tbuckley/cabot-search huggingface dataset:
80. Delayed Inflammatory Response to Intravitreal AAV Gene Transfer in Non-Human Primates
Authors: Sarah Wassmer, Jason Comander, Livia Carvalho, Ru Xiao, Eva Plovie, Aliete Langsdorf, Lawrence Lim, Brian Hafler, David M. Wu, Dean Eliott, Leo A. Kim, Luk H. Vandenberghe
Journal: Molecular Therapy (2016)

Introduction Adeno-associated virus (AAV) gene therapy in the eye via intravitreal injection has recently advanced into clinical trials. Here, we wanted to investigate the immunological response to AAV capsids within the vitreous of non-human primates. Methods Bilateral injections of AAV gene delivery were evaluated in five rhesus macaques. An intravitreal injection (IVT) was performed in one eye of the non-human primate, while a subretinal injection was performed in the contralateral eye. For the IVT eye, AAV2 or synthetic ancestral Anc80 capsid with GFP transgene was used at a concentration of 1E+11 particles. The surgical procedure for two animals was a normal IVT injection as performed in the clinic and the other two animals received an inner limiting membrane peel before viral injection. In the subretinal injection (SR) eye, animals were treated with AAV8 or 9, carrying the GFP or LacZ transgene at a concentration of 1E+10 or 1E+11 particles. Animals were monitored for 5/6 weeks before being sacrificed for histological analysis. Results In all eyes, inflammation in the first 2 weeks was mild or moderate and self-resolving. At weeks 3-5, all IVT treated eyes developed vitritis. None of the eyes injected subretinally developed vitritis. The most severe eye belonged to the IVT group, which developed hyphema and most of the IVT eyes developed anterior cataracts. Inflammation was well controlled with 4mg to 12mg of Triescence (triamcinolone acetonide) injected intravitrally. One animal was not given Triescence at the onset of inflammation (week 3), which became unmanageable within 48 hours, leading to the ultimate termination of the animal. Within the IVT group, similar amounts of late inflammation were seen between the intravitreal and peel/puddle eyes. Conclusion Our studies demonstrate that, in stark contrast to subretinal injection, an intravitreal injection of AAV expressing a non-self transgene has the potential to develop clinically significant inflammation at doses normally tolerated in the subretina. This inflammation can be treated with early administration of Triescence. Left untreated, the animal will develop severe immunological infiltration. These results warrant further study to determine the antigenic nature and inflammatory mechanism leading to the low inflammatory threshold to intravitreal AAV gene transfer.
Minimal Residual Disease (MRD) Status Following Induction Chemo-Immunotherapy Predicts Progression-Free Survival In Mantle Cell Lymphoma (MCL): CALGB 50403 (Alliance)
Authors: Noreen Fulton, Jeffrey Johnson, Lawrence D. Kaplan, Greg Koval, Greg Malnassy, Sin-Ho Jung, Steve Devine, Thomas C. Shea, John P. Leonard, Bruce D. Cheson, Wendy Stock
Journal: Blood (2013)
Pharmacokinetic Analysis of Subcutaneous Alemtuzumab as Consolidation Therapy To Achieve MRD-Negative Responses.
Authors: Mario Regazzi, Michela Montagna, Antonia Avanzini, Barbara Scarpati, Anna Colosimo, Silvio Veronese, Alessandra Tedeschi, Sara Miqueleiz, Francesca Ricci, Liliana Intropido, Enrica Morra, Marco Montillo
Journal: Blood (2005)
644. In Vivo Expression of Functional DNA Monoclonal Antibodies Targeting IL-6 and CD126
Authors: Sarah T.C. Elliott, Ami Patel, Seleeke Fllingai, Megan C. Wise, Karuppiah Muthumani, David B. Weiner
Journal: Molecular Therapy (2016)

