tbuckley/cabot-search huggingface dataset:
Abstract LB-132: Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes
Authors: Sheila R. Alcantara Llaguno, Zilai Wang, Daochun Sun, Jian Chen, Jing Xu, Euiseok Kim, Kimmo Hatanpaa, Jack Raisanen, Dennis Burns, Jane Johnson, Luis F. Parada
Journal: Cancer Research (2015)

Abstract A central question in glioblastoma multiforme (GBM) research is the hierarchy of tumor-initiating cells, and its contribution to the malignant phenotype and genomic make-up of GBM. We examine the potential of adult lineage restricted central nervous system (CNS) progenitors to form malignant gliomas. We show that targeting of Nf1,p53 and Pten mutations in adult CNS progenitors but not stem cells gives rise to fully penetrant GBM. We identify two phenotypically and molecularly distinct GBM subtypes that arise from different adult progenitor lineages. Using multiple inducible cre transgenic lines, we demonstrate that murine GBMs are molecularly separable based on the cell of origin. The oligodendrocyte progenitor cell-derived murine tumors have parallels with a subset of human high-grade gliomas with oligodendrocytic component, tumors that have been ascribed better prognosis compared to classic malignant astrocytomas. These studies indicate that two independent sources of GBM-initiating adult progenitors are susceptible to identical mutations and point to the cell of origin as a major determinant of GBM subtype. Citation Format: Sheila R. Alcantara Llaguno, Zilai Wang, Daochun Sun, Jian Chen, Jing Xu, Euiseok Kim, Kimmo Hatanpaa, Jack Raisanen, Dennis Burns, Jane Johnson, Luis F. Parada. Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes. [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-132. doi:10.1158/1538-7445.AM2015-LB-132
495. Activation of DNA Pattern Recognition Receptors After Plasmid Electrotransfer in Melanoma Cells and Tumors
Authors: Loree Heller, Masa Bosnjak, Katarina Znidar, Maja Cemazar
Journal: Molecular Therapy (2016)

In vivo electroporation or electrotransfer, the application of controlled electric pulses, enhances delivery of plasmid DNA to a wide variety of healthy tissues as well as many tumor types. Electrotransfer of pDNA encoding therapeutic genes substantially increases gene expression, enhancing subsequent therapeutic effects. Delivery of therapeutic plasmid DNA has reached clinical trials in the US and in Europe, primarily for cancer therapies and infectious disease vaccines. In several preclinical tumor models, delayed tumor growth, increased survival time, and even complete tumor regression can occur with intratumoral electroporation, also known as electrotransfer, of DNA oligonucleotides or plasmid DNA devoid of a therapeutic gene (empty vector). In B16.F10 mouse melanomas, these effects are preceded by significant elevation of several proinflammatory cytokines and chemokines including IFNβ, implicating the binding and activation of intracellular DNA-specific pattern recognition receptors in response to DNA electrotransfer. The purpose of this study was to investigate whether melanoma tumors and cells express cytosolic DNA sensors and whether these sensors respond to pDNA electrotransfer. Histologically, tumor necrosis independent of caspase-3 was observed. Although the mRNAs for several DNA sensors were detected in tumors, none was significantly upregulated. In B16.F10 cells in culture, IFNβ mRNA and protein levels were significantly upregulated after pDNA electrotransfer. The mRNAs for several DNA sensors were present in these cells and DAI, DDX60, and p204 mRNAs were significantly upregulated after pDNA electrotransfer. DDX60 protein levels were coordinately upregulated. Mirroring the observation of tumor necrosis, cells underwent a significant pDNA concentration-dependent decrease in proliferation and survival. Taken together, increased IFNβ and DNA sensor expression accompanied by cell death and tumor necrosis indicate that pDNA electrotransfer activates intracellular DNA sensors in B16.F10 cells and tumors, producing both in vitro and in vivo effects. The absence of activation of DNA sensors in vivo could be due to the lower transfection efficiency compared to that in vitro or to dilution by other tumor cell types. Electrotransfer is an efficient means of enhancing plasmid DNA introduction into tissues such as skin, muscle, and tumors for therapeutic application. Localized inflammation and induced cell death may contribute to cancer gene therapies but may impede gene therapies for which these effects are not desirable.
Combination of transarterial therapy with sorafenib for hepatocellular carcinoma.
Authors: R. Cabrera, D. S. Pannu, J. Caridi, R. Firpi, C. Soldevila-Pico, G. Morelli, V. Clark, T. J. George, D. Nelson
Journal: Journal of Clinical Oncology (2011)

