tbuckley/cabot-search huggingface dataset:
248. A Bona Fide Mammalian Replicator Enhances All Aspects of Episomal Gene Transfer Into Human Hematopoietic Progenitor Cells
Authors: Eleana F. Stavrou, Aristeidis Giannakopoulos, Alexandros Spyridonidis, Aglaia Athanassiadou
Journal: Molecular Therapy (2015)

Episomal gene transfer for gene therapy applications is limited at present mainly because of luck of long term persistence of episomes in the nucleus of cells. However, episomal vectors may offer a valid alternative to viral vectors as well as to gene editing strategies. To expand the potential of episomal vectors, we used the Initiation of Replication region, (IR), from β-globin gene locus, which is capable to promote DNA replication ectopically (Wang L et al 2004) and can rescue DNA replication within the context of Scaffold /Matrix Attachment Region (S/MAR) based episomal vector (Giannakoppulos A. et al 2009). We constructed two episomal vectors, derived from the protopype S/MAR based episomal vector pEPI-eGFP (6.7Kb), namely, pEP-IR and its control pEPI-SFFV, by replacing CMV promoter of eGFP by the Spleen Focus forming Virus (SFFV) promoter, while vector pEP-IR carries the IR element just upstream the SFFV promoter. Stress Induced Duplex Destabilization (SIDD) analysis of the novel plasmids indicated that these changes would not disrupt their function as episomal vectors and could be beneficial. All three vectors (pEP-IR and control vectors pEPI-SFFV and pEPI-eGFP) showed excellent episomal properties upon transfer into K562 cells. Additionally, they showed transfection efficiency around 30% upon transfer into CD34+ cells from peripheral blood, from adult, mobilised, healthy donors. CD34+/eGFP+ cells sorted by FACS were placed in semisolid cultures and produced differentiated cell-colonies within 14 days. Non-fluorescent colonies do not contain plasmids, as documented previously too (Papapetrou E. et al 2006). Vector pEP-IR shows an enhancement of all aspects of vector performance: 100% fluorescent colonies against (0%) for pEPI-eGFP as found previously (Papapetrou E. et al 2006) and 56% for pEPI-SFFV, in Fluorescent microscopy; increase of plasmid copy number per fluorescent cell, which was 1.78 for pEP-IR against 1.12 for pEPI-SFFV, as estimated by Real Time PCR. The ratio of the number of fluorescent, stably transfected colonies to the number of transfected, seeded cells presenting the rate of establishment in semisolid cultures of transfected CD34+ cells, was 5.5% for pEPI-SFFV and 15% for pEP-IR. It is thus determined that the relative capacity for establishment for pEP-IR is 3-fold higher than that of control vector pEPI-SFFV. Finally, estimation of eGFP mRNA showed that pEP-IR supports 3 times higher eGFP expression per plasmid copy, compared to pEPI-SFFV. Vector pEPI-IR in a series of over five transfections of CD34+ cells, routinely produced fluorescent cells in the area of 99.8%. Practically, vector pEP-IR is expected to be established in all cells that give rise to the differentiated cell-progeny of CD34+ cells, that is in 10% to 20% of the total sorted CD34+/eGFP+ cells. These estimates for vector pEPI-IR can be of clinical importance.
Treatment of 287 Patients(pts) with Severe Aplastic Anemia(SAA) Using Cyclosporine-A(Csa) and Prednisone(Pred): 15 Year Follow-Up from a Single Instituition.
Authors: Marco A. Bitencourt, Carmem M.S. Bonfim, Jefferson Ruiz, Daniela C. Setubal, Vaneuza M. Funke, Jose Zanis-Neto, Carlos R. deMedeiros, Ricardo Pasquini
Journal: Blood (2004)
Further Evidence That MDS and AML Cells Exhibit a Differential Capacity To Activate the DNA-Damage Response (DDR) Pathways.
Authors: Simone Boehrer, Lionel Ades, Lorenzo Galluzzi, Ken Olaussen, Thorsten Braun, Jennifer Grosjean, Claire Fabre, Stephane de Botton, Pierre Fenaux, Guido Kroemer
Journal: Blood (2007)
Digital technology in fixed implant prosthodontics
Authors: Tim Joda, Marco Ferrari, German O. Gallucci, Julia‐Gabriela Wittneben, Urs Brägger
Journal: Periodontology 2000 (2016)

