tbuckley/cabot-search huggingface dataset:
94. AAV Integration Site Determination Using Illumina Mate Pair Sequencing
Authors: Matthew R. Tiffany, Mark A. Kay
Journal: Molecular Therapy (2015)

Integration of AAV into genomic loci has been well studied using low throughput techniques, which has revealed clear integration hotspots. Recent studies using high throughput sequencing have uncovered new genomic loci where AAV may integrate. However, the low integration frequency combined with the AAV inverted terminal repeats (ITR) makes amplification technologically challenging and prone to artifacts that may mis-identify or miss some integration sites. Our lab has utilized a modified Illumina Mate Pair sequencing technique to uncover genomic integration sites and bypass the need to amplify through the AAV ITR. We believe that this technique can accurately establish bona-fide integration sites, uncover novel integration sites, and provide further evidence for existing known hotspots. At its core, mate pair sequencing involves self-circularization of fractured genomic fragments followed by recovery and sequencing of the junction. In essence, it bridges the low throughput shuttle vector systems used in the past with high throughput sequencing. Here we have utilized biotinylated loxP linkers added to the ends of genomic fragments and at unique sites in AAV vectors followed by Cre circularization (Van Nieuwerburgh, 2012). The circularized fragments are enriched by exonuclease treatment to remove linear fragments then fractured to ~400 bp. The fragments containing the loxP junction are purified using magnetic strepavadin coated beads and Illumina sequencing adapters are added before sequencing. Using this technique, we have successfully recovered control sequences of plasmids mixed with genomic DNA. Importantly, the Cre recombination reaction allows us to accurately distinguish self-circularized fragments from cross-recombined fragments and eliminate apparent false positive integration sites. We are working on applying this technique to DNA samples from mice injected with AAV. Continued study of AAV integration will be extremely important for establishing the safety profile of AAV used in clinical applications.
A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study
Authors: Jacob G Scott, Anders Berglund, Michael J Schell, Ivaylo Mihaylov, William J Fulp, Binglin Yue, Eric Welsh, Jimmy J Caudell, Kamran Ahmed, Tobin S Strom, Eric Mellon, Puja Venkat, Peter Johnstone, John Foekens, Jae Lee, Eduardo Moros, William S Dalton, Steven A Eschrich, Howard McLeod, Louis B Harrison, Javier F Torres-Roca
Journal: The Lancet Oncology (2016)
Abstract 3469: Measuring antitumor effect of c-Myc-Max heterodimerization inhibitor 100258-F4 on ovarian cancer cells using cellometer image cytometry
Authors: Leo Li-Ying Chan, Jiandong Wang, Xiaoli Ma, Fang Song, Weiyuan Zhang, Hannah M. Jones, Victoria L. Bae-Jump, Chunxiao Zhou
Journal: Cancer Research (2015)

Abstract Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. In this work, we aimed to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian cancer cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using Cellometer image cytometry for cell cycle and Annexin V apoptosis assays, flow cytometry, MTT assay, and colony formation, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. These novel findings suggest that targeting c-Myc-Max heterodimerization could be a potential therapeutic strategy for ovarian cancer. Note: This abstract was not presented at the meeting. Citation Format: Leo Li-Ying Chan, Jiandong Wang, Xiaoli Ma, Fang Song, Weiyuan Zhang, Hannah M. Jones, Victoria L. Bae-Jump, Chunxiao Zhou. Measuring antitumor effect of c-Myc-Max heterodimerization inhibitor 100258-F4 on ovarian cancer cells using cellometer image cytometry. [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 3469. doi:10.1158/1538-7445.AM2015-3469
Systemic siRNA Delivery with a Dual pH-Responsive and Tumor-targeted Nanovector for Inhibiting Tumor Growth and Spontaneous Metastasis in Orthotopic Murine Model of Breast Carcinoma
Authors: Bo Fan, Lin Kang, Liqing Chen, Ping Sun, Mingji Jin, Qiming Wang, You Han Bae, Wei Huang, Zhonggao Gao
Journal: Theranostics (2016)

