bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A191: DHMEQ: A novel NF-kappaB inhibitor with good results in pediatric medulloblastoma cell lines.
Authors: Ramos Priscila Maria Manzini , Castro-Gamero Angel Mauricio , Pezuk Julia Alejandra , Scrideli Carlos Alberto , Umezawa Kazuo , Tone Luiz Gonzaga 
Published: August 2014

Abstract
Medulloblastoma (MB) is the most common malignant central nervous system tumor of childhood representing 15-30% of pediatric brain tumors. The standard treatment involves surgery and chemotherapy and radiotherapy is used only for patients older than 3 years old. The risk of neurocognitive sequel, growth and endocrine systems leading the search for new therapeutic approaches. Great efforts have been made to improve treatments with high success rates and minimal toxicity, among them DHMEQ is a drug that has shown a low toxicity and high effectivity in blocking the NFkappaB, a key transcription factor that control the expression of a large number of genes related to cell proliferation, growth and apoptosis, showing antineoplasic effects in several cancer cell lines. There are no reports showing the effects of DHMEQ in MB. Cell proliferation, clonogenic capacity, wound healing assay, apoptosis (Annexin V), and combination with chemotherapeutic drugs (Cisplatin (CDDP), Temozolomide (TMZ) and Etoposide) or radiation were performed on three pediatric MB cell lines: UW402, UW473 e ONS76. Functional tests were performed using 0-20 µg/mL DHMEQ at 24, 48 and 72h. IC50 values of each drug and drug combination analyses were based in Chou-Talalay method, and simultaneous treatments of DHMEQ with CDDP (2:1 ratio), TMZ (1:200 ratio) or Etoposide (1:0,8 ratio) were performed for 48h or 72h. For gamma radiation clonogenic survival assays were used the doses of 2, 4 and 6 Gy. Statistical analysis was made by ANOVA and Pairwise Multiple Comparison de Holm-Sidak tests (SigmaStat 3.5). All experiments showed DHMEQ caused a decrease on cell proliferation, viability, migration ratio and clonogenic capacity, while increase apoptosis (P&lt;0.05). In the drug combination assay, DHMEQ acted additively with CDDP and synergistically with TMZ and Etoposide in all cell lines. Moreover, DHMEQ enhanced significantly the radiation effects on the three cell lines studied. These results support the biological importance of the NFkappaB as a promising therapeutic target for medulloblastoma treatment, and the potencial effect radio- and chemo- sensitizing of DHMEQ on MB cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A191.
Citation Format: Priscila Maria Manzini Ramos, Angel Mauricio Castro-Gamero, Julia Alejandra Pezuk, Carlos Alberto Scrideli, Kazuo Umezawa, Luiz Gonzaga Tone. DHMEQ: A novel NF-kappaB inhibitor with good results in pediatric medulloblastoma cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A191.
Abstract A205: Development and application of a platform for analysis of protein biomarkers in clinical biopsies of limited quantity.
Authors: Du Jinyan , Lahdenranta Johanna , Zhang Bo , Kudla Art , McDonagh Charlotte 
Published: August 2014

Abstract
MM-111 is a bispecific antibody that inhibits HER3 activation in HER2-expressing tumor cells. Using preclinical models, we have generated hypotheses on both pharmacodynamic and predictive biomarkers of MM-111’s antitumor activity. To evaluate these hypotheses in patients receiving MM-111, we are collecting tumor tissue samples from patients in clinical trials both prior to and following exposure to MM-111. Because of the limited quantity of tissue available, it is challenging to measure a broad spectrum of potential protein biomarkers in these specimens. Here we have optimized tissue processing procedures and developed multiplex Luminex protein assays in order to explore a more extensive biomarker panel from the frozen tumor biopsies collected from patients. To develop a method suitable for use with small tissue quantities, we simulated the clinical biopsy procedures in tumor-bearing mice. We collected 18G core needle biopsies from tumors in mouse xenograft models and flash-froze the samples in the same manner as is being executed in the clinic for patient biopsies. We then prepared total protein lysates from these biopsy samples and measured MM-111 biomarkers with multiplex Luminex protein assays. We found that a sufficient amount of protein could be isolated from 18G core needle biopsies for replicate Luminex assays. Signals were well correlated between two independent biopsies from the same xenograft. We also used this preclinical model system to define the parameters for sample collection in the clinic. We found that the phospho and total protein levels of key MM-111 biomarkers were maintained in tumor biopsy tissue stored for up to 60 minutes at ambient temperature before freezing. We are now using this system to further explore the mechanisms of MM-111 activity compared to other therapeutics that target HER2-expressing tumors. We have analyzed the signaling effects of MM-111 and pertuzumab in biopsies obtained from an esophageal xenograft model derived from a human cancer cell line and observed that MM-111 but not pertuzumab could effectively down-regulate EGFR and HER2 phosphorylation, which is consistent with in vitro data. In summary, we have developed a method for accurately measuring multiple biomarkers in core needle biopsy samples using multiplex Luminex protein assays. We plan to use this approach to test our biomarker hypotheses in MM-111 clinical trials.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A205.
