tbuckley/cabot-search huggingface dataset:
YC-1 inhibits proliferation of human hepatoma cells through a cyclic GMP-independent pathway
Authors: Shih-Wei Wang, Shiow-Lin Pan, Che-Ming Teng
Journal: Cancer Research (2005)

673  3-(5’-Hydroxymethyl-2’-furyl)-1-benzyl indazole (YC-1), a novel type of soluble guanylyl cyclase (sGC) activator, is useful in investigating the signaling of cGMP and may provide a new approach for treating cardiovascular diseases. Recently, YC-1 has been shown to inhibit the proliferation of vascular smooth muscle cells and endothelial cells, and blocks tumor angiogenesis by suppressing hypoxia-inducible factor-1 (HIF-1) activity. In the current study, we investigated whether YC-1 can directly affect cancer cell survival and growth and YC-1’s anticancer mechanism in human hepatoma. Our data showed that YC-1 inhibited the growth of HA22T human hepatoma cells in a concentration-dependent manner by SRB and [3H]thymidine incorporation assay. DAPI staining and trypan blue exclusion tests indicated that the YC-1-induced antiproliferative effect was not through direct cytotoxicity, but through the inhibition of cell growth. Flow cytometry showed that YC-1 induced a concentration-dependent increase in G1 phase with a concomitant decrease in the S and G2-M phases of the cell cycle. The role of cGMP in YC-1-induced growth inhibition in HA22T cells was examined. ODQ (a selective sGC inhibitor), and KT-5823 (a selective inhibitor of cGMP-dependent protein kinase) did not prevent the inhibition of cell growth that was induced by YC-1. SNP (an NO donor), IBMX (an non-specific phosphodiesterase inhibitor) did not significantly potentiate YC-1-mediated growth inhibition. Moreover, intracelluar cGMP levels were also not increased by YC-1 in HA22T cells. These data suggest that the sGC/cGMP signaling pathway is not involved in YC-1-induced inhibition of HA22T proliferation. Western blotting showed that YC-1 did induce a profound elevation in p21CIP1/WAF1 expression, and the formation of CDK2-p21 complexes, but not other CDK-CKI complexes, was increased by YC-1. The mRNA level of p21CIP1/WAF1was analyzed in YC-1-treated cells using RT-PCR. Immunohistochemical analysis revealed that the nuclear localization signal of p21CIP1/WAF1 was increased in YC-1-treated regressed tumor tissue. On the basis of our findings, we conclude that YC-1 induces cell cycle arrest and inhibits tumor growth both in vitro and in vivo via the up-regulation of p21CIP1/WAP1 expression. This YC-1-induced antiproliferation effect in human hepatoma cells is through a cyclic GMP-independent pathway.
Time to deterioration in dimensions of health-related quality of life (HRQL) for patients with recurrent glioblastoma multiforme (GBM): Results from the randomized, phase III trial of enzastaurin (ENZ) versus lomustine (CCNU)
Authors: M. J. van den Bent, W. Wick, A. M. Liepa, V. K. Puduvalli, A. F. Carpentier, L. Cher, W. P. Mason, M. J. Taphoorn, S. Hong, H. A. Fine
Journal: Journal of Clinical Oncology (2008)

2040 Background: One goal of therapy for recurrent GBM is to delay worsening in HRQL, with interventions expected to have greatest impact on physical and functional domains. HRQL assessment in recurrent GBM has been limited by deterioration of patient (pt) status. We report HRQL results from a multinational phase III trial. Methods: Pts with recurrent GBM were randomized 2:1 to ENZ 500 mg daily or CCNU 100–130 mg/m2 every 6 weeks. Pts and proxies completed the 50-item Functional Assessment of Cancer Therapy - Brain (FACT-Br) (version 4) prior to randomization, approximately every 3 weeks while on therapy and then 30 days after discontinuation. Time to deterioration (TtD) for each pt was defined as an 11-point decrease in the 148-point Trial Outcome Index (TOI; physical and functional well-being plus brain tumor-specific concerns) or death. Only pts with baseline FACT-Br data were included in the analysis. Proxy data were used when pts were unable to complete the FACT-Br and if there were sufficient dyad data to establish an imputation pattern. TtD was analyzed using Kaplan-Meier methods. To assess differences between arms in TOI subscales, change from baseline was analyzed with a mixed-effects analysis of variance model. Results: Enrollment was terminated after an interim analysis. Of 266 randomized pts, 159 / 174 (91%) ENZ and 82 / 92 (89%) CCNU pts were analyzed for TtD. Baseline scores for TOI were not statistically different between arms (p=0.638). Pt compliance for completing the FACT-Br on-study over the first 6 months was 77% for ENZ and 78% for CCNU; use of proxy data increased compliance to 79% and 81%, respectively. Median TtD was 2.27 months for ENZ and 2.33 months for CCNU with 6-month rates of 18% and 29%, respectively (hazard ratio = 1.12 [95% CI: 0.77–1.63]; log-rank p-value = 0.54; 47% censoring). There were no differences between arms in change from baseline in physical and functional well-being or in brain tumor-specific concerns (p>0.05). Conclusions: Assessment of HRQL is feasible in pts with recurrent GBM. No difference in time that physical and functional domains of HRQL were maintained was detected between ENZ and CCNU. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly, MGI Pharma, Pfizer Oncology, Schering-Plough Eli Lilly Eli Lilly, Merck, Pfizer Oncology, Schering-Plough Eli Lilly Schering-Plough
Snoring and Obstructive Sleep Apnea
Journal: Thorax (1995)

