tbuckley/cabot-search huggingface dataset:
cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity
Authors: Zining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, Xiaojun Xia
Journal: Journal of Clinical Investigation (2019)

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death–inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-κB activation and stimulator of IFN genes–dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.
Depression Synergy With Amyloid and Increased Risk of Cognitive Decline in Preclinical Alzheimer Disease
Authors: Carol Chan, Paul B. Rosenberg
Journal: JAMA Network Open (2019)

Jennifer R. Gatchel, MD, PhD; Jennifer S. Rabin, PhD; Rachel F. Buckley, PhD; Joseph J. Locascio, PhD; Yakeel T. Quiroz, PhD; Hyun-Sik Yang, MD; Patrizia Vannini, PhD; Rebecca E. Amariglio, PhD; Dorene M. Rentz, PsyD; Michael Properzi, BEng; Nancy J. Donovan, MD; Deborah Blacker, MD, ScD; Keith A. Johnson, MD; Reisa A. Sperling, MD; Gad A. Marshall, MD; for the Harvard Aging Brain Study
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer
Authors: Sahar Nissim, Ignaty Leshchiner, Joseph D. Mancias, Matthew B. Greenblatt, Ophélia Maertens, Christopher A. Cassa, Jill A. Rosenfeld, Andrew G. Cox, John Hedgepeth, Julia I. Wucherpfennig, Andrew J. Kim, Jake E. Henderson, Patrick Gonyo, Anthony Brandt, Ellen Lorimer, Bethany Unger, Jeremy W. Prokop, Jerry R. Heidel, Xiao-Xu Wang, Chinedu I. Ukaegbu, Benjamin C. Jennings, Joao A. Paulo, Sebastian Gableske, Carol A. Fierke, Gad Getz, Shamil R. Sunyaev, J. Wade Harper, Karen Cichowski, Alec C. Kimmelman, Yariv Houvras, Sapna Syngal, Carol Williams, Wolfram Goessling
Journal: Nature Genetics (2019)
Abstract 15068: Expression of PW1 Identifies a New Candidate Cardiac Progenitor Population in the Adult Heart
Authors: Elisa Yaniz-Galende, Nathalie Mougenot, Jiqiu Chen, Sophie Nadaud, Giovanna Marazzi, Valentin Fuster, Roger Hajjar, David Sassoon, Jean Sebastien Hulot
Journal: Circulation (2015)

Rationale: Adult myocardium contains a rare population of cardiac progenitor cells (CPCs), recruited in response to tissue injury, which are of central importance for the cardiac microenvironment after cardiac injury. However, their phenotype characterization and function in physiological and pathological has not yet been reported. Objective: Based on the identification of a cell population with very high expression of PW1 in different tissues, our goal was to determine the role that PW1+ cells play in the heart in a murine myocardial infarction model. Methods and Results: In this study we show that high expression of PW1 in cardiac cells (PW1+ cells), identified a rare population, located in the epicardium and interstitium in resting heart, increased in the injured and border area in response to myocardial infarction (MI). Using PW1-reporter mice, we defined three populations of CPCs that include fraction I (PW1-ckit+), II (PW1+ c-kit+) and III (PW1+ckit-) based on differential expression of PW1 and c-kit. We found that MI led to an increase of all the fractions especially fraction II. Furthermore, isolated PW1+ cells showed clonogenic capacity, measured as fibroblastic colony-forming units frequency, and differentiation capacity to give rise in vitro to several cardiac lineages. The phenotypic characterization of fractions I, II and III has also been studied by utilizing comparative gene expression profile as a screening tool. Taken together, these data identify a novel PW1+ cardiac progenitor population with the potential to undergo differentiation into multiple cardiac lineages, suggesting their involvement in cardiac repair in normal and pathological conditions. Conclusion: Based on the comparative phenotype analysis, we could demonstrate that the expression of PW1 identified a pure population of CPCs, augmented following MI, with clonogenic and multipotent capacity, which is likely to provide a novel target for therapeutic approaches aimed at improving cardiac repair.
Phase I Study of First-in-Class Oral Triplet Therapy DTRM-555 in Relapsed/Refractory Lymphoma Patients through Fixed-Dose Combination and Synthetic Lethality
Authors: Scott F Huntington, Stephen J. Schuster, Wei He, Tong Shen, Heather Walker, Laura Leary, Kylie Boyhen, Jennifer Gill, Elizabeth T Chatburn, Kaitlin Kennard, Sunita Dwivedy Nasta, Daniel J. Landsburg, David L. Porter, Ellen Napier, Mitchell E. Hughes, Tanya Latorre, Kristy Walsh, Colleen Dorsey, Jakub Svoboda, Victoria Addis, Barry Douglas Anderson, Emily Leblond, Yuqin Song, Jun Zhu, Lijuan Deng, Danielle M. Brander, Wei Ding, Allison C. Rosenthal, Han Tun, Anthony R. Mato
Journal: Blood (2018)
Master transcription factors form interconnected circuitry and orchestrate transcriptional networks in oesophageal adenocarcinoma
Authors: Li Chen, Moli Huang, Jasmine Plummer, Jian Pan, Yan Yi Jiang, Qian Yang, Tiago Chedraoui Silva, Nicole Gull, Stephanie Chen, Ling Wen Ding, Omer An, Henry Yang, Yulan Cheng, Jonathan W Said, Ngan Doan, Winand NM Dinjens, Kevin M Waters, Richard Tuli, Simon A Gayther, Samuel J Klempner, Benjamin P Berman, Stephen J Meltzer, De-Chen Lin, H Phillip Koeffler
Journal: Gut (2019)

