tbuckley/cabot-search huggingface dataset:
464. RCL-Pooling Assay: A Simplified Method for the Detection of Replication Competent Lentiviruses in Vector Batches Using Sequential Pooling
Authors: Corre Guillaume, Michel Dessainte, Jean-Brice Marteau, Bruno Dalle, David Fenard, Anne Galy
Journal: Molecular Therapy (2016)

Non-replicative recombinant HIV-1 derived lentiviral vectors (LV) are increasingly used in gene therapy clinical trials for various genetic diseases, infectious diseases or cancer. Before they are used in man, preparations of LV must undergo extensive biochemical and biological quality control testing. In particular, the legislation stipulates that the absence of replication-competent lentiviruses (RCL) must be demonstrated with suitable methods, on representative fractions of batches. Current standard and widely used methods based on cell culture are challenging because high titers of vector batches achieved translate into high volumes of cell culture that have to be tested. Since vector batch titers and sizes are continuously-increasing due to the improvement of production and purification methods, it is necessary to modify the current cell culture method. Here, we propose a practical optimization of the p24-decrease-based culture assay developed by Escarpe et al. (2003) using a pairwise pooling strategy enabling the test of higher vector inoculum volumes. These modifications significantly decrease material handling, operator time, leading to a cost effective method, while maintaining optimal sensibility of the RCL testing. This optimized RCL-pooling assay ameliorates the feasibility of the quality control of large-scale batches of clinical-grade LV while maintaining the same sensitivity.
Risk-Stratification Directed Prophylaxis with Additional Low-Dose of Methylprednisolone Can Reduce Acute Graft-Versus-Host Disease for Patients with Hematological Malignancies after Allogeneic SCT: A Randomized, Controlled, Clinical Trial
Authors: Ying-Jun Chang, Yu Wang, Lan-Ping Xu, Dai-Hong Liu, Kai-Yan Liu, Xiao-Hui Zhang, Fei-Fei Tang, Huan Chen, Yu-Hong Chen, Xiao-Dong Mo, Wei Han, Chen-Hua Yan, Feng-Rong Wang, Yu-Qian Sun, Xiao Jun Huang
Journal: Blood (2014)
APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis
Authors: Qingqing Ding, Chun-Ju Chang, Xiaoming Xie, Weiya Xia, Jer-Yen Yang, Shao-Chun Wang, Yan Wang, Jiahong Xia, Libo Chen, Changchun Cai, Huabin Li, Chia-Jui Yen, Hsu-Ping Kuo, Dung-Fang Lee, Jingyu Lang, Longfei Huo, Xiaoyun Cheng, Yun-Ju Chen, Chia-Wei Li, Long-Bin Jeng, Jennifer L. Hsu, Long-Yuan Li, Alai Tan, Steven A. Curley, Lee M. Ellis, Raymond N. DuBois, Mien-Chie Hung
Journal: Journal of Clinical Investigation (2012)

In the Results section, in the paragraph titled "Cavnoxin decreases both BP and vascular tone in an eNOS-dependent manner," the figure citation was incorrect.The correct sentence appears below.Cavnoxin, but not AP, reduced KCl-mediated contractility of the vessels and the contractile response to the α adrenoceptor agonist, phenylephrine (PE) (Figure 5A).The authors regret the error.
Abstract 2709: The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice
Authors: Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu
Journal: Cancer Research (2015)

