tbuckley/cabot-search huggingface dataset:
294. Myeloablative Conditioning Is Required for Efficient Engraftment of Gene-Modified Cells and Prevention of Antibody Production Against Transgene Products in a Rhesus Stem Cell Gene Therapy Model
Authors: Naoya Uchida, R. Patrick Weitzel, Charlotte Platner, Josiah Ballantine, Aylin C. Bonifacino, Sandra D. Price, Allen E. Krouse, Mark E. Metzger, Robert E. Donahue, John F. Tisdale
Journal: Molecular Therapy (2015)

Reduced intensity conditioning (RIC) regimens are desirable for hematopoietic stem cell (HSC)-targeted gene therapy. However, in previous gene therapy trials, low gene marking was reported in peripheral blood cells, raising the question that RIC might be insufficient for (1) opening niches for efficient engraftment and (2) inducing immunological tolerance to transgenes. Therefore, we sought to evaluate both engraftment and tolerance for genetically modified cells using our rhesus HSC gene therapy model following RIC. We performed a dose de-escalation of total body irradiation (TBI) (10, 8, 6, and 4Gy) as RIC transplantation (total 19 animals), in which mobilized rhesus CD34+ cells were transduced with a VSV-G-pseudotyped chimeric HIV-1 vector encoding GFP (or YFP) and these cells were transplanted into autologous animals following TBI. We evaluated GFP-positive rates (%GFP), average vector copy number per cell (VCN), and antibody titers against GFP and VSV-G in peripheral blood 6 months after transplantation. When we evaluated in vitro %GFP in transduced rhesus CD34+ cells, efficient transduction (22-71%) was observed among all TBI groups (without correlation). After transplantation of the transduced CD34+ cells, GFP-positive cells were detected in peripheral blood cells in all animals. Increasing doses of TBI resulted in higher %GFP with logarithmic regression in both granulocytes (R2=0.64, p<0.01) and lymphocytes (R2=0.67, p<0.01)(Figure). Similar results were observed between TBI dose and VCNs in both granulocytes (R2=0.54, p<0.01) and lymphocytes (R2=0.52, p<0.01). These data suggest that higher doses of TBI improve engraftment of gene-modified hematopoietic repopulating cells. To evaluate immunological tolerance for gene-modified cells, we measured both anti-GFP and anti-VSV-G antibody titers using serum samples from transplanted animals. Lower dose TBI allowed anti-GFP antibody production with logarithmic regression (R2=0.84, p<0.01)(Figure), while no significant effect of anti-VSV-G antibody was observed among all TBI groups (R2=0.003, p=0.87). These data demonstrate that higher dose TBI is important to induce immunological tolerance for gene-modified cells in a rhesus transplantation model. In summary, higher dose of TBI increased gene marking levels in transplanted rhesus macaques, while lower dose of TBI resulted in anti-GFP antibody production. Additional immunosuppressive therapy might be required in RIC to induce immunological tolerance for transgene products. Our findings should be valuable to consider conditioning regimens for clinical gene therapy.
Abstract 3034: A high-content screen to identify novel chromosome instability genes
Authors: Laura L. Thompson, Allison Baergen, Zelda Lichtensztejn, Kirk J. McManus
Journal: Cancer Research (2015)