Phenylboronic acid (PBA)-mediated tumor targeting nanovector is an attractive strategy for enhancing siRNA delivery and treatment of metastatic cancers. However, its nonspecific binding with various biological membranes containing cis-diol moieties restricts its potential application by systematic administration. Herein, we constructed a novel pH-activated "sheddable" PEG-coated nanoparticle for effective treatment of primary tumors and metastases, which was based on the conjugation of catechol group modified poly(ethylene glycol) (PEG-Cat) and PBA-terminated polyethylenimine (PEI-PBA) via the borate ester formed between PBA and Cat. By virtue of the pH-dependent stability of borate ester in an aqueous medium, the PEG-shell could "shield" the PBA ligand in systemic circulation to reduce its "off-target effect", while PEG was detached at tumor extracellular pH (~6.5) to expose intact PBA moiety. Simultaneously, the PBA ligand could bind with overexpressed sialic acid residues on cancer cells, giving rise to enhanced cellular internalization. In addition, the PBA moieties could also couple with each 3'-end ribose of double-stranded siRNA. siRNAs were used as both a payload and a pH-responsive intermolecular cross-linker, and thereby acquired sufficient stability during circulating in blood and a rapidly triggered release in response to acidic endosomal/lysosomal pH-stimuli. As a result, this dual pH-sensitive nanoparticle showed enhanced siRNA uptake, gene silencing efficacy and anti-metastatic effects in vitro. Furthermore, in vivo studies demonstrated that PBA-based nanoparticles effectively accumulated in tumor and inhibited tumor growth and metastasis in 4T1 orthotopic mammary tumor model after intravenous administration.
Abstract 3701: Health disparity characteristics on growth patterns of breast cancer mortality trends among the US Counties, 1989-2010
Authors: Wonsuk Yoo, George Rust, Shun Zhang, James Lillard
Journal: Cancer Research (2015)

Abstract Background: Group-based trajectory models are increasingly being applied to address questions related to the development of cancer mortalities over time and, more recently, there is a need to move away from the interpretation of trajectory groups as distinct entities. In this study, we aim to identify trajectory-patterns which have distinct epidemiologic disparity among US counties, and to assess whether health disparities in the socioeconomic characteristics are associated with a greater women health burden in breast cancer. Methods: Cases of breast cancer diagnosed between 1989 and 2010 were selected from Center for Disease Control's WONDER Online Databases using International Classification of Diseases for Malignant neoplasm of breast (ICD 10 - C50). Age-adjusted mortality rates of breast cancer between 1989 and 2010 were calculated by counties as well as race (African American and White). Growth patterns were identified using Growth Mixture Modeling (GMM) method and disparity characteristics including socioeconomic attributes were investigated through National Cancer Institute's Surveillance Epidemiology and End Results (SEER) County Attributes Dataset. Results: We identified the following three growth sub-patterns in the trajectories of breast cancer mortality rates between 1989 and 2010 among US counties: (1) a majority (61%) following a gradual decreasing trajectories, (2) a non-decreasing trajectories (31%), and the remainder following a trajectory with relatively rapid decreasing (7%). We compared disparity characteristics of education level, median household income, poverty percentage, percentages of older ages (65+) and younger ages (&amp;lt;18), and rural-urban continuum among above three sub-patterns. Conclusions: There is heterogeneity of the socioeconomic characteristics that are highly associated with growth patterns in trajectories of breast cancer mortality rates. Growth mixture models are an effective tool to be able to capture health disparities in heterogeneity among counties in the trajectory of breast cancer mortality. Note: This abstract was not presented at the meeting. Citation Format: Wonsuk Yoo, George Rust, Shun Zhang, James Lillard. Health disparity characteristics on growth patterns of breast cancer mortality trends among the US Counties, 1989-2010. [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 3701. doi:10.1158/1538-7445.AM2015-3701
Rituximab + ESHAP as Salvage Chemotherapy for Relapsed/Refractory Aggressive Non-Hodgkins Lymphoma: A Phase II Trial.
Authors: Lisa Hicks, R. Buckstein, E. Piliotis, J. Mangel, K. Imrie, D. E. Spaner, M. D. Reis, C. Foden, V. Milliken, A. Boudreau, P. Richardson, N. Pennell, N. Berinstein
Journal: Blood (2004)
736. Silencing Substituting the RHODODPSIN Gene to Treat Blinding Disorders
Authors: Salvatore Botta, Elena Marrocco, Nicola de Prisco, Fabiola Curion, Mario Renda, Martina Sofia, Mariangela Lupo, Maria Laura Bacci, Carlo Gesualdo, Settimio Rossi, Francesca Simonelli, Enrico Maria Surace
Journal: Molecular Therapy (2016)

