tbuckley/cabot-search huggingface dataset:
376. Overexpression of Pitx3 in the SNpc and Protection from MPTP Toxicity
Authors: Joanne Clark-Matott, Allison K. Graebner, Caroline E. Bass, David K. Simon
Journal: Molecular Therapy (2016)

In the brain, expression of the transcription factor Pituitary Homeobox 3 or Paired-Like Homeodomain Transcription Factor 3 (PITX3) is crucial to the development and maintenance of dopaminergic neurons. During brain development, PITX3 functions in concert with the transcription factors NURR1 and LMX1b to facilitate dopaminergic neuron maturation. In the mature brain, PITX3 promotes the dopaminergic phenotype by positively regulating tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2), either singly or in concert with NURR1. PITX3 also positively regulates expression of the pro-survival factors brain-derived neurotrophic factor (BDNF) and glial-derived neurotropic factor (GDNF). PITX3 is endogenously expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). However, in Pitx3 null mouse models, perturbations of cell number are observed only in the SNpc, a situation that resembles the relative sparing of the VTA in early-stage Parkinson's disease (PD). Systemic administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in the degeneration of SN dopaminergic neurons via a mechanism thought to involve the inhibition of mitochondrial respiration and the generation of reactive oxygen species, both of which are implicated in the pathogenesis of PD. Recent work in muscle demonstrates that PITX3 regulates expression of antioxidant enzymes and genes involved in mitochondrial biogenesis via the transcription factor NRF1. We have overexpressed murine Pitx3 (or mCherry control) from the CMV promoter in the SN of C57BL/6J mice using an AAV2/10 viral vector, and tested for neuroprotection in a sub-chronic MPTP model of PD (5 × 20 mg/kg MPTP over 9 days) by assaying for striatal dopamine, stratial TH and DAT immunoreactivity, and SN neuronal number. We will present results from these assays and changes in expression of Pitx3 target genes (TH, DAT, VMAT2, BDNF and GDNF) after Pitx3 overexpression in the SN.
Abstract 4423: Chemoresistance regulation by COL11A1 in ovarian cancer
Authors: Yi-Hui Wu
Journal: Cancer Research (2015)

Abstract Epithelial ovarian carcinoma remains the most lethal gynecologic malignancy. While initial response to first-line therapy (consisting of surgical cytoreduction and combination platinum/taxane therapy) is usually effective, the majority of patients will ultimately recur with chemotherapy-resistant cancer and succumb to disease. Biomarkers that predict patient's responsiveness to chemotherapy might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the molecular mechanisms of collagen type XI alpha 1 (COL11A1) in chemo-resistance of ovarian cancer. We analyzed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes linked with chemotherapy response. Among the 47 selected genes, collagen type XI alpha 1 (COL11A1) was the most highly elevated in chemo-resistance tumors. Small interfering RNA-mediated specific reduction of COL11A1 protein levels increased the sensitivity of ovarian chemoresistant cells to cisplatin and paclitaxel. A combination of experimental approaches, including real-time RT-PCR, western blotting, luciferase assay and chromatin immunoprecipitation (ChIP) assays, showed that the c/EBPβ binding site on the COL11A1 promoter was identified as the major determinant of cisplatin and paclitaxel-dependent COL11A1 activation. Furthermore, COL11A1 silencing suppressed phosphorylated Akt expression, which was in concert with increased PDK1 degradation in chemoresistant cells. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and poor clinical outcome. In conclusion, activation of COL11A1 by anticancer drugs confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization. Note: This abstract was not presented at the meeting. Citation Format: Yi-Hui Wu. Chemoresistance regulation by COL11A1 in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4423. doi:10.1158/1538-7445.AM2015-4423
Abstract 2630: Inhibition of angiogenesis contributes to enhanced radiation response in tumors following MDM2 inhibition by AMG 232
Authors: Lauryn R. Werner, Shyhmin Huang, Eric A. Armstrong, Fang Ma, Jude Canon, Paul M. Harari
Journal: Cancer Research (2015)

