tbuckley/cabot-search huggingface dataset:
Abstract 4655: Iron chelation inhibits mTORC1 signaling in tumor cells
Authors: Chaowei Shang, Hongyu Zhou, Shile Huang
Journal: Cancer Research (2016)

Abstract Iron chelators are commonly used for treatment of iron overload diseases. Recent studies have shown that iron chelators possess potent anticancer activities. Iron chelators (ciclopirox and 3-AP) are in clinical trials for cancer treatment. However, the molecular mechanism underlying the anticancer effect of iron chelation is not well understood. Mammalian/mechanistic target of rapamycin (mTOR) is a master kinase, regulating cell growth/proliferation and survival through sensing environmental cues. mTOR functions as at least two complexes (mTORC1/2). Here we show that two iron chelators, ciclopirox olamine (CPX) and Dp44mT, inhibit tumor cell proliferation by suppressing mTORC1 signaling in human rhabdomyosarcoma (Rh30) and lung cancer (A549 and A427) cells. This is evidenced by the findings that treatment with CPX or Dp44mT inhibited the phosphorylation of 4E-BP1 and S6K1, two best known effector molecules of mTORC1, which could be blocked by addition of ferrous sulfate. Addition of ferrous sulfate prevented the growth inhibitory effect of CPX. Ectopic expression of constitutively active mTOR also conferred resistance to CPX-induced growth inhibition. Mechanistically, iron chelation inhibition of mTORC1 was partially linked to the activation of AMPK, a negative regulator of mTORC1. Overexpression of a dominant-negative AMPK (DN-AMPK) in Rh30 cells attenuated the inhibitory effect of CPX or Dp44mT on the phosphorylation of S6K1 and 4E-BP1. In addition, iron chelation also transiently stabilized HIF-1α and further upregulated the expression of its downstream effector Bnip3, another negative regulator of mTORC1. Knockdown of Bnip3 partially attenuated the inhibitory effect of iron chelation on mTORC1. Furthermore, we found that iron chelation increased the translocation of mTOR from the cytoplasm to the nucleus. The co-localization of mTOR with the third negative regulator of mTOR, PML (promyelocytic leukemia), increased in the nucleus upon iron chelation. Moreover, iron chelation did not obviously alter the phosphorylation of IGF-1 receptor, PI3K or PTEN. The effect of iron chelation on mTORC2-mediated phosphorylation of Akt was cell line dependent. Taken together, the results suggest that the anticancer effect of iron chelation is in part related to inhibition of mTORC1 signaling, and iron chelation inhibits mTORC1 signaling via multiple mechanisms. (Supported by the FWCC, LSU Health Sciences Center) Citation Format: Chaowei Shang, Hongyu Zhou, Shile Huang. Iron chelation inhibits mTORC1 signaling in tumor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4655.
Abstract LB-238: Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas
Authors: Emily Slotkin, Lee Spraggon, Julija Hmeljak, Luciano Martelotto, Romel Somwar, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi
Journal: Cancer Research (2016)