Silencing and replacement strategy is a promising strategy to overcome mutational heterogeneity of genetic defects. In autosomal dominant retinitis pigmentosa (adRP) approximately 200 different mutations have been associated with rhodopsin gene (RHO). We recently described a system based on the delivery of a synthetic transcriptional repressor (DNA-binding-mediated silencing; ZF6-DBD), which upon Adeno-associated viral (AAV) vector delivery to the porcine retina, demonstrated selective somatic ablation of RHO in mutation independent manner, thus silencing both the wild-type and mutated alleles. To determine the actual therapeutic impact of DNA-binding-mediated silencing, we carried out the silencing-replacement strategy by coupling ZF6-DBD with RHO replacement (human RHO, hRHO CDS). To warrant simultaneous photoreceptor transduction of both ZF6-DBD and hRHO, we enclosed two expression cassettes into a single vector (DNA-binding repression and replacement, DBR-R). To generate the construct we evaluated key variables for balanced simultaneous RHO repression and replacement, which are the vector dose and promoter strength. To ensure high and rod-specific hRHO replacement, we opted for a high vector dose and the strength of the GNAT1 promoter elements. To decrease ZF6-DB expression levels at high vector dose, while keeping rod-specificity, we both shortened the human RHO promoter and deleted the 5' sequence of the ZF6-DB target. We used 1×1012 gc of vector of DBR-R (AAV8-RHOΔ-ZF6-DB-GNAT1-hRHO) to administer to porcine retina. Administration of the DBR-R vector resulted in concomitant rod-specific transcriptional repression of the porcine Rho (35%) and in balanced replacement with the exogenous hRHO (45%), as assessed by transcripts levels, protein expression and integrity of photoreceptor outer segments. The data support pre-clinical development including a dose-response and long-term efficacy and toxicity.
Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia
Authors: Sheeba K. Thomas, Wael A. Harb, Joseph Thaddeus Beck, Gabrail Nashat, M. Lia Palomba, Stephen M Ansell, Herbert Eradat, Edward N. Libby, Ranjana H Advani, Julio Hajdenberg, Leonard T Heffner, James Hoffman, David H. Vesole, Lindsey Simov, Nancy Wyant, Julie Brevard, James O'Leary, Sudhir Agrawal
Journal: Blood (2015)
Strong PSMA Radioligand Uptake by Rectal Carcinoma
Authors: Christian Stoykow, Sabine Huber-Schumacher, Nadja Almanasreh, Cordula Jilg, Juri Ruf
Journal: Clinical Nuclear Medicine (2016)

We present a case of a 71-year-old patient with newly diagnosed rectal adenocarcinoma and hepatic metastases. Restaging after chemotherapy revealed a good response of the rectal primary while liver metastases were progressive. As the patient also had a history of prostate cancer, a Ga-PSMA-HBED-CC PET/CT scan was performed to noninvasively further assess hepatic metastases. However, a definite differentiation between tumor entities was not possible because not only the liver metastases but also the rectal primary showed radioligand uptake (moderate and strong, respectively). Consecutive liver biopsy revealed a poorly differentiated adenocarcinoma of intestinal origin.
Breast cancer phenotype in women with TP53 germ-line mutations: An LFS consortium effort.
Authors: S. Masciari, D. Dillon, M. G. Dick, M. E. Robson, J. N. Weitzel, J. M. Ford, J. Balmaña, S. B. Gruber, D. Euhus, J. E. Garber
Journal: Journal of Clinical Oncology (2011)