While oesophageal squamous cell carcinoma remains infrequent in Western populations, the incidence of oesophageal adenocarcinoma (EAC) has increased sixfold to eightfold over the past four decades. We aimed to characterise oesophageal cancer-specific and subtypes-specific gene regulation patterns and their upstream transcription factors (TFs). DESIGN: To identify regulatory elements, we profiled fresh-frozen oesophageal normal samples, tumours and cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematical modelling was performed to establish (super)-enhancers landscapes and interconnected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs were investigated by ChIP-Seq, circularised chromosome conformation capture sequencing and luciferase assay. Biological functions of candidate factors were evaluated both in vitro and in vivo.We found widespread and pervasive alterations of the (super)-enhancer reservoir in both subtypes of oesophageal cancer, leading to transcriptional activation of a myriad of novel oncogenes and signalling pathways, some of which may be exploited pharmacologically (eg, leukemia inhibitory factor (LIF) pathway). Focusing on EAC, we bioinformatically reconstructed and functionally validated an interconnected circuitry formed by four master TFs-ELF3, KLF5, GATA6 and EHF-which promoted each other's expression by interacting with each super-enhancer. Downstream, these master TFs occupied almost all EAC super-enhancers and cooperatively orchestrated EAC transcriptome. Each TF within the transcriptional circuitry was highly and specifically expressed in EAC and functionally promoted EAC cell proliferation and survival.By establishing cancer-specific and subtype-specific features of the EAC epigenome, our findings promise to transform understanding of the transcriptional dysregulation and addiction of EAC, while providing molecular clues to develop novel therapeutic modalities against this malignancy.
Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma
Authors: Andrew B Satterlee, Denise E Dunn, Donald C Lo, Simon Khagi, Shawn Hingtgen
Journal: Neuro-Oncology (2019)

Abstract Background Tumor-homing tumoricidal neural stem cell (tNSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). Developing strategies for tNSC therapy to overcome intratumoral heterogeneity, variable cancer cell invasiveness, and differential drug response of GBM will be essential for efficacious treatment response in the clinical setting. The aim of this study was to create novel hybrid tumor models and investigate the impact of GBM heterogeneity on tNSC therapies. Methods We used organotypic brain slice explants and distinct human GBM cell types to generate heterogeneous models ex vivo and in vivo. We then tested the efficacy of mono- and combination therapy with primary NSCs and fibroblast-derived human induced neural stem cells (iNSCs) engineered with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) or enzyme-prodrug therapy. Results Optical imaging, molecular assays, and immunohistochemistry revealed that the hybrid models recapitulated key aspects of patient GBM, including heterogeneity in TRAIL sensitivity, proliferation, migration patterns, hypoxia, blood vessel structure, cancer stem cell populations, and immune infiltration. To explore the impact of heterogeneity on tNSC therapy, testing in multiple in vivo models showed that tNSC-TRAIL therapy potently inhibited tumor growth and significantly increased survival across all paradigms. Patterns of tumor recurrence varied with therapeutic (tNSC-TRAIL and/or tNSC–thymidine kinase), dose, and route of administration. Conclusions These studies report new hybrid models that accurately capture key aspects of GBM heterogeneity which markedly impact treatment response while demonstrating the ability of tNSC mono- and combination therapy to overcome certain aspects of heterogeneity for robust tumor kill.
Effects of two types of exercise training on psychological well‐being, sleep, quality of life and physical fitness in patients with high‐grade glioma (WHO III and IV): study protocol for a randomized controlled trial
Authors: Dominik Cordier, Markus Gerber, Serge Brand
Journal: Cancer Communications (2019)

