tbuckley/cabot-search huggingface dataset:
Effect of TLR4 engagement on TLR3-induced proinflammatory signaling in dendritic cells through IL-10, STAT3, and p38-dependent pathways and on antimelanoma CD8+ T-cell priming.
Authors: D. Bogunovic, O. Manches, A. Yewdall, I. Marie, D. E. Levy, N. Bhardwaj
Journal: Journal of Clinical Oncology (2010)

8568 Background: Toll-like receptor agonists have shown promise as adjuvants for immune therapy, but optimal combinations or pathways through which they signal have yet to be identified. Methods: DCs were stimulated with TLR3, TLR4 and TLR7/8 agonists and their combinations. Upon evaluation of phenotype and cytokine production these DCs were then used to prime anti-tumor CD8+ T cell responses. Results: DCs stimulated with the TLR3 agonist PolyI:C displayed the strongest inflammatory responses (heightened secretion of IL-12p70, TNF-α, IP-10, and IL-1beta) and induced the highest frequency of polyfunctional antigen-specific cells towards melanoma antigen Mart-1/MelanA. While the addition of TLR7/8 agonists improved these responses, the inclusion of LPS substantially suppressed pro-inflammatory cytokine production in vitro and in vivo. Inhibition was dependent upon the rapid, LPS-dependent induction of IL-10, and could be reversed by blockade of STAT-3, p38 or antibodies to IL-10 and its receptor. Conclusions: Our findings identify combinations of TLR agonists that can enhance or limit immune responses directed towards tumor antigens based on their relative ability to induce immune suppressive pathways that involve IL-10. No significant financial relationships to disclose.
Salvage treatment of patients (Pts) with multiply-relapsed, unresectable, metastatic germ-cell tumor (GCT), following failed multi-cycle, high-dose chemotherapy (HDC): Durable remission (DCR) is still possible
Authors: P. Morris, W. S. Ooi, P. Wroblickey, K. Duffy, P. Donnellan, J. Ballot, J. Armstrong, J. Thornhill, J. Crown
Journal: Journal of Clinical Oncology (2005)

4790 Background: HDC produces DCR in 20–40% of pts with resistant or multiply relapsed metastatic GCT. Patients who develop further relapse following HDC have an extremely poor prognosis, and successful salvage of inoperable recurrence is rare. Methods: Retrospective chart review. Results: Between 1994 and 2000 we treated 12 pts with HDC for relapsed or resistant metastatic GCT. Two of these pts remain in sustained remission at eleven and three years. The other ten relapsed, and were treated with further salvage therapies including oral VP16, paclitaxel, ifophamide, surgery and radiotherapy. Eight of these pts had either no response or a transient response. We report the cases of two pts who achieved DCR. Case 1: A 35 year old man was diagnosed in 7/1993 with metastatic non-seminomatous GCT of the retroperitoneum and over the next 3 years he received 5 lines of chemotherapy for episodes of relapse/resistance. This included single cycle HDC and subsequent tandem HDC given for two separate relapses. He also had two retroperitoneal lymph node dissections. He developed further vertebral relapse in 7/1996 and was treated with ifosphamide/paclitaxel followed by cisplatin/radiotherapy. He remains in remission 100 months later. Case 2: A 20 year old man was diagnosed in July 1995 with testicular teratoma, and lung, brain, supraclavicular and retroperitoneal metastases. He was treated with BEP, radiotherapy and surgery. Over the next four years he received 2 lines of chemotherapy, (and a thoracotomy) for separate relapses including tandem HDC, but in 4/99 developed a third relapse. He was treated with oral VP16 50 mg daily for 14 days out of 21. His HCG normalised, and he continued on this therapy until September 2003. He remains well, in DCR and off treatment, 68 months after starting VP16, and works full-time. Conclusions: Sustained remission, is possible in a minority of patients with multiply relapsed, GCT, even following failed multi-cycle HDC. Taxanes and oral VP16 might merit prospective study in this setting. Radiotherapy should also be considered in suitable patients. No significant financial relationships to disclose.
Abstract 326: Syndecan-4 Knockout Mice Exhibit Decreased eNOS Activity And Increased Blood Pressure Via Disruption Of mTOR Complex Assembly In Raft Domains
Authors: Chohreh Partovian, Zhen W Zhuang, Kathleen A Martin, Michael Simons
Journal: Circulation (2007)

