tbuckley/cabot-search huggingface dataset:
Abstract LB-154: Genome-wide analysis identified differentially methylated regions in head and neck squamous cell carcinoma anatomic subsites
Authors: Bianca L. Rivera, Oluwasina Folawiyo, Nitesh Turaga, Francesca Pirini, Ricardo Lopez, Roger Vazquez, Rafael Guerrero, Adriana Baez
Journal: Cancer Research (2015)

Abstract Introduction Several groups have identified hundreds of genes differentially methylated in head and neck squamous cell carcinoma (HNSCC) using genome-wide technologies. However, there is a paucity of studies examining differential methylation in HNSCC anatomic subsites. Objective Our principal objective is to determine DNA methylation differences between Head and Neck Squamous Cell Carcinoma (HNSCC) anatomic subsite: larynx, oral cavity and pharynx. Methods DNA was extracted from 24 HNSCC samples and 10 normal oral epithelium tissue samples of Puerto Rican Hispanic patients. To unveil the methylome of HNSCC anatomic subsites genomic DNA was enriched with Methylated DNA immunoprecipitation prior to labeling and hybridization to genome-wide oligonucleotide tilting arrays (3 × 720K Human CpG Island-Plus-Promoter Array, Roche/NimbleGen). Differentially methylated regions were identified with CHARM using the bumphunter algorithm. Downstream analyses were performed to identify differences in the methylation landscape of the three anatomic subsites: larynx, oral cavity and pharynx. Results When datasets were analyzed by anatomic site using DAVID v6.7 we identified 2565 differentially methylated genes common to the three subsites. We also identified 738 differentially methylated CpG loci in laryngeal cancer, 889 differentially methylated CpG loci in oral cavity and 363 differentially methylated CpG loci in pharyngeal cancer. We identified 11 key genes which were uniquely methylated in the larynx (CDH1, PAX1, BID, SMAD4, FGF19, BMP2, ITGA2, RXRA, IGFBP1, CDKN2D and RBL2). BCL2, AKT2, TRAF3, STAT5B, PTCH1, WNT9B, AXIN2, DVBL2, and APC were differentially methylated in oral cavity. In the pharynx, a comparatively lower number of differentially methylated genes were detected including B-catenin, RAF, BRAF, ATR, CTNNA1, FOXO1 and MED15. Conclusion We found evidence that HNSCC subsites (larynx, oral cavity and pharynx) manifest different methylation patterns that may be consistent with the clinical expression of the disease. A panel of differentially methylated genes identified will be further tested in a large cohort of HNSCC samples to determine their utility as prognostic biomarkers of HNSCC according to subsite. Citation Format: Bianca L. Rivera, Oluwasina Folawiyo, Nitesh Turaga, Francesca Pirini, Ricardo Lopez, Roger Vazquez, Rafael Guerrero, Adriana Baez. Genome-wide analysis identified differentially methylated regions in head and neck squamous cell carcinoma anatomic subsites. [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 LB-154. doi:10.1158/1538-7445.AM2015-LB-154
730. Permanent Correction of Diverse Muscular Dystrophy Mutations in Human Cardiomyocytes by Myoediting
Authors: Chengzu Long, Hui Li, Viktoriia Kyrychenko, Huayu Zhou, Samadrita Bhattacharyya, Cristina E. Rodriguez, John M. Shelton, Pradeep Mammen, Jay Schneider, Rhonda Bassel-Duby, Eric N. Olson
Journal: Molecular Therapy (2016)

Dilated cardiomyopathy (DCM) is one of the most common lethal features of Duchenne muscular dystrophy (DMD), caused by diverse mutations in the X-linked dystrophin gene (DMD). Without dystrophin, a large cytoskeletal protein, muscles degenerate, causing myopathy. Although several gene therapies have been tested, there is no curative treatment so far. In 2014, we first used CRISPR/Cas9-mediated genome editing (termed Myoediting) to correct the mutation in the germ line of mdx mice, the mouse model of DMD [Long et al. Science 345:1184-8]. Recently, we applied Myoediting to postnatal muscle tissues in mice