tbuckley/cabot-search huggingface dataset:
A phase II study of irinotecan, fluoroxuridine and leucovorin (IFLUX) as a first-line chemotherapy in advanced colorectal cancer
Authors: B. Ardalan, A. Livingstone, D. Franceschi, E. Santos, M. Lima, O. Kozyreva, K.-T. Tsai
Journal: Journal of Clinical Oncology (2005)

3599 Background: Irinotecan combined with bolus or infusion 5-Fluorouracil (5-FU) regiment has demonstrated efficacy in advanced colorectal cancer (ACRC). In our current study we have replaced 5-FU with Fluoroxuridine (FUdR) and we are reporting our Results: A phase II study was conducted to assess the efficacy and tolerability of substituting FUdR infusion for 5-FU in combination with irinotecan in patients with ACRC. Methods: Patients with measurable colorectal adenocarcinoma received intravenous (IV) irinotecan 110 mg/m2 days 1, 8, 15, and 22, followed by FUdR 120mg/Kg and Leucovorin 500mg/ m2 as a 24 hour infusion on days 1, 8, 15, and 22, followed by 2 weeks of rest. 38 patients were enrolled on this study; all were evaluable for toxicity and antitumor activity. There were 22 males and 16 females, the average age was 58 years with range 28–81 years, and median Karnofsky performance status was 90. Twenty-one of 38 patients who received adjuvant chemotherapy and upon relapse were placed on our therapy. A total of 766 cycles of treatment were given, the average number of cycles completed per patient was 5. Results: Five patients (13%) achieved complete response (CR), 10 patients (26%) achieved partial response (PR), 17 patients (45%) attained stable disease (SD), and 6 patients (16%) progressed. The median time to progression was 11.5 months (347.5 days) with 95% confidence interval (206, 389) days. The time to progression has ranged 1.8–34 months. The median survival of the patients in this trial was 36.6 months (1,098 days) with 95% confidence interval (694, NA) days. The upper limit has not been reached since 21 patients are still alive (55%). The most common grade 3/4 toxicity were diarrhea, neutropenia and anemia. Conclusions: The combination of irinotecan, FUdR and leucovorin (IFLUX) has promising antitumor activity with a median survival greater than 36 months and was well tolerated in patients with advanced colorectal cancer. No significant financial relationships to disclose.
Abstract B65: The combination of beta-cyclodextrin &amp; 2-deoxyglucose worked synergistically with TRAIL to induce apoptosis in 90% of Panc-1 cells at 10ng/ml of TRAIL
Authors: Ryuji Yamaguchi
Journal: Cancer Research (2016)

Abstract Since over 95% of pancreatic cancer cells express P-glycoprotein which could exclude chemotherapeutics from entering the cell, making it difficult to treat pancreatic cancer. To address this problem we used 2-deoxyglucose (2DG), beta-cyclodextrin (bCD) and TNFa-Related Apoptosis Inducing Ligand (TRAIL) combination to induce apoptosis in pancreatic cancer cells. 2DG can enter highly glycolytic cells through glucose transporters, while bCD could deplete cholesterol from the plasma membranes without entering the cell, inhibiting the signal transduction between PI3K and AKT, and TRAIL could activate TRAIL-receptors, activating caspases from outside. These three agents worked synergistically to induce apoptosis in Panc-1 pancreatic cancer cells; Panc-1 cells were incubated in medium containing 10 mM 2DG and 25 mM glucose for 90 minutes. Then 10 mM methyl-beta-cyclodextrin (MBCD) was added, and 30 minutes later, 10 ng/ml of TRAIL was added. 2 hours later, cells were washed and incubation continued. When cells were harvested 16 hours later, over 90% of cells were propidium iodide (PI) positive, while 0% of cells treated with TRAIL alone, and less than 30% of cells treated with 2DG-MBCD were PI positive. Citation Format: Ryuji Yamaguchi.{Authors}. The combination of beta-cyclodextrin &amp; 2-deoxyglucose worked synergistically with TRAIL to induce apoptosis in 90% of Panc-1 cells at 10ng/ml of TRAIL. [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 B65.
Predictive factors of efficacy of Somatostatine Analogs (SSA) in Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET)
Authors: S. Ricci, R. Marconcini, L. Galli, A. Antonuzzo, A. Farnesi, L. Derosa, E. Biasco, A. Falcone
Journal: Annals of Oncology (2015)
565. Human Dystrophin Expression in Rag/Mdx Mice Muscles Following the Graft Off Genetically Corrected Dystrophic hiPSCs
Authors: William-Édouard Gravel, Dominique L. Oulette, Chantale Maltais, Catherine Gérard, Hongmei L. Li, Akitsu Hotta, Jacques-P. Tremblay
Journal: Molecular Therapy (2016)