Abstract Many sarcoma subtypes including Ewing sarcoma (ES), alveolar rhabdomyosarcoma (ARMS), synovial sarcoma (SS), and desmoplastic small round cell tumor (DSRCT), are driven by oncogenic chimeric transcription factors. Outcomes for these diseases remain unacceptably poor despite intensification of standard therapies. Although these translocation positive sarcomas possess well-defined oncogenic drivers, as transcription factors that lack intrinsic enzymatic activity, they have been considered undruggable. We have developed a two-tiered pre-clinical therapeutic program 1) creating and characterizing faithful in vitro and in vivo models of these rare malignancies and 2) designing next generation antisense oligonucleotides (ASOs) to directly target the oncogenic chromosomal translocations underlying these multiple sarcoma subtypes. As proof of principle, we present here the program experience with DSRCT, a rare sarcoma for which there has been an overwhelming paucity of both biological tools for pre-clinical investigation, as well as clinical therapeutic options. We have extensively characterized two new DSRCT cell lines harboring the characteristic oncogenic EWSR1-WT1 t(11;22)(p13;q12) fusion, and have used these tools to develop orthotopic xenograft models. Utilizing these accurate model systems we have designed and evaluated a series of ASO compounds directly targeting the EWSR1-WT1 translocation product. Among the series of ASOs developed, we identified D2A, a selective and potent inhibitor of EWSR1-WT1. In vitro, we have shown D2A to abolish the EWSR1-WT1 fusion product with exquisite specificity in a dose-dependent fashion. D2A similarly exhibits efficacy in vivo, with anti-tumorigenic activity in our pre-clinical models resulting in an 80% reduction in xenograft tumor growth. With the aid of authentic in vitro and in vivo modeling systems, this ASO platform has wide-ranging implications for both biological as well as therapeutic advances. Citation Format: Emily Slotkin, Lee Spraggon, Julija Hmeljak, Luciano Martelotto, Romel Somwar, Elisa de Stanchina, Luca Cartegni, Marc Ladanyi. Direct targeting of oncogenic transcription factors using next-generation oligonucleotides as a novel therapeutic strategy for translocation-positive sarcomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-238.
Use of Clozapine in Schizophrenia
Authors: Feras Ali Mustafa
Journal: JAMA Psychiatry (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 Psychiatry 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 Psychiatry journal
Abstract 1046: Statin inhibits malignant mesothelioma cell growth by inactivating YAP1
Authors: Kosuke Tanaka, Taketo Kato, Akihiro Matsushita, Hiromi Furuta, Yuko Murakami, Hirotaka Osada, Yoshitaka Sekido
Journal: Cancer Research (2016)

Abstract The prognosis of patients with malignant mesothelioma (MM) remains very poor because of highly invasive tumor characteristics and therapeutic resistance of this tumor. Recent studies have shown that MM frequently shows Hippo signaling pathway inactivation, which leads to activation of YAP1 transcriptional co-activator. Although substantial data from clinical trials and epidemiological studies showed promising results for the use of statins in many cancers, few studies have argued about the underlying tumor-suppressive mechanisms of statins. Here, we show that statins act as an inhibitor of YAP1-dependent MM cell growth via mevalonate pathway. In cell culture, statins attenuate migration and invasion of H290 malignant mesothelioma cells with homozygous deletion of NF2, which encodes Merlin, an upstream regulator of Hippo pathway. In contrast, geranylgeranyl diphosphate (GGPP), a down-stream activator of mevalonate pathway, completely rescues H290 cell growth inhibition by statins. We also found that statins accelerate YAP phosphorylation/inactivation, which results in the downregulation of Hippo-pathway targeting gene transcriptions including CTGF, CYR-61 and ANKRD1. Moreover, among 11 MM cell lines, we demonstrated that five out of the six cell lines, which showed significant cell growth inhibition with statins, harbor NF2 and/or LATS2 mutations. Finally, we found that phospho-YAP/YAP ratio was increased in statin-sensitive cells, but not in statin-resistant cells. Together, our findings suggest that mevalonate pathway plays crucial roles in YAP-dependent MM cells by Hippo pathway inactivation, and therefore represents a potential therapeutic target for MM. Citation Format: Kosuke Tanaka, Taketo Kato, Akihiro Matsushita, Hiromi Furuta, Yuko Murakami, Hirotaka Osada, Yoshitaka Sekido. Statin inhibits malignant mesothelioma cell growth by inactivating YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1046.
Heart Disease and Stroke Statistics—2006 Update
Authors: Thomas Thom, Nancy Haase, Wayne Rosamond, Virginia J. Howard, John Rumsfeld, Teri Manolio, Zhi-Jie Zheng, Katherine Flegal, Christopher O’Donnell, Steven Kittner, Donald Lloyd-Jones, David C. Goff, Yuling Hong, Robert Adams, Gary Friday, Karen Furie, Philip Gorelick, Brett Kissela, John Marler, James Meigs, Veronique Roger, Stephen Sidney, Paul Sorlie, Julia Steinberger, Sylvia Wasserthiel-Smoller, Matthew Wilson, Philip Wolf
Journal: Circulation (2006)
Re-biopsy in advanced non-small cell lung cancer patients after the development of 3rd generation EGFR-TKI and new targeted therapies.
Authors: Kaname Nosaki, Eiko Inamasu, Shin-ichiro Shimamatsu, Tsukihisa Yoshida, Goji Toyokawa, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose
Journal: Journal of Clinical Oncology (2015)

