tbuckley/cabot-search huggingface dataset:
A phase II multicenter evaluation of ARQ 197 monotherapy in patients with relapsed or refractory germ cell tumors (GCTs).
Authors: D. R. Feldman, L. H. Einhorn, D. I. Quinn, A. Horwich, Y. Loriot, J. K. Joffe, D. J. Vaughn, A. Flechon, J. Hajdenberg, A. U. Pande, K. Liu, I. Gorbatchevsky, R. J. Motzer
Journal: Journal of Clinical Oncology (2011)

4638 Background: ARQ 197 is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the c-MET receptor tyrosine kinase. Preclinical and phase I data suggested a possible role for c-MET in the pathophysiology of GCTs and a potential clinical benefit from ARQ 197 in GCT patients. Methods: Men (≥ 16 years of age) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received continuous oral ARQ 197 (360 mg twice daily in 28-day cycles) until progressive disease (PD) or unacceptable toxicity. Responses were assessed every 4 weeks during the first 4 cycles, and every 8 weeks thereafter per RECIST v1.1. The primary endpoint was objective response rate within the first 4 cycles, with study termination for < 2 responses amongst the first 21 patients (Simon 2-stage optimal design). Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results: 27 patients (median age, 32 years) were enrolled from 9 sites in the US and Europe from February 2010 to November 2010. 25 had non-seminoma histology. Primary tumor sites included testis in 24, and mediastinum in 3. ECOG performance status was 0 (n = 9) or 1 (n = 18). All patients had received ≥ 2 prior lines of chemotherapy and 19/27 (70%) had received high-dose chemotherapy. Among 25 patients evaluable for efficacy, there were no objective responses and accrual was halted once the 21st patient became evaluable. Best response was stable disease in 7 and PD in 18. Median PFS was 32 days (95% CI = 29, 52) and 12-week PFS rate was 14%. Less than half (n = 12) patients have died. Reported grade 3/4 adverse events considered related to study drug were rare and included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions: ARQ 197 was well tolerated but did not demonstrate activity as a single agent in patients with relapsed/refractory GCTs. Correlative biologic data is pending but may provide insight into the lack of efficacy observed. Rapid accrual to this phase II trial was achieved in this rare patient population through multicenter collaboration. Future collaborative trials of novel targeted agents with sound biologic rationale are warranted in relapsed/refractory GCTs.
Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR -Mutated Non–Small Cell Lung Cancer
Authors: Pei Ni Ding, Sarah J. Lord, Val Gebski, Matthew Links, Victoria Bray, Richard J. Gralla, James Chih-Hsin Yang, Chee Khoon Lee
Journal: Journal of Thoracic Oncology (2016)
Is the combination of COX-2 inhibitor and calcitriol a new chemopreventive approach to decrease the incidence of breast cancer?
Authors: M. Thill, S. Becker, D. Fischer, T. Cordes, F. Hoellen, M. Friedrich, K. Diedrich, C. Dittmer
Journal: Journal of Clinical Oncology (2011)

e11103 Background: COX-2 is a potential molecular prognostic factor for breast cancer and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol (1,25(OH)2D3) mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. Methods: The expression of the prostaglandin (PG) metabolising enzymes (COX-2, 15-PGDH), the PG receptors, the vitamin D metabolising enzymes (1-alpha-hydroxylase, 24-hydroxylase) and the VDR were determined in benign and malignant breast cell lines as well as in normal and malignant breast tissue. Measurement of PGE2 and 25(OH)2D3 serum level in healthy women and breast cancer patients was performed in winter and summertime. Additionally, the influence of calcitriol on cell proliferation was determined. In addition we examined the effect of calcitriol on the enzyme expression. Results: We found an inverse correlation between the expression of the PG metabolising enzymes with the VDR as well as with the vitamin D metabolising enzymes by investigating the tissue samples. Moreover, we detected an inverse correlation between the PGE2 and 25(OH)2D3 serum level in breast cancer patients during wintertime. Furthermore the PG receptors were associated with an increased carcinogenesis. The breast cell experiments presented a dysregulated vitamin D metabolism, especially in the invasive breast cell line. Calcitriol showed an antiproliferative effect only in the benign but not in the malignant cell lines, and the expression of COX-2 and 15-hydroxyprostaglandindehydrogenase was influenced by calcitriol only in the benign breast cell line. Conclusions: These results suggest a link between vitamin D and PG metabolism and therefore a possible synergism between COX-2 inhibition and calcitriol in breast cancer cells. For the first time, we could show an inverse correlation between the two metabolisms in breast cancer on different levels. Thus, the chemopreventive combination of calcitriol and/or vitamin D analogue with a COX-2 inhibitor might decrease the incidence of breast cancer.
