bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of short course, high-dose valproic acid on proliferation in breast adenocarcinomas.
Authors: Cohen Adam Louis , Factor Rachel , Schabel Matthias , Bild Andrea , Werner Theresa Louise 
Published: March 2020

e13522 Background: Our in vitro and in vivo studies showed that single agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is effective in a subset of breast cancers. Whether VPA is effective as a single agent and what the optimal dosing would be are unknown. Methods: In an ongoing IRB-approved, window-of-opportunity study testing a genomic predictor of sensitivity to VPA (NCT01007695), we performed biopsies and DCE-MRI on women before and after seven days of escalating doses of VPA on untreated women with breast adenocarcinoma with an intact breast tumor. Within patient dose-escalation was done with a goal dose of 50 mg/kg. Proliferation was assessed with MIB-1 immunohistochemistry. Only correlative secondary endpoints are presented here. Results: Sixteen women have completed treatment and are evaluable. Total and free VPA levels on the last day of treatment averaged 136 µg/ml (range 15-242) and 30 µg/ml (range 1-90), respectively. Proliferation rate by MIB-1 decreased by and average of -7.25% (range +4% to -45%, p=0.04). The change in proliferation did not correlated with VPA levels, although only one of four women with VPA levels less than 100 µg/ml had a decrease in proliferation, compared to five of twelve women with VPA levels greater than 100 µg/ml. Four women had MIB-1 decreases of 10% or greater. Two women have had post-treatment biopsies with fibrosis similar to that seen with chemotherapy treatment effect. DCE-MRI parameters, including ktrans, vp, and kep, did not change significantly with VPA treatment or correlate with VPA levels. Conclusions: VPA as a single agent can reduce proliferation in a subset of women with breast cancers. Higher VPA levels are needed than those achieved at standard dose levels, but VPA levels by themselves do not predict effect. Other monitoring parameters, such as peripheral blood histone acetylation changes, or other predictors of benefit are needed. Clinical trial information: NCT01007695.
Use of combination treatment with the investigational RAF kinase inhibitor MLN2480 and the investigational MEK kinase inhibitor TAK-733 on the growth of BRAF-mutant and RAS-mutant preclinical models of melanoma and CRC.
Authors: Cunniff Elizabeth Grace Carideo , Zhang Julie , Chouitar Jouhara , Mettetal Jerome , Nakamura Kazuhide , Arita Takeo , Nakamura Akito , Okaniwa Masanori , Ishikawa Tomoyasu , Yoshida Sei , Fabrey Robyn , Vincent Patrick , Eng Kurt , Garcia Khristofer , Borrelli Deanna , Vagrhese Teena , Stroud Steve , Menon Saurabh , Kuranda Mike , Galvin Katherine 
Published: March 2020

e13529 Background: RAS mutant melanoma and colorectal cancer represent areas of significant unmet medical need. MLN2480 is an investigational class II RAF kinase inhibitor and TAK-733 is an investigational allosteric MEK kinase inhibitor; each of which is the subject of a single agent phase I clinical trial. The present studies have characterized the combination activity of these agents in BRAF mutant and RAS mutant preclinical models of melanoma and colorectal cancer. Methods: Combination effects of MLN2480 and TAK-733 on cell viability were studied using an ATP-based cell viability assay across a panel of BRAF and RAS mutant melanoma and CRC cell lines. Western blot analysis was used to compare effects on MAPK pathway signaling and response markers in cell lines showing a range of sensitivity to this combination. Pharmacodynamic responses and growth inhibitory effects of the combination were studied in xenografts of the same cell lines, as well as in primary human tumor xenografts, of RAS mutant melanoma and CRC. Results: MLN2480 inhibits MAPK pathway signaling in BRAF mutant and some RAS mutant preclinical cancer models at concentrations that are tolerated in vivo. MLN2480 is most potent in BRAF mutant melanoma models but also has single agent activity in some RAS mutant models. The combination of MLN2480 with TAK-733 inhibits the growth of a broader range of RAS mutant tumor models than single agent MLN2480, including primary human tumor xenograft models of melanoma and CRC. In vitroanalysis of this drug combination in cell proliferation assays demonstrates synergistic activity. Western blot analysis demonstrated the effect of MLN2480 in reversing feedback activation of MEK in response to TAK-733, leading to more concerted MAPK pathway inhibition. Conclusions: The activity of the RAF kinase inhibitor MLN2480 in preclinical models of BRAF and RAS mutant melanoma and CRC provides a rationale for clinical testing. The combination of MLN2480 with the MEK inhibitor TAK-733 represents an additional strategy for clinical research within these tumor types.
Evaluation of the toxicity and efficacy of paclitaxel nanoencapsulated with polyethyloxazoline polymers.
Authors: Yin Ray , Pan Jing , Zhou Bingsen , Zhang Yubei , Dougherty Jeffrey , Liu Joanna , Riesenberger Tracy A , Qin Dujie , Vallejo Yli Remo 
Published: March 2020