Snoring and obstructive seep apnea (OSA) are ongoing disease processes.Snoring once thought to be only a soc~al d~sease, may actually be a precursor to subsequent OSA.Treatment begins by eliminating or reducing causat~ve or exacerbating factors.The traditional plan involves weight loss, alteration of sleeping position, and avoidance of sedatives, smoking, and alcohol.In the management of all patients with OSA, weight loss with continuous positive airway pressure or surgery may be considered.There are several innovations in the surgical techniques available for treatment of patients with sleep-disordered breathing.Outpatient techniques such as laser-assisted uvulopalatoplasty (LAUP) and additional procedures designed to address hypopharyngeal and base of ' Department of Otolaryngology.Faculty of Medicine.Srinakhar~nwirot Univers~ty ' nln7.oikfnw18n ~~I ~~+?MEI I n ~z ~b w ~f l ~i f l m < a ~~i ~~1 f l i ~f l ~~n ~u w ' d ?~~w ' b i wuma:~mmiun'r5u~u~cjiu~innis%9/1"ni~?nwi~dau%uiliu~u$ ~'I~\YYI!' ~ \i I u n l l n !I i i u I , 1 1 , I , -I i!
In vivo imaging of specific biomarker expression during oral carcinogenesis
Authors: Petra Wilder-Smith, Marie J. Hammer-Wilson, Tatiana B. Krasieva, Joseph Morcos, Daniel Lee, Diana V. Messadi
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3849 

Background and Objective: Oral carcinogenesis is a multistep process in which genetic events cause disruption of the normal regulatory pathways controlling basic cellular function. Multiple genetic events lead to oral cancer, and various cellular genes are over expressed in oral squamous cell carcinoma. Goal of this study was to develop in vivo non-invasive imaging techniques to follow the expression and localization of specific biomarkers known to play a role in the angiogenesis and extracellular matrix (ECM) remodeling phases of oral cancer progression. Study Design/Materials and Methods: In thirty hamsters throughout DMBA induced carcinogenesis in one cheek pouch, in vivo, non-invasive multi-photon (MPM) fluorescence and second harmonic generation (SHG) techniques were used to image surface and subsurface fluorescence/SHG prior to and after the injection of the following biomarkers conjugated with AlexaFluor 430: Vascular Endothelial Growth Factor (VEGF); urokinase Plasminogen Activator (uPA) and Inhibitor (PAI-1); Matrix Metalloproteinases 1,2,9 (MMPs). In vivo spectroscopy confirmed biomarker-induced fluorescence, while time-based fluorescence measurements identified optimal imaging timepoints. In vivo fluorescence imaging identified the time-based three-dimensional localization and expression of the various biomarkers at different stages of carcinogenesis. At 0,4,6,8,10,12 weeks, one animal was sacrificed to provide parallel histopathological data. Results: Carcinogenesis-related structural and vascular changes were clearly visible. Biomarker expression was clearly identified, localized and quantified at all timepoints throughout carcinogenesis by green fluorescence. Collagen structure was imaged using SHG. Optimal imaging timepoints ranged from 1-3 hours after injection for the various biomarkers. Time-based three-dimensional localization and expression also differed considerably between the various biomarkers at different stages of carcinogenesis. uPA was confined to depths of 80-130 μm within the tissues, whereas the other biomarkers were less clearly localized with regard to tissue depth. Conclusion: Time- and spatially-resolved determination of (1) specific biomarker expression, (2) vascular and ECM changes throughout oral carcinogenesis provide valuable information on mechanisms of dysplastic and malignant changes. Supported by: CRFA 30003, NIH (LAMMP) P41 RR01192, AFOSR FA 9550-04-1-0101.
A phase II and pharmacogenomic study of Irinotecan and carboplatin in advanced non-small cell lung cancer (NSCLC)
Authors: G. A. Pillot, K. Hennenfent, W. Read, S. Marsh, H. L. McLeod, F. Gao, R. Govindan
Journal: Journal of Clinical Oncology (2005)