Antidotal Effects of Non-Specific Reversal Agents On Anticoagulant-Induced Inhibition of Thrombin Generation.
Authors: Daniele Pillitteri, Ann-Kathrin Pilgrimm-Thorp, Manuela Krause, Thomas Scholz, Rainer Schwerdtfeger, Tanja Behrendt, Carl Kirchmaier
Journal: Blood (2012)
Pyrimido-Indole Derivatives Are Novel Agonists of Human Cord Blood Hematopoietic Stem Cell Self-Renewal
Authors: Iman Fares, Jalila Chagaroui, Yves Gareau, Stéphane Gingras, Nadine Mayotte, Elizabeth Csaszar, Hans-Peter Kiem, Norman N. Iscove, R. Keith Humphries, Connie J. Eaves, Sandra Cohen, Anne Marinier, Peter W. Zandstra, Guy Sauvageau
Journal: Blood (2014)
Influence of induction chemotherapy on patients’ compliance to radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.
Authors: B. Atassi, O. Ozgursoy, G. H. Yoo, J. R. Jacobs, N. S. Bhatti, M. Mal, H. Kim, H. Lin, A. Sukari
Journal: Journal of Clinical Oncology (2011)

5558 Background: Induction chemotherapy (IC) is regaining its rule in the management of locally advanced head and neck squamous cell carcinoma (LAHNSCC). IC is a successful strategy for organ preservation, improves clinical response and reduces distant relapse, but it adds considerable morbidity and mortality. While large randomized trials comparing IC followed by chemo-radiotherapy with chemo-radiotherapy alone are ongoing, we are assessing the patient’s compliance to complete radiotherapy after IC. Methods: Retrospectively the medical records of patients with LAHNSCC, who were planned to receive IC followed by concurrent chemo-radiotherapy, were reviewed. Patients are considered compliant when they complete thirty five fractions of radiotherapy. Non-compliant is defined as; less than thirty fractions of radiation or more than one week interruption of radiation. Results: Seventy two patients were included, sixty one male and eleven female. IC regimens were cisplatin and 5-flurouracil (PF) in fifty one patients and docetaxel, cisplatin, and 5-flurouracil (TPF) in twenty one patients. Compliance was achieved in fifty two patients (72%), Compliance according to IC: 74.5% and 66% in the PF and TPF groups, respectively. Overall median survival was 34.7 months. Median survival was significantly more among compliant patients 38.4 vs 11.3 months P (0.0319). Of the 20 non-compliant patients; 6 had complications from radiation, 5 lost follow up, 4 had more than one week break during radiation, 2 died before starting concurrent chemo-radiotherapy, 1 developed thrombocytopenia, 1 died during concurrent chemo-radiotherapy and 1 had progressive disease. Conclusions: After induction chemotherapy, non-compliance to definite concurrent chemo-radiotherapy significantly decreases survival in locally advanced head and neck squamous cell carcinoma.
