tbuckley/cabot-search huggingface dataset:
Abstract 2483: Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression
Authors: Bok-Soon Lee, Sam Kang, Kyung-Ah Kim, Yun-Jeong Song, Kwang Ho Cheong, Hyun-Young Cha, Haeng-Jun Kim, Hye Sook Hwang, Yeon Soo Kim, Chul-Ho Kim
Journal: Cancer Research (2015)

Abstract Nasopharyngeal carcinoma (NPC) is a common malignant tumor with high invasive and metastatic potential. The hepatocyte growth factor (HGF)-Met signaling pathway has a critical role in mediating the invasive growth of many different types of cancer, including head and neck squamous cell carcinoma. HGF also stimulates NPC cell growth and invasion in the cell line model. In this study, we determined the inhibitory effect of Met, using a Met-targeting monoclonal antibody (SAIT301), on the invasive and growth potential of NPC cell lines. Met inhibition by SAIT301 resulted in highly significant inhibition of cell migration and invasion in both the HONE1 and HNE1 cell lines. In addition, we also found that co-treatment of SAIT301 and HGF decreased the anchorage-independent growth induced by HGF in HNE1 cell lines. After SAIT301 treatment, Met, together with its downstream signaling proteins, showed downregulation of p-Met and p-ERK, but not p-AKT, in both HONE1 and HNE1 cell lines. Interestingly, we found that HGF treatment of NPC cell lines induced early growth response protein (EGR-1) expression, which is involved in cell migration and invasion. In addition, co-treatment with SAIT301 and HGF inhibited the HGF-induced expression of EGR-1. Next, knockdown of EGR-1 using small-interfering RNA inhibited HGF-induced cell invasion in NPC cell lines, suggesting that the expression level of EGR-1 is important in HGF-induced cell invasion of NPC cells. Therefore, the results support that SAIT301 inhibited Met activation as well as the downstream EGR-1 expression and could have therapeutic potential in NPC. Taken together, we suggest that Met is an anticancer therapeutic target for NPC that warrants further investigation and clinical trials and SAIT301 may be a promising tool for NPC therapy. Citation Format: Bok-Soon Lee, Sam Kang, Kyung-Ah Kim, Yun-Jeong Song, Kwang Ho Cheong, Hyun-Young Cha, Haeng-Jun Kim, Hye Sook Hwang, Yeon Soo Kim, Chul-Ho Kim. Met degradation by SAIT301, a Met monoclonal antibody, reduces the invasion and migration of nasopharyngeal cancer cells via inhibition of EGR-1 expression. [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 2483. doi:10.1158/1538-7445.AM2015-2483
534. Development of Innovative Scalable Protocols for the Purification of Lentiviral Vectors Pseudotyped With GaLV-TR or Mutated Measles Virus Glycoproteins
Authors: Driss Boudeffa, David Fenard, Mirella Mormin, Anne Galy, Otto W. Merten
Journal: Molecular Therapy (2015)

Lentiviral (LV) vectors are powerful tools for gene transfer and genome editing in dividing and non-dividing cells but their clinical application requires complex and scalable processes of production which are not yet developed for all possible LV pseudotypes used in research. The ability of pseudotyping LV by different glycoproteins (gp) allows targeting of different tissues and types of cells. Modified Gibbon Ape Leukaemia Virus (GaLV-TR) gp pseudotyped LV are interesting to transduce specifically hematopoietic stem cells (HSC). Mutated measles virus gp engineered with single chain Fv can be redirected to specific cell surface receptors such as MHC Class II antigens (MV-CMH-II) enabling the transduction of dendritic cells. However, reliable and efficient purification schemes for these pseudotypes have not yet been developed. Here we report the development of a new upstream process (USP) protocol and for the first time novel downstream process (DSP) protocols allowing high yield production of stable and infectious LV-GaLV-TR and LV-MV-CMH-II particles. We identified critical conditions in chromatographic and tangential flow filtration (TFF) steps for preserving the infectivity/functionality of lentiviral vectors during purification. This was done by identifying for each step, the critical parameters affecting LV infectivity, including pH, salinity, presence of stabilizers, temperature, and secondly by defining the optimal order of these steps. A three-step process was optimized for LV-GALV-TR purification consisting of one TFF, and two chromatographic steps (ion-exchange and size exclusion chromatography, permitting recoveries of >50% (ip – infectious particles). With this process, purified GaLV pseudotyped LV vectors enabled the transduction of 70% human CD34+ cells in the presence of the Vectofusin peptide, whereas in the same conditions non-purified vector transduced only 9% of the cells. A comparable, but simplified purification protocol was developed for LV-MV-CMH-II vector in a two step protocol (TFF, size exclusion chromatography) leading to yields of 60% (ip). Our protocols will allow for the first time the purification of various LV pseudotypes that are biologically-active, stable and with sufficient recovery in the perspective of preclinical studies and clinical applications.
Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population
Authors: S. Budhathoki, M. Iwasaki, T. Yamaji, H. Yamamoto, Y. Kato, S. Tsugane
Journal: Annals of Oncology (2016)