e13538 Background: Paclitaxel’s antineoplastic activity is limited by its solubility and toxicity. Encapsulation with polyethyloxazoline (PEOX) branched polymers can increase its solubility, decrease toxicity and enhance its antitumor efficacy. Methods: Paclitaxel was mixed with PEOX-based branched polymers at drug loading percentages of 11 - 17% to form nanoparticles (< 90 nm in diameter). The product was purified and lyophilized as a white powder, designated FID-007. Its cytotoxicity was tested on normal human fibroblast cells and cell lines for human lung (A549), triple negative breast (MDA-MB-231) and ovarian (OV-90) cancers. Commercial paclitaxel drugs, Taxol and Abraxane, were similarly tested. Maximum tolerated dose (MTD) of the three drugs were determined in CD-1 mice. FID-007’s efficacy in controlling tumor growth was compared to the other drugs in vivo using xenograft tumor models in Scid mice with the three human cancer cell lines (20 mice per cancer). Saline and polymer were used as negative control treatments. Results: FID-007, Taxol and Abraxane showed similar cytotoxicity to all cancers.FID-007 was > 10-fold less active in normal fibroblasts. The single dose MTD in CD-1 mice was < 30 mg/kg for Taxol, 175 mg/kg for FID-007 and >180 mg/kg for Abraxane. FID-007 exhibited the best efficacy in controlling tumor growth in mice compared to Taxol and Abraxane with the three human cancers. Results from the lung tumor study are presented in the Table. Conclusions: Encapsulation with PEOX-based polymers reduced the toxicity and significantly improved the efficacy of paclitaxel in controlling tumor growth in vitro and in vivo. [Table: see text]
Clinical outcome for patients with metastatic colorectal cancer (mCRC) enrolled in phase I clinical trials: Single institution experience.
Authors: Shah Umang , Pendurti Gopichand , Swami Umang , Hou Yijuan , Ghalib Mohammad Haroon , Chaudhary Imran , Mani Sridhar , Goel Sanjay , Aparo Santiago 
Published: March 2020

e13550 Background: Phase I studies are a fundamental step in anti-cancer drug development. Prior meta-analysis looking at phase I studies showed an overall response rate (ORR) of 10.6 % and grade 4 toxicity rate of 14.3 %, and specifically, patients (pts) with mCRC enrolled in phase I trials had an ORR of 1.3 %. Herein, we report the results of a 12-year experience from our institution. Methods: Records from pts with metastatic colorectal adenocarcinoma enrolled in phase I studies at our institution from January 1999 to December 2010 were reviewed. Recorded data included treatment related responses, survival times and adverse events (AE). Kaplan-Meier analysis, t-test and X2 tests were used to analyze data. A Cox proportional-hazard model using clinical parameters at enrolment was used to predict survival. Results: Our cohort included 141 pts with mCRC (83% colon and 17% rectum) enrolled in 25 unique phase I trials. Median patient age at enrolment was 59 years, 66% were female and 81% had an ECOG PS of 0-1. Pts received a median of 3 lines of chemotherapy prior to enrolment. The median overall survival (OS) was 8.9 months. The ORR was 4.2%. The clinical benefit rate (ORR or stable disease for ≥ 4 months) was 22%. Univariate analysis showed that being female (P=0.02), Hb <12 g/dL (P=0.01), Alb < 4 g/dL (P=<0.001), Alkaline phosphatase > 150 U/L (P=<0.001) and LDH ≥ 300 U/L (P=<0.001) were independently associated with shorter survival. Multivariate analysis showed that females (HR of 2.81 95% CI 1.71-4.59, p= <0.001), Hb ≥ 12 g/dL (1.67, 95%CI 1.03-1.71, p=0.04), Alb < 4 g/dL (HR 2.51, 95% CI 1.59-3.98, p= <0.001) and LDH ≥300 U/L (HR 2.59, 95% CI 1.65-4.03, p= <0.001) were associated with shorter survival. Grade 3/4 non-hematological and hematological AE were seen in 25% and 45% of patients, respectively. Conclusions: This cohort of pts that received a median of 3 prior lines of therapy had a median OS and ORR of 8.9 months and 4.2%, respectively. These findings are similar to the ones reported in the recent phase III trial using regorafenib. Interestingly, multivariate analysis showed that a Hb of ≥ 12g/dL was associated with worse survival, in agreement with prior reports in which red cell growth factors were used.
Effective treatment of aggressive B-cell lymphomas by downregulated NIK-induced noncanonical NF-κB pathway activation through inhibition of BAFF.
Authors: Kuo Sung Hsin , Chen Li-Tzong , Yeh Kun-Huei , Tsai Hui-Jen , Lee Hsiao-Wei , Cheng Ann-Lii 
Published: March 2020