Citation Format: Jinyan Du, Johanna Lahdenranta, Bo Zhang, Art Kudla, Charlotte McDonagh. Development and application of a platform for analysis of protein biomarkers in clinical biopsies of limited quantity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A205.
Abstract A241: Differential roles of STAT3 depending on the mechanism of STAT3 activation in gastric cancer cells.
Authors: Okamoto Wataru , Okamoto Isamu , Tuchihara Katsuya , Yanagihara Kazuyoshi , Nishio Kazuto , Nakagawa Kazuhiko 
Published: August 2014

Abstract
Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated in response to growth factors and cytokines, and which contributes to the regulation of cell proliferation, apoptosis, and motility in many human tumor types.
Methods: We investigated the mechanisms of STAT3 activation and the function of STAT3 depending on its mechanism of activation in gastric cancer cells.
Results: All cell lines positive for constitutive MET activation manifested STAT3 phosphorylation. The MET-tyrosine kinase inhibitor (TKI) and cell transfection with a small interfering RNA (siRNA) specific for MET mRNA inhibited STAT3 phosphorylation in MET-activated cells, indicating that STAT3 activation is linked to MET signalling. Forced expression of a constitutively active form of STAT3 also attenuated MET-TKI-induced apoptosis, suggesting that inhibition of STAT3 activity contributes to MET-TKI-induced apoptosis in MET-activated gastric cancer cells. On the other hand, MKN1 and MKN7 cells, both of which are negative for MET activation, produced interleukin-6 (IL-6) that activated STAT3 through the Janus kinase (JAK) pathway but which did not appear to be required for cell survival. Depletion of STAT3 by transfection with a specific siRNA inhibited both the migration and invasion activities of MKN1 and MKN7 cells, suggesting that STAT3 activated by IL-6 contributes to regulation of cell motility.
Conclusion: Our data thus show that activated STAT3 contributes to either cell survival or cell motility in gastric cancer cells, and that these actions are related to different mechanisms of STAT3 activation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A241.
Citation Format: Wataru Okamoto, Isamu Okamoto, Katsuya Tuchihara, Kazuyoshi Yanagihara, Kazuto Nishio, Kazuhiko Nakagawa. Differential roles of STAT3 depending on the mechanism of STAT3 activation in gastric cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A241.
Abstract A280: Small molecule inhibition of atypical protein kinase C iota reveals a functional basis for oncogenesis.
Authors: Linch Mark , Sanz-Garcia Marta , Kjaer Svend , Soriano Erika , Riou Philippe , Knowles Philip , Dillon Christian , Roffey Jon , McDonald Neil , Parker Peter 
Published: August 2014

Abstract
Background: Atypical protein kinase C iota (PKCι) is a serine/threonine kinase that has been implicated in a variety of cellular processes including polarity, migration, proliferation and survival. PKCι is amplified in many cancers correlating with poor prognosis, however the upstream activating inputs and downstream effectors are not well defined.