Abstract We have reported that a malfunction of RXRα due to aberrant phosphorylation at serine 260 by MAPK is associated with the development of hepatocellular carcinoma (HCC) (Cancer Res 2001). The phosphorylated RXRα impairs normal receptor functions of either RXR or RAR, which are respective homodimeric or heterodimeric partner of RXRα, in a dominant-negative manner. Besides, these impaired receptor functions result in the downregulation of their target gene expression and inducing hepatocarcinogenesis by promoting cell proliferation and the inhibition of apoptosis, which suggesting that phosphorylated RXRα plays a crucial role in the development of HCC. However, these findings were revealed primarily using HCC cell lines that express the phosphorylated-RXRα (p-RXRα) proteins and it still remains unclear whether p-RXRα may impact in the process of hepatocarcinogenesis in vivo. Therefore, in order to investigate the biological functions of the p-RXRα in vivo, we generated doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress phosphomimic mutant of RXRα (T82D/S260D). We found that the T82D/S260D inducible ES cells kept undifferentiated state in differentiating media, which indicating that the phosphorylated form of RXRα plays an important role to maintain pluripotency of ES cells. On the other hand, the development of liver tumors induced by liver carcinogen diethylnitrosamine (DEN) was enhanced in the transgenic mice that overexpress T82D/S260D protein in the liver. Besides, the increased liver tumors in the transgenic mice resulted from the promotion of cell cycle progression, not the inhibition of apoptosis. Interestingly, expression of β-catenin and its target genes, cyclin D1 and c-myc, were increased in transgenic liver tumors, although the expression of retinoid-related genes, such as RARβ, p21 and p27, were not altered compared with control mice. These results suggest that a retinoid nuclear receptor, RXRα may prevent the development of DEN-induced liver tumors by regulating the canonical Wnt/β-catenin signaling pathways in mice. Citation Format: Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu. The role of the phosphorylated RXRα on cellular proliferation and liver tumorigenesis in mice. [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 2709. doi:10.1158/1538-7445.AM2015-2709
Site of metastatic disease influences adenoid cystic cancer (ACC) patients' outcome
Authors: M.C. Cau, S. Alfieri, S. Lo Vullo, C. Bergamini, P. Bossi, C. Resteghini, M. Imbimbo, M. Siano, R. Granata, L. Licitra, L. Locati
Journal: Annals of Oncology (2015)
Phase I Study of AVE9633, an AntiCD33-Maytansinoid Immunoconjugate, Administered as an Intravenous Infusion in Patients with Refractory/Relapsed CD33-Positive Acute Myeloid Leukemia (AML).
Authors: Francis Giles, Rodica Morariu-Zamfir, John Lambert, Srdan Verstovsek, Deborah Thomas, Farhad Ravandi, Dan Deangelo
Journal: Blood (2006)
Ifosphamide, Etoposide and Epirubicin (IVE) Is an Effective Combined Salvage and Peripheral Blood Stem Cell Mobilisation Regimen for Transplant-Eligible Patients with Lymphoma.
Authors: Mark J. Bishton, Richard Lush, Nigel H. Russell, Bronwen E. Shaw, Andrew P. Haynes
Journal: Blood (2006)
Crispr-Cas9 Induced MLL-Rearrangements Cause Clonal Outgrowth in CD34+ Hematopoietic Stem Cells
Authors: Jana Reimer, Sabine Knoess, Maurice Labuhn, Emmanuelle Marie Charpentier, Jan-Henning Klusmann, Dirk Heckl
Journal: Blood (2015)
Culture-Expanded Human Bone Marrow Stromal Stem Cells Organize Functional Bone Marrow Niches In Vivo.
Authors: Yasuo Miura, Zhigang Gao, Masako Miura, Byoung-Moo Seo, Wataru Sonoyama, WanJun Chen, Stan Gronthos, Li Zhang, Songtao Shi
Journal: Blood (2005)
PTU-070 Liver failure in association with hepatic amyloidosis and the role of liver transplantation: the King's College Hospital Experience
Authors: A J Stangou, M Rela, M Monaghan, C J Mathias, G Mufti, N Heaton, J O'Grady
Journal: Gut (2010)

<h3>Introduction</h3> The liver is frequently involved in systemic AL amyloidosis in association with B-cell dyscrasias, and some of the hereditary forms mainly apolipoprotein ApoAI amyloidosis. Extensive hepatic amyloid infiltrate can lead to liver failure. We report here the features, disease course, management and outcome of 28 patients with end-stage hepatic amyloidosis. <h3>Methods</h3> Twenty-eight patients with amyloid related liver failure, median age 53 (28–70) years. All patients had hepatomegaly, 14 (50%) had jaundice, ten had ascites, four patients had encephalopathy, and three were in renal failure. The amyloid type was determined by immunohistochemistry, serum/urine electrophoresis and DNA analysis. All patients had comprehensive systemic, cardiac and neurological evaluation. <h3>Results</h3> 22 patients had AL amyloidosis due to B-cell dyscrasias; none were eligible for chemotherapy. Six cases had hereditary amyloid due to variant fibrinogen A α chain, AFib (1) and apolipoprotein ApoAI (5). Extrahepatic amyloid deposits were present in all cases. 11/22 patients with AL liver failure were listed for liver transplantation (LT). All six patients with ApoAI or AFib amyloidosis who had liver and renal failure were considered for combined liver/kidney transplant (LKT). Nine AL patients received LT as a rescue procedure and two died with complications of hepatic rupture or multi-organ failure on the waiting list. The remaining 11 AL cases all died within 2–16 weeks with progressive cholestasis and subacute liver failure. Actuarial 1-year survival post LT in AL was 75%, 2-year 50%. Early mortality post LT was due to septic episodes, nephrotic syndrome and renal failure, and medium-term due to progressive amyloidosis and multiple organ falure. Only two AL patients exhibited over 5 year survival. Both had predominantly liver and splenic amyloid with no cardiac or renal involvement and were treated with stem cell transplant (SCT) after LT. Three ApoAI cases had successful LKT but two died with complications of liver failure on the wait list. The AFib patient has normal graft function at 13 years post LKT (cumulative LKT survival for ApoAI and AFib 100%). <h3>Conclusion</h3> LT is life saving for liver failure due to AL amyloidosis, but the outcome is ultimately determined by severity of systemic disease at the time of LT and eligibility for efficient treatment for AL after LT. Sequential SCT was associated with long-term remission in two LT recipients. The excellent outcome of LT in both ApoAI and AFib hereditary systemic amyloidosis strongly supports its use for these indications.
Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and Irinotecan toxicity
Authors: C. Kitagawa, M. Ando, Y. Ando, Y. Sekido, M. Usui, K. Takahashi, K. Shimokata, Y. Hasegawa
Journal: Journal of Clinical Oncology (2004)