Abstract Digital protocols are increasingly influencing prosthodontic treatment concepts. Implant‐supported single‐unit and short‐span reconstructions will benefit mostly from the present digital trends. In these protocols, monolithic implant crowns connected to prefabricated titanium abutments, which are created based on data obtained from an intraoral scan followed by virtual design and production, without the need of a physical master cast, have to be considered in lieu of conventional manufacturing techniques for posterior implant restorations. No space for storage is needed in the complete digital workflow, and if a remake is required a replica of the original reconstruction can be produced quickly and inexpensively using rapid prototyping. The technological process is split into subtractive methods, such as milling or laser ablation, and additive processing, such as three‐dimensional printing and selective laser melting. The dimensions of the supra‐implant soft‐tissue architecture can be calculated in advance of implant placement, according to the morphologic copy, and consequently are individualized for each patient. All these technologies have to be considered before implementing new digital dental workflows in daily routine. The correct indication and application are prerequisite and crucial for the success of the overall therapy, and, finally, for a satisfied patient. This includes a teamwork approach and equally affects the clinician, the dental assistant and the technician as well. The digitization process has the potential to change the entire dental profession. The major benefits will be reduced production costs, improvement in time efficiency and fulfilment of patients’ perceptions of a modernized treatment concept.
Association of Fc Receptor-Like Protein Family with Chronic Graft-Versus-Host Disease.
Authors: Makoto Onizuka, Masako Toyosaki, Shinichiro Machida, Rikio Suzuki, Minoru Kojima, Koichi Miyamura, Yoshihisa Kodera, Hidetoshi Inoko, Kiyoshi Ando
Journal: Blood (2007)
Specificity of radiographic lymphadenopathy for lymph node metastasis in renal cell carcnioma.
Authors: Matthew Mossanen, Manjiri Dighe, Bryan Wilson, Daniel W. Lin, Jonathan L. Wright, Jonathan D. Harper, John L. Gore
Journal: Journal of Clinical Oncology (2015)

442 Background: Approximately 30% of patients with renal cell carcinoma (RCC) will have metastatic disease at the time of diagnosis. Patients without preoperative lymphadenopathy (LAD) radiographically rarely have positive nodes at the time of nephrectomy. We sought to evaluate the specificity of radiographic LAD for lymph node metastases in patients with and without clinical metastatic RCC. Methods: We retrospectively reviewed all nephrectomies performed at our institution from 2003-2013. We identified patients with clinical stage classification T2-T3 (cT2-T3) RCC and stratified patients by clinical N and M classification. Lymphadenectomy was performed at surgeon discretion. Performance statistics for preoperative imaging for pathologic lymph node metastases and multivariable logistic regressions models to identify patient characteristics associated with lymph node metastases were generated. Results: A total of 223 patients were identified. Of these, 85 (38%) had clinical evidence of metastatic disease while 138 (62%) did not. In patients with clinical metastatic disease, LND was performed in 68%; of those without clinical metastatic disease, LND was performed in 48%. Radiographic LAD for those with clinical metastatic disease (26/85 patients, 31%) had sensitivity of 94%, specificity of 49%, positive predictive value (PPV) of 43%, and negative predictive value (NPV) of 95% for pathologically confirmed lymph node involvement. Radiographic LAD for patients without clinical metastatic disease (37/138 patients, 27%) had sensitivity of 90%, specificity of 52%, PPV of 25%, and NPV of 96% for pathologically confirmed lymph node involvement. On multivariate logistic regression analysis (adjusted for age, gender, smoking status, obesity, non-clear cell histology, and grade) having clinical metastatic disease was significantly associated with pathologic node positivity (RR = 3.37, 95% CI 1.19 – 20.6). Conclusions: Radiographic lymphadenopathy is a nonspecific finding in patients with RCC and LND is not routinely performed at our institution. However, in the setting of clinical metastatic disease, radiographic LAD is more likely to represent pathological lymph node metastases.
An Open-Label, Randomized, Parallel, Multi-Center Trial Comparing the Safety and Efficacy of rFVIIa When Administered as I.V. Bolus or I.V. Continuous Infusion to Hemophilia Patients with Inhibitors during and after Surgery.
Authors: Rajiv K. Pruthi, Prasad Mathew, Leonard A. Valentino, Stephanie V. Seremetis
Journal: Blood (2004)
Liver cancer drug is rejected for routine NHS use but will remain in Cancer Drugs Fund
Authors: Ingrid Torjesen
Journal: BMJ (2017)

The liver cancer treatment sorafenib should not be available routinely in the NHS in England, but it should continue to be available through the Cancer Drugs Fund, the National Institute for Health and Care Excellence (NICE) has recommended in draft guidance.

