tbuckley/cabot-search huggingface dataset:
Overview of the relevance of PI3K pathway in HR-positive breast cancer
Authors: N. Vasan, E. Toska, M. Scaltriti
Journal: Annals of Oncology (2019)

One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.
Abstract 12889: Impact of Educational Intervention on Reducing Inappropriate Telemetry Utilization in a Community Teaching Hospital
Authors: Abdelrahman Ali, Donna Asupan, Anand Narayanan, Damon H Cao, Tokhanh Nguyen, John Yoon, Shalini Reddy, Matthew Cerasale
Journal: Circulation (2018)

Introduction: Inappropriate cardiac telemetry creates increased expense, more frequent alarms and higher workloads for the nursing as well as being a major inconvenience for the patient. New clinic...
Microvascular Invasion and a Size Cutoff Value of 2 cm Predict Long-Term Oncological Outcome in Multiple Hepatocellular Carcinoma: Reappraisal of the American Joint Committee on Cancer Staging System and Validation Using the Surveillance, Epidemiology, and End-Results Database
Authors: Junichi Shindoh, Yuta Kobayashi, Yusuke Kawamura, Norio Akuta, Masahiro Kobayashi, Yoshiyuki Suzuki, Kenji Ikeda, Masaji Hashimoto
Journal: Liver Cancer (2019)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; For prognostication of hepatocellular carcinoma (HCC), the optimal size cutoff value and the significance of microvascular invasion (mvi) remain inconclusive. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; This study sought to revisit the inconclusive components of current American Joint Committee on Cancer (AJCC) staging system and to develop a new practical prognostication model for patients with HCC based on 2 large cohorts. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; In 1,175 patients who underwent resection for HCC (training cohort), prognostic significance of mvi, and optimal size cutoff value were revisited and a new staging model was established. Then, its performance was validated using 5,249 patients derived from a population-based database (validation cohort). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The optimal size cutoff value was 2 cm in multiple HCC, similar to that for solitary HCC. Multivariate analyses confirmed that mvi, a size &amp;#x3e;2 cm, and multiple lesions were independent predictors with similar weights for disease-specific survival. Based on these results, earlier stages of HCC were reclassified according to the number of the following factors: multiple tumors, &amp;#x3e;2 cm in diameter, and presence of mvi. Also, given the similar prognosis of Stages IIIB and IVA according to the AJCC 8th edition, these groups were reclassified into the same stage. This new staging model had a better performance than the AJCC 8th edition in both training cohort (c-statistics, 0.648 vs. 0.629) and the validation cohort (c-statistics, 0.646 vs. 0.645) regardless of the presence of cirrhosis. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Inclusion of a size cutoff value of 2 cm and mvi could reclassify the current version of the AJCC staging system and offer an alternative prognostication model using a single size-cutoff value of HCC.
An Educational Intervention for Improving Infant Sleep Duration—Why Won’t You Sleep, Baby?
Authors: Harriet Hiscock
Journal: JAMA Network Open (2019)

Iná S. Santos, PhD; Bianca Del-Ponte, PhD; Luciana Tovo-Rodrigues, PhD; Camila S. Halal, PhD; Alicia Matijasevich, PhD; Suélen Cruz, PhD; Luciana Anselmi, PhD; Mariângela Freitas Silveira, PhD; Pedro R. Curi Hallal, PhD; Diego G. Bassani, PhD
Preclinical Assessment with Clinical Validation of Selinexor with Gemcitabine and Nab-Paclitaxel for the Treatment of Pancreatic Ductal Adenocarcinoma
Authors: Asfar S. Azmi, Husain Yar Khan, Irfana Muqbil, Amro Aboukameel, Jasper E. Neggers, Dirk Daelemans, Amit Mahipal, Gregory Dyson, Mandana Kamgar, Mohammad Najeeb Al-Hallak, Anteneh Tesfaye, Steve Kim, Vinod Shidham, Ramzi M. Mohammad, Philip A. Philip
Journal: Clinical Cancer Research (2019)

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models.We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial.SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin-bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor-GEM-nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months.Our preclinical and ongoing clinical study lends support to the use of selinexor-GEM-nab-paclitaxel as an effective therapy for metastatic PDAC.
RIG-I Activation Is Critical for Responsiveness to Checkpoint Blockade
Authors: Simon Heidegger, Alexander Wintges, Florian Stritzke, Katja Steiger, Paul-Albert Koenig, Thomas Engleitner, Julius Clemens Fischer, Vladimir Makarov, Christof Winter, Roland Rad, Marcel R.M. van den Brink, Jürgen Ruland, Florian Bassermann, Timothy Chan, Tobias Haas, Hendrik Poeck
Journal: Blood (2019)
Emerging Insights Into the Association Between Nature Exposure and Healthy Neuronal Development
Authors: Argelinda Baroni, Francisco Xavier Castellanos
Journal: JAMA Network Open (2019)

