tbuckley/cabot-search huggingface dataset:
316. Evaluating AAV Hybrid Variants for Improved Tropism after Intravitreal Gene Delivery to the Retina
Authors: Annahita Keravala, Ming Mi, Gueorgui Todorov, Sharmila Vijay, Mehdi Gasmi, Thomas W. Chalberg
Journal: Molecular Therapy (2015)

AAV-mediated gene therapy has shown promise for some ocular diseases when injected sub-retinally. Intravitreal AAV administration, while less invasive, is far less efficient due to the inner limiting membrane (ILM), which is a particularly profound barrier in the primate retina. Recently AAV2.7m8, which has a 10 amino acid (aa) peptide insertion in the surface exposed loop region of AAV2, was identified using in vivo directed evolution (Dalkara et al., 2013). This variant has been shown to effectively transduce outer retinal cells resulting in extensive gene expression in the non-human primate retina following intravitreal injection. The purpose of our study was to identify AAV variants that could not only penetrate the outer retina from the vitreous, but also have a favorable neutralizing antibody (nAb) titer to allow beneficial AAV-mediated gene expression. We tested whether the 10-aa peptide loop from AAV2.7m8 could be inserted into other capsid backbones, and investigated the tropism and nAb profile of these hybrid capsids. The 10-aa loop was inserted at seven different positions in the receptor binding region of loop IV of capsid 2.5T, which is a chimeric variant of the VP1 region of AAV2 and VP2 and VP3 regions of AAV5 containing a single A581T point mutation (Excoffon et al., 2009). A majority of the 2.5T/7m8 hybrid capsids were successfully packaged and resulted in varying levels of GFP transgene expression following transduction in vitro. Additionally, in vitro transduction was blocked to a lesser extent by nAbs (IVIg) when compared to AAV2, which indicates that the 2.5T/7m8 hybrids may not be impeded by preexisting immunity in human patients. Finally, significantly higher GFP expression was observed with one of the 2.5T/7m8 hybrid variants as compared to the parental 2.5T capsid, following intravitreal administration in rodents.
667. Effects of Various Physical, Chemical, and Biological Exposures on rAAV Stability and Function
Authors: Alisha M. Gruntman, Lin Su, Christian Mueller, Terence R. Flotte
Journal: Molecular Therapy (2015)

With an increasing number of potential recombinant adeno-associated virus (rAAV) gene therapies progressing to clinical trials, much time and money are devoted to ensuring that means of handling the vector do not effect the subsequent gene expression. In this study we hope to answer some of the concerns that arise when clinical (and basic science) trials are being planned. The vector used in this study was a rAAV2/1 encoding a chimpanzee alpha-1 antitrypsin (chimpAAT) gene under the control of a chicken beta actin promoter and CMV enhancer. The vector used in the study was all from the same pooled batches. Prior to intramuscular injection in mice the vector was subjected to 1 of 30 different conditions. The conditions included different storage temperatures (-80C, 4C, room temperature), different numbers of freeze thaw cycles, different diluents (serum (human, mouse and complement depleted), sodium chloride, lactated Ringers and gadolinium), high and low pH, ultraviolet (UV) exposure, high temperature (55C and 72C), varying storage materials prior to injection (polypropylene, polyethylene, polystyrene, stainless steel, glass, and syringe). Five B6.129S7.Rag-/- mice per group were then injected intramuscularly with 1×10^11 vector genomes/mouse. Serum was collected from each mouse weekly for 12 weeks. A total human AAT ELISA (which we previously determined accurately detects chimpAAT) was then performed with the serum. We found that the only conditions that led to little or no chimpAAT expression in the mouse serum were UV exposure for 10min and 72C exposure for 20 min. All other conditions resulted in serum chimpAAT levels between approximately 20,000 and 40,000 ng/ml. Statistical analysis of these results as well as vector titer and tissue vector genome data are still pending. These results are encouraging in that a wide variety of conditions had little effect on the resultant protein levels in the serum. We hope that these results will aid investigators when planning both research and clinical trials as they make decisions on how to handle the vector prior to injection.