2009 Background: Irinotecan unexpectedly causes severe, occasionally fatal, toxicity of leukopenia or diarrhea. Irinotecan is metabolized by carboxylesterase to form an active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 to yield its b-glucuronide. Multidrug resistance-assocciated protein 2 (MRP2, ABCC2) transports SN-38-glucuronide from hepatocytes to the bile, as it transports bilirubin in the body. Methods: We examined the polymorphisms of ABCC2 gene, -24C>T, 1249G>A, 2366C>T, 2302C>T, 2375A>G, 2439+2 T>C, 3449 G>A, and 3517A>T, in 120 Japanese cancer patients who had been treated with irinotecan, including 27 patients who experienced severe toxicity of G4 leukopenia and/or G3 or worse diarrhea. Our hypothesis was that patients with the variant ABCC2 allele would have an increased risk of severe toxicity. Results: We detected the four variant alleles, -24C>T, 1249G>A, 2366C>T, and 2375A>G. The association between ABCC2 variants, -24C>T or 1249G>A, and severe toxicity was investigated (Table). Neither univariate analysis (odds ratio, 0.78; 95% confidential interval (CI), 0.21–2.35; odds ratio, 1.05; 95% CI, 0.41–2.56) nor multivariate logistic regression analysis (odds ratio, 0.98; 95% CI, 0.23–3.44; odds ratio, 1.17; 95% CI, 0.40–3.26) found any significant association between severe toxicity and the ABCC2 variants in 1249G>A or -24C>T, respectively. We detected a heterozygote for 2366C>T in one patient and a new heterozygote for 2375A>G in one patient. Severe toxicity was not occurred in these patients. There were no apparent associations between the ABCC2 variants and pharmacokinetics of irinotecan, SN-38 and SN-38 glucuronide. Conclusions: This pharmacogenetic study did not find any evidence that determination of ABCC2 genotypes would be useful for predicting severe toxicity by irinotecan. No significant financial relationships to disclose.
A Canadian Prospective, Observational, Open-Label, Pharmacovigilance Study to Assess the Safety of Humate-P® Injection Volume Reduced (ivr) in Patients with Von Willebrand Disease.
Authors: Alan Tinmouth, Victor S. Blanchette, Ramachandran Devaraj, Bruce Ritchie, David Barnes, Gigi van den Hoef
Journal: Blood (2009)
Development of a HER1 assay using individual human hair follicles
Authors: V. Knezevic, K. K. Iwata, G. Baibakova, J. Wolf, G. Biesecker, F. Richardson
Journal: Journal of Clinical Oncology (2004)