Bo-Yi Yang, PhD; Xiao-Wen Zeng, PhD; Iana Markevych, PhD; Michael S. Bloom, PhD; Joachim Heinrich, PhD; Luke D. Knibbs, PhD; Shyamali C. Dharmage, PhD; Shao Lin, PhD; Pasi Jalava, PhD; Yuming Guo, PhD; Bin Jalaludin, PhD; Lidia Morawska, PhD; Yang Zhou, PhD; Li-Wen Hu, PhD; Hong-Yao Yu, PhD; Yunjiang Yu, PhD; Guang-Hui Dong, MD, PhD
A Human Lung Challenge Model to Evaluate the Safety and Immunogenicity of PPD and Live Bacillus Calmette-Guérin
Authors: Malika Davids, Anil Pooran, Clemens Hermann, Lynelle Mottay, Fawziyah Thompson, Jacob Cardenas, Jinghua Gu, Thearith Koeuth, Richard Meldau, Jason Limberis, Phindile Gina, Shashikant Srivastava, Bridget Calder, Aliasgar Esmail, Michele Tomasicchio, Jonathan Blackburn, Tawanda Gumbo, Keertan Dheda
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: A human model to better understand tuberculosis immunopathogenesis and facilitate vaccine development is urgently needed.Objectives: We evaluated the feasibility, safety, and immunogenicity of live bacillus Calmette-Guérin (BCG) in a lung-oriented controlled human infection model.Methods: We recruited 106 healthy South African participants with varying degrees of tuberculosis susceptibility. Live BCG, sterile PPD, and saline were bronchoscopically instilled into separate lung segments (n = 65). A control group (n = 34) underwent a single bronchoscopy without challenge. The primary outcome was safety. Cellular and antibody immune signatures were identified in BAL before and 3 days after challenge using flow cytometry, ELISA, RNA sequencing, and mass spectrometry.Measurements and Main Results: The frequency of adverse events was low (9.4%; n = 10), similar in the challenge versus control groups (P = 0.8), and all adverse events were mild and managed conservatively in an outpatient setting. The optimal PPD and BCG dose was 0.5 TU and 104 cfu, respectively, based on changes in BAL cellular profiles (P = 0.02) and antibody responses (P = 0.01) at incremental doses before versus after challenge. At 104 versus 103 cfu BCG, there was a significant increase in number of differentially expressed genes (367 vs. 3; P < 0.001) and dysregulated proteins (64 vs. 0; P < 0.001). Immune responses were highly setting specific (in vitro vs. in vivo) and compartment specific (BAL vs. blood) and localized to the challenged lung segments.Conclusions: A lung-oriented mycobacterial controlled human infection model using live BCG and PPD is feasible and safe. These data inform the study of tuberculosis immunopathogenesis and strategies for evaluation and development of tuberculosis vaccine candidates.
Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse
Authors: Jian-Ping Zhang, Xin-Xin Cheng, Mei Zhao, Guo-Hua Li, Jing Xu, Feng Zhang, Meng-Di Yin, Fei-Ying Meng, Xin-Yue Dai, Ya-Wen Fu, Zhi-Xue Yang, Cameron Arakaki, Ruijun Jeanna Su, Wei Wen, Wen-Tian Wang, Wanqiu Chen, Hannah Choi, Charles Wang, Guangping Gao, Lei Zhang, Tao Cheng, Xiao-Bing Zhang
Journal: Genome biology (2019)

Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%).We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects.These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components.
Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis
Authors: Daniel J. Tyrrell, Muriel G. Blin, Jianrui Song, Sherri C. Wood, Min Zhang, Daniel A. Beard, Daniel R. Goldstein
Journal: Circulation Research (2019)

Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex
Authors: Saskia E. J. de Vries, Jerome A. Lecoq, Michael A. Buice, Peter A. Groblewski, Gabriel K. Ocker, Michael Oliver, David Feng, Nicholas Cain, Peter Ledochowitsch, Daniel Millman, Kate Roll, Marina Garrett, Tom Keenan, Leonard Kuan, Stefan Mihalas, Shawn Olsen, Carol Thompson, Wayne Wakeman, Jack Waters, Derric Williams, Chris Barber, Nathan Berbesque, Brandon Blanchard, Nicholas Bowles, Shiella D. Caldejon, Linzy Casal, Andrew Cho, Sissy Cross, Chinh Dang, Tim Dolbeare, Melise Edwards, John Galbraith, Nathalie Gaudreault, Terri L. Gilbert, Fiona Griffin, Perry Hargrave, Robert Howard, Lawrence Huang, Sean Jewell, Nika Keller, Ulf Knoblich, Josh D. Larkin, Rachael Larsen, Chris Lau, Eric Lee, Felix Lee, Arielle Leon, Lu Li, Fuhui Long, Jennifer Luviano, Kyla Mace, Thuyanh Nguyen, Jed Perkins, Miranda Robertson, Sam Seid, Eric Shea-Brown, Jianghong Shi, Nathan Sjoquist, Cliff Slaughterbeck, David Sullivan, Ryan Valenza, Casey White, Ali Williford, Daniela M. Witten, Jun Zhuang, Hongkui Zeng, Colin Farrell, Lydia Ng, Amy Bernard, John W. Phillips, R. Clay Reid, Christof Koch
Journal: Nature Neuroscience (2019)
Best Practices for Prognostic Evaluation of a Patient With Transthyretin Amyloid Cardiomyopathy
Authors: Kent Y. Feng, Rahul S. Loungani, Vishal N. Rao, Chetan B. Patel, Michel G. Khouri, G. Michael Felker, Adam D. DeVore
Journal: JACC CardioOncology (2019)

Transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as an increasingly identified etiology of heart failure. Fortunately, the disease now has an approved therapy, with many others under development. Assessment of prognosis in ATTR-CM is critical to inform patients about the disease course and guide clinical decisions. This review discusses the evidence behind clinical, biomarker, and imaging findings that inform prognosis in patients with ATTR-CM and can assist providers in the shared decision-making process during management of this disease.
Abstract C47: Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis
Authors: Makoto Sano, Hideaki Ijichi, Kazunaga Ishigaki, Ryota Takahashi, Koji Miyabayashi, Keisuke Tateishi, Hiroyuki Isayama, Kazuhiko Koike
Journal: Cancer Research (2019)

Abstract Cancer-associated thrombosis/thromboembolism (CAT) is a serious clinical complication and leads to occasional cause of death in patients with cancers, including pancreatic ductal adenocarcinoma (PDAC). However, diagnostic and inhibitory approach for CAT is still unestablished. We found that CAT with cardiomegaly and increase of plasma atrial natriuretic peptide (ANP) were frequently observed in the PDAC mice containing conditional KrasG12D mutation and knockout of TGF-β receptor type II (Tgfbr2) (PKF mice). Similar to usual thrombotic patients without cancer, high plasma level of cytokines including soluble cell adhesion molecule X was detected in the mice. Molecule-X was immunohistochemically observed in activated endothelium and thrombi. Injection of neutralized anti-molecule-X antibody reduced onset of CAT and cardiac weight in the PKF mice. Meanwhile, high plasma levels of ANP and/or molecule-X were detected in PDAC patients before and after diagnosis of CAT. Taken together, increase of ANP and/or molecule-X is a new risk factor of CAT in PDAC patients. Blocking molecule-X, at least in part, would be an inhibitory approach for CAT in PDAC. Citation Format: Makoto Sano, Hideaki Ijichi, Kazunaga Ishigaki, Ryota Takahashi, Koji Miyabayashi, Keisuke Tateishi, Hiroyuki Isayama, Kazuhiko Koike. Plasma ANP and soluble cell adhesion molecule X are novel risk factors for pancreatic cancer-associated thrombosis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C47.
Abstract A06: Elucidation of the extracellular adenosine pathway in metastatic pancreatic cancer
Authors: Anna M. Chiarella, Rustgi K. Rustgi
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is a deadly disease that is expected to kill over 45,000 people in the United States this year alone. More than 80% of pancreatic cancer patients begin treatment after the disease has already metastasized. We recently published on an autochthonous mouse model of pancreatic cancer (Pdx1-cre; LSL-KRASG12D/+; LSL-Trp53R172H; Rosa26LSL-YFP herein KPCY), whereby we studied the molecular consequences of losing the tumor suppressor P120-CATENIN (encoded by the gene Ctnnd1). We demonstrated that pancreas-specific Ctnnd1 heterozygous deletion (herein P120-het) in KPCY mice dramatically increased metastatic potential relative to KPCY control animals. Upon further investigation with co-immunofluorescence, we found that the metastatic lesions were largely devoid of any P120 protein. The metastatic cells with complete P120 loss appear more mesenchymal, a phenotype associated with tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and with increased metastatic potential. To determine the underlying processes downstream of P120 loss that may be driving EMT and metastasis, we performed RNA-sequencing on P120-WT (nonmetastatic) and P120-null (highly metastatic) tumor cells. Compared to the P120-WT tumor cells, the P120-null tumor cells revealed significant upregulation of several genes involved in extracellular adenosine signaling, Enpp3, Nt5e, and Adora2B. More recently, we confirmed upregulation of ENPP3, NT5E, and ADORA2B at the protein level, compared to healthy pancreas tissue, using immunohistochemistry (IHC). In the highly metastatic cells, Enpp3 (Ectonucleotide pyrophosphatase/phosphodiesterase-3) expression was increased 57-fold. ENPP3 is a type II glycoprotein involved in binding to and converting extracellular ATP into AMP. Nt5e/CD73 was increased 9-fold and also has ecto-nucleotidase activity to convert AMP to adenosine. Increases in extracellular adenosine can activate ADORA2B (a cell membrane receptor that binds adenosine and initiates downstream intracellular signaling), which was activated 4-fold. While this pathway has been shown to be important and therapeutically relevant in other cancers, it has yet to be fully characterized in the context of pancreatic cancer. In summary, using a model with increased metastatic capability, we have unraveled a novel panel of upregulated and functionally related genes that are related to increasing and sensing extracellular adenosine levels. Our recent data suggest that extracellular adenosine signaling may be a previously undiscovered mechanism for cells to acquire metastatic ability. Citation Format: Anna M. Chiarella, Rustgi K. Rustgi. Elucidation of the extracellular adenosine pathway in metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A06.
Efficacy of weekly paclitaxel-bevacizumab combination in advanced non squamous non-small cell lung cancer (NSCLC) progressing after immune checkpoint inhibitors - AVATAX , a retrospective multicentric study: Preliminary data
Authors: S.C. Valery, C. Chouaid, G. Rousseau-Bussac, I. Monnet, G. Bilger, P. Boré, J. Pinsolle, R. Descourt, M. Geier, A.C. Toffart, P. Cony-Makhoul, G. Robinet, F. Ennahdi, I. Zaccaria, C. Decroisette
Journal: Annals of Oncology (2019)
Mevalonate pathway inhibitors in the treatment of B-cell chronic lymphocytic leukemia.
Authors: Ravi Kiran Bobba, Indira Benakanakere, Smitha Bearelly, Monica Arya, Richard Sleigtholm, Carl Freter
Journal: Journal of Clinical Oncology (2012)