Available evidence from animal studies suggests that branched-chain amino acids (BCAAs) may have a protective effect against colorectal carcinogenesis. However, a possible effect of BCAAs against colorectal neoplasia has not been evaluated in humans. Here, we aimed to evaluate whether plasma concentrations of BCAA are associated with the risk of colorectal adenoma (CRA), a precursor lesion of colorectal cancer.CRA cases and controls were identified from examinees who underwent total colonoscopy as part of a cancer screening program between 2004 and 2005 and responded to self-administered dietary and lifestyle questionnaires. We measured plasma concentrations of leucine, isoleucine and valine in 629 patients with adenoma and 584 controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between BCAA and CRA risk after adjustment for potential confounders.High plasma concentrations of leucine, valine and total BCAA were inversely associated with CRA risk after adjustment of potential confounders. The multivariate-adjusted ORs for the highest versus lowest quartiles were 0.60 (95% CI 0.42-0.87, Ptrend = 0.006) for leucine, 0.68 (95% CI 0.48-0.97, Ptrend = 0.09) for valine and 0.68 (95% CI 0.48-0.98, Ptrend = 0.10) for total BCAA. Further analysis by gender revealed that this inverse association was clearly evident in men, but not in women: the corresponding OR for leucine, valine and total BCAA was 0.50 (95% CI 0.32-0.80, Ptrend = 0.003), 0.60 (95% CI 0.38-0.95, Ptrend = 0.01) and 0.58 (95% CI 0.37-0.93, Ptrend = 0.04), respectively, in men and 0.78 (95% CI 0.42-1.45, Ptrend = 0.44), 0.77 (95% CI 0.41-1.43, Ptrend = 0.85) and 0.84 (95% CI 0.45-1.57, Ptrend = 0.81), respectively, in women.Our finding suggests that BCAAs may have a beneficial influence against the process of colorectal carcinogenesis, at least in the early stage. The mechanisms underlying this potential association between BCAA and colorectal carcinogenesis warrant further investigation.
Efficacy of Nonmyeloablative Hematopoietic Cell Transplant (HCT) in Secondary Myelodysplastic Syndrome (MDS) and Its Impact on the Primary Disease.
Authors: F. Kerbauy, M. Maris, B. Storer, D. Maloney, D. Niederwieser, E. Agura, M. Pulsipher, T. Chauncey, R. Maziarz, S. Forman, A. Langston, J. Wade, B. Scott, J. Deeg, R. Storb, B. M. Sandmaier
Journal: Blood (2005)
Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials
Authors: J.F. Seligmann, D. Fisher, C.G. Smith, S.D. Richman, F. Elliott, S. Brown, R. Adams, T. Maughan, P. Quirke, J. Cheadle, M. Seymour, G. Middleton
Journal: Annals of Oncology (2016)
374. Therapeutic Effect of Platelet Transfusions for Acute Neuronopathic Gaucher Disease
Authors: Mei Dai, xiaohong Wang, Benjamin Liou, Venette Inskeep, Gregory Grabowski, Ying Sun, Dao Pan
Journal: Molecular Therapy (2015)

