tbuckley/cabot-search huggingface dataset:
Response to lenalidomide in relapsed/refractory T-cell lymphoma might be steroid-dependent.
Authors: V. Ivanov, D. Coso, P. Quittet, B. Chetaille, G. Chuto, J. Rey, A. Stoppa, J. Schiano De Colella, T. Aurran-Schleinitz, F. Broussais, N. Belmecheri, R. Bouabdallah
Journal: Journal of Clinical Oncology (2011)

e18556 Background: The prognosis of patients with relapsed/refractory (R/R) T-cell lymphoma (TCL) remains very poor. Novel therapeutic approaches are needed to further improve outcomes. Lenalidomide (LEN) is an immunomodulatory drug that has demonstrated efficacy in several lymphoid malignancies. Recent trial of Lenalidomide in R/R Tcell lymphoma showed some clinical activity with 30% ORR and median PFS of 96 d. Unfortunately no CR was obtained. This limited activity might be improved by combining of LEN with other active drugs. Recently it was confirmed that dexamethasone (DEX) enhances antiproliferative activity of LEN in myeloma and lymphoma cells. At the same time DEX antagonized the immunostimulatory effects of LEN, but in a dose-dependent manner. Methods: We report 2 patients with R/R TCL in whom the combination LEN+steroids permitted to obtain durable responses. Results: First patient was the 32 y.o. male with heavily pre-treated (5 lines) refractory ALK+anaplastic LCL. Patient received 18 cycles of LEN 25 mg/d for 21/28 d with DEX 10 mg/w (first 6 cycles), than with Prednisolone 20-30 mg/d for next 12 cycles with obtaining good clinical and partial radiological response. Because of psycotics episodes steroids were stopped for 2-3 weeks on several occasions. Cessation of steroids was accompanying by reappearance of B-sympthoms and peripheral lymphoadenopathy. Reintroduction of steroids was accompanied by rapid and complete disappearance of symptoms. Second patient was 63 y.o. man with R/R T angioimmunoblastic lymphoma progressing after 2 lines of chemotherapy (8 RCHOP+7 RDHAC in 16 months).Treatment with LEN 15 mg 21/28 days + weekly DEX 20 mg induced PET-negative CR after 4 cycles with remission duration of 9 months. In both patients clinical response was observed after the first month of treatment. Conclusions: It is possible that in R/R TCL the combination LEN + low dose steroids leeds to synergy of cytotoxic and immunomodulatory effects. Considering the rapid onset of response do we have to integrate less toxic and probably more efficacious new strategies at an earlier stade?
268. Enhanced Gene Expression of Factor VIII by Ultrasound-Mediated Gene Delivery in Dogs
Authors: Carol H. Miao, Misty L. Noble, Keith R. Loeb, James Harrang, Christian S. Kuhr, Scott S. Graves, Kyle P. Morrison, Timothy Nichols, Bryn Smith, Shuxian Song, Rainer F. Storb, George W. Keilman
Journal: Molecular Therapy (2015)

Previously we demonstrated that ultrasound (US)-mediated gene delivery (UMGD) can significantly enhance reporter gene transfer into the mouse and rat livers. This nonviral gene transfer strategy can bypass many obstacles encountered by viral gene therapy. Most significantly, we have achieved therapeutic levels of FVIII following UMGD into hemophilia A mice. Recently we have successfully developed prototype US systems including several unfocused and semi-focused transducers to treat large tissue volumes in canine and swine. In order to facilitate the translation of this technology to treat hemophilia, we have recently treated 2 normal dogs with UMGD of FVIII plasmids using an open surgery procedure. Four mg of a high-expressing, liver-specific pBS-HCRHPI-FVIIIA plasmid and 3 ml of Definity® MBs in 8 ml total PBS solution were injected via the segmental portal vein branch with simultaneous exposure of the target liver lobe to therapeutic US (1.1 MHz frequency, 20 cycle pulses, 50 Hz pulse repetition frequency) for 4 minutes using the large diameter transducers. A sham-treated dog received an equivalent pGL4/MB dose, but was not exposed to tUS. We used an apodized dual element unfocused transducer H105 at 2.5Mpa peak negative pressure (PNP) in the first dog experiment and observed low levels of hFVIII gene expression in the treated liver lobes. The second dog experiment was performed using a cylindrically 6.2 MPa at the focal area. One day following treatment, the treated liver lobes were sectioned, and representative sections were