tbuckley/cabot-search huggingface dataset:
335. Toward a Cellular Therapy for Metabolic Liver Disease: Gene Targeting of the Ornithine Transcarbamylase (Otc) Locus in Bipotential Murine Oval Liver Cells (BMOL) Using Adeno-Associated Virus
Authors: Grant J. Logan, Ken H. Woo, Christine M. Smyth, Sharon C. Cunningham, Jessica R. Trippit, Gustavo de Alencastro, George C.T. Yeoh, Ian E. Alexander
Journal: Molecular Therapy (2015)

Liver progenitor cells (LPC) possess significant potential as a cellular therapy as they are easily isolated, can differentiate into hepatocytes and cholangiocytes and maintain stable phenotype in long-term culture. However, their use to correct recessive genetic disease in an autologous context will require repair of mutant loci. Adeno-associated virus induced homologous recombination (AAV-HR) is a highly effective tool for this task as it is >1000-fold more efficient than alternative approaches such as plasmid DNA and adenovirus. As with other HR systems, the frequency of AAV-HR is increased by DNA strand breaks (DSB) at the target locus. To develop a model of gene targeting in LPC, an AAV vector was constructed to target the Otc locus in Spfash mice which would both correct the mutant base and insert Otc exons 5-10 as well as a polyadenylation signal to support transcription and translation of the targeted gene. A neomycin phosphotransferase expression cassette was also included to permit G418-selection of transduced cells. The capacity of the construct (OTCe4-neo) to correctly target was confirmed by restoration of OTC expression in hepatocytes of male Spfash mice injected as neonates with 2.2 × 1011 vg packaged in hepatotropic serotype 8 capsids. Using an enzyme activity assay, clusters of OTC positive cells were observed in liver tissue sections consistent with locus repair and subsequent replication of corrected cells. The vector was also used to target the Otc locus in BMOL-TAT-LacZ, a murine LPC line derived from a transgenic mouse after three weeks on a choline-deficient, ethionine-supplemented (CDE) diet to increase LPC frequency. In vitro targeting was detected by nested PCR analysis of G418 selected populations. Based on this promising data, cell lines were isolated from male Spfash mice maintained on the CDE diet and validated to be BMOL by (i) expression of LPC markers (E-Cad, A6, EpCAM, CD24 and CK19) using immuno-histochemistry and (ii) their differentiation into hepatoblasts or ductal epithelial cells when maintained in appropriate in vitro conditions. Ongoing experiments will test the capacity of OTCe4-neo to target the Otc locus in the BMOL-Spfash lines. We have also developed CRISPR technology to induce DSB in exon 4 of Otc and functionally validated the constructs in BMOL-Spfash. While not essential for success of the project, application of CRISPR should increase the basal frequency of AAV-HR in BMOL- Spfash and expedite downstream experiments designed to test the therapeutic efficacy of LPC.
The Role of the Slit-Robo Family in Adult Patients with Acute Myeloid Leukemia
Authors: Aleksandra Golos, Dorota Jesionek-Kupnicka, Tadeusz Robak, Ewa Wawrzyniak, Lidia Anna Gil, Mieczyslaw Komarnicki, Anna Wache, Agnieszka Wierzbowska
Journal: Blood (2015)
Abstract 1372: Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts
Authors: Simon P. Robinson
Journal: Cancer Research (2015)

Abstract Anti-angiogenic therapy has shown considerable efficacy in metastatic renal cell carcinoma (mRCC). However, the ability of drugs such as sunitinib to delay tumour progression and extend survival is limited, due to both innate and evasive drug resistance, thought to arise through alternative, VEGF-independent mechanisms of tumour re-vascularization. Furthermore, there are no validated biomarkers that predict which mRCC patients will benefit from anti-angiogenic therapy. In investigating the response of 786-O RCC xenografts to sunitinib, a model of acquired resistance has been established with chronic treatment. The aims were to evaluate fractional blood volume (fBV) derived from susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide (USPIO) particles as a non-invasive imaging biomarker of response, and interrogate the vascular phenotype of 786-O xenografts exhibiting acquired resistance to sunitinib. Mice bearing established xenografts underwent MRI prior to and two weeks after daily treatment with 40mg/kg sunitinib. USPIO particle uptake was reduced in all treated tumours, resulting in a highly significant reduction