tbuckley/cabot-search huggingface dataset:
Abstract 3113: Primate-specific miR-663 suppresses glioblastoma progression and predicts patient prognosis
Authors: Yu Shi, Yi-fang Ping, Xiu-wu Bian
Journal: Cancer Research (2015)

Abstract Purpose: miRNAs (microRNAs) have recently been recognized as important regulators of cancer biological behavior. However, the expression patterns and prognostic significance of miRNAs in GBM remain elusive due to the lack of large pools of clinical specimens for screening. This study was performed to identify miR-663 as a potential regulator of glioblastoma (GBM) malignant behaviors from miRNA profiles. The prognostic significance of miR-663 in GBM, its effect in tumor progression and the underlying mechanism were determined. Methods: Specimens from 256 cases of glioma patients, including 239 patients with follow-up information, were used to analyze the association between miR-663 and patients’ prognosis by Kaplan-Meier and multivariate Cox regression analyses. The effects of miR-663 on GBM cell proliferation and invasion were examined both in vitro and in vivo. Bioinformatics prediction and signal network analysis were applied to identify the putative targets of miR-663, which were further verified by luciferase reporter assay, rescue experiments as well as the immunohistochemistry (IHC) and Western blotting examination of downstream effectors. Quantitative reverse transcriptase-PCR (qRT-PCR) and IHC were applied to investigate the clinical association between miR-663 and its target in human GBM specimens. Results: miR-663 was identified from miRNA profiles and inversely correlated with glioma grades but positively correlated with patients’ survival. Furthermore, two distinct subgroups of GBM patients with different prognoses were identified based on miR-663 expression in our specimens and that from TCGA database. Overexpression of miR-663 significantly suppressed the proliferation and invasion of GBM cells in vitro and in vivo. Mechanistically, we discovered PIK3CD as a direct target of miR-663 and found that phosphorylated AKT and three key downstream effectors of PIK3CD, were down-regulated by miR-663 overexpression. Moreover, PIK3CD was inversely correlated with miR-663 in GBM specimens and predicted poor prognosis of GBM patients. Conclusion: miR-663 is a novel prognostic biomarker and a potential therapeutic candidate for GBM. Citation Format: Yu Shi, Yi-fang Ping, Xiu-wu Bian. Primate-specific miR-663 suppresses glioblastoma progression and predicts patient prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2015-3113
PTH-063 Nutritional requirements and prevalence of cholestasis in patients with a short bowel due to infarction
Authors: G P Rafferty, S Gabe, M Small, J Eastwood, C UgarteCano, J Nightingale
Journal: Gut (2010)

<h3>Introduction</h3> Patients with a short bowel and a retained colon due to ischaemia are now the most common indication for home parenteral nutrition in the UK.1 To date most studies have compared short bowel length and intravenous nutrition (IVN) requirements in patients with mixed aetiology of intestinal failure.2 IVN patients with &lt;50 cm residual small bowel (SB) have increased risk of chronic cholestasis.3 This study primarily aimed to determine the frequency of IVN in patients with a short bowel secondary to ischaemia. The secondary aim was to determine the prevalence of chronic cholestasis. <h3>Methods</h3> Retrospective data were collected using St Mark9s Intestinal Failure database. Biochemical parameters obtained from computer lab system. Chronic cholestasis was considered to be two of bilirubin, alkaline phosphatise or γ-glutamyl transferase &gt;1.5 times the upper limit of normal for &gt;6 months.3 <h3>Results</h3> Since 2003 a total of 88 patients (male 47%) have been referred to St Marks Intestinal Failure Unit with SB infarction. 12-month follow-up data were available for 57 patients diagnosed with arterial SB infarction (46% male, mean age at diagnosis 56.3 years) and four patients with venous SB infarction (male 25%, mean age at diagnosis 35.5 years). Following continuity surgery 92% of patients with SB length &lt;50 cm were still receiving IVN &gt;12 months after initial diagnosis. In comparison only 28% with SB length &gt;50 cm were receiving IVN. Comparing patients that were receiving and not receiving IVN there was a significant difference in residual SB length (p=&lt;0.001). Residual SB length corresponds to number of days per week that IVN is given: 26% patients with SB length &lt;50 cm managed three IVN free days per week compared to 60% patients with SB &gt;50 cm. Following continuity surgery 31% with residual SB &lt;50 cm had biochemical evidence of chronic cholestasis compared to 0% with SB length &gt;50 cm. All five patients (4 patients &lt;50 cm) that still had a jejunostomy &gt;12 months following diagnosis had chronic cholestasis. <h3>Conclusion</h3> Residual SB length corresponds to IVN requirements. Less than &lt;50 cm residual SB will result in long-term and frequent IVN. SB &lt;50 cm, and colon not in continuity, are chronic cholestasis risk factors.
Abstract 3062: miR-671-5p promotes epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer
Authors: Xiaohui Tan, Yebo Fu, Liang Chen, Shejuan An, Woojin Lee, Yinglei Lai, Katayoon Rezaei, Sana Tabbara, Christine B. Teal, Yan-gao Man, Robert Siegel, Rachel F. Brem, Sidney W. Fu
Journal: Cancer Research (2015)