fixed and stained for FVIII expression by histochemical staining using a polyclonal anti-FVIII antibody. Untreated normal dog liver and human liver were used as negative and positive controls. Significant hFVIII gene expression was obtained in both treated liver lobes with the expression levels slightly lower than control human liver lobe. Furthermore, fairly homogeneous distribution of FVIII gene expression was observed in hepatocytes. Next, we performed Western blot analysis to confirm if the staining is specific to human FVIII protein. A heavy chain band specific to hFVIII was observed in treated dog plasma and positive hFVIII control, but not in control normal dog plasma and pre-bleed plasma sample from the dog before treatment. Significant enhancement of FVIII-specific clotting activity was also obtained in the second treated dog compared to pre-treatment and the first treated dog. In addition, transaminase levels and histology analysis indicated minimal tissue damage in treated dog livers. Enhancement of FVIII gene expression by UMGD is currently evaluated in hemophilia dogs. Our results sugges that UMGD has great potential for therapeutic treatment of hemophilia A.
426. Multi-Pathogen-Specific T Cells: A Single T-Cell Product Simultaneously Targeting Multiple Pathogens for Adoptive Immunotherapy
Authors: Anastasia Papadopoulou, Panayotis Kaloyannidis, Maria Alvanou, Stergios Papadimitriou, Ioannis Batsis, Ioanna Sakellari, Achilles Anagnostopoulos, Evangelia Yannaki
Journal: Molecular Therapy (2016)

Viral infections, most commonly by cytomegalovirus (CMV), Epstein-Barr virus (EBV), polyoma virus type I(BK), andfungal infections, mainly by Aspergillus Fumigatus (Asp), are among the deadliest complications for patients undergoing allogeneic hematopoieticstem cell transplantation. Treatment with antiviral and antifungal pharmacological agents, which are today's standard therapy, is often ineffective or toxic whereas it can lead to the outgrowth of drug-resistant strains. Adoptive immunotherapy with the use of antigen-specific T-cells to restore antigen-specific immunity post-transplant, offers an attractive alternative approach to conventional drugs. We here, aimed to generate at large scale, multipathogen-specific T cells (mp-STs) that simultaneously target CMV, EBV, BK and Asp, from healthy donors, with a rapid, simplified, low-cost and minimally laborious protocol. A total of 1,5×107mononuclear cells, derived from 15-20ml blood of eight CMV and EBV seropositive donors, were pulsed with viral pepmixes(CMV: IE1, pp65;EBV: EBNA1, LMP2, BZLF1;BK: Large T, VP1) combined with either Asp lysate or Asp pepmixes (Crf1, Gel1 and SHMT) and cultured in the presence of IL-4/IL-7 for 10 days in G-rex bioreactors. The cells were characterized immunophenotypically by flow cytometry and their specificity/functionality was assessed by IFN-γ Elispot assay. Cells stimulated with either Asp lysate (n=4) or Asp pepmixes (n=4), had a similarexpansion, reaching a mean of 170±36×106and 206±46×106 cells, respectively. All cell lines were polyclonal, comprised predominantly of CD4+ cells (70±5% and 72±3% respectively) and CD8+ cells (19±4% and 18±2% respectively) and expressed central (CD45RA-/CD62L+: 36±6%, and 35±2% respectively) and effector memory markers (CD45RA-/CD62L-: 53±5%, and 54±3% respectively). Importantly, allmp-STs lines (8/8) were specific against all targeted pathogens [mean±SEM spot forming cells (SFC)/2×105 input cells, with lysate:CMV:211±41; EBV:1137±165; BK:551±109; Asp: 143±8; with peptides: CMV: 251±111; EBV: 1031±238; BK: 616±119 SFC; Asp: 463±132). Given that all donors were CMV and EBV seropositive and BK or Asp prior donor exposure wasnot tested, our data suggest that BK or Aspspecificity can be obtained practically from all healthy individuals, due to the particularly high exposure of the general population to these pathogens. Notably, the combination of Asp targeted-proteins (Crf1, Gel1 and SHMT) induced stronger Th1 responses compared to Asp lysate (p=0,049). Overall, we established arapid and simple, optimizedprotocol of generating clinically relevant numbers of mp-STs from a small amount of donor blood. Should mp-STs move to the clinic and prove safe and effective, they will be an ideal treatment for patients suffering from life-threatening, post-transplant infections.