by delivering gene editing components via a harmless adeno-associated virus. Cardiac and skeletal muscle showed progressive rescue of dystrophin protein [Long et al. Science doi: 10.1126/science.aad5725]. These studies paved the way for novel genome editing-based therapeutics in DMD. We have now advanced Myoediting to cells from human DMD patients by engineering the permanent skipping of mutant or out-of-frame exons in the genome of DMD patient-derived induced pluripotent stem cells (iPSCs). We have optimized Myoediting of DMD mutations using pools of sgRNAs to target the top 12 hot spot mutant exons. We targeted the conserved RNA splicing acceptor/donor sites of each exon. NHEJ-mediated indels efficiently abolished the splicing sites and skipped the mutated or out-of-frame exons. Based on the known DMD mutations, we established a publicly available online resource (Duchenne Skipper Database) for selecting the optimal target DMD sequences for Myoediting, which will rescue dystrophin function in 60-80% of DMD patients. We performed Myoediting on representative iPSC-derived cardiomyocytes from multiple patients with point, deletion or duplication mutations and efficiently restored dystrophin protein expression in cardiomyocytes. Rescued DMD cardiomyocyte shows enhanced function. Opportunities and obstacles in the path toward efficient and permanent elimination of the genetic cause of DMD and other DCM will be discussed.
Correlation of tumor regression grade (TRG), circumferential margin (CM), and epidermal growth factor receptor expression with disease-free survival (DFS) in locally advanced rectal cancer patients (LARC) treated with preoperative radiochemotherapy (preCh-RT).
Authors: F. Arias, D. Guerrero, M. L. Gomez Dorronsoro, M. Montes, R. Vera, G. Asin, F. Monzon, E. Balen, P. Armendariz, M. Vila, V. Chicata, A. Viúdez, E. Bandres, J. Garcia-Foncillas, M. A. DomÃ­nguez
Journal: Journal of Clinical Oncology (2011)

e14076 Background: EGFR overexpression has been associated with radioresistance and poor prognosis. The aim of this study was to determine the EGFR expression rate in LARC and to analyze if EGFR expression could predict pathological tumor response to pre Ch-RT. We also evaluate EGFR as prognostic factor (PF) for DFS and compare to other PFs as CM or TRG. Methods: Between April 2004 and October 2008, 92patients were included. Treatment consisted of preoperative pelvic radiotherapy (45Gy+ 5.4 Gy boost, at 180 cGy per fraction) and capecitabine (825 mg/m2/BID during radiotherapy). Surgical resection (TME) was performed 6–8 weeks after preCh-RT finished . Immunohistochemistry for EGFR was determined at the preradiation diagnostic biopsy. Immunostaining was performed using EGFR monoclonal antibody (Biogenex, MU 207-UC). Immunohistochemical staining was evaluated according to extension and intensity. We defined positive staining (EGFR+) as extension of 10% or more. TRG was determined by Mandard's criteria. Follow up of the series: 50 months (26-80 m) Results: Preoperative treatment resulted in pathologic complete remission in 13 patients (14%), and downstaging in 43 patients. EGFR+ was observed in 62 of 92 tumors (67.4%) and was associated with neither clinical tumor stage nor clinical nodal stage. TRG 1-2 was observed in 56% of low-EGFR expression (0-1) versus 36% of high- EGFR expression (2-3), p=0.09. According to TRG, 3-years DFS was 100% vs 71% for TRG 0-1 and TRG 2-3 (p=0.001) , respectively. Regarding CM, 3-year DFS was 86% vs 70% for CM<1mm vs >1mm (p=0.1). Finally, 3-year DFS was 85% vs 81% for EGFR negative (0-1) vs positive (2-3) (p=0.5). Conclusions: Although EGFR is significantly expressed in locally advanced rectal tumors, its expression is not predictive factor for response to preCh-RT. Based in our results, TRG is the strongest prognostic factor for clinical outcome patients treated with radiotherapy and concomitant capecitabine.