e13554 Background: We recently reported that autocrine BAFF (B cell–activating factor belonging to the TNF family) signal transduction pathway contributes to H. pylori-independent growth of gastric diffuse large B-cell lymphoma (DLBCL) (Blood 2008;112:2927-34; Ann Hematol 2010;89:431-6). In this study, we sought to investigate whether activation of BAFF signaling pathway can promote the survival and proliferation of aggressive B-cell lymphoma. Methods: Seven aggressive NHL cell lines (EBV-negative Burkitt’s lymphoma (Ramos), EBV-positive Burkitt’s lymphoma (Raji), EBV-negative undifferentiated lymphoma (MC116), activated B cell (ABC)-like DLBCL (OCI-Ly3, OCI-Ly10), and germinal center B cell (GCB)-like DLBCL (OCI-Ly7, and Pfeiffer) were used in this study. Cell cycle was analyzed by flow cytometry. The DNA-binding activity of NF-kB was determined by the luciferase assay. Expression of non-canonical NF-κB signatures-related proteins (BAFF, BAFF-R, NIK, cIAP1, TRAF2, cIAP1/2, TRAF3, IKKa, p100, p52 and RelB, BCL10, BCL3, and STAT3) was assessed by immunoblotting. Results: Our results showed that in GCB-DLBCL cell lines, activation of BAFF induced recruitment and degradation of TRAF3, which resulted in NIK kinase accumulation, BCL10 Ser138 phosphorylation, IKKa phosphorylation, and NF-kB p100 processing, thereby resulting in continuous activation of non-canonical NF-kB pathway. This phenomenon also resulted in BCL3 nuclear translocation and STAT3 activation, and subsequently activated STAT3 downstream-regulated genes (BCL2, survivin, and cyclin D1). Furthermore, we found that inhibition of BAFF by short hairpin RNA (shRNA) suppressed the growth of ABC-DLBCL cells and Burkitt lymphoma cells through the down-regulation of BAFF/BAFF-R/TRAF3/NIK/BCL3/NF-kB signaling pathway. Conclusions: Our results indicate that constitutive BAFF signaling activates NIK-induced non-canonical NF-kB signaling pathway in aggressive B-cell lymphoma, and inhibition of BAFF is particularly effective in the treatment of this subgroup of tumors.
Focal adhesion kinase inhibition as a therapeutic strategy in differentiated thyroid cancer.
Authors: O'Brien Shalana , Golubovskaya Vita , Zajac-Kaye Maria , Hochwald Steven N. , Cance William G. 
Published: March 2020