e14598 Background: Treatment with sorafenib (S) is reserved for advanced, unresectable hepatocellular carcinoma (HCC) but may provide greater efficacy when combined with transarterial therpay (T) in earlier disease. Aim: Because limited data exist on the T+S combination, this study evaluated the safety and tolerability of this combination in a series of patients with intermediate and advanced HCC who received concomitant T+S. Methods: From March 2007 to January 2011 consecutive cases were treated with the combination of T+S. The patients received S two to four weeks before the T. Baseline clinical parameters, safety, and toxicity data were collected. Survival analysis was also performed. Results: Forty six patients received the T+S combination. Baseline characteristics included: mean age of 61 years (range; 46-76); 69.6% male; ECOG performance status was 0-1 in 100%; Child Pugh status (A 74%, B 26%); mean MELD was 8.1 (2-17); BCLC stage (B 70%, C 30%); Etiology HCV (59%) and mean AFP was 2,696 ng/mL(3-35,923). The median follow-up was 12 months (2-46) and the median time on S was 6 months (0.1-26). The transarterial treatments included LC Bead TACE (85%), LC Bead and sirtex (11%) and sirtex (4%). Mean number of T was 3 (1-13). The majority of the patients (89%) experienced adverse events (AEs) related to S. The most common AEs were fatigue (52%), hand-foot skin reaction (52%), and diarrhea (41%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (67%). A number of patients needed drug interruption (41%) and dose discontinuation (43%). Drug discontinuation was due to drug related AEs and due to radiologic and symptomatic progression (19.6%). The main AE related to T was post-TACE syndrome (24%). Tumor responses using amended RECIST were PD 28%, SD 11%, PR 26%, and CR 24%. The median survival for T+S was 18.5 months (95%CI 16.1-30.8). When sub-stratifying by BCLC stage, the median survival for stage B was 18.5 months (95%CI 6.4-30.5) and stage C was 17.0 months (95% CI 1.9-32.0). Conclusions: The combination of T+S is associated with an encouraging survival advantage over existing standard TACE treatment alone. However, the challenging AE profile of T+S needs further study.
BMET-28. THE NOVEL BRAIN PENETRATING PEPTIDE-DRUG CONJUGATE ANG1005 SHOWS ACTIVITY IN LC SUBSET OF PATIENTS WITH RECURRENT CNS METASTASIS FROM BREAST CANCER
Authors: Priya Kumthekar, Shou-Chou Tang, Andrew Brenner, Santosh Kesari, David Piccioni, Carey Anders, Jose Carrillo, Pavani Chalasani, Peter Kabos, Manmeet S. Ahluwalia, Nuhad Ibrahim
Journal: Neuro-Oncology (2016)

ANG1005 is a novel peptide-drug conjugate, consisting of 3 paclitaxel molecules covalently linked to Angiopep-2, a peptide designed to utilize the LRP-1 receptor to cross the Blood-CSF-Barrier and the Blood-Brain-Barrier and to penetrate malignant cells. Early breast cancer brain metastasis (BCBM) studies of ANG1005, excluded patients with leptomeningeal carcinomatosis (LC). An ongoing multi-site, open label Phase II study of patients within recurrent BCBM was amended to enroll patients who also had LC. ANG1005 was administered IV at 600 mg/m2 q3w. HER2+ patients were allowed to continue trastuzumab +/- pertuzumab treatment. The only response data was for the BCBM index lesions (CNS or systemic) using RECIST criteria. As LC patients were not assessed specifically for LC response, we report the secondary endpoint 6 month OS in this subset as a clinically relevant outcome. Median age of patients with LC in addition to BM was 45 (29-65) years. Safety in this subset, as in the general enrolled population, was similar to that of paclitaxel with myelosuppression as the predominant toxicity. Like the entire population, LC patients received a median of 5 (1-25) prior therapies for breast cancer. For their BCBM, 23 (82%) patients received cranial surgery and/or radiation and 15 (54%) received systemic therapies. CNS clinical symptoms post-ANG1005 were improved in many LC patients. The 6 month OS was 63.6 % (95% CI: 42.9, 78.5). Kaplan-Meier estimated median OS was 34.6 weeks (95% CI: 24.1, 40.9) from first ANG1005 treatment for the 28 LC patients. This study shows that the subset of patients with LC had survival outcomes that were an estimated median OS of ~8 months, exceeding the historical median of ~4 months following therapy. A randomized study in patients with BCBM and LC with overall survival as primary endpoint and physician’s choice as comparator is planned.
684. Long-Term, Multilineage Engraftment of Zinc Finger Nuclease-Edited Hematopoietic Stem Cells in Nonhuman Primates
Authors: Christopher W. Peterson, Jianbin Wang, Patricia Polacino, Michael C. Holmes, Shiu-Lok Hu, Philip D. Gregory, Hans-Peter Kiem
Journal: Molecular Therapy (2015)