in fBV in the absence of any change in tumour volume (Table 1). This response was associated with a significant reduction in the uptake of the perfusion marker Hoechst 33342. The average pre-treatment tumour fBV was significantly positively correlated (R2 = 0.92, p&amp;lt;0.0001) with sunitinib-induced changes in tumour fBV across the cohort. Additional tumour-bearing mice exhibiting acquired resistance to sunitinib (designated 786-O-R) were imaged when their tumours reached at least 4x their volume at commencement of treatment. Resistant 786-O- R xenografts revealed a suppressed fBV whilst still being treated with sunitinib. Pre-treatment tumour fBV is a predictive biomarker of subsequent response to sunitinib in RCC. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O RCC xenografts. Table 1 786-O (n = 9)786-O-R (n = 4)PrePostPostTumour volume (mm3)153 ± 17148 ± 24471 ± 63fBV (%)8.3 ± 22.4 ± 0.5**2.1 ± 0.5fBV / Tumour volume6.8 ± 22.5 ± 1*0.5 ± 0.1Hoechst 33342 uptake (%)13.5 ± 56.4 ± 1*n.a. Citation Format: Simon P. Robinson. Acquired resistance to sunitinib is not associated with functional re-vascularization in 786-O renal cell carcinoma xenografts. [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 1372. doi:10.1158/1538-7445.AM2015-1372
Dose and Time-Dependent Association of Red Blood Cell Transfusion with Increased Risk of GvHD and Worse Survival after Allogeneic HSCT
Authors: Sakura Hosoba, Edmund K. Waller, Sheilagh Barclay, Kirk A Easley, Neeta Shenvi, John Roback, James C. Zimring, Cynthia R. Giver
Journal: Blood (2014)
Prenatal Exposure To Endocrine Disruptors And Respiratory Function In A Cohort Of Mexican Preschoolers
Authors: A. Barraza-Villarreal, M. C. Escamilla-Nunez, L. Hernandez-Cadena, D. Boyd-Barr, P. Sly, U. Ramakrishnan, I. Romieu
Journal: American Journal of Respiratory and Critical Care Medicine (2015)
PTU-014 Safety and efficacy of endoscopic resection followed by radiofrequency ablation for Barrett's high-grade dysplasia and intramucosal cancer
Authors: J Mannath, K Ragunath, B J Rembacken, R E Pouw, C M Sondermeijer, J J Bergman
Journal: Gut (2010)

<h3>Introduction</h3> Endoscopic resection (ER) is a minimally invasive treatment for Barrett9s high-grade dysplasia (HGD) and intramucosal cancer (IMC). However, a significant proportion of patients may develop malignant transformation of remaining Barrett9s. Radiofrequency ablation (RFA) is a new, safe and effective modality for eradicating dysplasia and intestinal metaplasia. However there are limited data on the safety and efficacy of a combined approach including ER followed by RFA. <h3>Methods</h3> The aim was to assess the feasibility, safety and efficacy of the combined approach. Patients were enrolled from two tertiary referral centres in UK, as part of a multicentre European trial (EURO II). All visible mucosal lesions were removed by ER. RFA was carried out at 6–8 weekly intervals for a maximum of five sessions. HALO 360 were used for circumferential ablation followed by HALO 90 for any remaining islands. <h3>Results</h3> 20 patients (average age 63, 19 males) with a mean Barrett9s length of 4.8 cm (range 2–11 cm) underwent ER of visible mucosal lesions. All patients had Paris 0-II lesions (IIa-14, IIb-5 and IIc-1) with a mean size of 12 mm (range 4–20 mm). ER was carried out using multiband mucosectomy device in 19 patients and ER cap in one patient. En-bloc resection was achieved in eight cases, the rest requiring a piecemeal approach. 10 (50%) patients were up-staged from HGD to IMC following ER. RFA was carried out at least 6 weeks after ER. After a median follow-up of 11 months (IQR 7.5–16.5) and a mean of 2.2 (range 1–5) RFA sessions, none of the patients had residual or recurrent dysplasia. On average, the combined approach resulted in 90% reduction in the endoscopically-observed extent of Barrett9s mucosa. In eight patients who had completed the treatment regimen, complete histological resolution of intestinal metaplasia was achieved. Three patients (15%) developed minor procedure-related complications including 1 food bolus obstruction which was managed endoscopically, 1 superficial mucosal tear and 1 episode of self-limiting chest pain. <h3>Conclusion</h3> Endoscopic resection followed by radiofrequency ablation is a feasible, safe and effective approach for eradicating dysplasia and intestinal metaplasia in Barrett9s oesophagus. Long-term follow-up is warranted before this treatment modality could be implemented in routine clinical practice.