e13556 Background: Thyroid cancer, themost common endocrine malignancy, can be curable with resection of low stage tumors, but new treatments are needed for advanced differentiated cancers with radioiodine resistance. Focal Adhesion Kinase (FAK), a tyrosine kinase involved in protein-protein interactions regulating crucial cellular functions, is upregulated in thyroid cancer, and is a drug target along with its autophosphorylation site Y397. Clinical trials are ongoing for FAK inhibitors PF04554878 and GSK2256098. 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15), a small molecule FAK scaffolding inhibitor targeting the Y397 autophosphorylation site, and TAE226, a FAK/Insulin-like Growth Factor-1 Receptor inhibitor are in preclinical studies . In this report, we compared the effects of these FAK inhibitors on thyroid cancer cell lines. Methods: Four human thyroid cancer cell lines were cultured in vitro: K1, BCPAP, TPC1 derived from papillary thyroid carcinoma, and TT derived from medullary thyroid carcinoma. Western blots detected expression of FAK and pY397 FAK. Clonogenicity and MTS assays measured effects of the inhibitors on cell viability and colony formation. Results: The most significant dose-dependent decrease of FAK Y397 autophosphorylation and p125FAK expression was seen with Y15, with significant decrease at 10μM and near complete inhibition at 50μM. PF04554878, GSK2256098 and TAE226 at 50μM showed lowered pY397 expression, but less effect than Y15 at 10μM concentrations. TAE226 had the most effect on clonogenicity, with complete colony inhibition at doses 1μM and higher. Least effect was with GSK2256098. Y15 and PF04554878 had moderate inhibition of clonogenicity. Y15 had greatest inhibition of cell viability, with IC50s less than 15μM, two to over five-fold more potent than TAE226, GSK2256098, and PF04554878. Conclusions: All FAK inhibitors caused dose-dependent effects on thyroid cancer cell viability, clonogenicity and expression of pY397 FAK. Y15 had the most potent effects on cell viability and expression of FAK and p397 FAK. Our data suggests targeting the FAK scaffold, as Y15 does, is more effective than targeting the kinase function as a potential therapeutic agent for thyroid cancer.
Cytotoxic activity of semi-synthetic ingenol derived from Euphorbia tirucalli on a large panel of human cancer cell lines.
Authors: Silva Viviane Aline Oliveira , Rosa Marcela Nunes , Tansini Aline , Lima Joao Paulo Da S.N. , Jones Chris , Pianowski Luiz Francisco , Reis Rui Manuel 
Published: March 2020

e13559 Background: The latex from Euphorbia tirucalli is used in Brazil as anticancer and other disease as folk treatment; however, little is known about its anticancer proprieties. We report in vitro activity of 3 semi-synthetic ingenol compounds derived from E. tirucalli, ingenol A (ingenol-3-trans-cinnamate), ingenol B (3-caproyl-ingenol) and ingenol C (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Methods: Anti-tumor effects of the 3 semi-synthetic compounds were assessed using MTS assays on 77 cancer lines from 13 tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide (TMZ) in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Ingenol A, B and C exhibited dose-dependent and time-dependent cytotoxic effects. Amongst the derived tested, ingenol C displayed the best activity across the tumor cell lines. In comparison with TMZ, ingenol C showed a median of 136 fold higher efficacy, range 15-511 fold, in the glioma cell lines analyzed. Conclusions: The semi-synthetic ingenol compounds, in particular the ingenol C, demonstrated a potent anti-tumor activity on all cancer cell lines evaluated. Our findings may provide insight into designing ingenol-based therapies for cancer patients. [Table: see text]
Everolimus (E) and octreotid (O) in metastatic high-risk MEN IIb disease: A case report.
Authors: Dresemann Antje , Dresemann Gregor Paul 
Published: March 2020

e13565 Background: Multiple endocrine neoplasia (MEN) type IIB is characterized by missense mutation in exon 16 of the RET-proto-onkogen. Malignant c-cell-(medullar)-carcinoma of the thyroid gland (MTC) is part of the disease. Prognostic factors for metastatic MTC (m-MTC) are tumor grading, vessel- and peri-neural infiltration, age and performance status (PS). Irradiation and chemotherapy have limited activity in m-MTC. Thyrosine-kinase inhibitors like vandetanib, sorafenib or sunitinib were not admitted in Germany in 2011, August. As mTor-pathway seems to play a role in m-MTC E was suggested to be a treatment alternative. In somatostatin receptor (SR) positive tumors O might be beneficial. Methods: In 2011, August, a 23 years old man presented with metastatic MEN IIB disease after palliative irradiation therapy. ECOG-PS was 2 to 3, Calcitonin was 3.615 pg/ml, CEA was 467 ng/ml. The patient (pt) had a non-resectable m-MTC, SR positive, with esophageal, pleural, tracheal and lymph node infiltration still with metabolic activity in PET-CT. Grading was G3 with strong vessel and peri-neural infiltration. Right adrenal tumor and tongue tumor were present. After written informed consent the pt started treatment with E 10 mg/day orally in 2011, November. A loperamide resistant diarrhea was treated with O 20 mg/4 weeks i. m. additionally since 2012, July. Results: During treatment with E Calcitonin and CEA levels continuously decreased and CT scans every 3 months demonstrated a continuous shrinkage of all tumor sites, especially after additional treatment with O, which also was associated with an improved PS. Since 2012, October, ECOG PS was 0 enabling the patient to go to work again. Since 2012, October no relevant treatment related side effects were present. Conclusions: E showed efficacy as single agent treatment in a young man with metastatic high risk MEN IIB disease, the addition of O seems to reduce side effects and to improve efficacy of single agent E in this case. Further investigation is needed to verify these results
Effect of salmonella typhimurium A1-R on quiescent cancer cells that do not respond to standard chemotherapy.
Authors: Yano Shuya , Zhang Yong , Uehara Fuminari , Hiroshima Yukihiko , Miwa Shinji , Hoffman Robert M. , Zhao Ming 
Published: March 2020