S1P Modulator FTY720 Targets Multiple Myeloma Cell Proliferation and Stromal Interactions Via CXCR4/CXCL12 and mTOR Pathways
Authors: Katia Beider, Evgenia Rosenberg, Hanna Bitner, Merav Leiba, Maya Koren-Michowitz, Michal Abraham, Shiri Klein, Hanna Wald, Avichai Shimoni, Amnon Peled, Arnon Nagler
Journal: Blood (2014)
Hot-melt sub- and outercoating combined with enteric aqueous coating to improve the stability of aspirin tablets
Authors: Xiuzhi Wang, Puxiu Wang, Chenglong Huang, Xiaoyang Lin, Haoyu Gong, Haibing He, Cuifang Cai
Journal: Asian Journal of Pharmaceutical Sciences (2016)

Aspirin is apt to hydrolyze. In order to improve its stability, a new method has been developed involving the application of hot-melt sub- and outercoating combined with enteric aqueous coating. The main aim was to investigate the influence of these factors on the stability of ASA and understand how they work. Satisfactory storage stability were obtained when the aspirin tablet core coated with Eudragit L30D55 film was combined with glycerin monostearate (GMS) as an outercoat. Hygroscopicity testing indicated that the moisture penetrating into the tablet may result in a significant change in the physical properties of the coating film observed by scanning electron microscopy. Investigation of the compatibility between the drug and film excipients shows that the talc and methacrylic acid had a significant catalytic effect on ASA. A hypothesis was proposed that the hydrolysis of ASA enteric coated tablets (ASA-ECT) was mostly concentrated in the internal film and the interfaces between the film and tablet core. In conclusion, hot-melt coating technology is an alternative to subcoating or outercoating. Also, GMS sub-coating was a better choice for forming a stable barrier between the tablet core and the polymer coating layer, and increases the structure and chemical stability.
Characterization of Immune Evasion Mechanisms at Diagnosis and after Chemotherapy in Patients with Acute Myeloid Leukemia
Authors: Hanna A. Knaus, Joshua F. Zeidner, Raul Montiel Esparza, Christopher G. Kanakry, Sudipto Ganguly, Ante Vulic, Amanda Blackford, B. Douglas Smith, Judith E. Karp, Leo Luznik, Ivana Gojo
Journal: Blood (2014)
Abstract 3909: Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer
Authors: Tia L. Harmon, Adriana Harbuzariu, Lily Yang, Ruben R. Gonzalez-Perez
Journal: Cancer Research (2015)

Abstract Background: Leptin is a cytokine secreted by adipose tissue that binds its receptor, OB-R, leading to increased growth and survival of cancer cells. High levels of leptin have been correlated with poorer outcomes in breast cancer patients, particularly those afflicted with triple negative breast cancer (TNBC). We have created a leptin peptide receptor antagonist, LPrA2, which has been shown to block leptin signaling in several cancer types. To increase its effectiveness, LPrA2 was coupled to iron oxide nanoparticles (IONPs). We aim to determine if IONP-LPrA2 will serve as an adjuvant treatment, when combined with chemotherapeutics, for human TNBC and mouse TNBC-like (Tamoxifen-resistant) breast cancer cells E0771-TAM. Methods: Conjugation of LPrA2 to IONPs was confirmed by Western Blot and inhibition assays. To evaluate the effects of IONP-LPrA2 in mouse TNBC-like cells, the E0771 cell line (progesterone receptor and HER2 negative) was made insensitive to estrogen stimuli by long-term treatment with Tamoxifen (TAM). Human TNBC and E0771 cells, both responsive and unresponsive to estrogen (E0771-TAM), were treated with recombinant leptin and culture medium containing fetal bovine serum plus chemotherapeutics and IONP-LPrA2. Cell cycle progression, cell viability and apoptosis were analyzed using the Cellometer Vision Image Cytometer ®. Results: IONP-LPrA2 was found to cause significant decrease in DNA synthesis during the S phase of the cell cycle in TNBC and TNBC-like cells when compared to E0771 cells. Additionally, IONP-LPrA2 showed additive effects on reduction of cell viability and apoptosis when combined with chemotherapeutics. Conclusion: These findings indicate that IONP-LPrA2 may be useful in the treatment and prevention of TNBC. Further, IONP-LPrA2 treatment may increase the effectiveness and allow for reduction of the dosage of chemotherapeutics. This will in turn attenuate undesired side effects of chemotherapy. These results may be beneficial for breast cancer patients, particularly those with TNBC who are overweight or obese lacking targeted therapy thus suffering the poorest outcomes. Citation Format: Tia L. Harmon, Adriana Harbuzariu, Lily Yang, Ruben R. Gonzalez-Perez. Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer. [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 3909. doi:10.1158/1538-7445.AM2015-3909
The effect of eicosapentaenoic acid in patients with nasopharyngeal cancer receiving concurrent chemoradiotherapy in an outpatient clinic: An open-label prospective randomized trial.