Abstract 001: The Investigation of Peptide Amphiphile Micelles for Detection of Vulnerable Atherosclerotic Plaques
Authors: Eun Ji Chung, Laurie Drews, Matthew Tirrell
Journal: Circulation Research (2013)

Atherosclerosis is an inflammatory disease that is complicated by progressively unstable plaques which are characterized by specific molecular events. While current diagnostic imaging technology aim to determine the stability of plaques by assessing their physical attributes, molecular imaging tools aim to assess the true nature of the plaque through targeting of molecular markers. Furthermore, these existing technologies can hardly meet the sensitivity and accuracy standards that are required for any clinical application for preventive measures. In order to preventatively intervene during the early pathology of plaque vulnerability, we are engineering monocyte-targeting, fluorescently-labeled peptide micelles (MFPMs) through the incorporation of the chemokine receptor CCR2-binding motif (residues 13-35) of the monocyte chemoattractant protein-1 (MCP-1). Since monocytes are found concentrated in plaques prone to rupture, and our molecular imaging tool binds specifically to monocytes, this nanoparticle system may provide a noninvasive, detection system for plaques of high risk. The MCP-1 peptide or Cy-7 was conjugated to DSPE-PEG-2000 and mixed to form self-assembled, fluorescently-labeled, monocyte-targeting peptide amphiphiles. The critical micelle concentration of MFPMs was determined to be approximately 1 μM with an average diameter of approximately 15 nm, confirmed via dynamic light scattering and transmission electron microscopy. Chemotaxis assays confirmed the chemoattractive capabilities of MFPMs using murine monocytes at 4 hours in vitro, and MFPMs were confirmed to be biocompatible using murine aortic endothelial cells and smooth muscle cells after 24 hours. Peptide amphiphile micelles can be synthesized with multiple functionality (i.e. targeting element, imaging dye, etc.) and our investigations will lay the ground work for peptide amphiphile micelle-mediated drug delivery at the site of vulnerable plaques.
Abstract 2349: EGFR is transferred from triple negative breast cancer cells to immune cells via trogocytosis and expression of EGFR on immune cells is associated with high tumor grade of triple negative breast cancer patients
Authors: Eiji Suzuki, Ayane Yamaguchi, Tatsuki R. Kataoka, Masahiro Hirata, Kosuke Kawaguchi, Mariko Nishie, Masakazu Toi
Journal: Cancer Research (2015)

Abstract We and others previously reported that HER2 was transferred from HER2 overexpressing breast cancer cells to CD14+ monocytes via trastuzumab dependent trogocytosis. In the current study, we report that EGFR of MDA-MB-231 (triple negative human breast cancer cell line) is also transferred to immune cells via trogocytosis and those immune cells express EGFR on the cell surface without antibody administration. Interestingly, the EGFR-trogocytosed MDA-MB-231 cells reduced the expression of EGFR and changed their morphology to the spindle shape (well known as mesenchymal transition) and acquired greater cell motility. These cancer cell properties are representative as higher malignant potentials in breast cancer patients. Thus, we hypothesized that EGFR expression on tumor infiltrating lymphocytes (TILs), which probably is caused via EGFR trogocytosis by TILs, is correlated with higher tumor grade. We evaluated the EGFR expression of TILs in 36 triple negative breast cancer specimens and found the correlation between EGFR expression status on TILs and higher tumor grade (P = 0.02). These findings may explain the reason why triple negative breast cancer with greater proportion of TILs exhibit higher tumor grade and poor prognosis. Citation Format: Eiji Suzuki, Ayane Yamaguchi, Tatsuki R. Kataoka, Masahiro Hirata, Kosuke Kawaguchi, Mariko Nishie, Masakazu Toi. EGFR is transferred from triple negative breast cancer cells to immune cells via trogocytosis and expression of EGFR on immune cells is associated with high tumor grade of triple negative breast cancer patients. [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 2349. doi:10.1158/1538-7445.AM2015-2349
Standard and Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantations (HSCT) from Related and Unrelated Donors for Chronic Lymphocytic Leukemia (CLL). a Long-Term Follow-up (10 years) Study from the EBMT Registry. (CLL Sub-Committee on Behalf of EBMT CLWP)
Authors: Mauricette Michallet, Quoc Hung Le, Peter Dreger, Mohamad Sobh, Dietger Niederwieser, Vladimir Koza, Tapani Ruutu, Nigel H. Russell, Leo Verdonck, Donald Milligan, Nathalie Dhedin, Tomas Kozak, Marc Boogaerts, Juergen Finke, Nathalie Tedone, Anja Van Biezen, Ronald Brand
