posterior wall of the gastric body and antrum ([Fig. 2]) ([Video 1]). The anterior gastric wall and duodenum appeared normal. Computed tomography (CT) angiogram of the abdomen revealed gastric pneumatosis ([Fig. 3]), a non-occlusive thrombus in the right and left portal veins, and portal venous gas ([Fig. 4]). The small bowel and colon appeared normal. In addition to management of the underlying COVID infection and respiratory complications, management included nasogastric decompression and intravenous heparin. A repeat abdominal CT 1 week later showed resolution of the intramural gastric and portal venous gas, and no residual portal vein thrombosis ([Fig. 5]).
Abstract 6236: Mil protein-shelled gold nanoparticle to treat glioblastoma multiform
Authors: Hyungshik Kim, In-Kyu Park, Kang-Moo Huh, Dong-Yun Lee
Journal: Cancer Research (2020)

Abstract Gold nanoparticle (AuNP) as a photothermal therapy (PTT) agent has been reported in various application due to its physical properties. If gold nanoparticle can be orally absorbed, its application may be extended. Unfortunately, it has low absorption efficiency from the gastrointestinal (GI) tract to blood stream. To overcome its limitation orally, here we newly synthesized lactoferrin (Lf; a milk protein)-conjugated gold nanoparticles (Lf-AuNP). Interestingly, this Lf-AuNP could be orally absorbed and targeted to the brain cancer cells due to its interaction with lactoferrin receptor (Lf-R) on the intestinal cells, Blood-Brain Barrier (BBB) and cancer cells. Based on these findings, the Lf-AuNP was orally absorbed with higher bioavailability and targeted to the brain cancer cells (U87MG cells) that was orthotopic animal model. Fortunately, when specified wavelength of laser was noninvasively irradiated to the head of orthotopic animals, the Lf-AuNP made the higher temperature to the head, thereby killing the brain cancer cells. Collectively this milk protein-based oral delivery of AuNP could be a promising strategy as a platform technology. Citation Format: Hyungshik Kim, In-Kyu Park, Kang-Moo Huh, Dong-Yun Lee. Mil protein-shelled gold nanoparticle to treat glioblastoma multiform [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6236.
Abstract 6569: Regulatory networks of liver carcinoma reveal sex specific patterns of gene regulation
Authors: Camila M. Lopes-Ramos, Marieke Kuijjer, Kimberly Glass, Dawn DeMeo, John Quackenbush
Journal: Cancer Research (2020)

Abstract Despite pronounced sex differences in cancer incidence, severity, and response to treatment, most current approaches to clinical management, as well as therapeutics development and selection, are sex-independent. For most cancer types, including liver cancer, males have a higher risk of developing the disease and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. We inferred patient-specific regulatory networks of liver hepatocellular carcinoma using data from TCGA. By comparing the female and male networks, we found marked sex differences in transcriptional regulatory processes relevant to disease development, progression, and response to therapy. We found that oncogenes have significantly higher regulatory targeting in males, while tumor suppressor genes have significantly higher targeting in females. Many “hallmark” cancer pathways, including the HEDGEHOG, WNT, and TGF-β signaling pathways, were significantly more highly targeted in males, while drug metabolism and immune related pathways were enriched for genes highly targeted in females. We also evaluated sex-biased somatic mutation patterns using mutation and copy number alteration data in TCGA. By summarizing mutations found in genes into pathway mutation scores, we found sex-biased mutation profiles for many pathways, providing additional support for biological sex differences associated with WNT, NOTCH, TGF-β, and HEDGEHOG signaling pathways. Our analysis uncovered patterns of gene regulation that differentiate male and female liver cancer and may be associated with sex differences in prognosis and treatment response. These findings provide insight into the mechanisms that drive clinically observed sex differences and underscore the importance of considering sex as a factor influencing disease etiology and in developing and prescribing therapies. Our network approach can provide insights into why some therapies have differential effect in males and females, and suggest new ways to optimize drug response in each sex. Citation Format: Camila M. Lopes-Ramos, Marieke Kuijjer, Kimberly Glass, Dawn DeMeo, John Quackenbush. Regulatory networks of liver carcinoma reveal sex specific patterns of gene regulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6569.
Abstract 4555: Selection of CD3 affinity allows generation of T-cell redirecting bispecific antibodies with unique pharmacokinetic and biodistribution properties
Authors: Lauric Haber, Kara Olson, Robert Babb, Marcus Kelly, Alison Crawford, Marc Retter, David DiLillo, Erica Ullman, Jennifer Finney, Lauren Canova, Arpita Pawashe, Danica Chiu, Kristin Vazzana, Priyanka Ram, Katja Mohrs, Amanda Dorvilliers, Jenny Xiao, Sosina Makonnen, Carlos Hickey, Cody Arnold, Jason Giurleo, Supriya Patel, Richard Tavare, Ya Ping Chen, Gang Chen, William Olson, Gavin Thurston, John Chia-Yang Lin, Aynur Hermann, Jessica Kirshner, Eric J. Smith
Journal: Cancer Research (2020)

Abstract T-cell redirecting bispecific antibodies are an emerging class of therapeutic agents designed to simultaneously bind to T cells (via CD3) and tumor cell specific antigens (TSA), with the goal of inducing T cell-mediated killing of tumor cells. Despite promising pre-clinical and clinical efficacy from TSAxCD3 antibodies, these agents have associated toxicities that remain challenging. Here we present findings from a series of bispecific antibodies that were engineered to have a range of CD3 affinities, but which retained the same binding affinity to the selected tumor antigen. These agents were tested for killing of tumor cells in vitro, and for biodistribution, serum half-life, and anti-tumor activity in vivo. By altering the binding strength for CD3, bispecifics were generated that maintained potent killing of TSA+ cells but displayed differential profiles of cytokine release, pharmacokinetics, and biodistribution. Our results suggest that tuning CD3 affinity is a promising method to improve the therapeutic window of T cell-engaging bispecific antibodies. Citation Format: Lauric Haber, Kara Olson, Robert Babb, Marcus Kelly, Alison Crawford, Marc Retter, David DiLillo, Erica Ullman, Jennifer Finney, Lauren Canova, Arpita Pawashe, Danica Chiu, Kristin Vazzana, Priyanka Ram, Katja Mohrs, Amanda Dorvilliers, Jenny Xiao, Sosina Makonnen, Carlos Hickey, Cody Arnold, Jason Giurleo, Supriya Patel, Richard Tavare, Ya Ping Chen, Gang Chen, William Olson, Gavin Thurston, John Chia-Yang Lin, Aynur Hermann, Jessica Kirshner, Eric J. Smith. Selection of CD3 affinity allows generation of T-cell redirecting bispecific antibodies with unique pharmacokinetic and biodistribution properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4555.