e19081 Background: Recent reports have demonstrated dramatic effects for newly developed targeted therapies. Performing a re-biopsy to confirm genetic alternations after prior EGFR-TKI therapy has also recently been actively encouraged. Methods: We retrospectively reviewed the medical records of patients with advanced non-small cell lung cancer (NSCLC) who had undergone re-biopsies at National Kyushu Cancer Center after prior chemotherapies. Genomic analysis of EGFR, ALK, RET and ROS1 was performed by commercial clinical laboratories. Results: A total of 65 patients were found to have undergone re-biopsies from Jan/2014 to Dec/2014. EGFR mutation/ALK translocation was identified in 33 and 4 patients before re-biopsy. A total of 75 procedures were performed; including transbronchial biopsy/CT guided core needle biopsy/thoracentesis/liver biopsy/lymph node excisional biopsy/thoracoscopic lung biopsy/others = 40/16/10/2/2/2/3. The purposes of re-biopsies were to detect T790M mutation (n = 39), genomic analyses in LC-SCRUM Japan (n = 21), pre-screening for enrolment into clinical trials (n = 3), histological confirmation (n = 3) and others (n = 9). T790M mutation was identified in 14 cases using re-biopsy samples. Seven of the T790M positive patients received 3rd generation EGFR-TKI in clinical trials. RET/ROS1 translocation was identified in 1 and 2 patients. All of these RET/ROS1 positive patients received RET-TKI or ROS1-TKI in clinical trials. Grade 3 hemorrhage after liver biopsy was observed in one case with a decreased platelet count. No other Grade 3 or 4 adverse events were observed. Conclusions: Ten patients (15%) received new targeted drugs after the re-biopsy. Additionally, 37% of the re-biopsies in this cohort would not have been necessary if frozen samples required for RNA analyses had been obtained at the first diagnosis. Information provided by a genomic analysis leads to appropriate therapies. Since new targeted drugs are currently being developed, performing re-biopsies and preserving extra frozen samples from the first diagnosis should be encouraged.
La pandémie de grippe et le plan d’alerte en Allemagne
Authors: R Fock, H Bergmann, H Bußmann, G Fell, E J Finke, U Koch, M Niedrig, M Peters, K Riedmann, D Scholz, A Wirtz
Journal: Eurosurveillance (2002)

Le cadre conceptuel decrit dans cet article a servi de base a la decision prise en commun par les ministres de la sante des 16 etats federaux d’Allemagne de mettre en œuvre un plan d’alerte pour la pandemie de grippe. Les donnees de la pandemie de  grippe espagnole  de 1918-20 ont servi de base au scenario catastrophe utilise. Nous avons determine les groupes prioritaires pour la vaccination, ainsi que les antiviraux potentiellement disponibles. Les politiques nationales beneficieraient certainement d’une strategie europeenne commune.
siRNA-coupled nanoparticles for improved therapeutic targeting of pancreatic cancer
Authors: Sebastian Lange, Dieter Saur, Roland Rad
Journal: Gut (2016)

Pancreatic cancer (PC) is one of the most lethal malignancies, characterised by a poor response to conventional chemotherapy and rapid development of secondary resistances. Compared with most other digestive tract cancers, progress in PC treatment has been miniscule over the past decades. The most frequently mutated genes, KRAS and p53 , are still difficult to target, and so far only EGFR inhibition (erlotinib) is routinely used in clinical practice for targeted therapy. PC treatment is further complicated by a dense tumour stroma and low vessel density, leading to impaired drug delivery and high adverse effects of systemic therapy.1 

In an elegant study published in Gut , Mahajan et al attempted to address issues related to drug delivery, efficacy and toxicity in PC by nanotechnology-based in vivo RNAi.2 They used superparamagnetic iron oxide nanoparticles (SPIONs) to carry small interfering RNA (siRNA) against polo-like kinase-1 (PLK1) as well as residues for ligand-directed specific targeting of cancer cells.