Abstract 3703: A prospective study of racial/ethnic disparities in pain experience among breast cancer patients undergoing radiotherapy
Authors: Eunkyung Lee, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Wei Zhao, Jennifer J. Hu
Journal: Cancer Research (2015)

Abstract Purpose: Pain is one of the multiple quality of life issues in breast cancer survivors. We sought to determine whether race/ethnic disparity exists in radiotherapy (RT)-induced pain and to assess associated risk factors. Methods and Materials: Consecutive 375 female patients undergoing adjuvant RT after breast-conserving surgery during 2009-2014 were evaluated. Pain score was assessed as mean of the four pain severity items (pain at its worst, least, average, and now) using 11-point numeric rating scale (0-10) at pre-RT and post-RT. Pain scores of 4 to 10 were regarded as clinically relevant pain. Pain presence and RT-induced change were examined. In multivariable logistic regression analysis, we evaluated risk factors for pre-RT, post-RT, and RT-induced pain. Results: A total of 15.5% participants self-identified as non-Hispanic white (NHW), 20.8% African American (AA), and 63.7% as Hispanic white (HW). AA patients were more likely to be obese, to report comorbidities, and to have advanced diseases. Pain prevalence was 15.9% at pre-RT and 31.3% at post-RT while 19.7% of patients experienced RT-induced pain. Post-RT pain severity and pain presence were associated with race/ethnicity, age, BMI, number of comorbidity, tumor stage, HER2 status, axillary surgery, fractionation, RT dose, breast volume, and hotspot volume (V105). Multivariable analyses identified HW and obese as independently associated with pre-RT pain while AA, HW, younger age (&amp;lt;50), number of comorbidity (≥2), V105, and pre-RT pain score with post-RT pain. Multivariable analysis also identified AA (OR = 3.23; 95% CI = 1.05-9.93, p = 0.041), younger age (OR = 2.45, 95% CI = 1.24-4.85, p = 0.010), and number of comorbidity (OR = 3.05, 95% CI = 1.29-7.21, p = 0.011 for 2; OR = 4.58, 95% CI = 1.46-14.37, p = 0.009 for at least 3) as risk factors for RT-induced pain. Conclusions: This prospective study demonstrates AA and younger women are more susceptible to RT-induced pain. In addition, the management of comorbidity conditions, such as diabetes, hypertension, and thyroid disease, deserves attention to prevent RT-induced pain in breast cancer patients. Citation Format: Eunkyung Lee, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Wei Zhao, Jennifer J. Hu. A prospective study of racial/ethnic disparities in pain experience among breast cancer patients undergoing radiotherapy. [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 3703. doi:10.1158/1538-7445.AM2015-3703
Abstract 2410: Cell-free DNA derived from ascites: Detection of copy number and somatic mutations using OncoScan FFPE® Assay
Authors: Hatim Husain, Sumathi Venkatapathy, German Gomez, Brian Woodward, Suzanna Lee, Lubena Khambaty, Lily Chen, Radha Duttagupta, Eric T. Fung, Razelle Kurzrock
Journal: Cancer Research (2015)

Abstract Background: There is increased interest in molecular analysis of cell-free DNA isolated from body fluids for the evaluation of tumor progression. These “liquid” biopsies are usually obtained from blood. Their advantages include the fact that they can be repeatedly accessed, are less invasive, and may be sensitive to changes in tumor profile from multiple metastatic sites. Materials and Methods: Eleven ascites samples from patients with metastatic epithelial neoplasms (gastric, N = 3; pancreas, N = 3; ovarian, N = 2; breast, N = 2; and lung cancer, N = 1) were investigated. Cell-free