Abstract Background There is existing evidence on whether and to what degree regular exercise training improves the quality of life (QoL) among cancer survivors. However, in regards to patients with high‐grade glioma (HGG; WHO grade III and IV), no conclusive study has been performed so far. The present trial aims to fill this gap by examining whether psychological well‐being, sleep, QoL and physical fitness might be improved with two different types of exercise, as compared to an active control condition. Active control condition represent individuals participating at regular meetings to talk about their current life situation, though, the meetings were not intended as that of the psychotherapy group. Regular meetings are of the same frequency, duration, and intensity as the exercise interventions. Methods A total of 45 patients with HGG after undergoing neurosurgery and adjuvant radiotherapy, chemotherapy, or chemoradiotherapy will be consecutively and randomly assigned to (a) an endurance training, (b) a resistance training or (c) to an active control condition. The intervention will last for 6 consecutive weeks, consisting of 2 weekly sessions (30–45 min per session). Measurements would take place at three time points, namely at the beginning of the study (baseline), 3 weeks after the beginning of the study, and 6 weeks after the beginning of the study. The last measurement also represents the end of the study. Aerobic exercise performance will be assessed objectively with a 6‐min walking test, and a handgrip test will be used to assess the upper body strength. Further, participants will complete a battery of questionnaires covering sociodemographic information, QoL, sleep quality and sleep patterns, coping with stress, state‐ and trait‐anxiety, depression, and fatigue. In parallel, experts will use the Hamilton Depression Rating Scale to determine and rate participants’ symptoms of depression. Significance The present study will be the first to investigate and compare the impact of two different exercise modalities, namely endurance and resistance training, on physical fitness and dimensions of well‐being, and sleep among patients with HGG who underwent neurosurgery followed by adjuvant radiotherapy, chemotherapy, or chemoradiotherapy. Importantly, unlike the majority of previous studies, the control condition consists of an active set‐up to detect possible factual beneficial effects of exercise training, irrespective of social interactions. Trial registration https://register.clinicaltrials.gov ; identifier: NCT03775369
Physician-Assisted Suicide and the Perils of Empirical Ethical Research
Authors: Daniel P. Sulmasy
Journal: JAMA Network Open (2019)

Luai Al Rabadi, MD; Michael LeBlanc, PhD; Taylor Bucy, BS; Lee M. Ellis, MD; Dawn L. Hershman, MD, MS; Frank L. Meyskens Jr, MD; Lynne Taylor, MD; Charles D. Blanke, MD
Telomerase reverse transcriptase regulation by TGF-β signaling through adaptor ELF and Smad3 that is independent of c-Myc.
Authors: Zhixing Yao, Young Woo Kim, Rupen Amin, Eugene Volpe, Wilma Jogunoori, Lopa Mishra, Bibhuti Mishra
Journal: Cancer Research (2008)