Experimental Procedures: 3D MDCK epithelial cell spheroids were grown in Matrigel and used to assess polarized morphogenesis and growth. PKCι was manipulated by inhibition with CRT0066854, or transfection with siRNA or cDNA variants. A PKCι binding interface was identified by X-ray crystallography and interrogated by mass spectrometry of wildtype or binding mutant immunocomplexes.
Results: To identify potential inputs into PKCι we assessed a panel of transformed MDCK cells; p110α, Src, Ras, ErbB2 and Raf. Parental MDCK cells form polarized cysts in Matrigel, however Ras, ErbB2 and p110α MDCK cells formed dysplastic spheroids. In the case of Ras and ErbB2, but not p110α MDCK spheroids, normal polarized morphogenesis could be rescued by siRNA-PKCι or partial PKCι inhibition with decreased spheroid size seen for all transformed cells lines. An effector binding site (PKCι RIPR motif) identified from the crystal structure of the kinase and characterized as a recruitment site for select targets including LLGL2 and Myosin X, was found to be critical for PKCι to confer polarized morphogenesis. Interestingly this binding motif shows a low frequency of mutation in a subset of human tumors.
Conclusions: Downstream of Ras and ErbB2, PKCι activity is enhanced with a resulting dysplasia and loss of polarization, that can be rescued by PKCι inhibition. Mutation of the PKCι-RIPR effector binding motif that is found in cancer, prevents interaction with LLGL2 and its expression also elicits growth as non-polarized, dysplastic epithelial spheroids. This indicates that PKCι may promote cancer, not only by amplification, but by upstream oncogenic inputs and somatic mutation. The oncogene dependent PKCι hyperactivation is pro-proliferative in 3D culture, providing compelling evidence that PKCι is a good target for Ras mutant tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A280.
Citation Format: Mark Linch, Marta Sanz-Garcia, Svend Kjaer, Erika Soriano, Philippe Riou, Philip Knowles, Christian Dillon, Jon Roffey, Neil McDonald, Peter Parker. Small molecule inhibition of atypical protein kinase C iota reveals a functional basis for oncogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A280.
Abstract A285: Inhibition of histone deacetylase enhances radiosensitivity in hepatocellular carcinoma by inhibiting nuclear translocation of HDAC4 and DNA repair.
Authors: Liu Wei-Lin , Cheng Jason Chia-Hsien , Gao Ming , Cheng Ann-Lii 
Published: August 2014

Abstract
Purpose: Tumor control of hepatocellular carcinoma (HCC) by radiotherapy (RT) remains unsatisfactory. The use of an effective molecularly targeted agent in combination with RT is a potential therapeutic approach. Histone deacetylase (HDAC) inhibitors are undergoing clinical evaluation for cancer therapy. HDAC modulates chromatin structure, involves the inhibition of DNA repair, and is considered to influence radio-response. The study aim was to assess the effect of combining a hydroxamic acid derivative HDAC inhibitor, LBH589, with RT on human HCC cells.
Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining LBH589 with irradiation. Western blot and immunofluorescence investigated the protein expressions after the combined treatment. Western blot analysis of proteins from nuclear and cytoplasmic fractions was done by using anti-HDAC4 antibody. Annexin-V immunofluorescence was used to measure apoptotic cells after the combined treatment.
Results: Clonogenic survival showed a greater than additive effect with LBH589 administered before RT as compared to RT alone. LBH589 significantly enhanced the accumulation of acetyl-histone H3. Notably, radiation itself induced translocation of HDAC4 to the nucleus. In contrast, treatment with LBH589 followed by irradiation resulted in HDAC4 confinement to the cytoplasm. The findings indicated that HDAC inhibition affects the nuclear localization of HDAC4. We studied the combined effect of LBH589 and RT on DNA repair in both cell lines. γ-H2AX foci representing DNA double-strand breaks (DSBs) were detected in the nuclei at 24 hours following 10-Gy irradiation. LBH589 administered before irradiation increased the persistence of ϒ-H2AX foci beyond 24 hours. Akt phosphorylation, active caspase-3, cleaved PARP in Western blot analysis, and annexin V immunofluorescence assay revealed a synergistic effect of combining LBH589 with RT on inducing apoptosis.