Background: Nuclease-mediated gene editing in hematopoietic stem cells (HSCs) holds great promise for diseases including HIV infection and hemoglobinopathies, but little information is available regarding the feasibility of this approach in large animal models. To better evaluate the function of HSCs following gene editing, we have engineered cells with disrupted CCR5 alleles and assessed engraftment following autologous transplant in the pigtailed macaque, M. nemestrina. Disrupted CCR5 alleles in this model should directly protect against infection with simian/human immunodeficiency virus (SHIV). We are evaluating the extent to which CCR5-disrupted cell progeny engraft in macaques, and testing whether these cells impede infection by SHIV. Methods: Zinc Finger Nucleases (ZFNs) are used to target the CCR5 locus in macaque HSCs. Engraftment and persistence of these autologous stem cells, and stem cell-derived lymphoid and myeloid cells, are measured ex vivo and in vivo. Animals are challenged with SHIV virus containing an HIV envelope; to approximate the status of an HIV+ patient, three-drug combination antiretroviral therapy (cART) is initiated following viral set point. Animals reach undetectable levels of plasma viremia prior to autologous transplant with gene-edited cells. Results: CCR5 targeting experiments yield up to 60% gene disruption in CD34+ cells ex vivo, translating to approximately 5% steady state bulk disruption in vivo. Gene-disrupted cells demonstrate long-term, multilineage engraftment in macaques, including comparable levels of disruption in CD3+, CD20+, CD14+, and granulocyte subsets. We also observe biallelic disruption of CCR5 in colony forming assays. Importantly, this approach is equally feasible in SHIV-naïve and in SHIV-infected, cART-suppressed animals. During robust SHIV replication, our preliminary data suggest that CCR5-deleted cells undergo positive selection in vivo. Conclusions: This is the first demonstration of successful long-term multilineage engraftment of ZFN-edited HSCs in a NHP transplantation model. The CCR5 gene editing/HSCT strategy presented here results in robust levels of target gene disruption in vivo, yet does not impair HSC engraftment or differentiation. CCR5-deleted cells can undergo positive selection following challenge with SHIV. Our model enables the evaluation of novel therapeutic approaches in a number of infectious and genetic diseases including HIV infection. Specifically, these results are applicable not only in the context of acute HIV exposure, but also in the clinically relevant setting of pre-existing latent HIV infection.
Autologous Bone Marrow Transplant after Failed Peripheral Blood Stem Cell Mobilization Does Not Adversely Affect Engraftment or Transplant Related Toxicity.
Authors: B. Rioux-Masse, J. Roy, R. Belanger, D.C. Roy, L. Busque, D. Fish, G. Sauvageau, T. Kiss, S. Cohen
Journal: Blood (2005)
Abstract 1501: Evaluation of tumor vascularity in colorectal cancer using contrast enhanced ultrasonograpy in comparison with microvessel density
Authors: Takaomi Okawa, Hiromi Nogami, Munenori Takaoka
Journal: Cancer Research (2015)