NICE originally published guidance in 2010 saying that sorafenib was not cost effective, even though it had considered the drug under its higher cost per quality adjusted life year (QALY) criterion for end of life treatments and …
577. DNA Ministrings: Linear-Covalently Closed Minivectors for Use in Non-Viral Gene Therapy with Applications Toward Ovarian Cancer
Authors: Shirley Wong, Roderick A. Slavcev
Journal: Molecular Therapy (2015)

Gene therapy depends on the successful transfer of genetic material into the nuclei of targeted human cells. Non-viral strategies address the safety concerns of viral gene delivery, but generally suffer from low transfection efficiencies. We previously constructed an enhanced linear covalently closed (LCC) minivector, a DNA ministring, which confers improved efficiency and safety over its plasmid, and even its isogenic circular counterparts. DNA minivectors are comprised solely of the eukaryotic expression cassette without the bulk of an immunogenic bacterial backbone, thus ensuring greater bioavailability, higher transfection efficiency, and prolonged duration of gene expression. The linear nature of DNA ministrings minimizes the potential for insertional mutagenesis from random genomic integration. DNA ministrings are produced through a bacteriophage (phage) -derived recombination system in recombinant Escherichia coli (Fig. 1A). The phage-derived protelomerase, Tel, regulated via a temperature-inducible expression system, acts on a parent plasmid to produce DNA ministrings in vivo, later purified for gene transfer applications. We report further development in DNA ministring production. By encoding a homing endonuclease under control of a separate promoter, and its respective target site onto the backbone of the parent plasmid, we eliminate residual parent plasmid and LCC backbone, simplifying ministring purification. We also began construction of a novel platform utilizing filamentous phage M13 to produce phage-encapsulated DNA ministrings as a one-step therapeutic production system, termed BEAM (Bacteriophage Encapsulated & Assisted Ministring) (Fig. 1B). Phages are exploited for drug delivery because they are safe, easy to produce, and genetically versatile. Since M13 packages single-stranded DNA (ssDNA), the parent plasmid must produce an ssDNA molecule that encodes both the ministring base sequence and its complementary sequence, which can anneal to form the double-stranded DNA (dsDNA) ministring prior to packaging. We report our initial developments for this plasmid. Last, we examine the applicability of DNA ministrings towards ovarian cancer therapy. We encoded negative dominant topoisomerase alleles, hypothesized to produce DNA-damaging derivatives mimicking the effect of common chemotherapeutics such as topotecan. We present the results of ministring delivery of such alleles in the treatment of ovarian cancer cell lines.
Abstract 1523: Prostaglandin E2 promotes colorectal cancer stem-like cell expansion and metastasis
Authors: Dingzhi Wang, Lingchen Fu, Haiyan Sun, Raymond N. DuBois
Journal: Cancer Research (2015)

Abstract Emerging evidence suggests that chronic inflammation and inflammatory mediators contribute to cancer stem-like cell (CSLC) formation, maintenance, and expansion. However, the mechanisms underlying their contribution to CSLC regulation are poorly understood. Here we demonstrate that an inflammatory mediator, prostaglandin E2 (PGE2), induces colorectal CSLC expansion in vivo and in vitro. PGE2 also accelerates liver metastatic tumor incidence and numbers in an orthotopic model. Furthermore, we show that NF-κB is required for PGE2 induction of CSLCs and colorectal tumor metastatic spread. PI3K and MAPK pathways mediate PGE2 activation of NF-κB in induction of CSLCs. These results demonstrate that PGE2 induces colorectal CSLC expansion by activating NF-κB via PI3K-Akt and MAPK pathways. Our findings not only uncover a previously unrecognized role of PGE2 in induction of CSLCs and metastasis, but also may delineate a novel therapeutic approach for CRC patients by targeting CSLCs via inhibition of the PGE2 signaling pathway. Citation Format: Dingzhi Wang, Lingchen Fu, Haiyan Sun, Raymond N. DuBois. Prostaglandin E2 promotes colorectal cancer stem-like cell expansion and metastasis. [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 1523. doi:10.1158/1538-7445.AM2015-1523
Abstract 2635: Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum
Authors: Ana Ruiz-Saenz, Manbir Sandhu, Yazmin Carrasco, Rebecca L. Maglathlin, Jack Taunton, Mark M. Moasser
Journal: Cancer Research (2015)