Authors: J. T. Chang
Journal: Journal of Clinical Oncology (2011)

e19550 Background: Evaluating the benefit of esicosapentaenoic acid (EPA) nutrition supplement in nasopharyngeal cancer (NPC) patients who receiving concomitant chemoradiotherapy Methods: Patients with previously untreated stage IIb-IV NPC who will receive concomitant chemoradiotherapy with cisplatin and oral tegafur with uracil are recruited. Patients are randomly assigned to one group with open label nutrition supplement containing EPA regimen (EPA) and the other group with isotonic, balanced nutrition formula (ISO). Each group patients receive 2 servings per day in addition to regular diet. The planned schedule is one month before RT and 2 months during radiotherapy. Patients’ daily intake is recorded by patient or major caregiver. Patient is held chemotherapy when poor general condition and/or low blood count were noted during the radical treatment course Results: One hundred and sixteen patients were randomized assigned to EPA (n=59) and ISO (n=57). Forty patients receive tube feeding during treatment period. Twenty two patients were admitted to ward because of infection. Eight patients do not complete planned radiotherapy. Only 44 (37.8%) patients complete the prescribed nutrition supplement. The mean using days are 49.7 for EPA and 58.5 for ISO. Fifty (43.1%) patients cease supplement for disliking favor. There is no significant difference in total energy intake, total radiotherapy dose, radiotherapy total treatment time, chemotherapy times, total cisplatin dose, supplement intake period, tube feeding and oral antibiotics used in the treatment period between both arms. However, there is significantly difference in infection that needs admission for infection; 6 (10.2%) in EPA group and 16 (28.1%) in ISO group (p=0.014). Nutrition supplement, diabetes and age are significant factors for infection admission. Conclusions: EPA supplement can significantly decrease the infection admission morbidity rate in this study. Further study is needed to know the reason for EPA decrease the infection admission rate and the impact of EPA in tumor control in NPC patients.
An Update of a Comparison of Nonmyeloablative Allografting with Autografting for Newly Diagnosed Myeloma.
Authors: B. Bruno, R. Sorasio, F. Patriarca, N. Mordini, B. Allione, F. Carnevale-Schianca, L. Giaccone, M. Rotta, P. Omedè, I. Baldi, S. Bringhen, M. Massaia, M. Aglietta, A. Levis, D. Mattei, R. Fanin, A. Palumbo, R. Storb, G. Ciccone, Mario Boccadoro
Journal: Blood (2007)
Abstract 2325: Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis
Authors: Pei-Yu Lin, Chien-Chang Su, Chi-Che Hsieh, Chia-Ning Shen
Journal: Cancer Research (2015)

Abstract Acinar-to-ductal metaplasia (ADM), an inflammatory lesion associated with replacement of acinar cells by tubular complexes, is thought to represent a condition with increased risk of neoplasia. However, the direct evidence linking acinar-to-ductal metaplasia and development of pancreatic neoplasm is still lacking. Glucocorticoid-mediated signaling pathway is known to be a part of the feedback control machinery of immune system that acts to suppress excessive immune activity. In the present study, we explored the role of GR in development of ADM and pancreatic intraepithelial neoplasia (PanIN) in mice with pancreatitis. We initially identified that evaluated levels of activated glucocorticoid receptors (GR) were observed in patients of chronic pancreatitis and pancreatic ductal adenocarcinomas (PDAC). Utilizing mice conditionally expressed KrasG12D in acinar cell with or without loss of GR, we demonstrated that GR activation was required for generation of metaplastic ductal lesion and development of pancreatic intraepithelial neoplasia (PanIN) in mice with experimental pancreatitis. Administration of dexamethasone, a potent synthetic glucocorticoid, was sufficient to induce development of PanINs and PDACs in KrasG12D mice that harbored single-allele deletion of p53. We further revealed that non-genomic activation of GR was a key action that led to evaluate c-Src signaling and trigger a pathological threshold of Ras activity necessary for neoplastic transformation. In contrast, treatment of dasatinib, a Src kinase inhibitor, suppressed development of PanINs and PDACs induced by dexamethasone. Importantly, Cre-lox based lineage-tracing mice was applied and identified that GR activation directly transformed GFP-tagged KrasG12D-expressing acinar cells to tumorigenic cells. The findings explained why inflammatory ductal reprogramming predisposes to development of pancreatic neoplasm. Citation Format: Pei-Yu Lin, Chien-Chang Su, Chi-Che Hsieh, Chia-Ning Shen. Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis. [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 2325. doi:10.1158/1538-7445.AM2015-2325
High Expression of Autophagy Related Proteins Negatively Impacts Clinical Outcomes in Acute Myelogenous Leukemia–Time to Target Autophagy to Improve Therapy Outcomes?
Authors: Gautam Borthakur, Michael Andreeff, Kevin R Coombes, Yi Hua Qiu, Seshagiri Duvvuri, Nianxiang Zhang, Vivian Ruvolo, Marina Konopleva, Guillermo Garcia-Manero, Peter P. Ruvolo, Jorge E. Cortes, Hagop M. Kantarjian, Steven M. Kornblau
Journal: Blood (2011)
385. Intravenous Delivery of AAV9-CMV-sFLT1 Reduces the Severity of Brain Arteriovenous Malformation Without Causing Significant Side Effects in a Mouse Model
Authors: Wan Zhu, Fanxia Shen, Lei Zhan, Shuai Kang, Rui Zhang, Dingquan Zou, John Forsayeth, Zhijian Wu, Peter Colosi, Hua Su
Journal: Molecular Therapy (2015)

Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current therapies are invasive and associated with high morbidities. We are developing a minimally invasive gene therapy strategy using adeno-associated viral vector (AAV) to deliver an anti-angiogenic agent, sFLT1, which contains the extracellular domains of vascular endothelial growth factor (VEGF) receptor 1. Here, we tested whether intravenous (IV) delivery of AAV9-CMV-sFLT1 reduces the severity of bAVM in a mouse bAVM model. Since IV-delivered vectors enter other organs in addition to the brain, which can cause unwanted side effects, we also analyzed the potential toxicity associated with this approach. To induce the bAVM phenotype, endoglin (Eng), an AVM-causative gene, was globally deleted in Rosa;CreER;Eng 2f/2f mice through intra-peritoneal injection of tamoxifen, and brain angiogenesis was stimulated by intra-brain injection of AAV1-CMV-VEGF (2×109 vg). AAV9-CMV-sFLT1 (1×1011 vg), or its control vector AAV9-CMV-GFP, was IV injected into the mice 8 weeks after model induction. Body weight was measured weekly. Blood and organs were collected 4 weeks after AAV9-CMV-sFLT1 injection. Brain sections were immunostained with antibodies specific to CD31 (an endothelial marker) to quantify abnormal vessels in the bAVM lesions, to CD3 (a lymphocyte marker) to assess lymphocyte infiltration, or to NeuN (a neuron marker) to assess neuronal loss. Creatinine levels and alkaline phosphatase activities were analyzed in the plasma samples to assess kidney and liver function, respectively. Histological changes in the liver were examined in hematoxylin- and eosin-stained (H&E) sections. The presence of the vector in the liver validated the success of IV-vector delivery. Compared with AAV9-CMV-GFP-treated mice, those treated with AAV9-CMV-sFLT1 had fewer abnormal vessels in the bAVM lesions. AAV-injected mice had comparable body weight to the age-matched WT mice during the 4-week treatment period. No neuronal loss or lymphocytic infiltration was observed in the brain of mice injected with AAV9-CMV-sFLT1. AAV-injected mice and WT mice had similar creatinine levels and alkaline phosphatase activities. H&E staining showed small clusters of inflammatory cells in the liver of 3 of 7 AAV9-CMV-GFP-treated mice, and 3 of 6 in mice treated with AAV9-CMV-sFLT1. IV injection of AAV9-CMV-sFLT1 reduces bAVM severity, does not cause neuronal loss and lymphocyte infiltration in the brain, and does not significantly alter liver and kidney function. Since inflammatory cell infiltration has been detected in the liver of AAV9-treated mice, strategies for limiting liver gene transduction and expression should be developed for systemic delivery of AAV-sFLT1 for treating bAVM.
