tbuckley/cabot-search huggingface dataset:
Abstract 534: Oncogenes alter mammary epithelial cell lineage identity prior to tumor formation
Authors: Jerrica Breindel, Felix Nampanya, Aditya Datye, Daniel H. Miller, Piyush Gupta, Charlotte Kuperwasser
Journal: Cancer Research (2018)

Abstract Background: Breast cancer is a heterogeneous disease encompassing multiple subtypes that differ in their molecular profiles, clinical course of progression, and response to therapeutics. Interestingly, breast cancers fall broadly into luminal and basal subtypes, which resemble the normal luminal and basal epithelial cells of the breast. This correlation suggests that the molecular mechanisms controlling epithelial cell lineage identity during normal mammary development may also influence tumor subtype during cancer formation. Since many breast cancers are driven by oncogenes that are important for normal mammary development, we hypothesize that dysregulated oncogene signaling may alter mammary epithelial cell lineage identity at an early step of cancer initiation, priming the breast tumor subtype that will be formed upon full tumorigenesis. Methods: Human breast cell lines, MCF10a and MCF10f, and primary human breast tissues were infected with virus expressing single breast cancer oncogenes. Flow cytometry and quantitative RT-PCR were performed on breast cell lines to determine changes in the balance of luminal to basal cells and expression of luminal or basal gene sets. Primary tissues were grown in hydrogels and stained for luminal and basal markers to determine the effect of oncogene expression on the growth of mammary ductal structures. Mouse tumor models, MMTV-Myc and MMTV-Wnt1, were investigated for changes in their mammary epithelial architecture by histology and flow cytometry at ages prior to tumor formation. Results: Oncogene overexpression in human breast cell lines causes shifts in basal and luminal cell balance that correlate with changes seen in mammary ductal growth in hydrogel cultures of primary human breast epithelial cells. In mouse models, individual oncogenes alter mammary epithelial architecture and cell balance at early stages prior to tumor formation. In both models, individual oncogenes are able to regulate mammary epithelial cell lineage identity in the absence of other tumor-initiating signals, indicating that oncogenes may influence breast cancer subtype through mammary epithelial cell lineage regulation at early stages of cancer progression. Citation Format: Jerrica Breindel, Felix Nampanya, Aditya Datye, Daniel H. Miller, Piyush Gupta, Charlotte Kuperwasser. Oncogenes alter mammary epithelial cell lineage identity prior to tumor formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 534.
Opioid Overdose After Surgical Discharge
Authors: Karim S. Ladha, Joshua J. Gagne, Elisabetta Patorno, Krista F. Huybrechts, James P. Rathmell, Shirley V. Wang, Brian T. Bateman
Journal: JAMA (2018)

Taylor A. Ochalek, PhD; Kirk L. Cumpston, DO; Brandon K. Wills, DO; Tamas S. Gal, PhD; F. Gerard Moeller, MD
Abstract 15751: Dosing Patterns and Evolution of Clinical Parameters in Patients Prescribed Sacubitril/Valsartan in Germany
Authors: Rolf Wachter, Daniel Viriato, Sven Klebs, Stefanie S Grunow, Matthias Schindler, Johanna Engelhard, Catia C Proenca, Frederico Calado, Raymond Schlienger, Markus Dworak, Bogdan Balas, Sara Bruce Wirta
Journal: Circulation (2017)

Introduction: Sacubitril/valsartan (sac/val) is a new treatment option for patients with heart failure and reduced ejection fraction. Limited data exist regarding its use outside of clinical trials...
Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches
Authors: Jean-Francois Poulin, Giuliana Caronia, Caitlyn Hofer, Qiaoling Cui, Brandon Helm, Charu Ramakrishnan, C. Savio Chan, Daniel A. Dombeck, Karl Deisseroth, Rajeshwar Awatramani
Journal: Nature Neuroscience (2018)
Abstract 2522: Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis
Authors: Kristopher A. Lofgren, David R. Meier, Megan A. Girtman, Esther A. Peterson, E. Charles Jenkins, Paraic A. Kenny
Journal: Cancer Research (2018)