Abstract There is increasing evidence implicating HER3 in several types of cancer, as a resilient copartner for HER2 in HER2-amplified cancers, and as a driver of resistance in many other types of cancer. However, the development of targeted therapies to inactivate HER3 function has been a challenging endeavor. Its tumor-driving functions are only sometimes driven by ligand-activation, and targeting its extracellular domain with antibody molecules has only limited effects. Its kinase domain functions in allostery, not catalysis, and we have previously shown that the classical ATP-analog class of tyrosine kinase inhibitors fail to inactivate it. Here we describe a novel approach that eliminates HER3 expression. This involves interfering with mechanisms critical for its cotranslational translocation into the endoplasmic reticulum (ER), resulting in the elimination of HER3 protein expression and loss of HER3 function. The small-molecule cotransin CT8 binds the Sec61 translocon channel in the ER membrane and prevents the signal peptide of the nascent HER3 protein from initiating its cotranslational translocation into the lumen of the ER, resulting in the degradation of HER3. Interestingly, CT8 treatment prevents HER3 translocation while the other HER proteins are unaffected. In addition, CT8 treatment suppresses the compensatory induction of HER3 that accompanies lapatinib treatment of HER2-amplified cancer cells, making for a durable suppression of HER2-HER3 signaling with the lapatinib-CT8 combination. Consistent with the effective inactivation of HER2-HER3 signaling, CT8 treatment synergistically enhances the apoptotic effects of lapatinib in HER2-overexpressing cancer cells. The target selectivities of cotransins are highly dependent on their structure and the signal sequence of targeted proteins and can be narrowed through structure-function studies. Our results thus highlight Sec61-dependent processing as a novel strategy to eliminate HER3 expression and function with considerable potential for the treatment of HER2-amplified and other types of cancers. Citation Format: Ana Ruiz-Saenz, Manbir Sandhu, Yazmin Carrasco, Rebecca L. Maglathlin, Jack Taunton, Mark M. Moasser. Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum. [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 2635. doi:10.1158/1538-7445.AM2015-2635
Secreted proteins defy the expression level–evolutionary rate anticorrelation
Authors: Felix Feyertag, Patricia M. Berninsone, David Alvarez-Ponce
Journal: Molecular Biology and Evolution (2016)

The rates of evolution of the proteins of any organism vary across orders of magnitude. A primary factor influencing rates of protein evolution is expression. A strong negative correlation between expression levels and evolutionary rates (the so-called E-R anticorrelation) has been observed in virtually all studied organisms. This effect is currently attributed to the abundance-dependent fitness costs of misfolding and unspecific protein-protein interactions, among other factors. Secreted proteins are folded in the endoplasmic reticulum, a compartment where chaperones, folding catalysts, and stringent quality control mechanisms promote their correct folding and may reduce the fitness costs of misfolding. In addition, confinement of secreted proteins to the extracellular space may reduce misinteractions and their deleterious effects. We hypothesize that each of these factors (the secretory pathway quality control and extracellular location) may reduce the strength of the E-R anticorrelation. Indeed, here we show that among human proteins that are secreted to the extracellular space, rates of evolution do not correlate with protein abundances. This trend is robust to controlling for several potentially confounding factors and is also observed when analyzing protein abundance data for 6 human tissues. In addition, analysis of mRNA abundance data for 32 human tissues shows that the E-R correlation is always less negative, and sometimes nonsignificant, in secreted proteins. Similar observations were made in Caenorhabditis elegans and in Escherichia coli, and to a lesser extent in Drosophila melanogaster, Saccharomyces cerevisiae and Arabidopsis thaliana. Our observations contribute to understand the causes of the E-R anticorrelation.
Abstract 3440: High-dose-rate brachytherapy as monotherapy for favorable-risk adenocarcinoma of the prostate delivered in a single 19 Gy fraction: Preliminary results of a prospective pilot study
Authors: Scott Dahlbeck, Chase C. Hansen, Werner deRiese, A. Robert Kagan, Carlos Torres, Maurizio Chiriva-Internati, Everardo Cobos, Jose A. Figueroa, Diane Nguyen, Lukman Tijani, Jaden D. Evans
Journal: Cancer Research (2015)