3442  Transforming Growth Factor-β (TGF-β) induced antiproliferative responses is a hallmark of many cancer cells. Smad proteins as intracellular mediators for TGF-β signaling and regulate target gene expression by activating or repressing gene transcription. Smads 2, 3 and 4 inhibit G1/S cell cycle progression mostly by suppression of c-Myc and cyclin-dependent kinases (cdks). Myc amplification, telomere maintenance, and telomerase reverse transcriptase (TERT) reactivation are common features of human foregut cancers, such as hepatocellular carcinoma (HCC). Emerging evidence indicates that ELF, a Smad3/Smad4 adaptor protein required for TGF-β signaling, is a powerful tumor suppressor [Science, 2005, 310(5745):68-71, Oncogene, 2007, 26(50):7103-10]. Elf+/-, elf+/-/Smad3+/- and elf+/-/Smad4+/-, (but not Smad3-/-) mice dramatically develop foregut cancers, including hepatocellular, pancreatic and gastric cancers. However, the specific role(s) of h-TERT, c-MYC and Elf, and their relation to the TGF-β pathway, in foregut cancer formation are poorly understood. Deletion of ELF results in a dramatic and spontaneous formation of liver and gastrointestinal cancers, with exon 15 mutations in 11% of human HCC and gastric cancer cell lines tested. Elf+/-andelf+/-/Smad3+/- mice develop visceromegaly and multiple GI cancers (70% of mice), spontaneously. This phenotype provides compelling evidence that elf+/-and elf+/-/Smad3+/- mice are a model of the hereditary human cancer syndrome Beckwith-Wiedemann (BWS). Aims: In this study, we investigated the mechanism of role of Elf, Smad3 and c-Myc in regulating human TERT gene expression by TGF-β in HepG2, PLC/PRF/5, SNU 298 cell lines and elf+/-/Smad3+/- mice tumor tissues in vitro and in vivo. Results show that: 1) TheElf+/-/Smad3+/-mice develop visceromegaly and multiple cancers, including metastatic pancreatic, hepatocellular, small bowel lymphomas, adrenocortical carcinomas, renal carcinomas and tumor tissues from elf+/-/Smad3+/- mice show a dramatic decrease of ELF mRNA; 2) TERT and c-Myc are markedly elevated in elf+/-andelf+/-/Smad3+/- mice; Interestingly, TERT levels are far higher than can be accounted for by c-Myc levels in elf+/-andelf+/-/Smad3+/- tumors; 3)Ectopic ELF and Smad3 suppress TERT greater than c-Myc in the absence of TGF-β. 4) Both ELF and Smad3 associate with c-Myc in TGF-β stimulated hepatocytes and suppress TERT. 5)Overexpression of ELF and/or Smad3 decreases hTERT RNA levels in PLC/PRF/5 and SNU 298 human cell lines. Conclusions: Taken together our preliminary data suggest that divergent pathways converge on ELF and Smad3 that then regulate TERT. Inactivation of the TGF-β signaling pathway with TERT activation provides a strong strategy for generating targeted therapeutics at TERT in these lethal human cancers.
GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia
Authors: Adriano Venditti, Alfonso Piciocchi, Anna Candoni, Lorella Melillo, Valeria Calafiore, Roberto Cairoli, Paolo de Fabritiis, Gabriella Storti, Prassede Salutari, Francesco Lanza, Giovanni Martinelli, Mario Luppi, Patrizio Mazza, Maria Paola Martelli, Antonio Cuneo, Francesco Albano, Francesco Fabbiano, Agostino Tafuri, Anna Chierichini, Alessia Tieghi, Nicola Stefano Fracchiolla, Debora Capelli, Robin Foà, Caterina Alati, Edoardo La Sala, Paola Fazi, Marco Vignetti, Luca Maurillo, Francesco Buccisano, Maria Ilaria Del Principe, Maria Irno-Consalvo, Tiziana Ottone, Serena Lavorgna, Maria Teresa Voso, Francesco Lo-Coco, William Arcese, Sergio Amadori
Journal: Blood (2019)
Prolactin Promotes Fibrosis and Pancreatic Cancer Progression
Authors: Manuj Tandon, Gina M. Coudriet, Angela Criscimanna, Mairobys Socorro, Mouhanned Eliliwi, Aatur D. Singhi, Zobeida Cruz-Monserrate, Peter Bailey, Michael T. Lotze, Herbert Zeh, Jing Hu, Vincent Goffin, George K. Gittes, Andrew V. Biankin, Farzad Esni
Journal: Cancer Research (2019)