Abstract microRNA (miRNA) dysfunction is associated with a variety of human diseases including cancer. Our previous study showed that miR-671-5p was deregulated during breast cancer progression. We aim to decipher the functional mechanism of miR-671-5p in breast cancer. We found that expression of miR-671-5p was decreased significantly in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) compared to normal and atypical ductal hyperplasia (ADH) in the microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), as an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. These data indicates that miR-671-5p functions as a tumor suppressor miRNA by directly targeting FOXM1 in breast cancer. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management. Citation Format: Xiaohui Tan, Yebo Fu, Liang Chen, Shejuan An, Woojin Lee, Yinglei Lai, Katayoon Rezaei, Sana Tabbara, Christine B. Teal, Yan-gao Man, Robert Siegel, Rachel F. Brem, Sidney W. Fu. miR-671-5p promotes epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3062. doi:10.1158/1538-7445.AM2015-3062
Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia
Authors: D A C Fisher, O Malkova, E K Engle, C A Miner, M C Fulbright, G K Behbehani, T B Collins, S Bandyopadhyay, A Zhou, G P Nolan, S T Oh
Journal: Leukemia (2016)
Abstract 2300: LIN28 cooperates with Wnt signaling to drive invasive intestinal and colorectal adenocarcinoma in mouse and human
Authors: Ho-Chou Tu, Sarah Schwitalla, Zhirong Qian, Grace LaPier, Alena Yermalovich, Yuan-Chieh Ku, Shann-Ching Chen, Srinivas R. Viswanathan, Hao Zhu, Reiko Nishihara, Kentaro Inamura, Sun A. Kim, Reppi Morikawa, Kosuke Mima, Yasutaka sukawa, Juhong Yang, Gavin Meredith, Charles S. Fuchs, Shuji Ogino, George Q. Daley
Journal: Cancer Research (2015)

Abstract Despite extensive investigation into the molecular basis of tumor development, colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding proteins that influence development, tissue regeneration and oncogenesis. Here we demonstrate that overexpression of LIN28 drives invasive intestinal adenocarcinoma and cooperates with the Wnt pathway to promote tumor initiation and progression in murine models. Importantly, conditional withdrawal of LIN28 reduced tumor volume and increased tumor differentiation, indicating that LIN28 contributes to tumor maintenance. Furthermore, co-expression of a LIN28-resistant form of the let-7 microRNA reduced tumor burden. We detected aberrant expression of LIN28 in 38% of a large series of tumor samples from human CRC, and LIN28 expression levels were associated with invasive tumor growth pattern. Our robust late-stage CRC murine model demonstrates strong roles for LIN28 in promoting CRC initiation, growth and progression, and suggests the therapeutic potential in targeting the LIN28/let-7 pathway. Citation Format: Ho-Chou Tu, Sarah Schwitalla, Zhirong Qian, Grace LaPier, Alena Yermalovich, Yuan-Chieh Ku, Shann-Ching Chen, Srinivas R. Viswanathan, Hao Zhu, Reiko Nishihara, Kentaro Inamura, Sun A. Kim, Reppi Morikawa, Kosuke Mima, Yasutaka sukawa, Juhong Yang, Gavin Meredith, Charles S. Fuchs, Shuji Ogino, George Q. Daley. LIN28 cooperates with Wnt signaling to drive invasive intestinal and colorectal adenocarcinoma in mouse and human. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2300. doi:10.1158/1538-7445.AM2015-2300
Treatment of Relapsed and Refractory Acute Myeloid Leukemia with a Salvage FLAG-IDA Chemotherapy Regimen Followed by a HLA Matched Related Allogeneic PBSC Infusion without Additional Conditioning.
Authors: Mammen Chandy, Vikram Mathews, T. Rajasekar, Auro Viswabandya, Kavitha M. Lakshmi, Joseph M. John, Biju George, Alok Srivastava
Journal: Blood (2007)
Abstract 305: An innovative 3D porous scaffold-based perfusion bioreactor system for the in vitro maintenance and expansion of primary breast cancer tissue
Authors: Manuele G. Muraro, Simone Muenst, Giulio C. Spagnoli, Daniel Oertli, Walter P. Weber, Savas D. Soysal
Journal: Cancer Research (2015)