Abstract Amphiregulin (AREG) is an estrogen-responsive ligand of the epidermal growth factor receptor. Mice with germline deletion of AREG are defective in pubertal mammary expansion. Using shRNA, we have previously reported that the estrogen-responsive growth of MCF7 xenograft tumors in immunocompromised mice is also AREG-dependent. Here we use a series of genetically engineered mouse AREG models (lacZ-knock-in, conditional knockout and germline knockout) to address two outstanding questions: (1) Among the numerous AREG-expressing cell types in the mammary gland and stroma, does the requirement for AREG in mammary gland development reside specifically in the luminal epithelial cells? (2) Is AREG required for mammary tumorigenesis in immunologically-intact mice? An initial characterization of mammary gland development using an AREG-lacZ knock-in allele identified AREG promoter activity in the luminal epithelial but not the myoepithelial compartment. We generated AREGfl/fl mice and achieved luminal epithelial cell specific AREG deletion using MMTV-Cre. Mice lacking AREG in the luminal epithelial compartment (but otherwise proficient in AREG expression) phenocopied the deficit in outgrowth seen in the AREG germline deletion, indicating that luminal epithelial AREG expression is essential for mammary gland development. To determine the extent to which AREG deletion affects mammary tumor latency and multiplicity in immune-intact animals, we used a Cre-regulated model of p53 mutation in mammary tissue (MMTV-Cre x p53LSL-R172H). We used this p53-dependent model to generate at-risk cohorts with AREG deficient (AREG-/-) and AREG proficient (AREG+/+ &amp; AREG+/-) genotypes. Although the cohorts are still maturing, the median age of mammary tumors observed in AREG proficient mice is 258 days (median tumor multiplicity is 2 per animal), while only a single tumor has been detected in the AREG deficient cohort (at 415 days). Together, these data point to two temporally distinct roles for amphiregulin–an essential function in mammary ductal expansion during puberty and a subversion of this developmental role during tumorigenesis later in life. Citation Format: Kristopher A. Lofgren, David R. Meier, Megan A. Girtman, Esther A. Peterson, E. Charles Jenkins, Paraic A. Kenny. Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2522.
Abstract 5499: A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells
Authors: Wenying Ren, Raghav Joshi, Paul Mathew
Journal: Cancer Research (2018)

Abstract Background: PTEN-loss is a highly prevalent genomic event associated with higher risk of metastatic progression and resistance to hormonal therapy in prostate cancer. Akt inhibitor therapy in combination with abiraterone demonstrates early promise in the clinical control of PTEN-deficient prostate cancers. We have previously implicated BCL-XL in the survival of PTEN-null PC-3 prostate cancer cells in vitro, regulated by integrin alpha 5 (ITGA5) (Ren, MCR 2016). Toward advancing therapeutic strategies in PTEN-deficient prostate cancer we further assessed the link between PTEN and BCL-XL mediated prostate cancer cell survival. Methods: Isogenic PTEN knockdown stable cell lines (VCAP and DU145) were generated by lentiviral transduction of pLKO-control-shRNA and two pLKO-PTEN-shRNAs, respectively. PTEN was exogenously expressed in PTEN-null prostate cancer cell lines (PC-3, LNCaP and C4-2B) by 1) transfecting cells with pCMV-Flag-vector or pCMV-Flag-PTEN 2) transfecting cells with pcDNA3-GFP-PTEN and then sorting GFP-PTEN-negative and GFP-PTEN-positive cells by flow cytometry. Cells were then treated with a single agent BCL-XL inhibitor (A1331852 or navitoclax (ABT263); AbbVie), PI3K (buparlisib; Selleck Chem) or Akt (ipatasertib, Selleck Chem) inhibitors or combined PI3K and BCL-2 family inhibitors. Cell survival was assessed by cell viability assay. Expression of pAkt, ITGA5 and apoptotic markers was assayed by Western blot analysis and/or flow cytometry. Results: Notwithstanding the reduction of phospho-bad expression with PI3K inhibition, the potent BCL-XL-targeting BH3 mimetic, A1331852, compared to single agent PI3K or Akt inhibitors in titrated doses was alone sufficient to induce apoptosis and loss of cell viability in all PTEN-null prostate cancer lines tested. PTEN expression reversed the apoptotic response to BCL-XL targeting and blocked the anti-proliferative effect of PI3K or Akt inhibition in PTEN-mutant cells. PTEN knockdown induced membrane expression of ITGA5 whereas PTEN overexpression diminished ITGA5 expression. Conclusions: PTEN regulates the apoptotic threshold in prostate cancer cells via BCL-XL independent of the PI3K/Akt pathway. The induction of ITGA5 membrane localization by PTEN loss defines a potential upstream signaling mechanism for the BCL-XL regulated apoptotic threshold in these cells. Highly potent BCL-XL inhibition requires further investigation as a therapeutic strategy in PTEN-deficient prostate cancer. Citation Format: Wenying Ren, Raghav Joshi, Paul Mathew. A potent BH3 mimetic targeting BCL-XL induces apoptosis regulated by PTEN loss and integrin alpha 5 in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5499.
Abstract 2669: Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients
Authors: Chun-Ho Park, Sun-Chul Hur, Joseph Kim, Dae Hee Lee, Yoon Sun Park, Jae-Sik Shin, Seung-Woo Hong, Jai-Hee Moon, Hyojin Kim, So Hee Lee, Hyebin Park, Joonyee Jung, Mi Jin Kim, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Il-Whea Ku, Hyun Ho Lee, Dong-Hoon Jin
Journal: Cancer Research (2018)