Abstract INTRODUCTION: We evaluated the acute genitourinary (GU) and gastrointestinal (GI) toxicities, health-related quality of life (HRQOL) factors, biochemical control rates, and technical feasibility of high-dose-rate (HDR) brachytherapy as monotherapy for favorable-risk prostate cancer delivered in a single 19 Gy fraction. METHODS: A single-institution, prospective pilot study was performed by evaluating 6 patients with low- and intermediate-risk prostate cancer treated with high-dose-rate (HDR) brachytherapy as monotherapy. Patients received a single 19 Gy fraction as HDR monotherapy without the use of a transperineal hyaluronic acid injection. Patients were assessed according to the Common Terminology Criteria for Adverse Events version 4.0 and Health-Related Quality of Life (HRQOL) questionnaires. Additionally, prostate specific antigen levels have been followed for evidence of biochemical failure. RESULTS: All 6 patients tolerated the implant well and were all discharged home the same day. Median follow-up was 15 months with all subjects followed for at least 12 months. No grade 3, 4, or 5 toxicities were observed. Two of the 6 patients experienced grade 2 GU toxicity. One patient experienced grade 2 GI toxicity. HRQOL bowel and urinary assessments revealed peak complaints at 3 months which returned to baseline at 6 months. There have been no biochemical relapses. CONCLUSION: This is the first study using HDR brachytherapy as monotherapy for favorable-risk prostate cancer using one implant delivered in a single 19 Gy dose in the United States. All patients demonstrated acceptable acute toxicities and were pleased with their cost-effective treatment choice. Citation Format: Scott Dahlbeck, Chase C. Hansen, Werner deRiese, A. Robert Kagan, Carlos Torres, Maurizio Chiriva-Internati, Everardo Cobos, Jose A. Figueroa, Diane Nguyen, Lukman Tijani, Jaden D. Evans. High-dose-rate brachytherapy as monotherapy for favorable-risk adenocarcinoma of the prostate delivered in a single 19 Gy fraction: Preliminary results of a prospective pilot study. [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 3440. doi:10.1158/1538-7445.AM2015-3440
Abstract 4374: DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma
Authors: Nathaniel Weygant, Dongfeng Qu, Randal May, Ryan M. Tierney, William L. Berry, Lichao Zhao, Shweta Agarwal, Parthasarathy Chandrakesan, Sripathi M. Sureban, Michael J. Schlosser, James J. Tomasek, Courtney W. Houchen
Journal: Cancer Research (2015)

Abstract Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and the 8th most common cancer overall in the US. RCC survival rates drop precipitously with regional and distant spread and recent studies have demonstrated that RCC presents an epithelial-mesenchymal transition (EMT) phenotype linked to increased recurrence and decreased survival. EMT is a key characteristic of tumor stem cells (TSCs) along with chemo-resistance and radio-resistance, which are also phenotypic of RCC. Targeting these factors is key to increasing the survival of RCC patients. Doublecortin-like kinase 1 (DCLK1) marks TSCs in pancreatic and colorectal cancer and regulates EMT and stemness. Analysis of the Cancer Genome Atlas’ RCC dataset revealed that DCLK1 is overexpressed and dysregulated on the mRNA and epigenetic level in more than 93% of RCC tumors relative to adjacent normal tissue. Immunohistochemistry using α-DCLK1 antibody confirmed overexpression and demonstrated a major increase in immunoreactivity in stage II-III tumors compared to normal kidney and stage I tumors. Small-interfering RNA (siRNA) mediated knockdown of DCLK1 resulted in decreased expression of EMT and pluripotency factors and significantly reduced invasion, migration, focal adhesion, drug-resistance, and clonogenic capacity. These findings suggest that DCLK1 is a novel, overexpressed factor in RCC progression that may be targeted to suppress EMT, metastasis, and stemness in early-stage and advanced RCC to increase patient survival. Moreover, the possibility that DCLK1 may mark a population of tumor stem-like cells in RCC should be further investigated in light of these findings. Citation Format: Nathaniel Weygant, Dongfeng Qu, Randal May, Ryan M. Tierney, William L. Berry, Lichao Zhao, Shweta Agarwal, Parthasarathy Chandrakesan, Sripathi M. Sureban, Michael J. Schlosser, James J. Tomasek, Courtney W. Houchen. DCLK1 is a broadly dysregulated target against epithelial-mesenchymal transition, focal adhesion, and stemness in clear cell renal carcinoma. [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 4374. doi:10.1158/1538-7445.AM2015-4374
Comparison of Outcomes for Non-Myeloablative (NMA) and Myeloablative (MA) Conditioning for Adults with Acute Lymphoblastic Leukaemia (ALL) in First and Second Complete Remission (CR): a Center for International Blood and Marrow Transplant Research (CIBMTR) Analyisis.
Authors: David I. Marks, Tao Wang, Waleska S. Peréz, Donald W. Bunjes, John F. DiPersio, Martin S. Tallman, Daniel J. Weisdorf
Journal: Blood (2009)