Abstract MDM2-p53 interaction and downstream signaling impacts cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We previously elucidated the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. In the current study, we examine the capacity of AMG 232 to inhibit angiogenesis and assess the resultant impact on AMG 232-induced radiosensitivity. We first examined the impact of AMG 232 on the growth and radiosensitivity of human umbilical vein endothelial (HUVEC) and dermal lymphatic endothelial cells (HDLEC). We found that AMG 232 inhibited the proliferation of both endothelial cell types in a dose dependent manner. Importantly, treatment with AMG 232 significantly reduced angiogenesis-related tube formation in both endothelial cell types. Using clonogenic survival analysis, we identified that treatment with AMG 232 significantly enhanced radiosensitivity. Immunoblot analysis showed that combined treatment with AMG 232 and radiation resulted in a profound impact on molecules involved in cell cycle progression, DNA damage repair, and apoptosis signaling, including FoxM1, ATM/ATR, CHK2, Rad51, and Bax. Flow cytometric analysis also showed a significant cell cycle arrest in G2/M phase with an increase of DNA damage related γH2AX level at 48 hrs following radiation and AMG 232 treatment. In H460 and SJSA-1 tumor xenografts, we found a markedly increased antitumor capacity of AMG 232 when combined with radiation. Immunohistochemical analysis revealed a significant reduction of cellular proliferation and vascular density in both tumor types following combined treatment of AMG 232 and radiation. Taken together, these findings reveal the potential anti-angiogenic capacity of AMG 232 that may contribute to augmentation of radiation response previously observed in tumor xenograft studies. A detailed investigation is in progress to examine changes in the tumor microenvironment following AMG 232 and radiation treatment, including hypoxia and vascular normalization, to assess their respective impact on tumor response to radiation. Citation Format: Lauryn R. Werner, Shyhmin Huang, Eric A. Armstrong, Fang Ma, Jude Canon, Paul M. Harari. Inhibition of angiogenesis contributes to enhanced radiation response in tumors following MDM2 inhibition by AMG 232. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2630. doi:10.1158/1538-7445.AM2015-2630
Nanoparticle albumin-bound paclitaxel as 2nd line chemotherapy for small cell lung cancer with interstitial lung disease
Authors: Masanari Hamaguchi, Motohiro Tamiya, Eriko Tani, Yuichiro Azuma, Ayako Tanaka, Takayuki Shiroyama, Naoko Morishita, Hidekazu Suzuki, Norio Okamoto, Tomonori Hirashima
Journal: Annals of Oncology (2015)
228. Safety and Efficacy of Tumor-Targeted Interleukin 12 Gene Therapy for the Treatment of Local and Metastatic Cancers
Authors: Jeffry Cutrera, Glenn King, Pamela Jones, Kristen Kicenuik, Elias Gumpel, Xueqing Xia, Shulin Li
Journal: Molecular Therapy (2015)

Interleukin 12 gene therapy is a potential method for utilizing the immunomodulatory power of IL12 to safely treat cancer; however, specifically accumulating the activity of the IL12 in the tumor environment is critical. Directly injecting the IL12 plasmid DNA into the tumor is ideal, but metastatic disease or non-accessible tumors can not be effectively treated. To overcome this impediment, tumor-targeted (tt) Interleukin 12 (IL-12) plasmid DNA can be safely delivered to accessible tumors, and these treatments can induce antitumor immune responses in both the treated and untreated tumors. Here, electroporation-mediated ttIL-12 pDNA treatments are shown to be safe and well tolerated in a dose escalation study in canines bearing naturally-occurring neoplasms. The final dose-escalation cohort received 3,800 mg pDNA distributed among five separate squamous cell carcinoma tumors in doses equivalent to those administered in a Phase I trial with wildtype IL-12 pDNA. No severe adverse events occurred in any patient at any of the five dose levels, and only minor, transient events were noted in any tested parameter. Analysis of clinical responses and immune marker mRNA in treated and non-treated lesions demonstrates that ttIL-12 pDNA treatments in only a few tumors can evoke antitumor immune responses in the treated lesions as well as distant metastatic lesions. These observations and data suggest that ttIL-12 pDNA can be safely administered at human clinical parameters, and these treatments can elicit a systemwide antitumor effect for controlling treated and some non-treated, metastatic lesions located in distant organs.
Abstract 2328: Targeting self-renewal in human colorectal cancer by inhibiting SUMOylation
Authors: Li Du, Yuan Chen
Journal: Cancer Research (2015)