Abstract AS19: The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer
Authors: Katherine Fuh, Erinn Rankin, Colleen Wu, Anh Diep, Amato J. Giaccia
Journal: Clinical Cancer Research (2015)

Abstract Objective: To evaluate the role of AXL in an immunocompetent model of ovarian cancer metastasis. Methods: Immunohistochemical staining of ovarian cancer tissue microarrays of advanced stage, high-grade epithelial ovarian cancer specimens for AXL expression was performed and correlated with overall survival. Metastatic endometrioid ovarian cancer was generated through intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model. LSL-K-rasG12D/+Ptenfl/fl Axl+/+ and LSL-K-rasG12D/+Ptenfl/flAxl−/−were used to evaluate the role of AXL. Necropsy was performed to evaluate burden of the primary and metastatic tumors. Hematoxylin and eosin (H&amp;E) staining was used to confirm tumor formation or lack of tumor. Western blotting was performed to evaluate protein expression. Results: Of the 80 patient-derived primary ovarian tumor specimens, 76% (61) of advanced stage, high-grade epithelial ovarian cancer specimens had 3+ transmembrane AXL staining whereas 24% (19) of advanced stage, high-grade epithelial ovarian cancer specimens had no AXL staining. When correlated with overall survival, patients with tumors that had no AXL expression had a median survival of 53 months vs. 45 months for those with 3+AXL expression (p=0.12). The majority of intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl Axl+/+ mice had primary (78%) and metastatic tumor formation (86%) whereas the majority of LSL-K-rasG12D/+Ptenfl/flAxl−/− had primary tumor formation (64%) but few had metastatic tumors (28%) (p&amp;lt;0.05). There was no difference in primary tumor weight between the two groups: 120mg for Axl+/+ vs. 110mg for Axl−/−. Metastatic tumors were microscopic and therefore unable to be resected and weighed prior to identification by H&amp;E staining. Western blotting of primary and metastatic tumors from LSL-KrasG12D/+Ptenfl/fl Axl+/+ showed high AXL expression compared to no AXL expression in the ovaries of normal mice. Conclusions: AXL expression in advanced stage epithelial ovarian cancer correlated with lower overall survival. Primary ovarian and metastatic tumors in this intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model express AXL. Deletion of the receptor tyrosine kinase, AXL, in this conditional genetically engineered mouse model of endometrioid ovarian cancer resulted in inhibition of metastatic tumor formation. AXL is a critical factor driving metastasis in this immunocompetent murine model of metastatic ovarian cancer. Citation Format: Katherine Fuh, Erinn Rankin, Colleen Wu, Anh Diep, Amato J. Giaccia. The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS19.
Comparison of ampullary adenocarcinomas and duodenal adenocarcinomas with regard to clinical outcomes and responsiveness to fluoropyrimidine-based chemotherapy.