e13576 Background: Quiescent cancer cells are a major impediment to treating solid cancer with chemotherapy, since in most tumors the majority of the cells are quiescent. Methods: The cell-cycle phase of each human MKN45 gastric cancer cell was imaged using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-labeled cancer cells in tumor spheres and subcutaneous tumor in nude mice were treated with Salmonella typhimurium A1-R. Results: Time-lapse confocal imaging showed that cancer cells in tumor spheres in serum-free culture become and remained quiescent. S. typhimurium A1-R infected and killed quiescent cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill the quiescent cancer cells in the tumor spheres. S. typhimurium A1-R targeting of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in the killing of quiescent cancer cells resistant to cytotoxic agents. Conclusions: S. typhimurium A1-R can kill quiescent cancer cells which suggests a new therapeutic paradigm potentially more effective than current therapeutics which are ineffective against quiescent cancer cells.
Effect of dormant cancer cells on angiogenesis after resisting chemotherapy.
Authors: Mii Sumiyuki , Tome Yasunori , Hiroshima Yukihiko , Uehara Fuminari , Miwa Shinji , Fujiwara Toshiyoshi , Hoffman Robert M. , Yano Shuya 
Published: March 2020

e13577 Background: Dormant cancer cells are a significant problem in clinical cancer as they are usually chemoresistant and can give rise to recurrence years after treatment. Methods: Dormant cancer cells were identified with a fluorescence ubiquitination cell cycle indicator (FUCCI) and confocal microscopy. FUCCI-expressing xenografts were established from MKN45 gastric cancer cells. Results: Within 7 days after implantation in nude mice, FUCCI-expressing tumors contained a mixture of cancer cells in G0/G1 and S/G2/M phases. Cancer cells in G0/G1 phase survived and become dormant after treatment with cytotoxic agents. As the tumors grew, proliferating cells were only found at the surface. Chemotherapy killed only the proliferating cancer cells at the surface and had little effect on the majority of dormant cancer cells in the tumor center. Furthermore, we investigated tumor chemoresistance using nestin-driven green fluorescent protein (GFP) transgenic mice that have GFP-expressing nascent tumor vessels. Chemotherapy-treated tumors had much more and deeper tumor vessels than control tumors. Conclusions: These results suggest that dormant cancer cells may protect themselves by inducing angiogenesis.
Downregulation of Let-7i to promote stem-like properties of head and neck cancer cells through activating ARID3B-Oct4 axis.
Authors: Liao Tsai-Tsen , Yang Muh-Hwa 
Published: March 2020

e13584 Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major male cancers worldwide, and the main therapeutic strategies include surgery, radiotherapy and chemotherapy. Cancer stem cells are a small population of tumor cells that are responsible for tumorigenesis, tumor recurrence and treatment resistance. let-7 family microRNAs have been shown to function as a tumor suppressor. Here we aim to investigate the role of let-7i in regulating stem cell properties in HNSCC. Methods: Luciferase reporter assay were used to identify the targets of let-7i; Western blot to analysis the correlation between ARID3B and Oct4; ChIP assay confirm the binding of ARID3B to Oct4 proximal promoter; Quantitative RT-PCR to analyzed the level of ARID3B, Oct4, and let-7i in the 52 pairs of samples containing primary tumor tissues and adjacent normal epithelium from head and neck cancer patients with different stage receiving surgery. Results: ARID3B, a member of the AT-rich interaction domain family proteins which plays an essential role during embryogenesis, is a bona fide target of let-7i. ARID3B promotes stem-like properties of HNSCC cells and upregulates a panel of stemness genes, and Oct4 is one of the most prominent ones to be upregulated. ARID3B direct binds to the AT-rich region of Oct4 promoter to activate its transcription. Downregulation of let-7i in HNSCC samples correlates with a corresponding upregulation of Oct4 and ARID3B. Conclusions: We propose a mechanism of let-7i repression-mediated stem-like properties through releasing the suppression of a novel let-7i target ARID3B, which leads to transcriptional activation of stemness genes. The results provide useful information in elucidating the mechanism of HNSCC progression and also provide potential targets in developing HNSCC-specific treatment.