211. Combination of Forced Transduction of P53 and an Agent That Blocks MDM2-p53 Interactions Produces Synergistic Cytotoxicity on Mesothelioma Defective of the INK4A/ARF Region
Authors: Masatoshi Tagawa, Takao Morinaga, Zhihan Li, Thao T.T. Nguyen, Boya Zhong, Shuji Kubo, Ikuo Sekine, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
Journal: Molecular Therapy (2016)

A majority of malignant mesothelioma specimens possesses the wild-type p53 gene with a homologous deletion in the INK4A/ARF locus which encodes the p14ARF and the p16INK4A genes. Consequently, the p53 downstream pathways are functionally inactivated since the p14 defect augments activities of MDM2 which mediates p53 degradation through the ubiquitination processes. Furthermore, a loss of p16 induces pRb phosphorylation and uninhibited cell cycle progression through up-regulated CKD activities. We then examined possible anti-tumor effects of MDM2 inhibitors, Nutlin-3a and RITA, on human mesothelioma cells in combination of adenoviruses expressing the p53 gene (Ad-p53). Nutlin-3a, inhibiting the MDM2-p53 interactions, increased p53 phosphorylation levels and suppressed viability of mesothelioma cells in a p53-dependent manner. RITA, although blocked the MDM2-p53 interactions and phosphorylated p53, inhibited viability of mesothelioma cells independently of the p53 geneotype. Transduction of mesothelioma cells with Ad-p53 induced apoptotic cell death irrespective of the genotype. Moreover p21 induced by Ad-p53 dephosphorylated pRb and subsequently inhibited cell cycle progression. A combinatory use of Ad-p53 and Nutlin-3a or RITA, produced synergistic cytotoxicity of mesothelioma irrespective of the p53 geneotype. In addition, we demonstrated that the combination produced anti-tumor effects in an orthotopic animal model, mesothelioma developed in the pleural cavity in nude mice. In contrast, heat shock protein 90 inhibitors, blocking functions of MDM4, a homologous gene product of MDM2 without ubiquitination activities, did not produce the synergistic cytotoxicity with Ad-p53. These data collectively showed that MDM2 inhibitors enhanced expression levels of endogenous and exogenously transduced p53 through increased stability of the gene produce, and consequently activated the p53-mediated apoptosis. The p53-directed therapy is thus a possible therapeutic strategy for mesothelioma with the INK4A/ARF deletion.
562. Fetal Hemoglobin Expression Can Be Increased by Targeted Disruption of the Gamma Hemoglobin Promoter in Human Peripheral Blood Stem Cells
Authors: Christopher T. Lux, Queenie Vong, Julia Yang, Brandon K. Hadland, Andy Scharenberg
Journal: Molecular Therapy (2016)

Hemoglobinopathies such as sickle cell disease and β-thalassemia are both common and morbid inherited genetic disorders. Mutations in the β -globin (HBB) gene result in the expression of pathologic globin molecules or the reduction in expression of the wildtype allele. Despite the high prevalence of these disorders, current treatment options are limited. Patients with a hereditary persistence of fetal hemoglobin (HPFH) have disease modifying mutations that result in the compensatory expression of gamma or delta hemoglobin and these patients tend to have a much less severe phenotype. A previously reported unique 13bp deletion identified in the gamma hemoglobin promoter of two sickle cell patients with HPFH (HbF >30%) offers a novel target for gene editing using targeted endonucleases. This region contains known binding sites for multiple regulatory factors including the DRED repressor complex and the CAAT-box binding factor (CBF). TALENs designed to target this 13bp site have been generated and the mRNA successfully transfected into human peripheral blood CD34 cells. Genomic analysis of TALEN transfected cells reveals the introduction of INDELs by NHEJ in both the γ1 (HBG1) and γ2 (HBG2) genes (33% and 8% respectively). TALEN edited human peripheral blood stem cells were then differentiated into erythroid progeny that express increased levels of fetal hemoglobin detected by both flow cytometry (>50% increase over control) and HPLC (>5-fold increase over control). CRISPR guides (traditional and chemically modified RNA guides) targeting the same locus are currently being compared to TALENs. These data suggest that the introduction of INDELs in this locus is capable of de-repressing the gamma globin gene in human CD34 cells. In vivo mouse xenografts are underway to further assess this approach as a means for a functional cure of a wide array of hemoglobinopathies.