6561 Background: B-cell chronic lymphocytic leukemia (CLL) cells are arrested in G0/G1 phase of the cell cycle and are resistant to programmed cell death, hypothesized to contribute to the resistance of CLL cells to standard chemotherapy with curative intent. Methods: Mec-2 cells and Wac-3 cells are CLL cells that have been shown to be resistant to fludarabine and rituximab. We tested a novel enzyme inhibitor’s ability to render CLL cells sensitive to fludarabine and rituximab. Results: BIBB515, a lanosterol synthase inhibitor, at a concentration of 10μM, was able to reduce the cell viability from 82% in controls to 65% after 72 hours. Fludarabine 10μM alone did not reduce the cell viability, 82 % in controls compared to 80%. BIBB515+ fludarabine treatment for 72 hours, at the dose of 10μM each decreased the cell viability to 37%. Cell proliferation by MTT assay was 0.66±0.010 in control compared to 0.37±0.01 in BIBB515+fludarbine and 0.21±0.01 in BIBB515+ fludarabine+ rituximab. There is a 68% down-regulation of cell proliferation using this treatment. There was a two fold induction of CD 20 with combination treatment, and BIBB515 treatment. The mechanism of cell death in the combination treatment of BIBB515 and fludarabine may be due to the up regulation of cell surface marker CD-20. WAC-3 is another CLL cell line that is sensitive to fludarabine, and resistant to rituximab. BIBB515 sensitizes WAC-3 cells to CD 20 antibody rituximab. There is a 68.7% decrease in cell proliferation with combination treatment of BIBB515 and rituximab. Proliferation of Mec-2 cells were inhibited by 60µM and 30µM terbinafine. Ro-48-8071, showed dose-dependent activity, alone or in combination to fludarabine was seen to induce cell death in Mec-2 cells. Fludarabine alone did not have any effect on these cells. Conclusions: Inhibitors of the mevalonate pathway make resistant CLL cells sensitive to current chemotherapeutic agents. Exploiting this mechanism could alter the current treatment regimens, leading to control of the disease in advanced stages by either inducing the leukemic cells to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.