Authors: M. J. Overman, Z. Jiang, A. Lal, J. B. Fleming, G. R. Varadhachary, J. L. Abbruzzese, R. A. Wolff
Journal: Journal of Clinical Oncology (2011)

204 Background: Though adenocarcinomas of the ampulla of Vater are classified as biliary cancers, the epithelium of origin and treatment approach for these rare tumors remains controversial. Gene expression profiling of periampullary carcinomas (GI ASCO 2011) suggest that ampullary carcinomas are more akin to duodenal than pancreaticobiliary carcinomas. Methods: Review of a M. D. Anderson Cancer Center (MDACC) periampullary surgical database from 1/1990 to 3/2010 identified 670 pancreatic, 41 extrahepatic biliary, 63 duodenal, and 131 ampullary adenocarcinomas resected at MDACC. Review of the MDACC tumor registry from 5/1990 to 1/2009 identified 240 stage I-III surgically resected ampullary adenocarcinomas seen at MDACC. 46 patients met the following inclusion criteria: MDACC confirmed pathology, distant metastatic relapse, and ≥1 cycle of either gemcitabine or fluoropyrimidine (5-FU) based first-line chemotherapy with follow-up imaging evaluation. Results: 5-year OS of patients with ampullary cancer did not differ from duodenal cancer (62% vs. 66%, p=0.19) but was significantly different from biliary (24%, p&lt;0.001), and pancreatic cancer (17%, p&lt;0.001). When ampullary (n=131) and duodenal (n=63) cases were stratified by T stage (T1/T2, T3/T4) or N stage (N0, N1) no statistically significant differences in OS were seen. First-line chemotherapy for metastatic ampullary carcinoma was 5-FU based in 27 patients (single agent 8, platinum 18, other 1) and gemcitabine based in 19 patients (single agent 7, platinum 8, other 4). Similar rates of prior adjuvant/neoadjvuant chemotherapy use (55% vs. 64%) and time to distant metastases (18 vs. 17m) were seen in the 5-FU and gemcitabine groups, respectively. 5-FU based chemotherapy was associated with an improved median TTP (9.1m v 4.8m, p=0.05) and trended to improve RR (44% v 21%, p=0.13) and median OS (16m vs. 12.7m, p=0.14). Conclusions: OS of resected ampullary carcinomas is similar to duodenal carcinomas but not biliary or pancreatic carcinomas. Preliminary data suggest that metastatic ampullary carcinomas may benefit more from a fluoropyrimidine-based as opposed to gemcitabine-based chemotherapy. [Table: see text]
Revisiting Splenectomy in Childhood Chronic Immune Thrombocytopenia At the Era of New Therapies: The French Experience
Authors: Nathalie Aladjidi, Raoul Santiago, Pondarré Corinne, Anne Lambilliote, Guy Leverger, Claire Godard Sebillotte, Helder Fernandes, Hervé Chambost, Pierre Rohrlich, Marlène Pasquet, Thierry Leblanc, Yves Perel
Journal: Blood (2011)
Association Between Diabetes, Level of Glycemic Control, and Eye Infection: A Cohort Study
Authors: Abdus Samad Ansari, Simon de Lusignan, Barbara Arrowsmith, William Hinton, Neil Munro, Andrew McGovern
Journal: Diabetes Care (2016)

Infections of the eyelids, nasolacrimal duct, conjunctiva, and corneal surface and infectious keratitis have all been suggested to occur more frequently in people with diabetes (1,2). However, despite the widespread assumption that people with diabetes are more susceptible to eye infections (3), there is a paucity of systematically collected data to support these assertions. A recent review of observational studies and clinical trials demonstrated a correlation between poor glycemic control and increased risk of a wide variety of infections in people with diabetes (4). We explored whether infectious disease affecting the external eye and surrounding structures is associated with diabetes and if poor glycemic control increases risk of ocular infection in the population with diabetes.