Abstract Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in the US. It is well recognized that cancer stem cells (CSCs) are responsible for treatment resistance, tumor metastasis and relapse, which cause treatment failure. SUMOylation is known to be important for pluripotency and is dysregulated in cancers to drive tumor growth and metastasis. Therefore, we investigate the role of SUMOylation in colorectal cancer CSC maintenance and self-renewal. In this study, we established that aldehyde dehydrogenase 1 (ALDH1) activity is a valid marker of colorectal CSCs, because ALDH+ cells in HT29 displayed CSC properties including self-renewal, clonal formation and tumor initiation in NSG xenograft mouse model, while ALDH- cells did not. Profiling ALDH+ and ALDH- cells showed that SUMO-activating enzyme (SAE) is highly enriched in ALDH+ cells along with enhanced global SUMOylation. Overexpression of the catalytic subunit of SAE, SAE2, increased the population of ALDH+ cells while knockdown of SAE2 decreased the population of ALDH+ cells. This result suggests that increased SAE level promotes stemness in colorectal cells. To characterize CSC maintenance and self-renewal quantitatively, we performed limited dilution assays in vitro with sphere initiation and in vivo using mouse xenograft models. In in vitro assays, we observed 4-fold reduction in CSC self-renewal frequency in SAE2 knockdown cells compared to control cells in the colorectal cancer cell line HT29. In four colorectal cancer patient-derived primary culture cells, the frequency was 2∼6 fold lower in SAE2 knockdown groups than control. In the in vivo experiment, SAE2 knockdown group showed 12-fold reduction in self-renewal frequency of HT29 cells. These data demonstrate that silencing of SAE2 causes a significant decrease in stemness of colorectal cancer cells, both in HT29 cell line and primary human tumors. Mechanistic analysis regarding how SUMOylation regulate colorectal cancer CSC is underway and will be discussed. In conclusion, our study indicates that SUMOylation, in particular the SAE, is an important regulator of colorectal CSC maintenance and self-renewal. Therefore, the data suggests that targeting SAE is a potential strategy to inhibit colorectal CSC. Citation Format: Li Du, Yuan Chen. Targeting self-renewal in human colorectal cancer by inhibiting SUMOylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2328. doi:10.1158/1538-7445.AM2015-2328
A New Standard for the Laboratory Diagnosis of Sporadic Creutzfeldt-Jakob Disease
Authors: Paul Brown
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Primary CNS Lymphoma Treated with HD-Methotrexate, HD-Busulfan/Thiotepa, Autologous Stem Cell Transplantation and Response-Adapted Whole-Brain Radiotherapy: Results of the Multicenter OSHO-53 Phase II - Study.
Authors: Michael Montemurro, Thomas Kiefer, Frank Schüler, Haifa-Katrin Al Ali, Hans-Heinrich Wolf, Regina Herbst, Antje Haas, Kirsten Helke, Anja Theilig, Christian Lotze, Carsten Hirt, Dietger Niederwieser, Matthias Schwenke, William Krüger, Gottfried Dolken
Journal: Blood (2005)
Head-to-Head Comparison of the AliveCor Heart Monitor and Microlife WatchBP Office AFIB for Atrial Fibrillation Screening in a Primary Care Setting
Authors: Pak-Hei Chan, Chun-Ka Wong, Louise Pun, Yu-Fai Wong, Michelle Man-Ying Wong, Daniel Wai-Sing Chu, Chung-Wah Siu
Journal: Circulation (2016)
High Resolution Genomic Profiling Using Single Nucleotide Polymorphism Microarrays Identifies Multiple Novel Genomic Lesions in Pediatric Acute Lymphoblastic Leukemia.
Authors: Charles G. Mullighan, Salil Goorha, Ina Radtke, James Dalton, Jing Ma, Stanley B. Pounds, Xiaoping Su, Ching-Hon Pui, Mary V. Relling, William E. Evans, James R. Downing
Journal: Blood (2006)
Combined Therapy with Lenalidomide and Prednisone Renders Durable Clinical, Histopathological, and Molecular Responses in Patients with Myelofibrosis
Authors: AlFonso Quintas-Cardama, Hagop M. Kantarjian, Deborah A. Thomas, Jorge Cortes, Farhad Ravandi, Stefan Faderl, Guillermo Garcia-Manero, Gautam Borthakur, Neda Bell, Catriona Byrne, Srdan Verstovsek
Journal: Blood (2008)
520. Arming a Tumor Targeted Oncolytic HSV Vector with MMP9 for Enhanced Distribution and Killing Activity
Authors: Paola Sette, Aofei Li, Marco Marzulli, Daniela Leronni, Mingdi Zhang, William Goins, Balveen Kaur, Chelsea Bolyard, Nduka Amankulor, Joseph Glorioso, Paola Grandi
Journal: Molecular Therapy (2016)

Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of glioblastoma multiforme, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, our central goal was to improve oncolytic vector delivery, replication, and spread while maintaining safety and tumor specificity. We had already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modified our vector by arming it with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. MMP9 degrades collagen type IV, a major component of the extracellular matrix (ECM) and basement membranes of glioblastomas. Here we show that: (i) MMP9 expression improves vector spread in GBM neurospheres in vitro; (ii) MMP9 enhances the oncolytic therapeutic efficacy in animal model of human GBM without compromising vector safety.
Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy
Authors: Vincent Chung, Shannon McDonough, Philip A. Philip, Dana Cardin, Andrea Wang-Gillam, Laifong Hui, Mohamedtaki A. Tejani, Tara E. Seery, Irene A. Dy, Tareq Al Baghdadi, Andrew E. Hendifar, L. Austin Doyle, Andrew M. Lowy, Katherine A. Guthrie, Charles D. Blanke, Howard S. Hochster
Journal: JAMA Oncology (2016)

KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.
Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial
Authors: Alok A. Khorana, Pieter W. Kamphuisen, Guy Meyer, Rupert Bauersachs, Mette S. Janas, Mikala F. Jarner, Agnes Y.Y. Lee
Journal: Journal of Clinical Oncology (2017)

Purpose Circulating tissue factor (TF) has been studied as a biomarker for predicting initial, but not recurrent, venous thromboembolism (VTE) in cancer, a setting in which predictors are incompletely understood. We evaluated the association of TF, clinical risk factors, and other biomarkers measured at the time of initial VTE with recurrent VTE in a prespecified analysis of the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial. Methods CATCH was a randomized, multicenter trial that investigated tinzaparin 175 IU/kg once daily or dose-adjusted warfarin for 6 months in patients with cancer and acute, symptomatic VTE. TF ELISA, soluble P-selectin, d-dimer, FVIII, and C-reactive protein were assayed. Fisher's exact test was used to screen for association with VTE; competing risk regression analysis of time to recurrent VTE was conducted, accounting for multiple variables. Results The study population comprised 900 patients (recurrent VTE, n = 76; 8.4%). Of these patients, 805 had samples available for TF assay. Mean and median TF levels were 72.5 pg/mL and 50.3 pg/mL, respectively (range, 15.6 pg/mL to 4,798 pg/mL). Patients in the highest quartile of TF experienced the greatest VTE recurrence (> 64.6 pg/mL; 38 [19%] of 203 patients v 34 [6%] of 602 patients; relative risk, 3.3; 95% CI, 2.1 to 5.1; P < .001). In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE (subdistribution hazard ratio [SHR], 3.3; 95% CI, 1.7 to 6.4). Other significant variables included venous compression from mass (SHR, 3.1; 95% CI, 1.4 to 6.5) and hepatobiliary cancer (SHR, 5.5; 95% CI, 2.3 to 13.6). Conclusion This is the first report, to our knowledge, to describe TF as a potential biomarker of recurrent VTE in patients with cancer who are on anticoagulation treatment. A risk-adapted strategy could help identify high-risk patients who may benefit from more intensive anticoagulation approaches.
Abstract 1613: β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs)
Authors: Zachary R. Moore, Sarai Stuart, Agnieszka Cholka, Ashwin Venkataraman, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch
Journal: Cancer Research (2015)

Abstract Atypical teratoid rhabdoid tumors (ATRTs) are aggressive malignant neoplasms that occur in the CNS, most commonly in children &amp;lt;3 years of age. Despite intensive chemo-radiotherapy and surgery, the outcomes for patients with this disease remain dismal, with ∼75% of patients dying from their disease at a median of 10 months after diagnosis. Thus, it is critical to identify and validate novel ATRT targets for new therapies. We found that the pathognomonic genetic lesion of ATRTs, loss of the SWI/SNF chromatin remodeling complex member INI1/hSNF5/SMARCB1, leads to high expression of NAD(P)H:quinone oxidoreductase 1 (NQO1), a two-electron oxidoreductase. Thus, we hypothesized that ATRTs will be vulnerable to drugs, such as ß-lapachone (ß-lap, ARQ761 in clinical form), that selectively kill NQO1-expressing cells. A panel of ATRT cell lines exhibited overall high NQO1 expression and low micromolar sensitivity to ß-lap (IC50 1.6-4 uM), with the exception of cell lines that were homozygous for the C609T NQO1 (*2) polymorphism, which exhibited no NQO1 activity and were resistant to ß-lap treatment (IC50 &amp;gt;15 uM). A two-hour pulse with ß-lap caused a burst of ROS-mediated DNA damage and PARP1 hyperactivation, resulting in NAD+ and ATP depletion and caspase-independent, mu-calpain-mediated apoptosis. Co-treatment with dicoumarol, a specific inhibitor of NQO1, prevented these effects by blocking the NQO1-dependent bioactivation of ß-lap. Low expression of NQO1 in normal brain and other pediatric tissues suggests a wide therapeutic window for ß-lap. These findings encourage the continued study of ß-lap and other NQO1 bioactivated therapeutics for the treatment of this recalcitrant disease. This work was supported by NIH/NCI R01 CA102972 to DAB and a REACH award from the Alex's Lemonade Stand Foundation to JFA and TWL. Citation Format: Zachary R. Moore, Sarai Stuart, Agnieszka Cholka, Ashwin Venkataraman, Jingying Xu, Anat Erdreich-Epstein, Dinesh Rakheja, David A. Boothman, James F. Amatruda, Theodore W. Laetsch. β-lapachone: a novel targeted therapy for atypical teratoid rhabdoid tumors (ATRTs). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1613. doi:10.1158/1538-7445.AM2015-1613