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant fibrosis. Recent findings have highlighted the profibrotic activity of tissue-resident macrophages in the pancreatic cancer microenvironment. Here, we show that neoplastic pancreatic epithelium, as well as a subset of tissue-resident macrophages, expresses the prolactin-receptor (PRLR). High mobility group box 1-induced prolactin expression in the pancreas maintained FAK1 and STAT3 phosphorylation within the epithelium and stroma. Gain-of-function and loss-of-function experiments demonstrated the essential role of prolactin in promoting collagen deposition and fibrosis. Finally, the signaling cascade downstream of prolactin/PRLR activated STAT3 rather than STAT5 in PDAC. These findings suggest that targeting prolactin together with IL6, a known major activator of STAT3, could represent a novel therapeutic strategy for treating pancreatic cancer. SIGNIFICANCE: Prolactin is a key factor in the cross-talk between the stroma and neoplastic epithelium, functioning to promote fibrosis and PDAC progression.
The emerging role of the piRNA/piwi complex in cancer
Authors: Yongmei Liu, Mei Dou, Xuxia Song, Yanhan Dong, Si Liu, Haoran Liu, Jiaping Tao, Wenjing Li, Xunhua Yin, Wenhua Xu
Journal: Molecular Cancer (2019)

Piwi interacting RNAs (piRNAs) constitute novel small non-coding RNA molecules of approximately 24–31 nucleotides in length that often bind to members of the piwi protein family to play regulatory roles. Recently, emerging evidence suggests that in addition to the mammalian germline, piRNAs are also expressed in a tissue-specific manner in a variety of human tissues and modulate key signaling pathways at the transcriptional or post-transcriptional level. In addition, a growing number of studies have shown that piRNA and PIWI proteins, which are abnormally expressed in various cancers, may serve as novel biomarkers and therapeutic targets for tumor diagnostics and treatment. However, the functions of piRNAs in cancer and their underlying mechanisms remain incompletely understood. In this review, we discuss current findings regarding piRNA biogenetic processes, functions, and emerging roles in cancer, providing new insights regarding the potential applications of piRNAs and piwi proteins in cancer diagnosis and clinical treatment.
Outcome of irinotecan and cetuximab treatment in colorectal cell lines. Correlation between signaling pathways, gene expression profile and cell cycle checkpoint.
Authors: Arnaud Vigneron, Erick Gamelin, Olivier Coqueret
Journal: Cancer Research (2006)

5085  The recent successful development of novel monoclonal antibodies that target key components of biologic pathways has expanded treatment options for patients with colorectal cancer. Cetuximab is a recombinant chimeric epidermal growth factor receptor (EGFR) monoclonal antibody that was approved for use in combination with irinotecan in the treatment of EGFR-expressing, metastatic colorectal cancer. In this report, we investigated the cellular and molecular effects of cetuximab, in combination with chemotherapy in human CIN (chromosomal instability) HT29 colorectal cell line and in MIN (microsatellite instability) HCT116 colorectal cell line. HCT116 cells exhibit relatively more sensibility than HT29 cell to SN38 alone, the active metabolite of irinotecan, as determined by clonogenic assays. By contrast, cetuximab treatment increased the cytotoxic effect of SN38 in HT29 cells whereas its effects were relatively weak in HCT116 cells. The signaling pathways of EGFR receptor (PI3K, MAPK and STAT3), the gene expression profile (repair, apoptotic and cell growth controlling gene) and the treatment outcome (mitotic catastrophe, apoptosis, and senescence) explain the difference of sensibility observed between the two cell lines. These effects are related to a modulation of cell cycle progression as observed by multiparameter flow cytometry analysis. These results provide a best comprehension of molecular events that can predict the chemotherapeutic activity of SN38 and cetuximab. New chemotherapy strategies against resistant tumors may be envisaged from these results.
Risk factors in lateral window sinus elevation surgery
Authors: Tiziano Testori, Tommaso Weinstein, Silvio Taschieri, Stephen S. Wallace
Journal: Periodontology 2000 (2019)

Abstract Maxillary sinus augmentation is the most predictable of the pre‐prosthetic surgical procedures. There are, however, known and well‐documented complications that can and do occur. The most common are the intraoperative complications of sinus membrane perforation and bleeding, and the postoperative complications of sinus graft infections, sinus infections, and sinusitis. The majority of these complications can be prevented, or their incidence greatly reduced, through a thorough understanding of maxillary sinus anatomy, the multifaceted etiologies of these conditions, and the steps that can be taken to avoid them. This volume of Periodontology 2000 will discuss both the preoperative and intraoperative procedures that will prevent these untoward outcomes and the necessary treatment modalities that will limit their adverse effects.