Abstract 4166: Targeting NF-κB by the curcumin and its analogs EF-31 and UBS-109 decreases growth and angiogenesis of colon cancer
Authors: Ganji Purnachandra Nagaraju, Mamoru Shoji, Bassel El Rayes
Journal: Cancer Research (2015)

Abstract Purpose/Objective: NF-κB plays an essential role in cancer cell growth and metastasis by stimulating angiogenesis. Curcumin decreases the activity of several oncogenic transcriptional factors including NF-κB and HIF-1α, thus we investigated whether curcumin and its analogs EF-31 and UBS-109, could disrupt angiogenesis using colorectal cancer cells (CRC). Methods: HCT-116 and HT-29 cells were used in these experiments. HUVEC tube formation assay, Matrigel plug assay, Western blotting, and VEGF activity assay were carried out to determine the curcumin, EF-31 and UBS-109 role in angiogenesis. A subcutaneous xenograft mouse model was used to evaluate the in vivo effects of curcumin analogues. Results: Conditioned medium from HCT-116 or H-T29 cells exposed to curcumin, EF-31 and UBS-109 in vitro significantly blocked HUVEC tube assembly in comparison to control. In vivo, EF-31 and UBS-109 blocked the vascularization of subcutaneous matrigel plugs and the growth of CRC xenografts. We observed significant inhibition of VEGF synthesis and secretion in both colon cell lines treated with curcumin, EF-31 and UBS-109 in concert with the loss of HIF-1α expression, of which transcriptionally regulated by NF-κB. Similar effects were observed in tumors from animals treated with EF-31 and UBS-109. Further, EF-31 and UBS-109 treatment significantly decreased the tumor growth compared to untreated tumors. These results suggesting that curcumin, EF-31 and UBS-109 inhibits VEGF production in part through the degradation of HIF-1α and increased the cytoplasmic accumulation of NF-κB. Conclusion: Taken together, destabilization of HIF-1α and inhibition of NF-κB from cytoplasm to nuclear translocation may be important contributing factors to the antiangiogenic action of curcumin, EF-31 and UBS-109 in CRC. Note: This abstract was not presented at the meeting. Citation Format: Ganji Purnachandra Nagaraju, Mamoru Shoji, Bassel El Rayes. Targeting NF-κB by the curcumin and its analogs EF-31 and UBS-109 decreases growth and angiogenesis of colon 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 4166. doi:10.1158/1538-7445.AM2015-4166
Promiscuous Cryptic Rearrangements of the MYC Locus Cis-Dysregulate MYC Expression and Are Present in the Majority of Patients with Hyperdiploid Myeloma
Authors: P Leif Bergsagel, Maurizio Affer, Oleg K Glebov, Wei-Dong D Chen, Jonathan J Keats, Leslie A Brents, Marta Chesi, Scott Van Wier, Sandra K Badar, Rafael Fonseca, W Michael Kuehl
Journal: Blood (2012)
The Scientific Basis of Guideline Recommendations on Sugar Intake
Authors: Jennifer Erickson, Behnam Sadeghirad, Lyubov Lytvyn, Joanne Slavin, Bradley C. Johnston
Journal: Annals of Internal Medicine (2016)