Nanoparticles are structures on the scale of 1–100 nm that can be exploited for drug delivery. There are different classes of nanoparticles, including lipid-based (organic lipids in a single or bilayer structure), polymeric (solid particles or …
miRNA Expression Profile of B-SLL Consistent with Normal Memory B Cells:BIC/miR–155 Specific Location in Proliferation Center.
Authors: Miao Wang, Jan-Lukas Robertus, Lu-ping Tan, Geert Harms, Tjasso Blokzijl, Rikst Niynke Schakel, Klaas Kooistra, Stefano Rosati, Lydia Visser, Rogier M. Reijmers, Steven T. Pals, P.M. Kluin, Anke van den Berg
Journal: Blood (2007)
Comparison of Glucose and Lipid Metabolism Abnormality during Nilotinib, Imatinib and Dasatinib Therapy – Results of Enigma 2 Study
Authors: Racil Zdenek, Petra Belohlavkova, Petr Cetkovsky, Edgar Faber, Hana Klamova, Malaskova Ludmila, Tomasz Sacha, Voglova Jaroslava, Daniela Zackova, Pavel Zak, Jiri Mayer
Journal: Blood (2014)
Prospective, noninterventional study of vinflunine treatment in advanced urothelial cell carcinoma (UCC) in routine clinical practice.
Authors: Margitta Retz, Patrick De Geeter, Peter J. Goebell, Ullrich Matz, Wito de Schultz, Axel Hegele
Journal: Journal of Clinical Oncology (2014)

e15505 Background: Vinflunine is recommended by the European guideline for the treatment of UCC after failure of platinum-based chemotherapy. In a prospective, non-interventional study (NIS) we investigated the efficacy and tolerability of vinflunine as well as a prognostic risk model for routine clinical practice. Methods: Data were prospectively collected on 77 platinum-pretreated UCC patients undergoing vinflunine treatment in 39 German hospitals or outpatient units. Dosing of vinflunine, tumor assessments and concomitant medications were performed according to physician’s usual practice. A prognostic risk model was evaluated with the four risk factors liver metastasis, ECOG performance status ≥1, hemoglobin level < 10g/dL and time from prior chemotherapy <6 months. Results: A vinflunine starting dose of 320 mg/m² was chosen in 48 % and 280 mg/m² in 39 % of all patients. The overall response rate (ORR) was 23.4 % and median overall survival (OS) was 7.7 months. Patients receiving a starting dose of 320 mg/m² had a median OS of 10.5 months (p=0.054). The treatment-related hematological toxicities grade ≥3 were leucopenia 16.9 %, neutropenia 1.3 %, neutropenic infections 2.6 %, anemia 6.5 % and thrombocytopenia 1.3 %. Using emesis (84 %) and constipation (71 %) prophylaxis the treatment-related non-hematological toxicities grade ≥3 were constipation 5.2 %, elevated liver enzymes 5.2 %, nausea 2.6 % and vomiting 2.6 %. Stratifying OS by the number of risk factors, patients with zero, one, two or > three risk factors displayed a median OS of 18.2, 9.5, 4.1 and 2.8 months, respectively (p=0.0005; HR=1.82). Mulitvariate Cox-regression analysis revealed liver metastases as the strongest risk factor (p=<0.0001). Conclusions: This prospective non-interventional study confirms that vinflunine delivers a meaningful benefit with good safety profile to patients with advanced UCC. The risk factor model could help to define the individual’s prognosis more accurately. The efficacy results seen in this unselected patient population are completely in line with the clinical trials performed with vinflunine. Clinical trial information: NCT 01103544.
In vitro characterization and pre-clinical pharmacokinetics of CP-870,893, a human anti-CD40 agonist antibody
Authors: V. Bedian, C. Donovan, J. Gardner, E. Natoli, T. Paradis, R. Alpert, H. Wang, R. Shepard, J. Wentland, R. Gladue
Journal: Journal of Clinical Oncology (2006)