Conclusion: This study identifies the inhibitory nuclear translocation of HDAC4 by adding LBH589 to RT, and recognizes the effect of LBH589 on sensitizing HCC cells to radiation-induced DNA DSBs and apoptosis. Taken together, LBH589 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A285.
Citation Format: Wei-Lin Liu, Jason Chia-Hsien Cheng, Ming Gao, Ann-Lii Cheng. Inhibition of histone deacetylase enhances radiosensitivity in hepatocellular carcinoma by inhibiting nuclear translocation of HDAC4 and DNA repair. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A285.
Abstract A39: Analysis of endoscopic ultrasound (EUS) - guided fine needle aspiration (FNA) samples from patients with suspected pancreatic ductal adenocarcinomas (PDACS) using plectin-1 (PLEC1) and KRAS oncogene mutation analysis.
Authors: Park Joo Kyung , Song Byung Jun , Ryu Ji Kon , Kim Yong-Tae , Lee Se-Hoon 
Published: August 2014

Abstract
Introduction: Pancreatic cancer remains an incurable and rapidly lethal cancer, with a 5-year survival rate of less than 10%. Little to nothing is known about advanced pancreatic cancer because of problems with tissue availability and usually insufficient quantity of tissue available for diagnosis and study. One of the key features of genetic basis of PDAC is the point mutation of KRAS oncogene occurred in 95 % of its pathogenesis. Plec1 was also recently identified as PDAC specific biomarker.
Aims and Methods: The aim of this study was to find out the techniques using minimal specimens in order to achieve accurate diagnosis of patients with suspected PDACs. DNA was extracted from EUS-guided FNA samples in 80 patients with suspected PDACs. Seven different somatic mutations of KRAS oncogene were evaluated using ARMS and Scorpions technology, and immunohistochemical staining of Plec1 antibody was done.
Results: The total of 80 study patients with suspected of PDACs underwent EUS-guided FNA and the final diagnosis were as follows; PDAC: 63 patients, pancreas neuroendocrine tumor: 4, autoimmune pancreatitis: 3, chronic pancreatitis: 1, metastasis to pancreas: 6, others: 3. The sensitivity and specificity of pathologic diagnosis in EUS-guided FNA samples were 87% and 88% respectively. When we combine KRAS oncogene mutational analysis and pathologic reports of FNA samples, we could get the following sensitivities and specificities; 95% vs. 97%. Also, adding the results of plectin-1 antibodies of immunohistochemical staining could increase the sensitivity of PDAC diagnosis.
Conclusion: Triple combinations of the techniques (pathologic reports, KRAS oncogene mutational analysis, Plec1 staining) could increase accuracy, however, cost-effectiveness and laborious work should be taken into consideration in clinical practice. Further investigation of using minimal specimens to study PDACs may enable us to understand biological behavior and to identify better tools for the diagnosis and treatment of this deadly cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A39.
Citation Format: Joo Kyung Park, Byung Jun Song, Ji Kon Ryu, Yong-Tae Kim, Se-Hoon Lee. Analysis of endoscopic ultrasound (EUS) - guided fine needle aspiration (FNA) samples from patients with suspected pancreatic ductal adenocarcinomas (PDACS) using plectin-1 (PLEC1) and KRAS oncogene mutation analysis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A39.
Abstract A5: Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants.
Authors: Shumaker Robert , Aluri Jagadeesh , Fan Jean , Martinez Gresel , Thompson Gary A. , Ren Min 
Published: August 2014

Abstract
Background: L is an orally administered multitargeted tyrosine kinase inhibitor of VEGF receptors 1, 2, 3; FGF receptors 1, 2, 3, 4; PDGFR-β; RET; and KIT under clinical investigation in solid tumors at doses of 24 mg/d. This study in volunteers assessed the influence of P-glycoprotein (Pgp) inhibition (single-dose R) and simultaneous CYP3A4 and Pgp induction (multiple-dose R) on L PK parameters.