Background: The relationship between sugar and health is affected by energy balance, macronutrient substitutions, and diet and lifestyle patterns. Several authoritative organizations have issued public health guidelines addressing dietary sugars. Purpose: To systematically review guidelines on sugar intake and assess consistency of recommendations, methodological quality of guidelines, and the quality of evidence supporting each recommendation. Data Sources: MEDLINE, EMBASE, and Web of Science (1995 to September 2016); guideline registries; and gray literature (bibliographies, Google, and experts). Study Selection: Guidelines addressing sugar intake that reported their methods of development and were published in English between 1995 and 2016. Data Extraction: Three reviewers independently assessed guideline quality using the Appraisal of Guidelines for Research and Evaluation, 2nd edition (AGREE II), instrument. To assess evidence quality, articles supporting recommendations were independently reviewed and their quality was determined by using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods. Data Synthesis: The search identified 9 guidelines that offered 12 recommendations. Each of the reviewed guidelines indicated a suggested decrease in the consumption of foods containing nonintrinsic sugars. The guidelines scored poorly on AGREE II criteria, specifically in rigor of development, applicability, and editorial independence. Seven recommendations provided nonquantitative guidance; 5 recommended less than 25% to less than 5% of total calories from nonintrinsic sugars. The recommendations were based on various health concerns, including nutrient displacement, dental caries, and weight gain. Quality of evidence supporting recommendations was low to very low. Limitation: The authors conducted the study independent of the funding source, which is primarily supported by the food and agriculture industry. Conclusion: Guidelines on dietary sugar do not meet criteria for trustworthy recommendations and are based on low-quality evidence. Public health officials (when promulgating these recommendations) and their public audience (when considering dietary behavior) should be aware of these limitations. Primary Funding Source: Technical Committee on Dietary Carbohydrates of the North American branch of the International Life Sciences Institute. (PROSPERO: CRD42015029182)
Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling
Authors: Yoku Hayakawa, Kosuke Sakitani, Mitsuru Konishi, Samuel Asfaha, Ryota Niikura, Hiroyuki Tomita, Bernhard W. Renz, Yagnesh Tailor, Marina Macchini, Moritz Middelhoff, Zhengyu Jiang, Takayuki Tanaka, Zinaida A. Dubeykovskaya, Woosook Kim, Xiaowei Chen, Aleksandra M. Urbanska, Karan Nagar, Christoph B. Westphalen, Michael Quante, Chyuan-Sheng Lin, Michael D. Gershon, Akira Hara, Chun-Mei Zhao, Duan Chen, Daniel L. Worthley, Kazuhiko Koike, Timothy C. Wang
Journal: Cancer Cell (2016)
Circulating Long Noncoding RNAs in Personalized Medicine
Authors: David de Gonzalo-Calvo, Franziska Kenneweg, Claudia Bang, Rocío Toro, Rutger W. van der Meer, Luuk J. Rijzewijk, Johannes W.A. Smit, Hildo J. Lamb, Vicenta Llorente-Cortes, Thomas Thum
Journal: Journal of the American College of Cardiology (2016)
Donor Lymphocyte Infusions and Rituximab Are An Effective Treatment Strategy for B-Cell Lymphoma Relapsing After Reduced Intensity Allogeneic Stem Cell Transplantation.
Authors: Francesco Spina, Francesca Patriarca, Lucia Farina, Vittorio Montefusco, Anna Dodero, Cristiana Carniti, Renato Fanin, Paolo Corradini
Journal: Blood (2009)
Prognostic impact of bone marrow involvement for patients with diffuse large B-cell lymphoma in the era of rituximab.