DNA was isolated from supernatant of ascites fluid (50 ml) after centrifugation using commercially available DNA purification kits (Norgen Bioteck Corp and Qiagen), and analyzed using the OncoScan FFPE Assay kit. Results: Cell-free DNA yields ranged from 1.7 ng to 230 ng per mL of ascites fluid, indicating wide variability in DNA content. Of the 11 patients, all had detectable aberrations, including copy number alterations affecting from &amp;lt;1%- 37% of the genome. A sample from a patient with metastatic breast cancer had apparent chromosome 12 chromothripsis (chromosome breakage with numerous clustered chromosomal rearrangements). Another sample (metastatic lung cancer) had high overall genomic stability (T); the lung tumor tissue did not show these alterations though the patient has never smoked. Other aberrations were seen in genes including: p53 (N = 4 patients), EGFR (N = 3), ERBB2 (N = 2), PI3KCA (n = 2). Conclusions. Combined copy number and somatic analysis of ascites cell-free DNA revealed clinically relevant aberrations, including ones not found in primary tumor tissue. Comparison to circulating cells in ascites, cell-free DNA in blood, as well as tumor molecular profile is ongoing. Citation Format: Hatim Husain, Sumathi Venkatapathy, German Gomez, Brian Woodward, Suzanna Lee, Lubena Khambaty, Lily Chen, Radha Duttagupta, Eric T. Fung, Razelle Kurzrock. Cell-free DNA derived from ascites: Detection of copy number and somatic mutations using OncoScan FFPE® Assay. [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 2410. doi:10.1158/1538-7445.AM2015-2410
254. Hepatocyte Growth Factor Gene Modification Enhances the Inflammation-Alleviating Effect of Umbilical Cord Derived Mesenchymal Stem Cells in a Bronchiolitis Obliterans Model
Authors: Xiao-Pei Cao, Dong-Mei Han, Li Zhao, Zi-Kuan Guo, Feng-Jun Xiao, Yi-Kun Zhang, Xiao-Yan Zhang, Lisheng Wang, Heng-Xiang Wang, Hua Wang
Journal: Molecular Therapy (2015)

BACKGROUNDS: Bronchiolitis obliterans is a serious, steadily, noninfectious, and fatal pulmonary complication. Currently specific and effective therapeutics for prevention or reversal of bronchiolitis obliterans is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stem cells (MSCs) on bronchiolitis obliterans. METHODS: A mouse model of experimental bronchiolitis obliterans was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients. These model mice were administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The distribution of the transplanted cells was detected by using real-time PCR (rt-PCR). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using FACS for lymphocyte immunophenotype of spleen, ELISA and rt-PCR for cytokine expression, and histopathological analysis for the transplanted trachea. RESULTS: The administrated MSCs mainly distributed in the transplanted trachea, blood, liver and lung of the recipients; HGF gene modification could enhance the engraftment of MSCs. The histopathological recovery of allografts tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGFtreated mice. Furthermore, the allo-transplantation induced immunophenotype disorders of the spleen cells, including Treg, Th1, Th2 and Th17 cells, were attenuated in both cell treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma and increased expression of anti-inflammatory cytokine IL-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor-beta.b. CONCLUSIONS: Treatment of bronchiolitis obliterans with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allografts tracheas histopathology in a mouse model. These findings might provide an effective therapeutic strategy for bronchiolitis obliterans.