Abstract Chromosome instability (CIN) is defined as an increase in the rate at which whole chromosomes or large chromosomal fragments are gained or lost. It is a characteristic of virtually all cancer types that is frequently observed in highly aggressive, drug resistant tumors. Despite this, the majority of human CIN genes have yet to be elucidated, highlighting the need for studies aimed at identifying the defective genes that underlie CIN. In this study we developed image-based approaches capable of detecting CIN-associated phenotypes following RNAi-based silencing of candidate CIN genes. The first assay involves quantifying nuclear areas following silencing, where changes in mean nuclear area relative to controls act as a surrogate marker of CIN. The second approach monitors micronucleus (MN) formation where increases in the number of micronuclei are indicative of CIN. These assays were employed in a high-content screen of 164 human candidate CIN genes in two unrelated cell lines, HT1080 and hTERT. In HT1080, the nuclear area and MN enumeration assays identified 43 and 83 putative CIN genes, respectively. In hTERT, the nuclear area and MN assays identified 55 and 48 putative CIN genes, respectively. Preliminary data collected through Western blotting, mitotic spreads and flow cytometry, has provided evidence to support the validation of a subset of these putative CIN genes (e.g. SKP1), as bona fide human CIN genes. Identifying novel CIN genes will provide critical insights into CIN and tumorigenesis, as well as identify potential targets that could be exploited for the development of superior therapeutic strategies. Citation Format: Laura L. Thompson, Allison Baergen, Zelda Lichtensztejn, Kirk J. McManus. A high-content screen to identify novel chromosome instability genes. [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 3034. doi:10.1158/1538-7445.AM2015-3034
Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma: Long Term Follow up and Factors Predicing Outcome in 345 Patients
Authors: Martha Q Lacy, Shaji K. Kumar, Betsy R. LaPlant, Kristina Laumann, Morie A Gertz, Suzanne R Hayman, Francis K Buadi, Angela Dispenzieri, John A. Lust, Stephen Russell, David Dingli, Steven R Zeldenrust, Rafael Fonseca, P.Leif Bergsagel, Keith Stewart, Vivek Roy, Taimur Sher, Asher Chanan-Khan, Craig Reeder, S. Vincent Rajkumar, Joseph R. Mikhael
Journal: Blood (2012)
Comparative Analysis of the Constitutively Active MPLW515L and JAK2V617F Alleles in a Murine Bone Marrow Transplant Model of Myeloproliferative Disease.
Authors: Y. Pikman, R.L. Levine, B.H. Lee, Z. Tothova, T. Mercher, M. Wadleigh, S.J. Lee, D.G. Gilliland, G. Wernig
Journal: Blood (2006)
Past use of hormone therapy and breast cancer risk.
Authors: W. Y. Chen, B. A. Rosner, S. E. Hankinson
Journal: Journal of Clinical Oncology (2011)

1502 Background: Although current use of hormone therapy (HT) is clearly associated with breast cancer risk, most studies have not seen an increased risk among past users of HT. However, the effects of longer term past use of HT have not been well quantified. Methods: We examined the relationship between past HT use and invasive breast cancer risk within the Nurses’ Health Study, a prospective cohort of 121,700 registered nurses aged 30-55 in 1976 who update information on cancer risk factors and outcomes through biennial questionnaires. For this analysis, the follow-up period was 1980 through 2006 and only included person-time for postmenopausal women. Status of HT use (never, past, or current), type of HT (oral unopposed estrogen (E alone) or combination oral estrogen + progesterone (E+P)), and duration of HT use were assessed every 2 years and defined prospectively. Proportional hazards models controlled for age, body mass index, parity, age at first birth, family history of breast cancer, benign breast disease, alcohol consumption, type of menopause, and ages at menarche and menopause. Results: During 1,458,952 person-years of follow-up among postmenopausal women, invasive breast cancer was diagnosed among 1653 women who had never used HRT, 365 past users of E+P and 532 past users of E alone. Regardless of duration of use, past use of E alone was not associated with breast cancer risk. Although past use of E+P for less than 10 years was not associated with breast cancer risk (RR (95% CI) 0.91 (0.77-1.06) for < 5 years and 1.06 (0.88-1.27) for 5-9.9 years), past use of E+P for greater than 10 years was associated with an increased risk of breast cancer (RR 1.37 (1.06-2.77) for 10-14.9 years and 1.46 (0.97-2.21) for 15-19.9 years, p for trend=0.004). Results were similar regardless of time since last use, but stronger for hormone-receptor positive tumors. Conclusions: Although shorter-term past use of E+P was not associated with breast cancer risk, past use of E+P for greater than 10 years was associated with persistenly increased breast cancer risk even after HT discontinuation.
Abstract 1143: EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect
Authors: Qilin Xu, Qunzhou Zhang, Ahn D. Le
Journal: Cancer Research (2015)