Human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have shown self-renewal capacity and can potentially differentiate into all types of cell lineages. They represent an unlimited source of cells for the therapy of degenerative diseases, such as Duchenne Muscular Dystrophy (DMD), a disease characterized by a rapid degeneration of muscles that starts early in life. Dystrophic hiPSCs have been corrected by our collaborator, Dr. Hotta, by inserting of a single base pair in the exon 45 with Transcription Activator-Like Effector Nucleases (TALENs) to restore the reading frame of the gene. Our laboratory has developed a two-step procedure to differentiate hiPSCs into myogenic cells. We first used a myogenic culture medium especially developed in the laboratory (called MB-1) to promote the differentiation of hiPSCs into mesenchymal-like precursor cells. We next transduced them with a lentivirus expressing the myogenic transcription factor MyoD under the control of the composite CAG promoter, in order to induce their differentiation into myoblasts. Transduced cells have been grafted in the Tibialis anterior muscle of Rag/mdx mice where they fused with existing muscle fibers. The presence of the human dystrophin protein has been confirmed by immunohistofluorescence in muscles grafted with the genetically corrected cells and in a control graft with myoblasts of a healthy donor. Cell therapy shows great promises for DMD patients since it allows the expression of a normal gene capable of producing a functional dystrophin in muscle fibers and increases the regenerative capacity of the muscle and the muscle strength.
Do elderly chemorefractory NSCLC patients derive benefit from salvage targeted therapy? Subgroup analysis of clinical outcome and toxicity from the BATTLE trial.
Authors: A. S. Tsao, S. Liu, J. J. Lee, C. M. Alden, E. S. Kim, G. R. Blumenschein, R. S. Herbst, S. M. Lippman, I. I. Wistuba, W. K. Hong
Journal: Journal of Clinical Oncology (2011)