7114 Background: The one-year survival rates for patients with metastatic NSCLC is approximately 35%. We conducted a phase II study of irinotecan (I) and carboplatin (C) in patients with stage IIIB(pleural effusion) and IV NSCLC. Preliminary results have been presented previously (ASCO 2003 #2704, 2004 #7364). Methods: Eligible patients had a diagnosis of metastatic NSCLC with no history of prior chemotherapy. Pts received I 200 mg/m2 over 90 minutes followed by C at an AUC of 5 over 1 hour, every 21 days for a maximum of 6 cycles. The dose of I was reduced from 250 mg/m2 to 200 mg/m2 because of hematological toxicity after treating first 5 pts. Reevaluation occurred every 2 cycles. Genetic polymorphisms for CYP3A4*1B, ABCB1 3435, GSTP I105V, XPD K751Q, XRCC1 R399Q, and UGT1A1*28 were evaluated by Pyrosequencing to correlate with response and toxicity. Results: 42 patients were enrolled in this study. 32 patients (76%) completed 2 or more cycles and are evaluable for response. 40% received all 6 cycles. A total of 158 cycles have been administered, 54 of which were delayed. Grade III/IV toxicities: hematological: 55% neutropenia, 19% febrile neutropenia, 36% thrombocytopenia. Related grade 3 or 4 non- hematological toxicities (occurring in greater than 10%): nausea 12% and diarrhea 12% One pt died from treatment related complications. Response rates in 32 evaluable patients: partial response: 8 (25%) SD: 16 (50%); 8 patients (25%) developed PD during treatment. Survival: One year- survival 45%, median overall survival 11.9 months, and median time to disease progression: 6.6 months. Genotyping was performed for 22 patients. Patients with a UGT1A1*28 allele (n=11) were more likely to achieve partial response (45% vs. 11%), but with an increase in grade 4 neutropenia (45% vs. 22%) compared to wild-type patients. Conclusions: Response rates of I and C administered every three weeks are encouraging and comparable to other commonly used regimens in NSCLC. The main toxicities are hematologic. The UGT1A1*28 allele was associated with both response and toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Neopharm, Orion Genomics, Sanofi- Synthelabo, Veridex AstraZeneca, Aventis, Bristol-Myers Squibb, Genentech, Lilly Oncology, Merck, Pfizer AstraZeneca, Aventis, Bristol-Myers Squibb, Ligand, Lilly Oncology, Pfizer
Late-breaking abstract: Local and systemic distribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure
Journal: European Respiratory Journal (2011)

DNAzymes represent a new class of antisense molecules that combines the specificity of DNA base pairing with an inherent RNA-cleaving enzymatic activity. We developed the DNAzyme hgd40 which was shown to effectively target the transcription factor GATA-3 that plays an important role in the regulation of Th2-mediated immune mechanisms in allergic bronchial asthma.  The aim of this study was to investigate local and systemic distribution of hgd40 after local exposure in mice, rats and dogs.  Using fluorescently labelled hgd40 we could demonstrate that the DNAzyme was evenly distributed in inflamed mouse lungs after single application. Moreover, hgd40 could be intracellularly detected in T cells, Goblet cells, AE type 1 cells and macrophages 2 h after i.n. application. Systemic distribution was investigated in rats and dogs in the course of toxicological studies following single and subchronic (28 d) exposure. Generally, only very low systemic hgd40 levels were detected. In rats, the highest serum concentration of hgd40 was observed 1 h post application (p.a.) and decreased over time to non-detectable levels at 24 h p.a. After 27 d of subchronic, daily inhalation, no accumulation of hgd40 occurred. The results were similar for both sexes and three different doses. Similar results were observed in dogs.  Our results indicate that local hgd40 DNAzyme admimistration can target different lung cells expressing GATA-3 and thus modulate Th2-driven immune responses. Low concentration in blood and lack of accumulation after subchronic inhalative exposure indicate that GATA-3-specific DNAzyme hgd40 leads only to marginal systemic distribution.
A genomic and transcriptomic approach to distinguish primary and metastatic ovary tumors
Authors: J. Meyniel, P. H. Cottu, M. Stern, I. Lebigot, L. Mignot, S. Roman-Roman, X. Sastre-Garau
Journal: Journal of Clinical Oncology (2009)