Abstract Head and neck cancer is one of the 10 most common cancers worldwide. Over-expression of EGFR has been demonstrated in approximately 90% of head and neck cancers, which is associated with progressive tumor growth, metastasis, recurrence, and resistance to chemo- and radiation therapies. Recurrent tumors are often therapy-resistant and may have their origin in resistant cancer stem cells (CSCs) and/or in tumor cells with an epithelial-mesenchymal transition (EMT) phenotype. Recently it is increasingly accepted that metabolic changes in cancer cells can drive tumor formation and progression. In our study, we used 20ng/ml EGF to treat human tongue cancer cell line, SCC-1 cells. Our results demonstrated that EGF induces EMT in oral SCC cells as characterized by a downregulation of E-cadherin (an epithelial marker), an upregulation of vimentin (a mesenchymal marker), increased invasive and metastatic capacities, and acquisition of stem-like properties such as the increased expression of ALDH1 and enrichment of CD44+/CD24− proportion of cancer cells. We also found that EGF treatment concomitantly enhanced L-lactate production and blocking glycolysis by 2-DG robustly reversed EGF-induced EMT and CSC-like phenotypes of OSCC cells. Then we further demonstrated that EGF regulates glycolysis/EMT/CSCs axis through downstream EGFR/PI3K signaling pathways in an EGFR/PI3K-dependent but AKT-independent manner. Importantly, we showed that in vivo treatment with 2-DG remarkably reduced the expression of ALDH1 and vimentin at both the in situ tumors and regional lymph nodes. Taken together, these findings have demonstrated that EGF drives tumor growth and metastasis through induction of EMT and CSC generation, which is orchestrated by an enhanced glycolytic metabolic program in OSCC cells. This work was supported by National Institute of Health Research Grant, R01DE 019932, Oral and Maxillofacial Surgery Foundation (OMSF) Research Grant, and the Schoenleber funding support Citation Format: Qilin Xu, Qunzhou Zhang, Ahn D. Le. EGF induces epithelial to mesenchymal transition and cancer stem-like cell properties in human head and neck cancer cells via promoting Warburg Effect. [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 1143. doi:10.1158/1538-7445.AM2015-1143
The Receptor for Hyaluronic Acid Mediated Motility (RHAMM): Characterization as an Immunotherapeutical Target in Chronic Lymphocytic Leukemia (CLL) and First Results of RHAMM-Derived Peptide Vaccination Trial.
Authors: Krzysztof Giannopoulos, Andreas Buhler, Jinfei Chen, Alexander Krober, Malgorzata Kowal, Anna Dmoszynska, Jacek Rolinski, Jochen Greiner, Hartmut Dohner, Stephan Stilgenbauer, Michael Schmitt
Journal: Blood (2007)
580. In Vivo Analyses of Aptamers and siRNA Therapeutics Against HIV-1 in Humanized Mouse Model
Authors: Sangeetha Satheesan, Haitang Li, Mayumi Takahashi, Jiehua Zhou, John Burnett, John J. Rossi
Journal: Molecular Therapy (2015)

Nucleic acid-based therapeutics are quickly emerging as a strong alternative or co-therapy to the chemical antiviral agents currently used to treat HIV-1/AIDS. Systemic delivery of siRNAs typically requires a carrier to prevent renal clearance, minimize the inflammatory response, and enhance the cellular uptake. This is particularly true for siRNAs against HIV, which require systemic intravenous injection to access the cells and tissues that are sites of HIV infection. Human CCR5 (C-C chemokine receptor type 5), a protein expressed by T-cells and macrophages, is an important coreceptor for macrophage-tropic virus, including HIV-1 R5 isolates.
Current state of the art of computer‐guided implant surgery
Authors: Jan D'haese, Johan Ackhurst, Daniel Wismeijer, Hugo De Bruyn, Ali Tahmaseb
Journal: Periodontology 2000 (2016)