7550 Background: BATTLE was a phase II trial that randomized 255 patients (pts) into 4 separate trials: erlotinib (E), erlotinib-bexarotene (E-B), vandetanib (V), and sorafenib (S). Treating elderly chemo-refractory NSCLC pts is often challenging; we sought to determine if older pts on the BATTLE trial had worse outcomes or more adverse events (AE). Methods: Chemorefractory NSCLC pts with PS 0-2 and any line of prior therapy were enrolled. Following tumor biomarker evaluation, pts were randomized to oral therapy with E (150 mg daily), E + B (400 mg/m2 daily), V (300 mg daily), or S (400 mg twice daily) with Q8 wk radiographic assessment. AE were assessed by NCI-CTC v. 3.0. Subgroup analysis was conducted via Fisher’s exact test for age groups (≥ 65 v > 65 years; ≥ 70 v 70 years; ≥ 75 v > 75 years), treatments, and gender. Kaplan-Meier method, log-rank tests, and Cox proportional hazards models were also used. Results: In the ITT population, median age 62 (range 26-84); 16% age ≤ 50, 29% age 51-60, 34% age 61-70, 22% > 70 yrs; 46% F, 9% PS 0, 77% PS 1, 14% PS 2. No differences in RR or OS were seen between any age groups. However DCR at 8 wks was better in older women ≥ age 70 yrs (p=0.06) and men ≥ 65 yrs (p=0.008); also, men ≥ 65 yrs (p=0.0068) and men ≥ 70 yrs (p=0.09) had better PFS. Treatment-specific analyses showed that older men ≥ 65 yrs treated with V had a better PFS (p=0.03). Male pts ≥ 70 yrs had an improved DCR with E (p=0.05) and an improved OS with S (p=0.04). However, women age ≥ 70 yrs had a worse PFS with V (p=0.03) but no difference in DCR nor OS. There was no difference between the age groups in grade 3-4 heme AE. However, Women ≥ 65 yrs had a higher rate of grade 3-4 non-heme AE (p=0.05) that was primarily seen with S (p=0.04). Older pts were more likely to report diarrhea and GI symptoms. Women age ≥ 65 and age ≥ 70 were more likely to require dose reductions but this was not treatment specific. Conclusions: Fit elderly NSCLC patients should be considered for salvage targeted therapy as there is no adverse impact on survival; in fact, older men ≥ 65 yrs derive significant clinical benefit to certain agents. Gender differences in tolerance were seen in older women.
Abstract 4922: Analysis of copy number changes in HNSCC by MLPA
Authors: Nejat Dalay, Orkun Gurbuz, Elif Baltaci, Emin Karaman, Nur Buyru
Journal: Cancer Research (2015)

Abstract Gene amplification is a common finding in a broad spectrum of tumor types, often leading to increased levels of gene expression, a mechanism by which genetic changes contribute to the initiation or progression of cancer. HNSCC is among the neoplasias that frequently show amplification of specific genomic regions. Previous cytogenetic and molecular genetic studies by Fluorescence in situ Hybridization (FISH) and comperative genome hybridization (CGH) and other molecular methods showed that frequently amplified chromosomal regions in primary HNSCC tumors are 3q, 8q, 8p, 11q, 9q. Generally, proto-oncogenes reside in these amplified regions and amplification of these often leads to increased levels of gene expression. Therefore, in this study we investigated amplification of 22 different oncogenes mapping to these regions. The analyses were performed by MLPA on an ABI 3100 genetic analyzer and relative peak areas of the amplification products were evaluated using the Coffalyser MLPA analysis software. Analysis of 50 HNSCC tumor tissue samples showed that the most frequently amplified genes were from the regions 17q12 (MED1), 11q13.3 (CCND1), 8q (MYC and MTDH) and 8p (ZNF703) with frequencies of 24%, 24%, 20%, 20% and 18%, respectively. In total, Copy Number Alterations of the CCND1 and MED1 genes were observed in 12 of 50 tumor samples. For the CCND1 gene 6 of these alterations were heterozygous duplications and the remaining 6 were triplications. On the other hand, for the MED1 gene duplications were observed in 8 samples and trriplications were detected in 4 samples. Triplication of the MTDH gene was not observed in any of the amplified samples. However, one third of the ZNF703 amplifications were triplications. Amplification of the CCND1 and MYC genes are frequently observed in different types of cancers including HNSCC. More recently overexpression of MTDH has been associated with lymph node metastasis and poor-survival in HNSCC. However, to our knowledge there is no data in the literature investigating the ZNF703 gene in HNSCC. Our data indicate that ZNF703 may represent a candidate gene the role of which warrants more detailed analysis in HNSCC. Citation Format: Nejat Dalay, Orkun Gurbuz, Elif Baltaci, Emin Karaman, Nur Buyru. Analysis of copy number changes in HNSCC by MLPA. [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 4922. doi:10.1158/1538-7445.AM2015-4922
277. Small Molecule-Regulated Antigen Recognition System for Inducible T Cell Targeting of Cancer Cells
Authors: Wai-Hang Leung, Michael Certo, Holly Horton, Iulia Diaconu, Tracy VandenBerg, Jordan Jarjour, Alexander Astrakhan
Journal: Molecular Therapy (2016)