e22150 Background: Distinction of primary ovarian tumors from metastatic tumors involving the ovary is in some cases challenging for final pathologic diagnosis and for treatment with efficient chemotherapy Methods: We gathered from our biobank 16 pairs of breast/ovarian tumors for some of which the diagnosis was uncertain. We investigated the possibility to improve diagnosis using genomic and transcriptomic tools. The pangenomic profiles of 16 pairs of primary breast carcinoma and ovary tumors (primary tumors or metastases from breast carcinoma) from the same patients were analyzed using the Affymetrix GeneChip Mapping 50K (XbaI) SNP arrays. The data were normalized with ITALICS algorithm. We analyzed the transcriptome of the paired samples using Affymetrix U133plus2 arrays. The data were normalized with GCRMA algorithm and a hierarchical clustering of these samples was performed, together with a dataset of primary and secondary ovary tumors. Results: Primary infiltrating lobular carcinoma (ILC) was observed in 6 patients, infiltrating ductal carcinoma (IDC) in 7 patients, 1 patient had one ILC and one IDC, 1 patient had a mixed IDC+ILC and 1 patient an undifferentiated cancer. All patients received adequate loco-regional and systemic therapies. Median time to diagnosis of ovarian tumor was 54 months. Ovarian tumors were considered as primary in 7 patients, and metastatic in 9 patients, and diagnosis was ambiguous in 4 of them. Four patients developed extra-abdominal metastases. Median survival from breast cancer diagnosis was 78 months, and from ovarian tumor diagnosis was 29 months. CGH array: In 12 pairs, the comparison of genomic profiles one with each other, confirmed the pathological characteristics of the tumors. In 4 cases, the genomic profiles established clearly the status of the ovary tumor whereas the pathological analysis did not. Transcriptome: The status established by the transcriptomic analysis was for each sample in total agreement with the status established by the genomic analysis. Conclusions: We clearly established in this training series that CGH array analysis could help to discriminate between primary and secondary ovarian tumors from breast cancer. Transcriptomic data confirmed these results. Further validation data are warranted. No significant financial relationships to disclose.
A novel rationally designed agonist antibody fragment that functionally mimics thrombopoietin
Authors: M. Renshaw, S. Frederickson, B. Lin, X. Su, Y. Wang, K. Bowdish
Journal: Journal of Clinical Oncology (2006)

2541 Background: Thrombocytopenia, or low platelet count, is a significant clinical problem associated with ITP, cancer chemotherapy, or other clinical settings. To avoid transfusions, agents that stimulate platelet production are in development. Clinical trials with recombinant versions of thrombopoietin (TPO), which stimulates platelet production in a lineage specific manner by binding to cMpl receptor (cMpl-R) on megakaryocytic progenitors, were demonstrated to increase platelet counts in humans. However, the possible generation of an anti-TPO immune response that cross-reacts with and impairs the function of the endogenous cytokine is a significant disadvantage of this treatment approach. Alternate thrombopoietic agents that lack native TPO primary sequences have been developed to address this concern. Methods: Using rational design, antibody fragments (Fabs) that mimic TPO were created. A peptide with cMpl-R binding capability was grafted into different CDRs of a fully human Fab scaffold. Functional presentation of the peptide was optimized using phage display and cell-based panning. Select antibodies and fragments containing two grafted peptides were assayed for their ability to stimulate cMpl-R in vitro. In vivo stimulation of platelet production was tested in normal mice injected daily for five days with either rhTPO (90 μg/kg) or Fab59 (0.2 mg/kg, 2 mg/kg or 5 mg/kg) or negative control Fab (5mg/kg). Results: Several candidates demonstrated agonist activity in an in vitro cMpl-R signaling reporter assay, including Fab59 which was estimated to be equipotent to TPO. In vivo, a rise in peripheral platelet counts comparable to rhTPO was seen with Fab59 at 2 mg/kg and 5 mg/kg. Serum antibodies generated in response to dosing with Fab59 did not cross-react with murine or human TPO. Conclusion: These rationally-designed mimetic Fabs may provide a therapeutic intervention for thrombocytopenia while avoiding the potential generation of neutralizing antibodies to endogenous TPO. [Table: see text]
Cetuximab (C225) in recurrent and/or metastatic salivary gland carcinomas (RMSGCs): A monoinstitutional phase II study
Authors: L. F. Licitra, L. D. Locati, P. Potepan, F. Crippa, P. Bossi, C. Bergamini, G. Rinaldi, C. Liberatoscioli, F. Perrone, M. Losa, S. Pilotti
Journal: Journal of Clinical Oncology (2006)