3044 Background: Previous reports have described reduction of HER1 phosphorylation and phosphorylation of proteins downstream of HER1 in the skin and the hair follicles of patients treated with HER1 inhibitors such as erlotinib. Methods: Individual hairs from normal volunteers were collected at various time points and fixed. Proteins from each hair follicle was transferred to multiple P-FILM membranes. The membranes were blotted with antibodies to HER1, pHER1, ERK and pERK. Fluorescent images were quantitated using image analysis software. Results: Human hair collected from three regions of the body showed different levels of detectable protein. Scalp hair showed the highest, consistent level of both total protein and staining by antibodies to HER1 signal transduction proteins. Detection of HER1 signal transduction proteins in fixed hair samples was stable for greater than two weeks. Hair samples from five individuals showed approximately four-fold intrasubject differences in HER1 signal intensity. Hairs collected from the same individual at one time point gave a pHER1/HER1 ratio with a %CV of approximately 20%. Hairs collected from the same individual collected at different time points over a two week period showed a similar variability in the pHER1/HER1 ratio. Based upon this intrasample variability, a sample size of four hair follicles per subject and time point was selected for future studies. Conclusions: HER1 signal transduction phosphoproteins could be quantitated from individual scalp hair follicles. The level of HER1 phosphoproteins was similar in hairs collected from an individual at the same time and at various time points over a period of two weeks. The use of hair is minimally invasive, in comparison to skin biopsies, and offers an approach to quantitate the pharmacodynamics of HER1 inhibitors, such as erlotinib, thereby offering the possibility of optimizing dose and treatment scheduling. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration 20/20 Gene Systems; OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals
The peripheral neuropathy with paclitaxel after oxaliplatin for the patients with gastric cancer
Authors: Akitoshi Hakoda, Tetsuji Terazawa, Masahiro Gotoh, Takayuki Kii, Shin Kuwakado, Hitoshi Nishitani, Fukutarou Shimamoto, Ken Asaishi, Takahiro Miyamoto, Kazuhide Higuchi
Journal: Annals of Oncology (2015)
Prognostic and Predictive Gene Expression Profiling (GEP) Markers Confirmed in Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Treated Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts)
Authors: Martin van Vliet, Jagoda Jasielec, Dominik Dytfeld, Ravi Vij, Belinda Dumee, Lizanne Bosman, Leonie C.M. deBest, Mattina Alonge, Shaun Rosebeck, Malathi Kandarpa, Kathryn McDonnell, Kent A. Griffith, Erik H van Beers, Andrzej Jakubowiak
Journal: Blood (2014)
242. Genetically Engineered Mesenchymal Stem Cell Spheroids for Brain Tumor Therapy
Authors: Smruthi Suryaprakash, Hon Fai Chan, Juli Rodriguez, Shawn Hingtgen, Kam W. Leong
Journal: Molecular Therapy (2016)

Gliobastoma is one of the most aggressive forms of brain cancer. Each year 18,000 people are diagnosed with glioblastomas with an average survival of 10 to 12 months. MSC are an attractive candidate for cell based therapy since they can be easily isolated, manipulated and have no immune rejection. MSC transduced with TRAIL are capable of migrating towards the tumor cells and kill the tumor cells due to bystander effect1Sasportas L.S. et al.Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 4822-4827Crossref PubMed Scopus (375) Google Scholar. However, for cell based therapy migration, survival and retention are the major factors. MSC in spheoridal form has shown to have increased expression of CXCR4 which is critical for migration towards tumor cells2Bartosh T.J. et al.Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 13724-13729Crossref PubMed Scopus (660) Google Scholar. The spheroidal form also might help the cells to survive for longer and prevent it from getting washed out due to the extracellular matrix surrounding the cells and larger size respectively. Hence MSC in spheroidal created using a microfluidic platform was used for cell based therapy to treat glioma. The MSC self assembled to form spheroids within the double emulsion in 150 mins. Live/dead staining demonstrated high viability of the cells in the spheroid. Semi-quantitative RT-PCR demonstrated enhanced expression of CXCR4 in the MSC spheroids. This translated to higher migration of the MSC spheroids compared to MSC as seen by increased directionality, velocity, euclidian distance and displacement of the center of mass. MSC was shown to produce TRAIL constantly for 6 days. Condition media collected from MSC-sTRAIL single and spheroids were collected and showed higher caspase 3/7 activation and effectively killed the cancer cells. Hence MSCs in spheroidal form are an excellent candidate for treating glioblastomas. In the future the spheroidal retention and survival will be tested in vivo. This will be followed by survival analysis to ascertain the therapeutic efficacy of MSC-TRAIL.
Abstract 4456: Prevention of MICA shedding from HBV infected hepatocytes to activate NK cells for better clearance of malignant foci and virus-infected cells
Authors: Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike
Journal: Cancer Research (2015)