Abstract As the representative targeted anticancer drug for colon cancer patients, Erbitux is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild-type colon cancer patients. Even some patients with KRas wt gene did not respond to Erbitux. However, there is no treatment available for Erbitux-resistant patient group with KRAS WT gene, which is almost 50% of KRAS WT gene holders. Recently, our team identified Erbitux primary resistant related proteins named as CRG (Cetuximab-Resistant Gene) by array analysis based Erbitux responder or nonresponder colon cancer patients derived tissues and confirmed by in vitro and in vivo assay system. Based on these results, we synthesized a novel series of CRG targeted inhibitor. CRG inhibitor (CRG i;WM compound) is a lead compound for treating colon cancer patients who do not respond to Erbitux and have KRAS wild-type gene. CRG i has potent in vitro enzyme activity and high anticancer activity against various colon cancer cell lines with good selectivity in in vitro and in vivo system. Furthermore, the compound has good potent ADME/Tox. profiles for optimized lead. CRG i also displays strong anticancer effect in in vivo xenograft models and patient-derived xenograft (PDX) models. In addition, CRG i shows promising signs of overcoming Erbitux resistance in CRG knockout cells-derived xenograft model. We continue to discover improved preclinical candidates with better selectivity and ADME/Tox. profiles and validate predictive biomarker in colon cancer patients. In these efforts, we found some compounds with better profiles than CRG i. We are also trying to develop small molecules having highly potent activity against mutant CRG. In conclusion, active CRG is a promising biomarker and target for Erbitux-resistant KRAS wt colon cancer patients. Our compounds can be promising therapeutic agents for Erbitux-resistant KRAS wt colon cancer patients. Citation Format: Chun-Ho Park, Sun-Chul Hur, Joseph Kim, Dae Hee Lee, Yoon Sun Park, Jae-Sik Shin, Seung-Woo Hong, Jai-Hee Moon, Hyojin Kim, So Hee Lee, Hyebin Park, Joonyee Jung, Mi Jin Kim, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Il-Whea Ku, Hyun Ho Lee, Dong-Hoon Jin. Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2669.
Endothelial Dysfunction and Cytomegalovirus Replication in Pediatric Heart Transplantation
Authors: JacobSimmonds, MatthewFenton, CatherineDewar, ElizabethEllins, ClareStorry, DavidCubitt, JohnDeanfield, NigelKlein, JulianHalcox, MichaelBurch
Journal: Circulation (2008)