Abstract Background : The relationship between tumor vascularity and malignant potential in colorectal cancer a(CRC) is reported by many authors. Therefore, to assess the tumor vascularity before surgical treatment is thought to be one of very important factors in CRC patients. Contrast enhanced ultrasonography (CEUS) can visualize the tumor vascularity vividly. We aim to determine the reliability of CEUS for the assessment of vascularity of CRC and to analyze the relationship between tumor vascularity and clinicopathological characteristics. In addition, to find the clinical application, we assessed the efficacy of chemotherapy in unresectable advanced CRC patients by CEUS. Methods : 56 patients undergoing surgical resection of CRC were studied. An ultrasound system (GE health care, LOGIC 7) is used and visualized the colo-rectal tumor using a 4.5MHZ probe. The 2nd generated ultrasonic contrast medium (Belfulbuttan, Sonazoid) is injected intravenously. Approximately 20 s after injection, microbubbles were obtained to enhance the B-mode image. Using the tumor image showing the strongest vascularity, region of interest were determined to measure mean echo intensity in the tumor. Their images were analyzed with NIH image program (developed by the US National Institutes of health) and calculated tumor vascularity as Vascular Index (VI). The clinicopathological features are based on the TNM classification from UICC. Using surgical specimens, tumor vascularity was assessed by immunohistochemistry as microvessel density in order to do statistical analysis for the correlation between VI, clinicopathologic features and microvessel density. Results : CEUS could visualize the tumor vascularity in all patients. In advanced CRC patients, we observed that the tumor invaded into other organ, such as prostate gland, small intestine and so on. The VI correlated significantly with depth of tumor invasion, liver metastasis and microvessel density. Furthermore, in patients with abundant vascularity in tumor before treatment, chemotherapy led to the reduction of VI prior to the radiographically visible difference in tumor size. Conclusion : CEUS can evaluate the tumor vascularity non-invasively and is very useful for the evaluation of their pathological diagnosis and the efficacy of chemotherapy in CRC. Citation Format: Takaomi Okawa, Hiromi Nogami, Munenori Takaoka. Evaluation of tumor vascularity in colorectal cancer using contrast enhanced ultrasonograpy in comparison with microvessel density. [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 1501. doi:10.1158/1538-7445.AM2015-1501
Abstract 528: PP4C plays a braking role in Akt-driven cancer migration/invasion
Authors: Ming-Yi Ho, Shu-Mei Liang, Chi-Ming Liang
Journal: Cancer Research (2015)

Abstract Treatment of lung cancer cells with growth factors and PGE2 activates phospho-AktS473 to transiently up-regulate phosphorylation of IKK and NF-κB within 1 hour, resulting in the elevation of cellular COX-2/PGE2, E-cadherin suppressor Snail and epithelial-mesenchymal transition (EMT) 24-31 hours later. In this study, we further found that in the cells treated with PGE2 or growth factors, the activated phospho-AktS473 declined to basal level 2 hours after treatment and increased again to reach a plateau 24-31 hours later but this resurgence of phospho-AktS473 was no longer associated with phosphorylation of IKK and NF-κB. To identify which factors or proteins cause dephosphorylation of IKK and NF-κB during phospho-AktS473 resurgence, we used immunoprecipitation, immunoblotting and activity assay approaches. Our results showed that during 12-31 hours of PGE2 treatment, the activity of protein phosphatase (PP) 4C and its association with IKK was increased. In comparison, there was no association between PP1, PP2A and PP5 with IKK. PP4C knockdown in PGE2 treated lung cancer cells increased their IKK/IκB/NF-κB signaling leading to the sustainment of COX-2 and Snail for much longer time. Knockdown of PP4C also increased the cellular EMT, migration and invasion of the lung cancer cells significantly. These findings demonstrated that PP4C downregulates IKK/IκB/NF-κB signaling to play a braking role in the Akt-driven lung cancer migration/invasion. Citation Format: Ming-Yi Ho, Shu-Mei Liang, Chi-Ming Liang. PP4C plays a braking role in Akt-driven cancer migration/invasion. [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 528. doi:10.1158/1538-7445.AM2015-528
250. The Cellular Origins of Regenerating Nodules and Malignant Formation in the FAH Model of Liver Injury After Bone Marrow Transplantation
Authors: Pei-Rong Wang, Yi Li, David W. Russell
Journal: Molecular Therapy (2015)