Enzyme replacement therapy has led to resolution of most visceral manifestations in Gaucher disease (GD), but it is also limited by the instability of acid beta -glucosidase enzyme (GCase) in circulation, liver 1st bypass, and high cost. In addition, intravenous enzyme administration has not been effective for ameliorating central nervous system (CNS) deficits. Platelets are blood elements that contain cytoplasmic secretory vesicles. The involvement of platelet containing proteins in inflammation and angiogenesis has recently been indicated. We have recently shown that platelets/megakaryocytes could serve as efficient and protective depots for lysosomal enzyme generation and distribution. In this study the potential therapeutic benefits of platelet transfusion in treating neuronopathic GD (nGD) was evaluated using a murine model of acute nGD (4L;C). This model resembles the CNS phenotype and biochemistry of types 2 and 3 Gaucher disease, and premature death results from progressive CNS disease. Platelets containing significant amounts of wild type GCase (19 U/109 plt) were isolated from GFP mice and transfused weekly for four times into 4L;C mice beginning at 21 days of age. The average percentages of donor-derived platelets were at mean of 10% to 12.9% (ranging from 7.2 to 16.1%) as measured one hour after each transfusion by flow cytometry analysis with anti-CD41 staining for GFP-positive donor platelets. Clearance curves of transfused platelets were similar in 4L;C and wild-type recipients with comparable half-life of GFP+ platelets (t1/2=50 h), suggesting the lack of an immune-response against platelet-derived normal GCase in nGD mice. Importantly, the life-span of treated 4L;C mice was significantly extended from 46 days [untreated 4L;C (n=22)] to 54 days [treated, (n=7)]. Potential CNS benefits were assessed using hindlimb gait analysis that evaluated motor function. In comparison to normal controls, the untreated 4L;C mice exhibited abnormal splaying of their hindlimbs and progressive paresis. The platelet-treated 4L;C mice improved significantly toward normal behavior and had delays in the age of onset for CNS signs. Immunohistochemistry analysis showed that numbers of CD68+ cells were decreased in the cerebellum, brainstem and cortex of treated 4L;C mice, indicating the reduction of pro-inflammation by platelet transfusion. The clearance of GFP+ platelets by liver and spleen was shown by GFP signals detected in those organs of treated 4L;C mice. Quantification of the pathogenic lipids, glucosylceramide and glucosylsphingosine, is in progress to assess potential metabolic correction in various regions of brain and visceral organs in platelet-treated nGD mice. More studies are underway to further investigate possible mechanism(s) involved. In summary, our results demonstrate that repeated, moderate levels of platelet transfusion could extend the life span of nGD mice and improve CNS deficits. abbbb
p53 Inactivation in CLL: Pattern of 110 TP53 Mutations.
Authors: Thorsten Zenz, Martin Trbusek, Jana Smardova, Sonja Häbe, Tina Denzel, Jitka Malcikova, Michael Doubek, Jiri Schwarz, Hartmut Dohner, Stephan Stilgenbauer
Journal: Blood (2007)
The Women, Infants, and Children Food Package and 100% Fruit Juice—Reply
Authors: Jason M. Nagata, Jennifer T. Djafari, Lisa J. Chamberlain
Journal: JAMA Pediatrics (2016)

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Abstract 4799: Variation in mutational landscape among small colonic polyps with differential growth rates
Authors: Chelsie K. Sievers, Perry J. Pickhardt, Kristina Matkowskyj, Dawn Albrecht, Luli Zou, David Kim, Meghan Lubner, Mark Reichelderfer, Richard Halberg
Journal: Cancer Research (2015)

Abstract Background: Benign adenomatous colonic polyps are transformed into cancers through the stepwise accumulation of mutations. However, not all polyps will progress. A significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and currently there are no biological characteristics that can reliably predict which polyps will grow or progress into invasive cancer. A multiancestral origin contributes to tumor heterogeneity and might provide additional growth promoting signals via increased genetic diversity. Methods: Utilizing a unique cohort of patients with small (&amp;lt;9mm) colorectal polyps in which growth was followed over a mean of 2.3 years by CT colonography, we performed next generation sequencing followed by micro-dissection and quantitative PCR to determine tumor origin. Results: The mutational landscape of small polyps is highly heterogeneous. Polyps carried 0 - 5 pathogenic mutations, with the most commonly altered gene being APC, which is considered the gatekeeper of the intestine. Interestingly, the percentage of cells harboring mutations in APC within a single polyp ranged from 2.0% to 70.6% with an average of 22.1%. In contrast, the frequency of a common APC single nucleotide polymorphism was 0% for non-carriers (n = 3), 55.9% for heterozygotes (n = 6), and 97.9% for homozygotes (n = 10). In the presence of an APC mutation, the average frequency of a second pathogenic mutation within a sample was 6.2% (n = 10). Conclusions: These data indicate that early intratumoral heterogeneity arising as a consequence of multiancestral origin affects tumor formation and growth. By determining the relative fitness advantage of heterogeneous polyps, we can begin to better predict which polyps may be more likely to progress into adenocarcinomas and which patients are predisposed to developing advanced disease. Citation Format: Chelsie K. Sievers, Perry J. Pickhardt, Kristina Matkowskyj, Dawn Albrecht, Luli Zou, David Kim, Meghan Lubner, Mark Reichelderfer, Richard Halberg. Variation in mutational landscape among small colonic polyps with differential growth rates. [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 4799. doi:10.1158/1538-7445.AM2015-4799
Abstract 4969: Metformin causes AR degradation via Skp2-mediated ubiquitination
Authors: Joy C. Yang, Allen C. Gao, Christopher P. Evans
Journal: Cancer Research (2015)