Background— Cardiac allograft vasculopathy is the major limiting factor to the long-term success of pediatric heart transplantation. Cytomegalovirus (CMV) has been shown to be a significant risk factor for the development of cardiac allograft vasculopathy. Recent work has demonstrated CMV DNA in leukocytes in the absence of direct allograft infection, suggesting that vascular changes may not be limited to the allograft. Method and Results— Systemic arterial endothelial function was assessed with high-resolution ultrasound to determine brachial artery flow-mediated dilation in 50 pediatric heart transplant recipients (8 to 17 years of age; 27 male). Patients were separated into 2 groups according to CMV status: those without evidence of CMV replication after transplantation (n=38; 19 male) and patients with evidence of viremia after transplantation (n=12; 8 male). No patient had detectable viremia at the time of study. Flow-mediated dilation was significantly impaired in patients with evidence of CMV repli...
Inherited mutations in DNA repair genes in men with metastatic castration-resistant prostate cancer.
Authors: Peter Nelson, Joaquin Mateo, Himisha Beltran, Navonil De Sarkar, Olivier Elemento, Mark A. Rubin, Jacob N. Vinson, Julie Filipenko, Dan R. Robinson, Arul M. Chinnaiyan, Eliezer Mendel Van Allen, Andrea Garofalo, Mary-Ellen Taplin, Levi A. Garraway, Suzanne Carreira, Robert B. Montgomery, Colm Morrissey, Heather H. Cheng, Johann S. De Bono, Colin C. Pritchard
Journal: Journal of Clinical Oncology (2016)

5009 Background: Inherited mutations in genes that regulate DNA repair processes such as BRCA1 and BRCA2 associate with increased risks of developing lethal prostate cancer (PC), and with response to poly-ADP ribose polymerase (PARP) inhibition and platinum chemotherapy. While the prevalence of such mutations in men with localized PC unselected for family predisposition is insufficient to warrant routine testing, the frequency of germline DNA repair gene (DRG) mutations in men with metastatic prostate cancer (mPC) is not established. Methods: We recruited men with mPC (n = 569) through five IRB-approved studies enrolling across seven institutions designed to ascertain molecular aberrations in mPC. Men were unselected for family history of cancer and were documented to have mPC based on a biopsy of a metastatic site. We isolated germ-line DNA from blood lymphocytes, saliva, or tissue uninvolved with cancer and used multiplex sequencing assays to assess germline mutations in 20 DRGs associated with autosomal dominant cancer predisposition syndromes. Results: Sixty-six deleterious DRG germline mutations were identified in 65 men (11.4%), including BRCA2 (n = 29, 5.1%), ATM (n = 10, 1.8%), CHEK2 (n = 7, 1.2%), BRCA1 (n = 5, 0.9%), PALB2 (n = 3, 0.5%), RAD51D (n = 3, 0.5%), ATR (n = 2, 0.3%) and 1 man each with mutation in FAM175A, GEN1, MRE11A, MSH2, MSH6, RAD51C, and NBN. One patient had mutation in ATM and CHEK2. Overall, the frequency of germline DRG mutations in mPC significantly exceeded the 5% frequency identified in localized PC (n = 499; p < 0.001) which included men with high-risk PC, and 3.1% in the Exome Aggregation Consortium (ExAC) database, which includes individuals with cancer (n = 60,706; p< 0.005). Conclusions: The identification of a germline aberration in a DNA repair pathway gene has implications for treatment selection in view of the potential for therapeutic responses to PARP inhibitors and platinum chemotherapy, and also for identifying families at risk for cancer predisposition. These results suggest that men with mPC, regardless of family history of cancer, should be considered for germline genetic testing of DNA repair genes.
Abstract 2412: The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation
Authors: Aditya Dutta, Cory Abate-Shen
Journal: Cancer Research (2018)