Journal: Blood (2008)
TLR-9 and B-Cell Antigen Receptor Triggering of Primary B Cells From Mantle Cell Lymphoma Induce Cell Proliferation and Telomerase Activity,
Authors: Sonal Temburni, Ryon M. Andersen, Steven L. Allen, Jaqueline C. Barrientos, Jonathan E. Kolitz, Kanti R. Rai, Nicholas Chiorazzi, Rajendra N Damle
Journal: Blood (2011)
Abstract A45: Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression
Authors: Stephano S. Mello, Carolyn Sinow, Pawel K. Mazur, Hannes Vogel, John Rinn, Laura D. Attardi
Journal: Cancer Research (2016)

Abstract p53’s role as a critical tumor suppressor is well illustrated by the fact that it is found mutated in more than half of all human cancers. In addition, the highly penetrant cancer predisposition observed in Li-Fraumeni patients with germline mutations in p53 and in p53 null mice further highlight the importance of p53 in tumor suppression. p53 is a transcription factor, able to sense stress signals such as DNA damage and hyperproliferative signals, promoting in turn the expression of a network of target genes to induce anti-proliferative responses such as cell cycle arrest or apoptosis. Although studies of genes in the p53 network have largely focused on protein-coding genes, in recent years the role of p53-regulated non-coding (nc) RNAs in p53 biology has been increasingly recognized. To identify new p53-regulated ncRNAs that could contribute to tumor suppression, we leveraged chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing (RNA-seq) data we generated previously in p53 wild-type and p53-/- mouse embryonic fibroblasts (MEFs). This analysis uncovered the lincRNA Neat1 as a p53 target gene. We showed that Neat1 is induced by different DNA damaging agents in a p53-dependent manner in different mouse and human cell types, including pancreatic ductal cells. Although we found that Neat1 is not involved in DNA damage-induced p53-dependent cell cycle arrest or apoptosis responses, we found that it does play a role in p53-dependent transformation suppression in both oncogene-expressing fibroblasts and pancreatic cancer cells. Furthermore, using oncogene-expressing fibroblasts, we showed that Neat1 loss promotes cancer in vivo in a subcutaneous xenograft model. Preliminary evidence suggests also that Neat1 loss promotes acinar to ductal metaplasia, bolstering its importance in pancreatic cancer suppression. These findings highlight the importance of Neat1 for p53 tumor suppressor function. Detailed analyses of Neat1’s mechanism of action will provide insights in its function as a tumor suppressor. Citation Format: Stephano S. Mello, Carolyn Sinow, Pawel K. Mazur, Hannes Vogel, John Rinn, Laura D. Attardi.{Authors}. Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A45.
Abstract A56: Targeting eIF4A dependent translation as therapeutics in pancreatic cancer
Authors: Kamini Singh, Stefan G. Stark, Agnes Viale, Prathibha Mohan, Man Jiang, Gunnar Rätsch, Hans-Guido Wendel
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is one of the most aggressive cancers with no targeted therapy available. RNA translation is activated in aggressive pancreatic cancer and at the same time is also refractory to mTor inhibition. We have used a translation inhibitor for eIF4A, RNA helicase that is downstream of mTOR signaling and can be functionally targeted in pancreatic cancer. We establish that Silvestrol and its analog CR-31B showed potent anti-tumor activity in pancreatic cancer cell lines in vitro and in vivo. Silvestrol/CR-31B reduced pancreatic cancer cells and organoids growth derived from mouse model of pancreatic cancer and human patient samples in vitro. Further we identify the genome wide translational targets of Silvestrol in pancreatic cancer cell line that lacks response to mTOR signaling through loss of EIF4EBP1. Silvestrol down regulate translation of many key oncogenes and others cellular factors involved in oncogenic signaling in pancreatic cancer. Silvestrol targets were also enriched for G-quadruplex structure in their 5’UTR. With this study we establish a new mechanism of targeting pancreatic cancer cells through translation inhibition and identify more proteins as therapeutic targets that are regulated independent of mTOR signaling. Citation Format: Kamini Singh, Stefan G. Stark, Agnes Viale, Prathibha Mohan, Man Jiang, Gunnar Rätsch, Hans-Guido Wendel.{Authors}. Targeting eIF4A dependent translation as therapeutics in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A56.