Abstract The invention of computerized axial tomography (now known as computerized tomography) and developments of interactive software to allow virtual planning, with the aim to guide the surgery precisely toward a specific target, has dramatically improved general, as well as oral, surgery. Virtual dental implant planning allows for a prosthetically driven approach, resulting in the best possible design of the prosthesis, better esthetics, optimized occlusion and loading. This approach has also changed the surgical paradigm of using extensive flaps to obtain a proper view of the surgical area because flapless implant surgery, with or without immediate loading, has become more predictable. Two types of guided implant surgery protocols – static and dynamic – are described in the literature. The static approach, better known as computer‐guided surgery, refers to the use of a tissue‐supported surgical template. This reproduces the virtual implant position directly from computerized tomographic data and this information can be converted to guide templates to be used during surgery, with or without raising a mucoperiosteal flap. Dynamic guided surgery, also called navigation, reproduces the virtual implant position directly from computerized tomographic data and uses motion‐tracking technology to guide the implant osteotomy preparation. As the technology developed further, different levels of evidence were presented that showed various degrees of accuracy. Several protocols for guided surgery are available in the literature and are distinguished by different guide production techniques, methods of support and drilling/placement protocols. Currently, implant planning software using cone‐beam computerized tomography data has made it possible to plan the optical implant position virtually the optimal implant position, taking the surrounding vital anatomic structures and future prosthetic requirements into consideration. This paper summarizes the evolution and ongoing trends in digital and virtual planning and in implant surgery. The purpose of this overview was to clarify the different concepts in guided surgery and their respective advantages, disadvantages and limitations. The outcome of guided surgery is assessed in terms of implant survival, precision and complications. Clinical cases are given to demonstrate briefly the workflow and clinical guidelines for safe use of these approaches.
Effective Targeting of the PI3-K Pathway in CLL with NVP-BEZ235, a Novel Orally Available Dual PI3K/mTOR Inhibitor
Authors: Medhat Shehata, Susanne Schnabl, Dita Demirtas, Stefanie Tauber, Martin Hilgarth, Martin Bilban, Katrina Vanura, Edit Porpaczy, Christa Fonatsch, Stephan Stilgenbauer, Josef D. Schwarzmeier, Rainer Hubmann, Alexander Gaiger, Christoph Zielinski, Sauveur-Michel Maira, Carlos Garcia-Echeverria, Wolfgang Hackl, Ulrich Jaeger
Journal: Blood (2008)
2. Hepatitis C Virus Can Evolve Resistance To microRNA-122 Inhibitors
Authors: Gavriel Mullokandov, Benjamin Israelow, Judith Agudo, Marion Sourisseau, Ali Bashir, Andres Y. Maldonado, Arvin C. Dar, Matthew J. Evans, Brian D. Brown
Journal: Molecular Therapy (2015)

Hepatitis C virus (HCV) replication is dependent on a liver-specific microRNA (miRNA), miR-122. A recent clinical trial reported that transient inhibition of miR-122 using locked nucleic acid (LNA) oligonucleotides reduced viral titers in HCV infected patients. Though viral resistance was not reported, the transient nature of these studies makes it unclear whether HCV can evolve resistance to miR-122 inhibition. To address this important question, we generated liver cells in which miR-122 was stably inhibited using a lentiviral vector-based miR-122 decoy. Strikingly, after 20 days in culture we observed the emergence of an HCV variant that was resistant to miR-122 knockdown. Deep-sequencing of the resistant virus revealed that this was due to a single nucleotide change at position 28 (G28A) of the HCV genome, which falls between the two miR-122 seed-binding sites in the virus. We could recapitulate resistance into a wildtype virus by introducing the G28A mutation, which confirmed that this single nucleotide change was responsible. We also found that the G28A mutation makes HCV similarly resistant to miR-122 knockdown by LNA. Importantly, HCV isolates that were innately G28A were similarly resistant to miR-122 inhibition by miR-122 decoy and LNA, indicating that our findings apply to natural strains of the virus, and to inhibition using oligonucleotides. To better understand the mechanism by which G28A confers resistance, we precisely quantitated both wild-type and mutant virus miR-122 stoichiometric requirements. Our results indicate that in the presence of excess miR-122 to viral genomes, there was no difference in target site interaction. Instead, when the bioavailable concentration of miR-122 become rate-limiting, the G28A target site became preferentially regulated. These results indicate that target site selection is strongly influenced by microRNA concentration, and demonstrate that subtle differences in viral sequence, even outside the seed-binding site, greatly affect HCV's miR-122 concentration requirement. This study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has broader implications for the development and use of microRNA-based drugs and for our understanding of microRNA target site selection.
The burden of common skin diseases assessed with the EQ5D™: a European multicentre study in 13 countries
Authors: F. Balieva, J. Kupfer, L. Lien, U. Gieler, A.Y. Finlay, L. Tomás-Aragonés, F. Poot, L. Misery, F. Sampogna, H. van Middendorp, J.A. Halvorsen, J.C. Szepietowski, A. Lvov, S.E. Marrón, M.S. Salek, F.J. Dalgard
Journal: British Journal of Dermatology (2016)