1519 Background: Breast cancer (BC) is the most common tumor in women with germ-line TP53 mutations with 49% risk by age 60, and significant risk before age 40. The histopathological profile of BC in TP53 carriers has recently been described in small cohorts showing a higher likelihood of HER2+ BC (Wilson et al. J Med Genet.Nov;47:771-774; Melhem-Bertrandt ARK et al. 2010 San Antonio Breast Cancer Symp; Poster Session 3). We expanded our original cohort of 17 women with BC and Li Fraumeni syndrome (LFS), in whom we had complete markers only in 9 cases (Masciari S et al. JCO, 2006 ASCO Annual Meeting Proc, abstr 10031), to characterize the histopathological features of BC in LFS. Methods: We identified 15 BC from germ-line TP53mutations carriers from the LFS registry at Dana-Farber Cancer Institute and 14 cases from collaborators in the LFS consortium. Information on histology, hormone receptor and HER2 status was collected from medical records. Central histology review is ongoing and complete data from the cohort will be available shortly, including 13 additional cases. Results: We identified 7 DCIS and 22 invasive ductal carcinoma (IDC) in 26 women, 1 with both and 2 with bilateral IDC. The median age at IDC was 31 years (range 22-46). 64% were high grade, 17 (77%) were ER+ and 16 (72%) were PR+. 68% of IDC and 71% of DCIS were HER2+. 45% of IDC were ER+/PR+/HER2+; other ER/PR/HER2 combinations were observed (Table). Conclusions: This is the largest collection of BC with characterized subtype reported in women with LFS. Most DCIS and IDC in LFS are hormone receptor positive; HER2+ frequency is also increased. These findings suggest that modern treatments may improve outcomes for women with LFS-associated BC. It is important to identify them to permit consideration of radiation issues and additional primary malignancies. Histopathologic characteristics of BC in LFS. N ER+ PR+ HER2+ ER+/PR+ ER-/PR- ER+/PR- HER2+ HER2- HER2+ HER2- HER2+ DCIS 7 4 3 5 1 2 3 0 1 IDC 22 17 16 15 10 6 4 1 1 Total 29 21 19 20 11 8 7 1 2
The Potential Role of STAT's in Anti-Leukemic Therapy with Different Drugs
Authors: Hatice Demet Kiper, Burcin Tezcanli Kaymaz, Ozlem Purclutepe, Ceyda Tunakan Dalgic, Nur Selvi, Aysegul Dalmizrak, Cigir Biray Avci, Buket Kosova, Fahri Sahin, Cagdas Aktan, Guray Saydam
Journal: Blood (2012)
Inhibition of NF-κB Activation Augments the Effect of 5-Azacytidine On Acute Myeloid Leukemia Cell Line
Authors: Tomiteru Togano, Makoto Nakashima, Mariko Watanabe, Kazuo Umezawa, Toshiki Watanabe, Masaaki Higashihara, Ryouichi Horie
Journal: Blood (2012)
<i>TSC1/2</i>mutations define a molecular subset of HCC with aggressive behaviour and treatment implication
Authors: Daniel W H Ho, Lo K Chan, Yung T Chiu, Iris M J Xu, Ronnie T P Poon, Tan T Cheung, Chung N Tang, Victor W L Tang, Irene L O Lo, Polly W Y Lam, Derek T W Yau, Miao X Li, Chun M Wong, Irene O L Ng
Journal: Gut (2016)

<h3>Objective</h3> We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. <h3>Design</h3> We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. <h3>Results</h3> We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of <i>TSC1</i> and <i>TSC2</i> genes in the HCC samples. The spectrum of <i>TSC1/2</i> mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of <i>TSC1</i> and <i>TSC2</i> was also observed in HCC cell lines and our PDTX models. <i>TSC</i>-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant <i>TSC2</i>-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. <h3>Conclusions</h3> Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent <i>TSC1/2</i> mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.
Oxaliplatin and capecitabine combination chemotherapy for patients with advanced gastric carcinoma: A pilot study results
Authors: Y. H. Park, B. S. Kim, B.-Y. Ryoo, S. H. Yang
Journal: Journal of Clinical Oncology (2005)