Differential Radiographic Appearance of<i>BRAF</i>V600E–Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location
Authors: Chloe E Atreya, Claire Greene, Ryan M McWhirter, Nabia S Ikram, I Elaine Allen, Katherine Van Loon, Alan P Venook, Benjamin M Yeh, Spencer C Behr
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: BRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan-Meier and Cox regression methods. Results: The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02). Conclusions: Greater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location.
PTU-062 Transarterial chemoembolisation in inoperable hepatocellular carcinoma: a tertiary centre experience
Authors: M McMahon, R K Popuri, N Chalmers, M I Prince
Journal: Gut (2010)

<h3>Introduction</h3> Hepatocellular carcinoma (HCC) remains a leading cause of death among cirrhotic patients in the UK.1 Transarterial chemoembolisation has been shown previously to produce modest survival advantages in some patients with inoperable disease.12 Our aim was to assess the impact of chemoembolisation on survival, and on tumour response, of patients treated in our unit. <h3>Methods</h3> All patients undergoing transartertial chemoembolisation from 2002 to 2009 were identified from radiological records. A retrospective case note analysis was carried out, and CT scans were reviewed. <h3>Results</h3> Thirty-one patients were identified of whom 21 were male. Mean age at presentation was 63 years (range 31–84 years). One patient was identified as being non-cirrhotic. Of the remainder, 17 patients were known to be cirrhotic and five patients presented during routine surveillance of cirrhosis. The most common aetiology was Hepatitis C. The majority of patients had Childs-Pugh A cirrhosis (80%). The median serum α feto protein (AFP) at presentation was 87 (inter-quartile range 7–3004). 61% had serum AFP &gt;200. Six patients had evidence of extra-hepatic spread at diagnosis. The mean number of treatments was 1.95 (SD 1.23). Assessment of tumour response was obtained for 23 patients. Nine patients (39%) achieved partial3 tumour response on initial follow-up CT scan. The range of time to follow-up scan was between 6 and 20 weeks (mean 10). Four patients (17%) had stable disease and 10 patients (43%) had evidence of progressive disease. There were two treatment related deaths, one from hepatic necrosis with acute renal failure, one from hepatic necrosis with hepatic decompensation. Mean follow-up was 13.7 months (SD 12.6). Median survival was 359 days (95% CI 254 to 464). Survival at 1 year was 59% (16/27 patients), and 29% (6/21 patients) at 2 years. <h3>Conclusion</h3> Objective tumour response rates and survival rates were inferior to those achieved by other centres.1 However, in our patient cohort, stage of disease was more advanced. The use of independent predictors of survival may allow more selective treatment allocation.
Aurora Kinase a: A New Component of Imatinib Resistance in Chronic Myeloid Leukemia
Authors: Manuela Mancini, Simona Soverini, Elisa Leo, Fausto Castagnetti, Caterina De Benedittis, Gabriele Gugliotta, Gianantonio Rosti, Maria Alessandra Santucci, Michele Cavo, Giovanni Martinelli
Journal: Blood (2015)
PF-05212384 + irinotecan Phase II study in metastatic colorectal cancer (mCRC): B2151005 Japanese lead-in-cohort (J-LIC)
Authors: Takayuki Yoshino, Kohei Shitara, Hiroya Taniguchi, Nicoletta Brega, Masayuki Ohkura, Chiho Ono, Mie Suzuki, Jennifer Vermette, Kei Muro
Journal: Annals of Oncology (2015)