A two-stranded study was carried out using data from the Royal College of General Practitioners Research and Surveillance Centre database. The two strands consisted of 1 ) a whole-population cohort study to …
Selectin Inhibition Disrupts Multiple Myeloma Cells Interaction with the Bone Marrow Microenvironment and Sensitizes Them to Therapy
Authors: Abdel Kareem A. Azab, Phong Quang, Feda Azab, John Magnani, John Patton, Theodore Smith, Arun Sarkar, Patricia Maiso, Hai T Ngo, Aldo M. Roccaro, Antonio Sacco, Yang Liu, Yong Zhang, Brittany Morgan, Kenneth C. Anderson, Andrew L. Kung, Ruben Carrasco, Irene M. Ghobrial
Journal: Blood (2010)
Abstract 1046: The role of NF-kB activation in the immortalization of nasopharyngeal epithelial cells
Authors: George Sai-Wah Tsao, Dan Dan Zhu, Jun Zhang, Wen Deng
Journal: Cancer Research (2015)

Abstract NF-κB is a key regulator of inflammatory response and is frequently activated in human cancers including nasopharyngeal carcinoma (NPC), which is closely associated with Epstein-Barr virus (EBV) infection and a common cancer in Southern China including Hong Kong. However, it is well-established that EBV infection alone is not sufficient for NPC development. Other genetic alterations in host cells and the interaction between EBV infection and host cell microenvironment are required for NPC development. Our group has been involved in illustrating molecular events underlying the immortalization of nasopharyngeal epithelial (NPE) cells. Molecular changes which facilitate immortalization may represent early genetic events in human carcinogenesis. We found that the activation of NF-κB was a common feature in telomerase-immortalized NPE cell lines. We further showed that canonical NF-κB activation pathway was involved in the immortalization of NPE cells. The activation of NF-κB was essential for the proliferation of the immortalized NPE cells because suppression of NF-κB activity could selectively inhibit the proliferation of immortalized but not primary NPE cells. The upregulation of c-Myc and Bmi-1, known to promote cell proliferation, were associated with NF-κB activation in the immortalized NPE cell lines. Interestingly, mTOR was found to be the upstream activator of NF-κB. We further showed that EGFR/Erk(1/2) pathway was the upstream regulator of mTOR/NF-κB pathway, revealing the pathway of EGFR/Erk(1/2)/mTOR/NF-κB for NF-κB activation in telomerase-immortalized NPE cells. Elucidation of specific pathway leading to NF-κB activation in immortalized NPE cells may open up opportunity for early intervention to suppress or prevent NPC development. Citation Format: George Sai-Wah Tsao, Dan Dan Zhu, Jun Zhang, Wen Deng. The role of NF-kB activation in the immortalization of nasopharyngeal epithelial cells. [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 1046. doi:10.1158/1538-7445.AM2015-1046
Global Epigenomic Profiling Demonstrates That Myelodysplasia Is Characterized by a Distinct Epigenetic Signature with Aberrant DNA Methylation Changes Involving Various Malignant and Hematopoietic Pathways.