Background: Growth factor-induced NO release requires PI3K- and mTOR-dependent Akt activation that in turn controls eNOS phosphorylation. Several studies have shown that syndecan-4, a heparan sulfa...
Time dependence of critical deletions as prognostic factor for relapse-free survival (RFS) in localised GIST. A Spanish Group for Sarcoma Research (GEIS) study
Authors: J. Martin, A. Gutierrez, J. Garcia del Muro, J. Maurel, L. M. Gonzalez de Sande, J. Martinez, A. De Juan, N. Lainez, F. Losa, A. Poveda
Journal: Journal of Clinical Oncology (2008)

10508
Prediction of response in patients (pts) with advanced gastric cancer (AGC) who received paclitaxel-based chemotherapy: Expression of class III beta tubulin (bTubIII) and ABCB1 gene polymorphisms.
Authors: M. Jung, X. Zhang, W. Kwon, J. Jung, H. Jeung, J. K. Roh, H. C. Chung, S. Y. Rha
Journal: Journal of Clinical Oncology (2010)

e14528 Background: Several studies looked for predictive biomarkers for treatment outcome of paclitaxel, but still now no reliable biomarkers are available. To predict clinical outcome in pts with AGC received paclitaxel-based chemotherapy, we evaluated expression of bTulIII and ABCB1 (multidrug resistance) gene polymorphisms. Methods: Sixty Pts with AGC were treated with paclitaxel combined with an infusional 5-fluorouracil and low-dose leucovorin. Expression of bTubIII was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumors from the primary gastric cancer. Tumors were classified as bTulIII “low (< 100)” and “high (≥ 100)” according to IHC score (intensity [0-3]*portion [0-100]). gDNA from peripheral blood mononuclear cells were used to genotype ABCB1 2677G>T/A and 3435C>T polymorphisms. The expression of bTubIII and gene polymorphisms were investigated for their association with tumor response and progression free survival (PFS). Results: The 11 of 60 Pts (18.3%) with high expression of bTubIII showed higher disease control rate (DCR) than those with low expression (90.9 % vs. 51 %, p = 0.019). High bTubIII expression was associated with longer PFS, however there was not statistically significant (5.0 vs. 2.7 months, p = 0.456). The frequencies of ABCB1 2677 genotypes were GG 19.1%, GT + GA 60%, others 20.9% and that of 3435 genotypes were CC 40%, CT 45%, and TT 15%, respectively. ABCB1 2677 GG showed a significantly higher DCR than others (100% vs. 47.4%, p = 0.004). However, ABCB1 2677 genotypes were not associated with PFS and ABCB1 3455 genotypes were not predictive of both DCR and PFS. Conclusions: These results suggested expression of bTubIII and ABCB1 2677 genotypes were predictive markers in pts with AGC received paclitaxel-based chemotherapy. No significant financial relationships to disclose.
Spatiotemporal release of BMP-2 and VEGF enhances osteogenic and vasculogenic differentiation of human mesenchymal stem cells and endothelial colony-forming cells co-encapsulated in a patterned hydrogel
Authors: Danial Barati, Seyed Ramin Pajoum Shariati, Seyedsina Moeinzadeh, Juan M. Melero-Martin, Ali Khademhosseini, Esmaiel Jabbari
Journal: Journal of Controlled Release (2015)
Association of the EGFR gene polymorphisms with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with gefitinib
Authors: F. Ma, D. Lin, T. Sun, D. Chu, X. Zhang, Z. Wang, J. Wang, Y. Shi, Y. Sun, B. Xu
Journal: Journal of Clinical Oncology (2008)