5547 Background: EGFR is expressed in 70% of salivary gland carcinomas (SGC). Investigations of anti EGFR treatment seems rational. Aim: To assess activity of C225 in patients with RMSGCs in terms of clinical benefit (CB), defined as occurrence of objective response (CR or PR) or stable disease (SD) for at least 6 months. To correlate treatment outcome with skin toxicity degree and EGFR analysis. Methods: One prior chemotherapy regimen was allowed, except for pts with adenoid cystic carcinoma (ACC) and acinic cell carcinoma for whom 2 lines were allowed. Prior exposure to targeted treatment was not allowed. C225 (Erbitux) was administered iv weekly at 400 mg/mq followed by 250 mg/mq until disease progression, major toxicity or voluntary discontinuation. MRI or CT and PET scan were performed every 6 weeks q4, and q12 thereafter. RECIST response criteria and CTC 3.0. were adopted. Results: From April to December 2005, 30 RMSGCs pts (20 F/10 M; median age 50 yrs), 50% with major SGC, were enrolled. Histotypes were: 23 ACC; 2 mucoepidermoid; 3 myoephitelial; 1 cystadenocarcinoma and 1 acinic cell carcinoma. Thirteen pts (43%) received prior chemotherapy. Localregional (LR) and metastatic (M) disease was present in 13 cases, M in 12, and LR in 5. A median number of 11 drug administration (range 2–31) was given. G2 skin toxicity was recorded in 24 cases. G2 fatigue in 2. At a median FU of 6 months (range 0–8), 2 pts died of PD. Of 22 pts evaluable for response with ≥ 3 months of potential FU, there were 11 SD, 9 PD, while 2 pts refused to continue after 1 months. Currently, 7 of these pts are progression-free at ≥ than 6 months, qualifying for CB definition according to study protocol. Preliminary EGFR analysis showed a high or intermediate expression score in 5 (3 ACC, 1 acinic cell, 1 cistoadenocarcinoma) out of 7 cases, no gene amplification nor chromosome 7 polisomy were found in 3 of 3 analysed ACC. PET results are under evaluation. Conclusions: Hints of activity of C225 in RMSGCs were observed. The early analysis for the CB rate in 23 pts is planned for April 2006, when all of them will have a potential follow-up of ≥ 6 months, and results thereof will be reported. [Table: see text]
Gemcitabine and concurrent radiation as a salvage treatment of chest wall recurrence in breast cancer
Authors: A. Shaharyar, Z. Alauddin, K. Shabbir, M. Hafeez, E. U. Rehman, I. Abbasi
Journal: Journal of Clinical Oncology (2007)

11027 Background: Chest wall recurrences are seen despite postoperative chemotherapy and radiotherapy. For patients with unresectable lesions who have previously received radiotherapy no standard treatment is available. We devised a protocol of low dose gemcitabine as radiosensitizer concurrent with low dose of radiation and conducted this study with the objectives to document the efficacy and toxicity of this protocol. Methods: From January 2003 to August 2005, 48 patients were included in this study. A histopthological or cytological evidence of chest wall recurrence was required. Females between 18–70 years, with previous modified radical mastectomy, post operative radiation and adjuvant chemotherapy were included. Patients with metastatic disease were excluded. Written informed consent was obtained. A dose of 150 mg / m 2 of gemcitabine in 200 ml of normal saline was infused in 2 hour on day 1, 8, 15 and 22 of radiation. Radiation was delivered 2 hours after the completion of infusion. Conventional fractionation was used to deliver a total dose of 36 Gy given in 3.5 weeks. RECIST and RTOG criteria were used. Results: Twenty recurrences were related to the scar, 10 to the involved internal mammary lymph node region invading sternum and ribs and 18 were associated with the soft tissue masses outside the scar area. All patients were evaluable for response and toxicity. Complete response was seen in 6 (12.5 %) patients, (95 % CI, 13.87_37.16), partial response was seen in 30 (62.5 %) (95 % CI, 44.92 -71.40) with an over all response rate of 75 % (95 % CI, 70.57—91.40) Stable disease was seen in 9 (18.8 %) patients and disease progression in 3 (6.3 %) patients. Grade I skin reaction was seen in 15 (31.2 % ) patients grade II in 11 ( 22.9 % ) and grade III in 3 ( 6.3 % ) patients. No systemic toxicity was seen. Conclusions: Low dose gemcitabine and concurrent radiotherapy is a reasonable salvage treatment in chest wall recurrence in breast cancer patients who have previously received adjuvant chemotherapy and full dose of radiotherapy. This approach has acceptable toxicity. No significant financial relationships to disclose.