Recent reports have described the ability of donor-derived cells to form unexpected tissue types after transplantation. Exciting results were found in a mouse strain with mutations in the fumarylacetoacetate hydrolase gene (Fah-/-) by transplantation with hematopoietic cells. In the previous reports, we and other groups have shown that the proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes. To address how proliferated pattern of regenerating nodules and malignant formation and their origin, we created a transgenic mouse strain (ROSAnZ) that expresses a gene encoding nuclear-localized β-galactosidase from the ROSA26 promoter and used this strain to cross FAH strains to generated a new strain Fah-/- – ROSAnZ. Our results revealed both of β-Gal+ hepatocyte nuclei from host and donor-derived hepatocytes expressed Fah or GFP in their cytoplasm from donor were observed in regenerating nodules in Fah-/- – ROSAnZ after bone marrow transplantation. We showed that only hepatocytes were donor-derived, as we did not detect the presence of the other cell types present in regenerating liver nodules. We also demonstrated that hepatocytes created by fusion with bone marrow cells did not form malignant tumors, and the hepatic malignancies found in these mice were host origins and lacking in evidence of cell fusion in tumor formation in transplanted mice. In addition, we demonstrated that mesenchymal stem cells were recruited to the tumor and inflammatory cell infiltration was involved in forming malignant tumors and promoting tumor growth.
PTH-102 Renal dysfunction is an early morbid event in intestinal transplantation
Authors: R Sivaprakasam, A Wiles, J Woodward, S Duncan, H Tincknell, C Watson, A Butler, S Gabe, R Praseedom, N N V Jamieson, S J Middleton
Journal: Gut (2010)

<h3>Introduction</h3> Renal dysfunction (RD) following intestinal transplantation (SBTx) contributes to significant morbidity and is associated with reduced patient survival. RD has been shown to occur within the first two postoperative years, but renal function in the early postoperative period is poorly described. <h3>Methods</h3> The study was performed in a single centre on patients who had a minimum survival of 6 months following small bowel/multivisceral transplantation. A total of 20 transplants were performed during the study period and 11 were eligible for this study. The data collected were recipient demographics, pre-transplant renal function, donor demographics, immunosuppressive therapy. Renal function (measured by serum creatinine and e-GFR), serum Tacrolimus levels were at 7, 14 and 21 days, 6, 12, 18 and 24 months and 3 years. In addition, number of admissions, acute rejection episodes, need for modulation of immunosuppressants and function of the allografts. The data were retrieved from a prospectively collected database. <h3>Results</h3> 8/11 patients had deterioration in the renal function with mean serum creatinines at Day 14, 21 of 172.4 and 161.2 μmol and at 3 and 6 months 163.1 and 143.9 μmol, respectively. The serum Tacrolimus levels were well controlled between 8.27 and 9.17 μg/l throughout the study period. The RD was treated by 3/8 patients being converted to m-TOR inhibitors and in the other 5/8 patients reduced Tacrolimus levels were used. The renal function for patients converted to MTOR inhibitors improved. The mean number of admissions in the first year after the transplant was 3.66 and 4.13 during 3 years. There was an association between the number of readmissions and renal dysfunction suggesting that these patients had a poorer outcome as previously observed by others. However, we did not find an association between RD and Tacrolimus levels which other have reported. <h3>Conclusion</h3> In our cohort, the renal dysfunction was noted in 73% (8/11) of patients and it occured within the first month of the SBTx. The association with readmission suggests it is related to impaired outcome, its cause remains speculative.
High-Dose of Epoietin Alfa in Patients with Low-Risk Myelodysplastic Syndromes (MDS): A Single Institution Experience.
Authors: Giuseppe Mele, Clelia Musto, Rosella Matera, Maria Luigia Vigliotti, Alfredo Tartarone, Giampiero Romano, Mariarosa Coccaro, Nicola Di Renzo
Journal: Blood (2004)
A Phase 3 Study of Tenofovir Alafenamide (TAF) Compared With Tenofovir Disoproxil Fumarate (TDF) in Patients With HBeAg-negative, Chronic Hepatitis B (CHB): Week 48 Efficacy and Safety Results
Authors: Henry Lik-Yuen Chan, Scott Fung, Wai Kay Seto, Wan-Long Chuang, Chi-Yi Chen, Hyung Joon Kim, Aric Josun Hui, Harry Janssen, Abhijit Chowdhury, Tak Yin Owen Tsang, Rajiv Mehta, Edward Gane, Seng Gee Lim, John F. Flaherty, Benedetta Massetto, Kathryn Kitrinos, Phillip Dinh, Mani Subramanian, John McHutchison, Yiwei Lu, Young-Suk Lim, Sibrat Acharya, Kosh Agarwal
Journal: Clinical Gastroenterology and Hepatology (2016)