2539 Background: CD40 is expressed on B-cells, monocytes, dendritic cells, other normal tissues and tumors. Previous studies showed that CD40 stimulation enhances antigen presentation, breaks tolerance, bypasses T-cell help, and induces apoptosis in CD40 pos tumor cells. We report the in vitro activity and primate pharmacokinetics of a human anti-CD40 agonist antibody, CP-870,893, currently in clinical trials for the treatment of cancer. Methods: CP-870,893 was identified as a CD40 agonist antibody by screening lead molecules generated through the Abgenix Xenomouse® platform. Agonist activity was determined using upregulation of B-cell and monocytes derived dendritic cell surface markers, as well as dendritic cell IL-12 induction. BIAcore and equilibrium binding were utilized to determine affinity, and competition studies with CD40L were conducted on BIAcore. CP-870,893 was administered to cynomolgus monkeys i.v. at various doses, serum antibody levels were evaluated over time in an ELISA assay, and B-cell markers were monitored by FACS. Results: CP-870,893 (IgG2, kappa) binds CD40 with sub-nanomolar affinity, and does not block binding of CD40L. When human whole blood is incubated with CP-870,893, upregulation of key surface molecules involved in antigen presentation (MHC Class II, CD80, CD86, CD23 and ICAM-1) is observed with an EC50 of 5–50 ng/ml. Human monocytes derived dendritic cells, when stimulated with CP-870,893, upregulate activation markers (MHC Class II, CD80 and CD83) with an EC50 of 100–300 ng/ml, and secrete high levels of IL-12p40. In the presence of a second stimulus, such as LPS, human dendritic cells also secreted bioactive IL12-p70 when stimulated with CP-870,893 (EC50 ∼ 150 ng/ml). In addition, a CD40 positive human B-cell tumor line, when stimulated with CP-870,893, becomes susceptible to killing by human CTLs. In cynomolgus monkey studies, the clearance of CP-870,893 decreased with increasing dose. Circulating B-cell numbers decreased, and surface molecules were upregulated on B-cells. Conclusions: These data support the potential utility of CP-870,893 as an immune enhancing agent in cancer immunotherapy, by activating antigen presenting cells, and by enhancing the immunogenicity of CD40 positive tumor cells. [Table: see text]
Abstract 1095: S100A4 is post-transcriptionally inhibited by miR-505-5p and miR-520c-3p in colorectal cancer
Authors: Giridhar Mudduluru, Katharina Ilm, Steffen Fuchs, Ulrike Stein
Journal: Cancer Research (2016)

Abstract The calcium binding protein S100A4 induces epithelial mesenchymal transition (EMT), migration, invasion, angiogenesis and metastasis. Its induced expression is reported in several cancer types and correlates with poor prognosis. S100A4 is transcriptionally regulated by Sp1, AP1 and CCAAT/enhancer binding protein β transcription factors and its regulation epigenetically controlled by CpG hyper methylation. However, apart from S100A4 functional and transcriptional regulatory aspects, post-transcriptional regulation is not yet elucidated. In this study, we show that specific microRNAs (miR) target the 3’UTR of S100A4. Luciferase-reporter assays with wild-type and mutated miR-505-5p and miR-520c-3p seed sequences of S100A4-3’UTR confirmed the specificity of targeting. Similarly, overexpression of these miRs reduced the S100A4 and inhibition of these miRs function increased the S100A4 protein significantly. Moreover, co-transfection of either S100A4 expressing vector or siRNA-S100A4 along with the miR-505-5p and miR-520c-3p significantly altered the S100A4 mediated migration and invasion in colorectal cancer (CRC) cell lines (p = 0.05). Both these miRs were down-regulated in CRC cell lines and 5 Aza treatment increased these miRs expression and reduced the S100A4 protein amounts. Moreover, in a panel of CRC resected patient tissues (n = 59), miR-520c-3p significantly down regulated (p = 0.03). miR-520c (located in Chr 19, in a big cluster) upstream region was checked for methylation status using methylation specific PCR and combined bisulfite restriction analysis (COBRA) in CRC cell lines, metastatic and non-metastatic CRC resected tissues. We found the upstream promoter region hyper methylated irrespective of metastasis status of patients and in all CRC cell lines checked. 5 Aza treatment of S100A4 less or no expressing cells line Colo206 and Colo320 showed induced miR-520c expression and reduced S100A4 protein in Colo320. Colo206 cells did not show any alternations in expression of S100A4. Taken together, our findings demonstrate that S100A4 is post-transcriptionally regulated by tumor suppressor genes miR-505c and miR-520c and especially miR-520c expression is epigenetically silenced in CRC. Citation Format: Giridhar Mudduluru, Katharina Ilm, Steffen Fuchs, Ulrike Stein. S100A4 is post-transcriptionally inhibited by miR-505-5p and miR-520c-3p in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1095.