14516 Background: Mutations in the EGFR gene appear to confer sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Genetic polymorphisms are more prevalent than mutations in human genome. We evaluated the association of polymorphisms in the EGFR gene with the clinical outcomes in the patients with advanced NSCLC treated with gefitinib, an EGFR-TKI. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms within the EGFR gene range. Four most representative tagging single nucleotide polymorphisms (SNPs), one well-known CA simple sequence repeat (CA-SSR) in intron 1, and several common SNPs in the region encoding tyrosine kinase domain of EGFR were included in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and directly DNA sequencing approach were used to determine the genotypes of 84 advanced NSCLC patients treated with gefitinib. Results: Rs2293347 in exon 25 and CA-SSR in intron 1 were addressed by the candidate loci approach. For rs2293347, the clinical benefit rates were 71.2% and 37.5% (P = 0.0043) in wild-type (G/G genotype) and variation allele carriers (A/G or A/A genotypes). The progression-free survival were 11 months and 3 months (P = 0.0018), respectively, while the results for overall survival were similar. For CA-SSR, the clinical benefit rate was 88.5% in patients carrying at least one shorter CA repeat allele [≤16 (CA)n], and 48.3% in patients carrying two longer CA repeat alleles [>16 (CA)n] (P = 0.0005). However, CA- SSR polymorphism was not found to be associated with the progression-free survival and overall survival. Conclusions: Rs2293347 and CA-SSR polymorphisms may be predictive for clinical outcomes in patients with advanced NSCLC treated with gefitinib. No significant financial relationships to disclose.
Implication of insulin-like growth factor (IGF)/IGF binding protein-3 and alpha-tocopherol in the chemopreventive activity of 9-<i>cis</i> retinoic acid in lung cancer
Authors: H.-Y. Lee, J.-Y. Han, Y. S. Chang, H. Tran, J. M. Kurie, R. Lotan, D. D. Liu, J. J. Lee, J. S. Lee, W. K. Hong
Journal: Journal of Clinical Oncology (2004)

1005 Background: High level of IGF-I is associated with increased susceptibility for several types of cancer, whereas high levels of IGFBP-3 and vitamin E tend to attenuate the risk. This study was designed to investigate whether 9-cis-retinoic acid (9cRA) treatment affects the serum IGF-I/IGFBP-3 and alpha-tocopherol (AT), the most active form of vitamin E. Experimental Design: Individuals (n = 226) who had smoked at least 20 pack-year (PY) and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9cRA (100 mg) or placebo arm. During the clinical trial, participants were informed to visit every month and blood samples were taken. After treatment, participants were followed up for another 3 months. Serum levels of IGF-I, IGFBP-3, and AT of participants, who were enrolled in 9cRA (n=49) and placebo (n=55), were measured by the use of HPLC. All statistical tests were two-sided. Results: In 9cRA group, the levels of IGF-I and IGF-I:IGFBP-3 molar ratio were significantly lower, whereas, the levels of IGFBP-3 were significantly higher compared with placebo treated group (P=0.03, <0.01, and 0.03, respectively; Wilcoxon test). The level of IGF-I, IGFBP-3, and its molar ratio in this study population were not affected by the PY and the duration from the smoking cessation to the study. There was no significant difference in the baseline serum AT level between 9cRA and the placebo group. However, the serum level of AT was significantly increased during treatment with 9cRA. It peaked within 1 month and maintained the peak level during 9cRA treatment. Thus the serum level of AT was significantly increased in the 9cRA group compared with the placebo group (r=0.45; p<0.01). There was significant correlation between baseline serum concentration of IGFBP-3 and AT (Pearson's correlation (r)=0.23, p<0.01) and the level of these components was proportionally increased with 9cRA treatment (r=0.45; P<0.01). Conclusions: 9cRA modulated IGF axis and increased serum level of AT in former smokers. These findings suggest that 9cRA has a potential chemopreventive activity in former smokers. No significant financial relationships to disclose.
Mpv Salvage Regimen Followed by Hdt/Asct and Whole Brain Irradiation for Secondary Cns Lymphoma: a Follow-Up Data
Authors: Ikuo Shimizu, Naoaki Ichikawa, Wataru Takeda, Toshimitsu Ueki, Yuki Hiroshima, Masahiko Sumi, Mayumi Ueno, Hikaru Kobayashi
Journal: Annals of Oncology (2014)
Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist
Authors: D J Nikolic-Paterson, H Y Lan, P A Hill, J L Vannice, R C Atkins
Journal: Journal of the American Society of Nephrology (1994)