4199 Background: Oxaliplatin is active in colorectal carcinoma (CRC), especially when combined with 5-FU/leucovorin (LV). Superior response rate and time to disease progression observed with the addition of oxaliplatin to 5-FU/LV. Synergistic activity of fluoropyrimidines and oxaliplatin can partly overcome clinical resistance to fluoropyrimidines. No overlap in key toxicities. Recently, oxaliplatin/capecitabine combination therapy is feasible and exhibited promising antitumour activity in patients with colorectal carcinoma. We aimed to define the role of this combination chemotherapy for treating advanced gastric carcinoma. Methods: The study population comprised histologically confirmed non-resectable advanced gastric adenocarcinoma patients who were initially diagnosed or recurred. Patients were to receive a maximum of 8 cycles. This combination chemotherapy consists of oxaliplatin 130 mg/m2 over 2 hours on day 1 of each cycle. Capecitabine was administered orally at a dose of 1000 mg/m2 twice daily according to the standard intermittent schedule (14 days of treatment followed by a 7-day rest period). Results: Twenty evaluable patients (17 men, 3 women) were included. The median age was 64 years (range, 38–75 years), and most of the patients (18; 90%) had a good performance status. The overall response rate to this combination chemotherapy was 60% (95% confidence interval, 39%–81%). Total 77 chemotherapy cycles were treated. Complete response was in one patient, partial response was shown in 11 patients. Median progression-free and overall survival was not reached. Toxicity was mild. Grade IV hematologic toxicity was not detected on next cycle CBC. Anemia was common (12; 60%). Grade I or II thrombocytopenia was seen in 5 patients. Grade I or II neutropenia was seen in 6 patients. The most common non-hematologic toxicity was neuropathy. Other non-hematologic toxicities were hand-foot syndrome and diarrhea. Conclusions: This combination chemotherapy is highly active and well tolerated for patients with advanced gastric carcinoma. We planned to start a multi-institutional large phase II study. No significant financial relationships to disclose.
Dynamic Changes in the Clonal Structure of MDS and AML in Response to Epigenetic Therapy
Authors: Geoffrey L. Uy, Eric J. Duncavage, Gue Su Chang, Meagan A. Jacoby, Christopher A. Miller, Jin Shao, Sharon Heath, Robert S. Fulton, Catrina C. Fronick, Michelle O'Laughlin, Camille N. Abboud, Amanda F. Cashen, John F. DiPersio, Richard K Wilson, Daniel C. Link, John S. Welch, Peter Westervelt, Timothy J. Ley, Timothy A. Graubert, Matthew J. Walter
Journal: Blood (2015)
Abstract 2812: The chemo-prevention effect of statin on hepatocellular carcinoma cell lines
Authors: Aram Ghalali, Javier Martin-Renedo, Johan Högberg, Ulla Stenius
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol lowering drugs. Recent epidemiology suggests that statins prevent aggressive HCC development (J Clin. Oncol. 2012; 30:623-630). In previous cell experiments we have shown that statins down-regulate nuclear Akt responses to insulin (J Biol Chem 2010; 285, 27900). We showed that atorvastatin decreases nuclear phosphorylated Akt (pAkt) levels in pancreatic and lung cancer cell lines within minutes. This rapid effect was apparently not mediated by HMG-CoA reductase inhibition; instead there were indications that it was mediated by the P2×7 receptor. Akt has oncogenic activity in HCC and many other cancer types, and we have now tested the possibility that the P2×7-Akt pathway is of importance for the anticipated anticancer effects of statins in HCC. We performed western blotting, immunocytochemistry and transfections assays and found that statins decrease insulin induced pAkt levels in the nucleus. Further, statin decrease the proliferation of liver cells significantly. Hepatocytes lacking P2×7 receptor was insensitive to these effects of statins. Overexpression of P2×7 restituted the statin effect on pAkt levels. Overexpression of Hepatit B X protein vector has been shown to increase pAkt levels (FEBS J 279, 1220) and we found that statin counteract the Hepatit B vector-induced pAkt. These data provide evidence for a signaling pathway by which statins decrease pAkt and its downstream effect on pGSK3β Ser9 in hepatocytes via the P2×7 receptor. As the Akt pathway is deregulated and may act as a driver in HCC development this signaling pathway may have a role in the indicated chemo-preventive effect of statins. Citation Format: Aram Ghalali, Javier Martin-Renedo, Johan Högberg, Ulla Stenius. The chemo-prevention effect of statin on hepatocellular carcinoma cell lines. [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 2812. doi:10.1158/1538-7445.AM2015-2812