Redirecting T cells against tumors by introducing chimeric antigen receptors (CAR) has demonstrated promising clinical results in certain cancers. However, the constitutive activity of these receptors limits which antigens can be targeted with this approach and may result in persistent elimination of healthy antigen-expressing cells. Successful CAR-T targeting of CD19+ tumors, for example, produces chronic B cell aplasia and necessitates life-long intravenous immunoglobulin (IVIG) treatment. Daric is an alternative antigen targeting approach that aims to: i) minimize the long-term toxicity of CAR-T treatment; ii) allows targeting of previously inaccessible antigens; and iii) is amenable to multiplex antigen targeting and other advanced targeting designs and strategies. The Daric system separates the antigen recognition and signaling functions of a CAR into two distinct polypeptides that contain the FKPB12 and FRB dimerization domains but lack signaling activity in the absence of a dimerization agent. Addition of the FKBP12-FRB bridging drug rapamycin or a non-immunosuppressive rapamycin analogue AP21967 heterodimerizes the signaling and antigen recognition components and restores signaling competency for antigen-dependent T cell activation. Importantly, the FKB12 and FRB dimerization partners are located extracellularly, minimizing interference with endogenously expressed signaling components and eliminating the requirement for rapamycin/AP21967 cell penetrance. A range of extracellular linkers and transmembrane domains were used to design a variety of CD19-targeting Daric constructs that exhibit minimal basal activity and robust drug-dependent antigen-specific cytolytic activity and cytokine production. The CD19-specific Daric T cells exhibited comparable levels of cytokine release, proliferation and cytolytic activity compared to a CD19-targeting CAR T cells. In vitro, Daric T cells were activated at sub-nanomolar to nanomolar concentrations of rapamycin or AP21967. No differences in cellular phenotype, expansion or functional responsiveness of Daric T cells compared to CAR T cells were observed. As expected, rapamycin was immunosuppressive to CAR T cell functionality, however Daric T cells continued to produce high level of cytokines even in the presence of rapamycin. These results highlight the potential of the Daric system to target highly expressed antigens and minimize the off-tumor on-target toxicity associated with traditional CAR designs.
Abstract 3130: Discovery of tumor suppressor microRNA using smoking-related lung carcinogenesis cell model
Authors: Jae Sook Sung, Jong Won Lee, Yeul Hong Kim
Journal: Cancer Research (2015)

Abstract Cigarette smoking is an important risk factor for lung cancer and induces DNA hypermethylation. Hypermethylation can silence tumor suppressor miRNAs. However, it is less known regarding the role of miRNA methylation in lung carcinogenesis, especially smoking-related lung cancer. We are now to discover the smoking-induced altered tumor suppressor miRNA in human lung carcinogenesis cell model. First, we examined miRNA expression profiles using Affymetrix GeneChip miRNA4.0 in human lung carcinogenesis cell model; NHBE, BEAS2B, 1799, 1198, 1170I cells (PNAS. 89:6693-97. 1992, Cancer Biol Ther. 5:665-73. 2006). And we have validated candidate tumor suppressor miRNAs by TaqMan real time PCR. We first discovered 6 candidate tumor suppressor miRNAs (miR-4448, miR-3180-3p, miR-584-5p, miR-3658, miR-8064, miR-371b) and we confirmed known decreased expression of several miRNAs in lung carcinogenesis cell model. Next, we tested methylation of candidate tumor suppressor miRNAs promoter CpG site by pyrosequencing. Increase of methylation was observed for 4 of the 6 candidate tumor suppressor miRNAs in human lung carcinogenesis cell model. Furthermore, methylation of miR-584-5p, miR-3658, miR-8064, miR-371b were greater in 1198 and 1170I cells exposed to cigarette smoking condensate (CSC). In the further study, we will confirm the role of tumor suppressor miRNA in smoking-related lung carcinogenesis by functional study. These finding suggest that tumor suppressor miRNAs are miRNA silenced by epigenetic mechanisms during smoking-induced lung carcinogenesis. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2062146) and the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HI13C1611). Citation Format: Jae Sook Sung, Jong Won Lee, Yeul Hong Kim. Discovery of tumor suppressor microRNA using smoking-related lung carcinogenesis cell model. [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 3130. doi:10.1158/1538-7445.AM2015-3130
Development of an inducible CD40-dendritic cell vaccine for prostate cancer
Authors: Natalia Lapteva, Mamatha Seethammagari, Brent Hanks, Jonathan Levitt, Kevin Slawin, David Spencer
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2724 