Authors: B. W. Kang, Y. J. Lee, Y. S. Chae, J. H. Moon, J. G. Kim, S. K. Sohn, J. S. Suh, T. I. Park, M. K. Kim, M. S. Hyun, H. J. Kim, J. Lee, D. H. Yang, S. H. Bae, H. Ryoo, K. Y. Kwon, J. Y. Kim, Y. R. Do, K. U. Park, H. Kim
Journal: Journal of Clinical Oncology (2011)

e18514 Background: We investigated the prognostic impact of bone marrow (BM) involvement in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Methods: Thus, 567 consecutive patients with newly diagnosed DLBCL and treated with rituximab-CHOP (RCHOP) between August 2003 and December 2009 were included in the current study. All the patients underwent a BM study at the initial staging and the clinical characteristics and prognosis of these patients with or without BM involvement were retrospectively analyzed. Results: The total cohort included 567 patients. The median age was 61.0 years (range, 16-89) and 56.3% were male. Two hundred thirty patients (40.6%) had stage III and IV at diagnosis. One hundred seventy-seven patients (31.2 %) were categorized as high or high-intermediate risk according to their IPI. The overall incidence of BM involvement was 8.5%. A high number of abnormalities in the CBC profile was associated with a higher incidence of BM involvement (P<0.001). With a median follow-up duration of 33.2 months (range, 0.1-80.7) for the patients alive at the last follow-up, the 5-year overall survival (OS) and event-free survival (EFS) rate in the patients without BM involvement (67.5% and 76.3%) was statistically higher than that in the patients with BM involvement (40.1% and 44.3%). In a multivariate analysis, BM involvement was significantly associated with OS and EFS. Conclusions: BM involvement at diagnosis affected the survival of the patients with DLBCL who received RCHOP. Although RCHOP can significantly improve the therapeutic effect of the DLBCL, BM involvement is still a negative prognostic factor of DLBCL patients in the era of rituximab.
Impact of immune modulation on sentinel lymph node positivity and outcome in melanoma patients.
Authors: R. C. Medicherla, M. W. Ma, M. Qian, E. Vega-Saenz de Miera, R. S. Berman, R. L. Shapiro, A. C. Pavlick, N. Bhardwaj, Y. Shao, I. Osman, F. Darvishian
Journal: Journal of Clinical Oncology (2011)

8561 Background: The interplay between melanoma and the immune system is multifactorial. Immune modulation is a key factor in melanoma metastasis, but its impact on patient management and potential prognostic relevance at the time of primary melanoma diagnosis are not well studied. We investigated the relationship between immune modulation and sentinel lymph node (SLN) positivity and correlated it with outcome in melanoma patients. Methods: We examined T regulatory cells (Tregs: Foxp3+), myeloid dendritic cells (myDCs: CD11c+), and mature dendritic cells (maDCs: CD86+) in lymph node (LN) and primary tissues from 84 melanoma patients prospectively accrued and followed up at New York University Medical Center using immunohistochemistry to detect Foxp3, CD11c, and CD86. The immune response in positive SLN biopsies (SLN+) was compared to that in negative SLN biopsies (SLN-) from patients matched for age, sex, primary tumor thickness/ulceration and negative LNs (LN-) from the same nodal basins of SLN+ patients. Immune cells were quantified as the absolute number in a representative HPF. Decreased immune response was defined as increased Tregs, decreased myDCs, or decreased maDCs. Associations between the expression of these immune modulators, clinicopathologic variables, and outcome were evaluated using univariate and multivariate analyses. Results: Anti-tumor immune response was downregulated both in the SLN+ (n=31) compared to the SLN- (n=53) with significant increase in Tregs (p=0.0002) and decrease in myDCs (p=0.00002) and in the 31 SLN+ compared to the LN- from the same basin with significant increase in Tregs (p=0.0005). Logistic regression models revealed that myDCs and maDCs in the primary tissue were associated with SLN status (p=0.001, 0.01, respectively). Adding Treg expression in the SLN as a predictor variable for recurrence improved the odds ratio in the logistic regression model for stage III from 5.99 to 10.42. Conclusions: Immune response is progressively downregulated with increased tumor involvement of the LNs. Our data support immunosuppression in the SLN as a predictor of worse outcome and suggest that evaluation of local immune profiles can guide the selection of therapy in the adjuvant setting.