Abstract Introduction: Development of cancer treatment protocols has traditionally been based on studies in experimental animal models or taking advantage of human established tumor cell lines for in vitro and in vivo assays. Here we present an innovative method to culture breast cancer tissues in porous 3D scaffolds by using a perfusion-based bioreactor system. Experimental procedures: Freshly excised estrogen-receptor positive breast cancer specimens were fragmented and cultured in a 3D “sandwich-like format” between porous scaffolds under perfusion flow, with “on-line” monitoring of environmental condition. DMEM/F12, supplemented with 10% autologous human serum, was used as a culture medium in the presence or absence of estrogens. The ability of tumor cells to survive and expand into the scaffold in perfusion culture as well as their ability to recapitulate features of the original breast cancer specimens was histologically assessed. Results: With this innovative method we were able to preserve viability and to promote the expansion of breast cancer cells from surgical specimens together with accompanying stromal and immune cells into the porous scaffold. Expanding cancer cells were viable after 21 days and recapitulating the initial histology with formation of glands. Administration of estrogen to the culture medium was associated with increased expansion of cancer cells into the scaffold starting at 14 days of culture. Conclusions: Culture of breast cancer tissue in a 3D scaffold-based bioreactor preserves malignant, interstitial and immunocompetent cells present in surgically excised breast cancer samples, thus allowing direct testing of basic cancer research hypotheses in intact, complex human tumor microenvironments. Furthermore, it might allow a direct evaluation of the effects of various treatments on malignant and non-transformed cells. This engineered in vitro model could be extended beyond the context of our primary scientific interest, namely breast cancer, as a broader platform allowing animal-free testing of innovative approaches for the treatment of human malignancies, possibly in the direction of personalized medicine. Citation Format: Manuele G. Muraro, Simone Muenst, Giulio C. Spagnoli, Daniel Oertli, Walter P. Weber, Savas D. Soysal. An innovative 3D porous scaffold-based perfusion bioreactor system for the in vitro maintenance and expansion of primary breast cancer tissue. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 305. doi:10.1158/1538-7445.AM2015-305
CD4+ T-cell count to predict the response to new H1N1 vaccination in pediatric patients with cancer.
Authors: A. M. C. Mavinkurve-Groothuis, M. van der Flier, F. Stelma, C. van Leer-Buter, F. Preijers, P. Hoogerbrugge
Journal: Journal of Clinical Oncology (2011)

9087 Background: The efficacy of vaccination in (pediatric) cancer patients is still a topic of debate. We aimed to study the immunologic determinants of influenza vaccination response in pediatric cancer patients. Methods: We measured the vaccination response to the new swine-origin influenza A H1N1 in relation to lymphocyte subpopulations in 33 pediatric cancer patients, being treated with chemotherapy or within 6 months after the end of chemotherapy. All patients were vaccinated twice with an intramuscular injection with inactivated split-virion preparation of the A/California/07/2009(H1N1)v like strain (X-179A), which contained 7.5μg of hemagglutinin per dose of 0.5 ml. A protective response was defined as achieving a HI antibody titer ≥ 1:40 following vaccination. Results: From the 33 included patients, 19 (58%) had a protective immune response. We showed a significant relation between response on vaccination and levels of all of the different lymphocyte subpopulations (p<0.001 for the CD4+ T-cells and p=0.001 for total T-cells, CD8+ T-cells and B-cells). Patients with an absolute CD4+ T-cell count less than 200/mm3 did not have a protective vaccination response to new H1N1. Conclusions: Absolute CD4+ T-cell count predicts the response to influenza vaccination in pediatric cancer patients treated with chemotherapy. This finding has important implications for the establishment of a response on vaccination in pediatric cancer patients during treatment with chemotherapy.
A Phase II Study of an Oral VEGF Receptor Tyrosine Kinase Inhibitor (PTK787/ZK222584) in Patients with Myelodysplastic Syndrome (MDS): Cancer and Leukemia Group B Study 10105.
Authors: Pankaj Gupta, Ben L. Sanford, Daohai Yu, Ravi Vij, David D. Hurd, Olatoyosi Odenike, Clara D. Bloomfield, Robert P. Hasserjian, Richard A. Larson
Journal: Blood (2006)
Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes
Authors: Benjamin A. Steinberg, Peter Shrader, Laine Thomas, Jack Ansell, Gregg C. Fonarow, Bernard J. Gersh, Peter R. Kowey, Kenneth W. Mahaffey, Gerald Naccarelli, James Reiffel, Daniel E. Singer, Eric D. Peterson, Jonathan P. Piccini
Journal: Journal of the American College of Cardiology (2016)

Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria. This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice. We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality. Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007). A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817)
328. Proof-of-Principle Study Shows Efficient Skipping of Exon 2 Using Antisense Morpholino Oligomers
Authors: Tabatha R. Simmons, Nicolas Wein, Felecia Gumienny, Hannah Huang, Kevin M. Flanigan
Journal: Molecular Therapy (2016)

Currently, exon skipping therapies for Duchenne muscular dystrophy (DMD) have been developed for patients with out-of-frame deletions where treatment will lead translation of an internally truncated but partially functional dystrophin protein. In contrast, we are focusing on treating duplications mutations, accounting for around 6% of all mutations, resulting in wild-type transcript and a full-length protein. Modeling the most common single exon duplication we have developed the first duplication mouse containing a duplicated exon 2. We have performed a proof-of-principle study using antisense oligomer (AO)-induced exon 2 skipping using this Dup2 mouse. Intramuscular (TA) injections of exon 2-directed different antisense peptide-morpholino conjugates (PPMO) were performed at either 10 or 20 ug total PPMO (N=6 muscles each) doses. Mice were injected at 8 weeks and sacrificed 1 month later for muscle analysis of DMD mRNA and dystrophin protein expression. Additionally, systemic (tail vein) injections are being conducted of at a dose of 30 ug/kg, at 1 week, 2 week and 1 month timepoints. For the IM studies, a gradient of exon 2 exclusion was seen by RT-PCR at both doses with corresponding high levels of properly localized dystrophin protein by IF and western blot. Analyses of RT-PCR and protein expression are underway for the systemic delivery PPMOs. These data suggest that skipping of a duplicated exon 2 may be a feasible therapeutic approach, particularly because skipping of exon 2 may be associated with an apparently unlimited therapeutic window. Over-skipping - to the exclusion of exon 2 entirely - results in activation of an internal ribosome entry site (IRES) located in exon 5 of dystrophin that allows for cap-independent translation from an alternative initiation site within exon 6. This alternate dystrophin isoform is highly functional despite being N-truncated, consistent with the observation that patients expressing it have minimally symptomatic (or even asymptomatic) Becker muscular dystrophy (BMD), and suggesting a potential route to therapy for any of the approximately 5% of patients with mutations in the 5' end of the gene.
Abstract 412: Phytochemical pterostilbene suppresses lung cancer stem cell generation via modulating tumor-associated macrophages
Authors: Wen-Chien Huang
Journal: Cancer Research (2015)

Abstract Tumor associated macrophages have been shown to play key roles in tumor progression in different cancer types including lung. Here we investigated the role of M2-tumor associated macrophages (TAMs) in the generation of lung cancer stem cells (LCSCs) and the potential of modulating TAMs to inhibit the generation of LCSCs. Elevated Muc1 expression has been reported in inflammatory lung macrophages and associated with lung cancer development. We first found that Muc1 is overexpressed in lung cancer patients and associated with poor survival rates from public database; importantly, we showed that when co-cultured with TAMs, the level of Muc1 along with stemness genes significantly increased in lung cancer cells. Pterostilbene dose-dependently suppressed self-renewal ability in TAMs-cocultured lung cancer cells via downregulating Muc1, NF-kB, CD133, β-catenin and Sox2 expression. Subsequently, we demonstrated Muc1-silenced TAMs exhibited a significantly lower ability to promote the generation of LCSCs and a decreased level of NF-kB, CD133 and Sox2. Collectively, we demonstrated that Muc1 played an important role in TAMs-induced LCSC generation and pterostilbene treatment inhibited this phenomenon. Modulation of TAMs using pterostilbene may be of future clinical use for treating lung cancer patients. Note: This abstract was not presented at the meeting. Citation Format: Wen-Chien Huang. Phytochemical pterostilbene suppresses lung cancer stem cell generation via modulating tumor-associated macrophages. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 412. doi:10.1158/1538-7445.AM2015-412