Clinical trials utilizing dendritic cell (DC)-based cancer vaccines have been performed in patients with a variety of cancers including prostate, melanoma, renal, and colorectal. Despite some encouraging observations in these trials, vaccine-induced antigen-specific T cell responses have been largely insufficient to effectively reduce tumor burden or prevent tumor progression in most patients, suggesting that further enhancements in the potency of DC-based cancer vaccines are required to achieve a meaningful clinical response. To enhance a human DC-based vaccine, we used the combination of an inducible CD40 receptor (iCD40) and TLR-4 ligands. The iCD40 receptor permits targeted, reversible activation of CD40 in vivo and previously has been shown to enhance tumor regression in mouse models more efficiently than DCs activated with LPS and CD40L in vitro.

Human DCs were generated by stimulation the precursors with 800 U/ml GM-CSF and 500U/ml IL-4 in DC medium (CellGenix). On day 5 of culture, immature DCs were pulsed with tumor antigen, transduced with Ad5/f35-iCD40 and activated with TLR4 ligands and AP20187 dimerizer drug. The frequency of antigen-specific T cells was evaluated using IFN-gamma ELISPOT, tetramer staining and chromium release assays. Using iCD40 in combination with LPS or MPL, we enhanced multiple parameters associated with DC activation, including levels of maturation markers expression (CD80, CD83 and CD86), IL-12p70 and IL-6 production, and HLA class I and II epitope-specific T cell responses, as well as DCs migration in vitro and in vivo. Furthermore, use of iCD40-modified and LPS-stimulated DCs led to targeted expansion of autologous T cells against the self-protein and attractive tumor-associated antigen prostate-specific membrane antigen (PSMA).

This novel approach is the basis of a promising strategy for cancer immunotherapy and forms the technological foundation for a planned phase I/II trial in patients with advanced, hormone-refractory prostate cancer.
49. In Vivo Gene Therapy of Mobilized Hematopoietic Stem Cells With AD5/35 Vectors Encoding a Sleeping Beauty Transposase Integration Machinery
Authors: Maximilian Richter, Roma Yumul, Donna Palmer, Philip Ng, Thalia Papayannopoulou, Jing Liu, Anja Ehrhardt, Wolfgang Uckert, Andre Lieber
Journal: Molecular Therapy (2015)