Abstract An emerging hallmark of cancer is reprograming of energy metabolism, in which mitochondrial plasticity plays a central role. Mitochondrial plasticity, particularly in response to oxidative stress, is coordinately orchestrated by both mitochondrial- and nuclear-encoded genes. Recent reports highlight the association of mitochondrial dysfunction and prostate cancer, one of the leading causes of cancer and cancer-related death for men. One of the earliest events in prostate cancer etiology is loss of functional NKX3.1, a homeoprotein that is known to play essential roles in prostate differentiation and prostate cancer by regulation of nuclear-encoded genes. We now show that in response to oxidative stress, NKX3.1 is localized to the mitochondria where it directly protects against reactive oxygen species (ROS). NKX3.1 regulates mitochondrial function by directly binding to the D-loop (mitochondrial DNA control region) to specifically regulate mitochondrial genes coding for the electron transport chain. Moreover, we show that aberrant NKX3.1 function in the mitochondria leads to enhanced reactive oxygen species and DNA damage, both of which are reversed by metformin, a biguanide class of anti-diabetic drug that targets the mitochondrial electron transport chain. This uncovers the potential for metformin administration to individuals with NKX3.1 loss as a precision prevention approach against prostate cancer initiation. These observations highlight novel functions for homeoproteins as direct regulators of mitochondrial DNA, and demonstrate the critical role of the mitochondrial stress response in enabling prostate cancer initiation with potential novel therapeutic implications. &amp;gt; Citation Format: Aditya Dutta, Cory Abate-Shen. The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2412.
Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mary-Ellen Taplin, Emmanuel S. Antonarakis, Karen J. Ferrante, Kerry Horgan, Brent A. Blumenstein, Fred Saad, Jun Luo, Johann S. De Bono
Journal: Journal of Clinical Oncology (2017)

5005 Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC. Gal is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. ARMOR3-SV was designed to test the hypothesis that in mCRPC patients with AR-V7+ CTCs, Gal could improve radiographic progression-free survival (rPFS) versus Enz. Methods: In this randomized, open-label, multicenter phase 3 study (NCT02438007), men with treatment-naïve mCRPC were screened for CTC-specific AR-V7 (Qiagen), and AR-V7+ men were randomized 1:1 to Gal or Enz. rPFS (by independent blinded central review) was the primary endpoint. Planned sample size was 148, with 120 rPFS events to achieve 90% power to detect a hazard ratio of ≤0.55. Results: 953 patients were screened globally for AR-V7 from Sept 2015 through study closure; 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–, and 630 (66%) had no CTCs/AR present (unevaluable). AR-V7 detection was associated with higher PSA levels ( &gt; vs &lt; median; P &lt; 0.01), more bone metastases ( &gt; 20 vs 11-20 vs 6-10 vs 0-5; P &lt; 0.01), presence of M1 disease at diagnosis (dx) (yes vs no; P = 0.04), shorter time from dx to screening ( &lt; vs &gt; median; P &lt; 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P &lt; 0.01) and prior docetaxel use (yes vs no; P &lt; 0.01). Among the AR-V7+ men, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced. On the recommendation of the DSMB, the study was closed early as it was unlikely to meet its primary endpoint. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA 50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals. Conclusions: In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients. Clinical trial information: NCT02438007.
Effect of Glycoprotein IIb/IIIa Receptor Blockade on Recovery of Coronary Flow and Left Ventricular Function After the Placement of Coronary-Artery Stents in Acute Myocardial Infarction
Authors: Franz-JosefNeumann, RudolfBlasini, ClausSchmitt, EckhardAlt, JosefDirschinger, MeinradGawaz, AdnanKastrati, AlbertSchömig
Journal: Circulation (1998)

Background—Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction. Methods and Results—In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired ...
Single-cell RNAseq for the study of isoforms—how is that possible?
Authors: Ángeles Arzalluz-Luque, Ana Conesa
Journal: Genome biology (2018)

Single-cell RNAseq and alternative splicing studies have recently become two of the most prominent applications of RNAseq. However, the combination of both is still challenging, and few research efforts have been dedicated to the intersection between them. Cell-level insight on isoform expression is required to fully understand the biology of alternative splicing, but it is still an open question to what extent isoform expression analysis at the single-cell level is actually feasible. Here, we establish a set of four conditions that are required for a successful single-cell-level isoform study and evaluate how these conditions are met by these technologies in published research.