Abstract Introduction: Hepatocellular carcinoma (HCC) is an important issue to public health of the world. By a genome-wide association study, we previously identified that a single nucleotide polymorphism (SNP) in the promoter region of the MHC class I polypeptide-related sequence A (MICA) gene is significantly associated with the risk of hepatitis-virus-related HCC. MICA is a ligand for NKG2D, a cell receptor of NK cells, which activates NK cells to clear the pathogenic cells expressing MICA such as infected cells or malignant cells as a “danger” signal. However, unexpectedly, the Hepatitis B virus (HBV)-infected patients with risk allele of MICA gene showed higher levels of serum MICA. This suggested that the serum MICA, which is excreted from the infected hepatocytes by a shedding mechanism, may work as a decoy for NK cells and inhibit their activities. Therefore, increasing cellular MICA levels by preventing those shedding and release may contribute to the clearance of the pathogenic cells and the prevention of HCC. In this study, we constructed a convenient MICA shedding assay system and, by a comprehensive screening, we identified several compounds which may prevent MICA shedding from the cells. Methods: We constructed lentivirual vector expressing MICA protein tagged with nano-luciferase (nanoLuc) in its N terminal because N terminal of MICA is excreted from the cells by shedding. We expressed this construct in HBV replicating cells, HepG2.2.15, and after adding compounds, we determined the luciferase activities in the supernatant and cell lysates. Results: We picked up the samples which showed low activities in supernatant with high activities in the cell lysates, indicating low levels of shedding and high levels of remaining cellular MICA. Out of over 1,000 compounds screened, we determined four candidate compounds which efficiently prevented MICA shedding. We confirmed the effects of these compounds in other cell systems infected with HBV. Conclusion: Because these compounds enhanced the expression levels of cellular MICA and decreased its shedding in HBV-replicating human hepatocytes, using these compounds may be favorable during HBV chronic infection to enhance the NK cell-mediated clearance of the pathogenic hepatocytes and to prevent HCC. Citation Format: Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike. Prevention of MICA shedding from HBV infected hepatocytes to activate NK cells for better clearance of malignant foci and virus-infected cells. [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 4456. doi:10.1158/1538-7445.AM2015-4456
164. Improvement of Gene Therapy for Wilson Disease
Authors: Oihana Murillo, Daniel Moreno, Cristina Gazquez, Iñigo Navarro-Blasco, Jesus Prieto, Ruben Hernandez-Alcoceba, Gloria Gonzalez-Aseguinolaza
Journal: Molecular Therapy (2016)

Wilson's disease (WD) is an autosomal recessively inherited copper storage disorder due to mutations in ATP7B gene that causes hepatic and neurologic symptoms. Current treatments are based on lifelong copper chelating drugs, which may cause side effects and do not restore normal copper metabolism. We have recently demonstrated that the administration of an AAV vector expressing ATP7B under the control of a liver specific promoter induces full restoration of copper homeostasis in a mouse model of Wilson's disease. However, the size of the vector genome surpasses the optimal size for AAV packaging, limiting the use of large promoters or additional regulatory sequences such as introns or bigger poly A sequences. In the present work we have designed two truncated versions of ATP7B protein (T1 and T2), and have analyzed their functionality and therapeutic efficacy. ATP7B contains 6 metal binding sites (MBS) in the N-terminal region. T1 presents a deletion of 1 MBS and a fragment of the adjacent one, whereas T2 lacks the first 4 MBS. Both proteins were active since they were able eliminate intracellular excess of copper in an in vitro system. The administration of recombinant AAV vectors carrying the truncated proteins under the control of a liver specific promoter was able to reduce liver damage and urinary copper excretion in the murine model, but T1 was less efficient than the WT ATP7B gene. In contrast, T2 showed full capacity to normalize these parameters. Furthermore, T2 was more efficient than WT in restoring ceruloplasmin oxidase activity in serum. In conclusion, we have identified a fully functional truncated version of ATP7B protein that will reduce the size of the therapeutic AAV vector genome and allow the introduction of additional regulatory elements.
Quantitative Assessment of Molecular Remission Following Autologous Stem Cell Transplantation Predicts Long Term Remission in Mantle Cell Lymphoma.
Authors: Christiane Pott, Carsten Schrader, Stefan Gesk, Lana Harder, Markus Tiemann, Thorsten Raff, Monika Brüggemann, Matthias Ritgen, Michael Unterhalt, Martin Dreyling, Wolfgang Hiddemann, Reiner Siebert, Peter Dreger, Michael Kneba
Journal: Blood (2005)
Lymphomas with Concurrent T(14;18) and 8q24 Translocations Are Under- Reported and Clinical Outcome Depends on the MYC Partner
Authors: Nathalie A Johnson, Kerry J. Savage, Susanna Ben-Neriah, Christian Steidl, Richard Klasa, Joseph M. Connors, Randy D. Gascoyne, Douglas E. Horsman
Journal: Blood (2008)