Current protocols for hematopoietic stem cell (HSC) gene therapy involve the collection of HSCs from donors/patients, in vitro culture, transduction with retrovirus vectors, and retransplantation into myelo-conditioned patients. Besides its technical complexity, disadvantages of this approach include the necessity for culture in the presence of multiple cytokines which can affect the pluripotency of HSCs and their engraftment potential. Furthermore, the requirement for myeloablative regimens in patients with non-malignant disorders creates additional risks. We therefore explored the potential for in vivo transduction and genome editing of HSCs. Previously, we and others reported that human HSCs express high levels of CD46, a complement regulatory protein, and can therefore be efficiently transduced by CD46-targeting adenovirus vectors such as Ad5/35 vectors. In a CD46-transgenic mouse model we showed that HSCs could be flushed from the bone marrow using a mobilizing regimen of GCSF and the CXCR4 antagonist AMD3100. These mobilized HSCs could then be transduced with intravenously injected, GFP-encoding Ad5/35 vectors. Upon transduction, mobilized HSCs relocalized back to the bone marrow, expressed the transgene and were clonogenically active in colony forming unit assays. When we followed transgene expressing HSCs in vivo over a course of 2 weeks we saw a loss of transgene expression over time. This is most likely due to leaky viral gene expression of the first generation Ad vector used in these studies. To avoid these cytotoxic effects, we employed a Helper-dependent Ad (HDAd) vector that is devoid of all viral genes. We compared the transduction performance of the HDAd to the first generation vector both in the CD46-transgenic mouse model as well as in a humanized NOG mouse model. Adenoviral vectors do not integrate into the genome of the host cell and we have therefore only been able to follow transduced cells for limited periods of time. In order to be able to track transduced HSCs and their progeny for extended periods of time and to assess their long-term repopulating potential we are developing a set of HDAd vectors that allow for genomic integration of the transgene using a sleeping beauty transposon approach. In in vitro transduction studies we were able to show that the HDAd-encoded integration machinery can be used to insert a GFP cassette into the genome of HSCs, that the transduced HSCs remain clonogenic and that the transgene is passed on to progeny cells. Preliminary in vivo transduction studies in mobilized CD46-tg mice show GFP expression in up to 2.5% of bone marrow-derived lineage-depleted cells at 4 weeks after vector injection, indicating stable in vivo transduction of HSCs.
R-CHOEP-14 Is Associated with Superior Overall Survival Compared to R-CHOP-21 and R-CHOP-14 in Patients with DLBCL ≤70 Years – a Swedish Lymphoma Registry Population Based Study
Authors: Tove Wästerlid, Erzsebet Szekely, Linda Werner Hartman, Mats Jerkeman
Journal: Blood (2014)
Clinical Significance of Circulating Ki-67 Protein and Caspase-3 Activity Levels in Patients with Acute Myeloid Leukemia.
Authors: Jean-Marie Bruey, Hagop M. Kantarjian, Zeev Estrov, Wanlong Ma, Chen-Hsiung Yeh, Anthony Sferruzza, Elihu Estey, Maher Albitar
Journal: Blood (2009)
Newborn Haemoglobinopathy Carrier Screening: Towards Comprehensive and Improved Patient Care of Sickle Cell Disease in Oman, a Cost Effective Analysis.
Authors: Salam Alkindi, Anil Pathare, Ali Al Madhani, Shoaib Al Zadjali, S. Muralitharan, Hamood Al Haddabi, Qamariya Al Abri, David Gravell, Shahina Daar, J. David Dennison, R. Krishnamoorthy
Journal: Blood (2007)
Re: Alexander Kutikov, Marc C. Smaldone, Robert G. Uzzo, Miki Haifler, Gennady Bratslavsky, Bradley C. Leibovich. Renal Mass Biopsy: Always, Sometimes, or Never? Eur Urol 2016;70:403–6
Authors: Patrick O. Richard, Micheal A.S. Jewett, Antonio Finelli
Journal: European Urology (2016)
Morphological Atypia Represents Favorable Prognosis of Chronic Lymphocytic Leukemia in Japanese Patients
Authors: Junji Suzumiya, Sadao Aoki, Yasushi Isobe, Masatsugu Ohta, Jun Takizawa, Koji Izutsu, Ritsuro Suzuki, Kunihiro Tsukasaki, Kazutaka Kuriyama, Koichi Ohshima, Kazuo Tamura
Journal: Blood (2011)
Pegylated Versus Glycopegylated G-CSFs and Their Biochemical and Physiological Properties
Authors: Afsaneh Abdolzade-Bavil, Bridget A. Cooksey, Christian Scheckermann, Andreas Lammerich, Laurie Pukac, Philip Krasney, Hermann Allgaier, Wenyan David Shen, Udo Müller, Patrick Liu, Aaron von Kerczek
Journal: Blood (2013)