305. A Screening Strategy for Selecting Recombinant Adeno-Associated Viral Vectors That Selectively Transduce Viral Infected Cells
Authors: Gustavo de Alencastro, Nicole K. Paulk, Katja Pekrun, Mark A. Kay
Journal: Molecular Therapy (2015)

Recombinant adeno-associated viral (rAAV) vectors constitute one of the most promising tools for gene transfer. Desired properties include the lack of pathogenicity in humans, broad tissue tropism, ability to transduce both dividing and non-dividing cells, and the potential to establish long-term and stable transgene expression in quiescent tissues. Additionally, the majority of transduction events are episomal, making the risk of insertional mutagenesis lower than integrating vectors. Preclinical studies have successfully utilized rAAV vectors to combat viral infections after delivering short-hairpin RNA (shRNA) expression cassettes for knocking down viral coding genes in infected cells. A viral infection can also be reduced using shRNAs against host cellular genes, which are required for the life cycle of the pathogen. Although combining both the targeting of viral and cellular genes has the potential to increase the success in combating viral infections, promiscuous targeting of host cellular genes in the majority of cells that remain uninfected in a tissue may be detrimental. Therefore, we have designed a strategy to select for rAAV capsids that will selectively transduce infected over uninfected cells. The selection is based on the fact that most viral infections cause phenotypic changes in a cell that likely affect at least one of the many parameters involved in rAAV transduction. For proof-of-concept, we are selecting for rAAV capsids that selectively transduce Hepatitis B virus (HBV)-infected hepatoma cells, in part because it was recently reported that HBV infection increases AAV2 and AAV8 transduction. We are currently characterizing a new highly diverse rAAV capsid library generated by shuffling of 18 parental capsids placed into a wild-type AAV genome. This library will be co-infected with wild-type Adenovirus-5 (helper virus) allowing the rAAV genomes to replicate in HBV-infected human cells. Isolation of replicating rAAV over successive passages in cultured cells will allow for stringent selection as all steps in AAV transduction, including cell entry, intracellular transport, nuclear entry and capsid uncoating, must occur in the selection scheme. After selection is completed, we will sequence and vectorize the most abundant capsids. These will be individually tested for their relative transduction of hepatoma cells that are identical except for their HBV infection status. Identifying such a rAAV capsid specific for HBV-infected cells will provide a reagent or therapeutic that can deliver a transgene that will allow one to selectively modify or potentially kill infected but not the uninfected cells contained within the liver. Moreover, we believe this strategy has the potential to be broadly applied for the selection of rAAV capsids specific for cells infected with other viruses or any disease state that results in phenotypic changes to a cell.
500. Gene Therapy Rescues Disease Phenotype in the Oculopharyngeal Muscular Dystrophy Mouse Model
Authors: George Dickson, Alberto Malerba, Pierre Klein, Susan Jarmin, Houria Bachtarzi, Arnaud Ferry, Gillian Butler-Browne, David Suhy, Michael Graham, Capucine Trollet
Journal: Molecular Therapy (2016)

Among triplet expansion diseases, oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a short trinucleotide repeat expansion in the polyadenylate-binding protein nuclear 1 (PABPN1) gene that results in an N-terminal expanded polyalanine tract. PABPN1 controls several biological processes such as the length of mRNA poly(A) tails, the mRNA export from the nucleus and the alternative poly(A) site usage. OPMD is characterized by nuclear aggregates of expanded PABPN1, fibrosis and muscle atrophy. Here we demonstrate that treating mice affected by OPMD over 4 months with an AAV gene therapy strategy based on DNA-directed RNA interference to silence the endogenous expPABPN1, combined with the re-expression of a healthy sequence-optimized human PABPN1 gene, significantly reduced the amount of nuclear aggregates in affected muscles, decreased the intramuscular fibrosis and reverted the muscle strength to the level of healthy wild-type muscles. Furthermore, although muscle atrophy was not reverted, the expression of a healthy PABPN1 markedly increased the cross sectional area of muscle fibres. These results obtained in a relevant mammalian animal model of OPMD pave the way for the clinical application of a gene therapy approach as a treatment for OPMD patients.
Differentiation, phenotype, and function ofinterleukin-17-producing human V{gamma}9V{delta}2 T cells
Authors: Giorgio Stassi, Nadia Rosalia Caccamo, Carmela La Mendola, Matilde Todaro, Francesco Dieli, Serena Meraviglia, Guido Sireci, Jean Jacques Fournié, Valentina Orlando
Journal: Blood (2011)