Interleukin-1 is a proinflammatory cytokine produced in glomerulonephritis. Blocking the action of interleukin-1 by the administration of the interleukin-1 receptor antagonist (IL-1ra) has been shown to prevent renal function impairment, reduce glomerular injury, inhibit leukocyte infiltration, and suppress tubulointerstitial damage in experimental antiglomerular basement membrane disease. A key mechanism in the entry of leukocytes into the kidney is the interaction between the interleukin-1 inducible intercellular adhesion molecule-1 (ICAM-1; CD54) and lymphocyte function-associated antigen-1 (CD11a/CD18). Therefore, this study investigated whether the inhibition of this mechanism was the means by which IL-1ra suppressed leukocyte infiltration in rat accelerated antiglomerular basement membrane glomerulonephritis. Disease was induced in two groups of six rats; animals were treated by constant sc infusion of recombinant human IL-1ra or saline from the initiation of disease until being euthanized 14 days later. In saline-treated animals, there was marked up-regulation of ICAM-1 in the glomerulus and interstitium, In which was associated with leukocyte infiltration. In particular, focal accumulation of CD11a+ and CD18+ cells was apparent in areas of tubulointerstitial damage exhibiting intense ICAM-1 expression. IL-1ra treatment partially reduced glomerular ICAM-1 expression and leukocyte infiltration. However, IL-1ra treatment resulted in a dramatic inhibition of interstitial ICAM-1 expression, interstitial leukocyte infiltration, and tubulointerstitial damage. In conclusion, this study has shown that interleukin-1 is a major inducer of ICAM-1 expression within the renal tubulo-interstitium--a process associated with focal leukocyte infiltration and tubulointerstitial damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of colchicine on risk of cardiovascular events among patients with gout: as evidence accrues, is it time for a randomised trial?
Authors: Georgios Giannopoulos, Spyridon Deftereos
Journal: Annals of the Rheumatic Diseases (2016)

Effects of colchicine on risk of cardiovascular events among patients with gout: as evidence accrues, is it time for a randomised trial?We read with great interest the paper by Solomon et al 1 on the effects of colchicine on risk of cardiovascular events and mortality among patients with gout.The authors should be commended on a well-planned and informative study, which, despite the non-randomised retrospective design, adds valuable evidence on a potential new role of this old drug in cardiovascular disease-a prospect which has come under scrutiny over the past few years. 2 We would like to contribute a few comments and pose some questions.With regard to the reported apparent lack of a doseeffect relationship between colchicine and studied outcomes, from our experience with clinical studies of colchicine, [3][4][5][6] gastrointestinal side effects-diarrhoea and nausea in particular -are important limiting factors for patient compliance and adherence to colchicine treatment.As a consequence, it is possible that patients who are prescribed high dosages of the drug end up discontinuing treatment earlier and taking a lower total dose and this may explain the authors' findings.In this frame of thought, we have noted that the authors do not provide data regarding daily doses used in the studied patient population.We believe it would be useful to have an idea of exposure to colchicine, in terms of median daily dose levels and treatment duration.Another point of interest would be the proportion of patients who took colchicine for an acute gout attack as opposed to those who used it as a preventive measure (eg, when started on a uric-acid-lowering treatment).If the number of patients in the latter group is not too small, it would be interesting to see whether there was an interaction between presence of an acute inflammatory state (ie, a gout attack) and the effectiveness of colchicine in reducing the risk of cardiovascular outcomes.In spite of accumulating data, 7 8 a large prospective randomised clinical trial of colchicine with enough power to evaluate hard outcomes is lacking and, considering the absence of industry interest, would probably be rather difficult to finance.In addition to the principal question of the efficacy of colchicine in reducing cardiovascular risk, such a study would have to address several other unresolved issues, including what is the optimal clinical setting for colchicine treatment, what dose levels should be employed and which patient populations really stand to gain benefit.
Preliminary results of a phase II trial utilizing gemcitabine in patients with advanced non-small cell lung cancer and a performance status 2
Authors: M. A. Neubauer, C. H. Reynolds, M. Joppert, T. Whittaker, Y. H. Ahmad, H. Ghaddar, T. Marsland, L. Asmar
Journal: Journal of Clinical Oncology (2004)