Authors: L. Zhou, J. Opalinska, D. Sohal, R. Thompson, Y. Li, V. Kotla, P. Pahanish, S. Parmar, S. Kambhampati, M. Figueroa, K. Ye, E. Friedman, A. Wickrema, A. Melnick, J. Greally, A. Verma
Journal: Blood (2007)
Abstract 677: Possible role of nimbolide in prevention and therapy of prostate cancer
Authors: Jingwen Zhang, Muthu K. Shanmugam, Amudha Deivasigamani, Alan P. Kumar, Kam M. Hui, Gautam Sethi
Journal: Cancer Research (2015)

Abstract Prostate cancer is one of the most commonly diagnosed cancers worldwide. Current therapies for metastatic prostate cancer are only marginally effective, and hence novel treatment modalities are urgently needed. Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of prostate cancer. Thus agents that can suppress these inflammatory mediators could form the basis of novel therapy for prostate cancer patients. In our study, we focused on analyzing the potential anticancer effects of nimbolide, a terpenoid lactone derived from Azadirachta indica (Neem tree) against prostate cancer. Data from the in vitro studies indicated that nimbolide could inhibit cell proliferation, induce apoptosis and suppress cellular invasion and migration. Interestingly, nimbolide also abrogated the activation of pro-inflammatory STAT3 transcription factor, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS), whereas depletion of ROS attenuated p-STAT3 inhibitory effects of the drug. The in vivo efficacy of nimbolide was also analyzed in transgenic adenocarcinoma of mouse prostate (TRAMP) model, in which this triterpenoid significantly suppressed the tumor progression and growth without exhibiting any significant adverse effects. Overall our findings indicate that nimbolide exhibits significant anticancer effects in prostate cancer, and these effects may be mediated at least in part through the modulation of STAT3 signaling pathway. Citation Format: Jingwen Zhang, Muthu K. Shanmugam, Amudha Deivasigamani, Alan P. Kumar, Kam M. Hui, Gautam Sethi. Possible role of nimbolide in prevention and therapy of prostate 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 677. doi:10.1158/1538-7445.AM2015-677
P1254 : Hepatitis C spontaneous clearance may induce partial protection against reinfection among persons who inject drugs: Results from a cohort study
Authors: J. Bruneau, G. Zang, D. Jutras-Aswad, N. Bédard, M.-E. Turcotte, R. Bouchard, N. Shoukry, E. Roy
Journal: Journal of Hepatology (2015)
176. Novel Molecules That Enhance Adenovirus Transduction of the Airway Epithelium: Reinvigorating Adenovirus-Mediated Gene Therapy
Authors: Katherine J. D.A. Excoffon, Priyanka Sharma, James M. Readler, Mahmoud S. Alghamri
Journal: Molecular Therapy (2016)

Adenovirus remains the most common vector system used in gene therapy clinical trials worldwide and several adenoviral vectors show promise in phase III clinical trials. One major limitation to the efficacy of adenovirus-mediated gene therapy is low transduction due to the limited primary receptor availability in most tissues. Interventions able to boost adenovirus transduction would have significant implications for both improving transduction and lowering the viral dose below the immunogenic threshold. Most human and several key animal adenoviruses share a common receptor with group B coxsackieviruses named the coxsackievirus and adenovirus receptor (CAR). CAR has several alternatively spliced isoforms. We have recently discovered that the eight-exon isoform (CAREx8) can specifically localize to the apical membrane of polarized primary human airway epithelia where it can mediate apical adenovirus infection. Moreover, we have discovered that CAREx8 is both positively and negatively regulated by the cellular scaffolding protein MAGI-1. We hypothesized that cell permeable decoy peptides targeting the interaction between MAGI-1 and CAREx8 would increase CAREx8 protein levels and increase AdV transduction. Tat-conjugated peptide entry into polarized epithelia was confirmed by mass spectrometry and fluorescence microscopy. Relative to control, peptides increased the levels of CAREx8 at the apical surface of polarized epithelia and significantly increased AdV entry and transduction, as measured by apical surface biotinylation, qPCR, and AdV5-β-Gal transduction. Moreover, AdV5 transduction was increased by 300-500% after intranasal peptide administration in mice demonstrating in vivo activity. To determine the mechanism of action, we followed the synthesis and co-localization of CAREx8 with key molecules in the cellular ER-Golgi-vesicular trafficking pathways. We found that CAREx8 was in compartments distinct from MAGI-1 and spread throughout the apical trafficking pathway and at the apical surface of the epithelium. Removal of the peptides reversed both the amount and localization of CAREx8 and returned the susceptibility of the epithelium to baseline. Taken together, these data indicate that decoy peptides able to block the MAGI-1-CAREx8 interaction transiently increase adenovirus-mediated gene transfer and offer the potential to increase the efficacy of adenovirus-mediated gene therapy.