Generic instruments measuring health‐related quality of life (HRQoL), like EQ5D™, enable comparison of skin diseases with healthy populations and nondermatological medical conditions, as well as calculation of utility data. To measure HRQoL in patients with common skin diseases and healthy controls across Europe using the EQ5D. This multicentre observational cross‐sectional study was conducted in 13 European countries. Each dermatology clinic recruited at least 250 consecutive adult outpatients to complete questionnaires, including the EQ5D. There were 5369 participants (4010 patients and 1359 controls). Mean ± SD self‐rated health state reported by patients was 69·9 ± 19·7; for controls it was 82·2 ± 15·5. When adjusted for confounding factors, including comorbidity, mean patient EQ visual analogue scores were 10·5 points lower than for controls (standardized β = −0·23). Odds ratio with 95% confidence interval for impairment in all five dimensions of EQ5D adjusted for confounders was doubled for patients compared with controls. Patients with hidradenitis suppurativa (HS), blistering conditions, leg ulcers, psoriasis and eczemas had the highest risk for reduction in HRQoL in most dimensions (2–10‐fold). Data on differences of impairment by dimensions offer new insights. This study confirms the large impact skin conditions have on patients' well‐being, differentiating between aspects of HRQoL. Patients with HS, blistering diseases, leg ulcers, infections and most chronic skin diseases reported reduced HRQoL compared with patients with chronic obstructive lung disease, diabetes mellitus, cardiovascular disease and cancers. These findings are important in the prioritization of resource allocation between medical fields and within dermatological subspecialities.
Factors Associated With Delays in Chemotherapy Initiation Among Patients With Breast Cancer at a Comprehensive Cancer Center
Authors: Katya Losk, Ines Vaz-Luis, Kristen Camuso, Rafael Batista, Max Lloyd, Mustafa Tukenmez, Mehra Golshan, Nancy U. Lin, Craig A. Bunnell
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: National guidelines endorse time-dependent quality metrics for breast cancer care. We examined factors associated with delays in chemotherapy initiation at an NCI-Designated Comprehensive Cancer Center. Patients and Methods: We identified 523 patients who received postoperative adjuvant chemotherapy between January 2011 and December 2013 at our center. We defined 28 days from last definitive surgery (LDS) to chemotherapy as the target time frame, and an unacceptable delay in chemotherapy initiation (UCD) as greater than 42 days from LDS. Multivariate regression models were used to identify factors associated with UCD and the impact of Oncotype DX testing in patients with hormone receptor (HR)–positive breast cancer. Results: Median days between LDS and chemotherapy initiation was 34 (interquartile range, 15), with 30% of patients starting within 28 days of LDS and 26.9% having UCD. Tumor characteristics such as subtype and stage affected UCD; patients with HR-positive or HER2-positive tumors were more likely to be delayed compared with those with triple-negative breast cancer. Patients with stage I disease, those undergoing mastectomy with or without immediate reconstruction, and those whose pathology sign-out was greater than 10 days postoperatively were more likely to be delayed. A higher proportion of UCD was found in HR-positive patients (31%) for whom Oncotype DX testing was ordered compared with those in whom it was not ordered (20%). Conclusions: This study provides insight into subpopulations that may be at risk to experience delays in chemotherapy initiation, directing interventions to improve the timeliness of care.
Abstract 3029: Role of eIF3a expression in cellular sensitivity to radiation treatment
Authors: Rima A. Tumia
Journal: Cancer Research (2015)

Abstract Translation initiation involving eukaryotic translation initiation factors (eIFs) is a crucial mechanism in controlling gene expression. eIF3a has been shown previously to regulate protein synthesis and cellular response to cisplatin treatment. Its expression has also been shown to negatively associate with prognosis. In this study, we tested a hypothesis that eIF3a regulates synthesis of DNA repair proteins, which in turn regulates cellular response to ionizing radiation (IR) treatments. We found that eIF3a overexpression sensitizes cellular response to IR while its knockdown causes resistance to IR. We also found that eIF3a over-expression increases IR-induced DNA damage and decreases Non-Homologous End Joining (NHEJ) repair activity by suppressing expression level of NHEJ repair proteins such as DNAPKcs. Consistently, eIF3a knockdown decreases IR-induced DNA damage and increases Non-Homologous End Joining (NHEJ) repair activity by enhancing expression level of NHEJ repair proteins. Together, we conclude that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating synthesis of DNA repair proteins and, thus, eIIF3a likely plays an important role in the outcome of cancer patients treated with DNA-damaging strategies. Note: This abstract was not presented at the meeting. Citation Format: Rima A. Tumia. Role of eIF3a expression in cellular sensitivity to radiation treatment. [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 3029. doi:10.1158/1538-7445.AM2015-3029