Methods: This was a single-center, single-dose, open-label, sequential, 3-period study. Subjects were administered 3 regimens with a 14-day washout between each treatment. Subjects received a single oral dose of L 24 mg on Day 1 (Period 1), Day 15 (Period 2), and Day 43 (Period 3). In Period 2 on Day 15, subjects received a single oral dose of rifampin 600 mg coadministered with L. In Period 3, subjects received oral rifampin 600 mg/d for 21 days (Days 29 to 49).
Results: 15 subjects were enrolled and completed the study. Single-dose rifampin increased free (unbound) L AUC0-∞ (32%) and Cmax (30%). Multidose rifampin decreased free L AUC0-∞ (9%) without a corresponding decrease in Cmax; mean t1/2(free L) decreased by ∼2.5 h (to ∼17 h) following single-dose rifampin and by ∼5 h following multidose R. The 90% confidence intervals (CIs) of the geometric least squares (GLS) mean ratios for Cmax and AUCs were above the upper CI boundary of the prespecified bioequivalence interval of 80%-125% following a single rifampin dose but within the prespecified bioequivalence interval following multidose R. Headache (n=3, 20%) was the most frequently reported treatment-emergent adverse event (TEAE); 5 subjects reported mild or moderate treatment-related TEAEs (n=5, 33%) most frequently nausea (n=3, 20%) and diarrhea (n=2, 13%).
Conclusions: L exposure was increased by single-dose rifampin but decreased by multiple rifampin doses. The magnitude of these changes was relatively small and likely not clinically meaningful.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A5.
Citation Format: Robert Shumaker, Jagadeesh Aluri, Jean Fan, Gresel Martinez, Gary A. Thompson, Min Ren. Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A5.
Abstract A79: Delivery of multiple genes to neuroblastoma using peptide-conjugated polymeric nanoparticles for cancer therapy.
Authors: Lee Jangwook , Choi Chang Seon , Lee Sang Kyung , Lee Kuen-Yong 
Published: August 2014

Abstract
Tissue-specific delivery of functionalized polymeric nanoparticles has found potential for the treatment of various diseases including cancer. Theragnosis is an emerging approach that can perform diagnosis and therapy simultaneously, and has made great progress in cancer diagnosis and therapy. In this presentation, we report the preparation and characterization of tumor-targeting polymeric nanoparticles delivering both imaging probe and multiple anticancer genes. Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) and siRNAs (c-Myc, VEGF, and Bcl-2) were fabricated by a W/O/W double emulsion method, followed by chemical modification with rabies virus glycoprotein (RVG) peptide using a carbodiimide chemistry. The RVG peptide, derived from rabies virus, binds specifically to acetylcholine receptors substantially found on the membrane of neuroblastoma. We evaluated in vitro cellular uptake and gene silencing efficiency of the nanoparticles using N2a cells. The cellular uptake and gene silencing efficiency of RVG-conjugated nanoparticles significantly increased compared with non-conjugated nanoparticles. We also monitored biodistribution and tumor-targeting ability of the nanoparticles after intravenous injection into a neuroblastoma-bearing mouse model. At 24 h post-injection, the whole body fluorescence was clearly detected at the tumor site when RVG-conjugated nanoparticles were injected into the mice. From ex vivo quantitative analysis, prominent fluorescence intensity of RVG-conjugated nanoparticles was found in tumor, compared with non-conjugated nanoparticles. Finally, in vivo anticancer efficacy of the nanoparticles was evaluated. The target specificity of the nanoparticles led to remarkable anticancer efficacy in the mouse model. This approach suggests that tumor-targeting polymeric nanoparticles are useful for delivery of both imaging probe and multiple anticancer genes specifically to neuroblastoma, which may be critical in the design and tailoring of theragnostic systems for various diseases including cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A79.
Citation Format: Jangwook Lee, Chang Seon Choi, Sang Kyung Lee, Kuen-Yong Lee. Delivery of multiple genes to neuroblastoma using peptide-conjugated polymeric nanoparticles for cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A79.