7121 Background: The role of chemotherapy for patients (pts) with advanced NSCLC and poor performance status (PS) remains unclear. This trial was designed to determine the 1-year survival rate, tumor response rate, time to progression (TTP), and toxicity of gemcitabine monotherapy in pts with Stage IIIB (with pleural effusions) and IV NSCLC and ECOG PS2. Methods: Gemcitabine 1250 mg/m2 was administered IV on Days 1 and 8 of each 21-day cycle. Treatment consisted of 6 cycles of chemotherapy, but pts who were still showing evidence of further response could receive 2 additional cycles. Results: Between March and Nov 2002, 42 pts from 31 sites were enrolled. Most of the pts were white (90.5%), 74% had stage IV disease, and 17% had stage IIIB. Median age was 73 years (range, 58–84), 25 (59.5%) were males, 43% had prior surgery, and 19% received prior palliative radiation therapy to areas outside of the thorax. Patients received a median of 3 cycles (range, 1–8). The median survival for all pts was 4.9 months (range, <1 –16.4) and the 1-year estimated survival rate was 23%. Median TTP was 2.7 months (range, 2–13.8) and progression-free survival at 1 year was 19%. Twenty-seven pts have died of progressive disease, 2 myocardial infarction, 1 for each of brain herniation, pneumonia and respiratory failure. 4 pts were not evaluable for response; 2 refused further treatment and 2 failed treatment due to toxicity. Among 38 evaluable pts, 4 (11%) had PR, 11 (29%) had SD and 23 pts (60%) progressed. Drug related ≥Grade 3 toxicities included neutropenia (16.7%); dyspnea and anemia (7.1%). Conclusions: Our results suggest that selected pts with ECOG PS 2 may benefit from the use of single agent therapy with Gemcitabine. Models to select pts with poor performance status who may benefit from chemotherapy are needed. Also further studies comparing single agent to combination chemotherapy for this group of pts are necessary. Supported by Eli Lilly and Company, Indianapolis, IN, USA Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly
Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow
Authors: Regina Miftakhova, Andreas Hedblom, Julius Semenas, Brian Robinson, Athanasios Simoulis, Johan Malm, Albert Rizvanov, David M. Heery, Nigel P. Mongan, Norman J. Maitland, Cinzia Allegrucci, Jenny L. Persson
Journal: Cancer Research (2016)

Abstract Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453–64. ©2016 AACR.
Molecular portrait of a rare case of metastatic glioblastoma: somatic and germline mutations using whole-exome sequencing
Authors: Sara Franceschi, Francesca Lessi, Paolo Aretini, Chiara M. Mazzanti, Michele Menicagli, Marco La Ferla, Veronica De Gregorio, Davide Caramella, Antonio G. Naccarato, Generoso Bevilacqua, Angelo G. Bonadio, Francesco Pasqualetti
Journal: Neuro-Oncology (2016)
Melanoma Cells Block PEDF Production in Fibroblasts to Induce the Tumor-Promoting Phenotype of Cancer-Associated Fibroblasts
Authors: Nkechiyere G. Nwani, Maria L. Deguiz, Benilde Jimenez, Elena Vinokour, Oleksii Dubrovskyi, Andrey Ugolkov, Andrew P. Mazar, Olga V. Volpert
Journal: Cancer Research (2016)

Abstract Loss of pigment epithelium-derived factor (PEDF, SERPINF1) in cancer cells is associated with poor prognosis and metastasis, but the contribution of stromal PEDF to cancer evolution is poorly understood. Therefore, we investigated the role of fibroblast-derived PEDF in melanoma progression. We demonstrate that normal dermal fibroblasts expressing high PEDF levels attenuated melanoma growth and angiogenesis in vivo, whereas PEDF-depleted fibroblasts exerted tumor-promoting effects. Accordingly, mice with global PEDF knockout were more susceptible to melanoma metastasis. We also demonstrate that normal fibroblasts in close contact with PEDF-null melanoma cells lost PEDF expression and tumor-suppressive properties. Further mechanistic investigations underlying the crosstalk between tumor and stromal cells revealed that melanoma cells produced PDGF-BB and TGFβ, which blocked PEDF production in fibroblasts. Notably, cancer-associated fibroblasts (CAF) isolated from patient-derived tumors expressed markedly low levels of PEDF. Treatment of patient CAF and TGFβ-treated normal fibroblasts with exogenous PEDF decreased the expression of CAF markers and restored PEDF expression. Finally, expression profiling of PEDF-depleted fibroblasts revealed induction of IL8, SERPINB2, hyaluronan synthase-2, and other genes associated with tumor promotion and metastasis. Collectively, our results demonstrate that PEDF maintains tumor-suppressive functions in fibroblasts to prevent CAF conversion and illustrate the mechanisms by which melanoma cells silence stromal PEDF to promote malignancy. Cancer Res; 76(8); 2265–76. ©2016 AACR.