Abstract LB-027: Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia
Authors: Tatsuro Watanabe, Naoko Aragane, Eisaburo Sueoka
Journal: Cancer Research (2015)

Abstract Adult T cell leukemia (ATL) is one of the aggressive malignant lymphomas induced by the infection of human T-cell Lymphotropic virus-1. Advanced stages of ATL patients still have a poor prognosis and novel therapeutic approaches are needed. Since mammalian target of rapamycin (mTOR) is a key molecule in cell growth and survival in a number of hematological malignancies, we here focused on mTOR signaling pathway consisting from mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). It has been already reported that inhibition of mTOR with rapamycin, a classical mTOR inhibitor, or its derivatives induces growth inhibition in ATL cells, and we found that Torin2, a second generation ATP-competitive mTOR inhibitor, has more beneficial effects than rapamycin does. Although Torin2 showed weaker growth inhibitory effect against ATL cell lines than rapamycin did at low concentrations (&amp;lt; 10 nM), its effect exceeded at higher concentrations (&amp;gt; 10nM) in CCK-8 assay and Trypan blue staining assay. To understand differences of mechanism of action between Torin2 and rapamycin, we first studied apoptosis and cell cycle arrest of the ATL cell line stained with annexin-FITC; Although both Torin2 and rapamycin caused G1 cell cycle arrest, a small number of ATL cells died in apoptotic manner at higher concentration of Torin2 but not of rapamycin. It is important to note that inhibition of mTOR pathway with rapamycin induced feedback activation of Akt (phosphorylation of Akt at Ser471), down stream of mTORC2, at high concentrations (&amp;gt; 50 nM) but Torin2 inhibited phosphorylation of Akt dose-dependently. Based on these results, we think Torin2 inhibits mTORC1 and mTORC2 followed by G1 cell cycle arrest, however rapamycin inhibits only mTORC1 and it induces feedback activation of Akt at high concentration resulting in resistance to apoptotic cell death. Thus, inhibition of mTOR pathway with Torin2 is new potent therapeutic approach in the treatment of ATL. Citation Format: Tatsuro Watanabe, Naoko Aragane, Eisaburo Sueoka. Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia. [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-027. doi:10.1158/1538-7445.AM2015-LB-027
A Cell‐Based Self‐Assembly Approach for the Production of Human Osseous Tissues from Adipose‐Derived Stromal/Stem Cells
Authors: Todd Galbraith, William P. Clafshenkel, Fabien Kawecki, Camille Blanckaert, Benoit Labbé, Michel Fortin, François A. Auger, Julie Fradette
Journal: Advanced Healthcare Materials (2016)

Achieving optimal bone defect repair is a clinical challenge driving intensive research in the field of bone tissue engineering. Many strategies focus on seeding graft materials with progenitor cells prior to in vivo implantation. Given the benefits of closely mimicking tissue structure and function with natural materials, the authors hypothesize that under specific culture conditions, human adipose-derived stem/stromal cells (hASCs) can solely be used to engineer human reconstructed osseous tissues (hROTs) by undergoing osteoblastic differentiation with concomitant extracellular matrix production and mineralization. Therefore, the authors are developing a self-assembly methodology allowing the production of such osseous tissues. Three-dimensional (3D) tissues reconstructed from osteogenically-induced cell sheets contain abundant collagen type I and are 2.7-fold less contractile compared to non-osteogenically induced tissues. In particular, hROT differentiation and mineralization is reflected by a greater amount of homogenously distributed alkaline phosphatase, as well as higher calcium-containing hydroxyapatite (P < 0.0001) and osteocalcin (P < 0.0001) levels compared to non-induced tissues. Taken together, these findings show that hASC-driven tissue engineering leads to hROTs that demonstrate structural and functional characteristics similar to native osseous tissue. These highly biomimetic human osseous tissues will advantageously serve as a platform for molecular studies as well as for future therapeutic in vivo translation.
Clinical Profile of Multiple Myeloma in Asia - an Asian Myeloma Network (AMN) Study
Authors: Jae Hoon Lee, Kihyun Kim, Jin Seok Kim, Chang Ki Min, Sung-Soo Yoon, Kazuyuki Shimizu, Takaaki Chou, Hiroshi Kosugi, Kenshi Suzuki, Hiroyuki Hata, Wenming Chen, Jian Hou, Jin Lu, Shang-Yi Huang, Wee-Joo Chng, Daryl Tan, Gerrard Teoh, James Chor Sang Chim, Noppadol Siritanaratkul, Weerasak Nawarawong, Brian GM Durie
Journal: Blood (2012)
Treating Ph+ Acute Lymphoblastic Leukemia (ALL) in the Elderly: The Sequence of Two Tyrosine Kinase Inhibitors (TKI) (Nilotinib and Imatinib) Does Not Prevent Mutations and Relapse.
Authors: Cristina Papayannidis, Paola Fazi, Alfonso Piciocchi, Francesco Di Raimondo, Giovanni Pizzolo, Angelo Michele Carella, Mario Cazzola, Antonio Cuneo, Pietro Leoni, Mario Luppi, Enrica Morra, Giorgina Specchia, Emanuele Angelucci, Monica Bocchia, Renato Fanin, Giuseppe Saglio, Daniele Vallisa, Sandra De Simone, Antonella Vitale, Ilaria Iacobucci, Simona Soverini, Anna Ferrari, Claudia Venturi, Caterina De Benedittis, Nicoletta Testoni, Antonio Curti, Stefania Paolini, Miriam Fogli, Giovanni Martinelli, Michele Baccarani
Journal: Blood (2012)