Abstract One of the mechanisms for prostate cancer cells to escape the new androgen receptor (AR) signaling inhibitor Enzalutamide (Enza) is through autophagy. Combination of anti-diabetic drug metformin with Enza demonstrated improved tumor suppression in the LNCaP C4-2B orthotopic model. Through delineating the mechanism in the metformin benefit, we discovered degradation of AR in cells treated with metformin alone and more in the combination with Enza and Abiraterone (Abi). The mRNA for AR in metformin-treated cells did not change significantly by qPCR assays. This degradation was inhibited when proteasome inhibitor MG132 was added prior to the treatments. Use of the FDA approved proteasome inhibitor Bortezomib also protected AR from degradation in the presence of metformin. Immunoprecipitation of AR with its antibodies showed ubiquitination; the reverse immunoprecipitation with anti-ubiquitin followed by anti-AR probing also showed similar results; suggesting ubiqutination responsible for AR degradation. With a paper by Li et al. proposing Skp2 being a novel E3 ubiquitin ligase targeting AR for ubiquitination, we attempted to knock-down Skp2 with transient siRNA transfection. Degradation of AR was lessened with Skp2 knockdown. This study supports that use of metformin in combination with Enza or other ARSI drugs may not only block autophagy survival but also cause AR degradation that leads to PC cell death. Citation Format: Joy C. Yang, Allen C. Gao, Christopher P. Evans. Metformin causes AR degradation via Skp2-mediated ubiquitination. [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 4969. doi:10.1158/1538-7445.AM2015-4969
Abstract 3667: Synthesis and biological evaluation of vitamin D3 analogues as selective Hedgehog pathway inhibitors
Authors: Chad A. Maschinot, Kyle Hadden
Journal: Cancer Research (2015)

Abstract Constitutive signaling of the Hedgehog (Hh) pathway has been linked to the development of a variety of cancers, specifically basal cell carcinoma (BCC) and medulloblastoma (MB). In recent years, vitamin D3 (VD3) was identified as an inhibitor of the Hh pathway. However, studies indicated that it is non-selective and activates canonical vitamin D signaling through the Vitamin D Receptor (VDR). One of the focuses of our lab is the development of VD3 analogues that will result in increased potency and selectivity for the Hh pathway. Previous studies indicated that the northern region of VD3 maintained approximately 95% of the inhibitory activity associated with intact VD3 with minimal activation of canonical vitamin D signaling. In initial SAR studies of the A-ring motif, the incorporation of a phenolic A-ring motif with an ester linkage to Grundmann's alcohol proved to be a potent, selective inhibitor. Utilizing a phenolic A-ring motif, SAR studies have continued with the development of the next generation of VD3-based analogues. Progress towards the next generation of analogues as well as results of biological studies will be described herein. Citation Format: Chad A. Maschinot, Kyle Hadden. Synthesis and biological evaluation of vitamin D3 analogues as selective Hedgehog pathway inhibitors. [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 3667. doi:10.1158/1538-7445.AM2015-3667
Abstract 1401: Low proteasome activity and cancer stemness in colorectal cancer
Authors: Mamoru Uemura, Koji Munakata, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori
Journal: Cancer Research (2015)

Abstract Background and aims: Emerging evidence indicates that existence of cancer stem-like cells (CSCs) is one of the main reasons of treatment resistance. Recently, several reports have indicated that some CSCs would be characterized by low proteasome activity. Material and methods: We engineered human colorectal cancer (CRC) cells to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg supposed to be accumulated in CSCs as a result of low activity of the 26S proteasome. The feature of Gdeghigh cells (low proteasome activity cells; LPACs) were analyzed by sphere formation assay, surface marker analysis, reactive oxygen species (ROS) analysis and assessment of chemotherapy and radiation therapy sensitivity. In addition, we explored the mechanism of treatment resistance of LPACs by using microarray analysis and clinical samples. Results: LPACs of CRC cells had significant radioresistance and chemoresistance (5-FU and oxaliplatin). Cancer stemness of LPACs was confirmed by CSC marker, sphere formation assay, ROS activity analysis, cell cycle assay, and in vivo tumorigenicity examination. Microarray analysis identified EID3 (EP300 Interacting Inhibitor of Differentiation 3) as a key factor related to treatment resistance of LPACs. Functional analyses of EID3 and analysis using clinical samples confirmed the role of EID3 in LPACs. Conclusions: CRC with low proteasome activity had character of treatment resistance and capacity of stemness. EID3 was a key factor related to treatment resistance of LPACs, and might be a novel therapeutic target. Citation Format: Mamoru Uemura, Koji Munakata, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Low proteasome activity and cancer stemness in colorectal 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 1401. doi:10.1158/1538-7445.AM2015-1401
Incidence and Characteristics of Acute Promyelocytic Leukemia in Adult Patients. A Single Centre Registry Study.
Authors: Pau Montesinos, Guillermo Martin, Jesus Martinez, Mariluz Perez-Sirvent, Jaime Sanz, Ignacio Lorenzo, Ninotchka Mendoza, Lorenzo Algarra, Amparo Sempere, Jose Cervera, Guillermo Sanz, Isidro Jarque, Javier de la Rubia, Susana Cantero, Javier Palau, Leonor Senent, David Martinez, Federico Moscardo, Miguel Sanz
Journal: Blood (2007)