Pro-inflammatory cytokine interleukin-6 (IL-6) and its receptor (CD126) are multi-faceted immune therapy targets. IL-6 plays a substantial role in innate inflammation and sepsis. Elevated levels of IL-6 are clinically linked to poor cancer prognoses; numerous studies demonstrate an association between IL-6 signaling and tumor development in multiple myeloma, lung cancer, colorectal cancer, renal cell carcinoma, cervical cancer, breast cancer, and ovarian cancer. Currently, therapeutic antibodies targeting IL-6 (Siltuximab) and CD126 (Tocilizumab) are approved for treatment of multicentric Castleman disease and rheumatoid arthritis, respectively. Manufacture and delivery of these purified protein antibodies are cost-prohibitive. Furthermore, anti-IL-6 and anti-CD126 protein antibodies must be re-administered weekly-to-monthly, an especially challenging consideration in treatment of chronic conditions such as cancer and auto-immune disease. Use of gene therapy to deliver antibodies, with enhanced potency and long-term expression in vivo, provides an economical and practical alternative to protein-based therapy. DNA is relatively inexpensive to manufacture, has an excellent safety profile, and lacks complications of pre-existing serology associated with some viral vectors. Here, we demonstrate functional DNA monoclonal antibodies (DMAb) targeting IL-6 and CD126 are expressed in vivo. We constructed codon-optimized variable region DNA sequences from four anti-IL-6 and two anti-CD126 monoclonal antibodies on the human IgG1 constant domain. Plasmid DNA encoding each antibody was delivered intramuscularly with electroporation to nude and immune-competent mice. We optimized multiple aspects of DMAb delivery - including antibody sequence, plasmid heavy and light chain arrangement, and formulation - to enhance in vivo expression. Anti-IL-6 and anti-CD126 DMAb were expressed in serum with levels ranging from 1.5 µg/mL to 7.1 µg/mL in BALB/c mice. We also observed long-term DMAb expression in nude mice. Serum DMAb retained functional binding to purified IL-6 and CD126. Serum DMAb also blocked downstream IL-6 cell signaling in vitro. Studies are underway to investigate anti-IL-6 and anti-CD126 DMAb for their role in controlling sepsis, limiting inflammation during acute viral infection, and slowing tumor progression. These studies not only provide a novel method to further define the role of in vivo IL-6 signaling in immune pathologies, but also define DMAb as an alternative to protein antibody therapies.
OC-059 Scent: final report of the first UK prospective, randomised, head-to-head trial of transnasal vs oral upper gastrointestinal endoscopy
Authors: E J Despott, M Baulf, J Bromley, S Gupta, C Fraser
Journal: Gut (2010)

<h3>Introduction</h3> Transnasal upper GI endoscopy (TN-OGD) minimises stimulation of the pharyngeal reflex by eliminating tongue contact; this contrasts with conventional (oral) upper GI endoscopy (C-OGD) which uses the root of the tongue as a fulcrum for insertion and withdrawal. TN-OGD is a promising alternative to C-OGD in view of its potential to improve patient experience and obviate the need for sedation. SCENT (St Mark9s Conventional Endoscopy vs trans-Nasal endoscopy Trial) is the first prospective, randomised head-to-head trial of TN-OGD vs C-OGD in a UK cohort. <h3>Methods</h3> Evaluation of patient experience, feasibility, safety and diagnostic capability of TN-OGD as compared to C-OGD in a UK setting. 200 patients fulfilling the study criteria were randomised to TN-OGD or C-OGD. Standard (10 cm) visual analogue scales (VAS) and Likert (5 point) scales were used. Patient safety was assessed by recording vital parameters during and post-procedure. Doses of sedation and topical anaesthetic, duration of patient preparation and procedure and recovery times were documented. Endoscopic views of each procedure were digitally recorded for evaluation of diagnostic capability by a panel of expert endoscopists. <h3>Results</h3> The final analyses of data from SCENT demonstrate significant differences between TN-OGD (n=94) and C-OGD (n=106) groups. VAS scores for overall patient discomfort (higher score = greater discomfort) were significantly lower in the TN-OGD group compared to the C-OGD group (1.8 vs 4.0, respectively, p&lt;0.001). VAS discomfort scores for TN-OGD were also significantly lower than VAS scores for C-OGD done with a slim endoscope (1.9 vs 3.2, respectively, p=0.001). Mean patient preparation time was longer for TN-OGD than for C-OGD (5.5 vs 4.6 min, respectively, p&lt;0.001). Procedure duration was also longer for TN-OGD than for C-OGD (10.0 vs 7.0 min, respectively, p=0.004) but recovery times after TN-OGD compared to C-OGD were significantly shorter (5.0 vs 10.0 min, respectively, p&lt;0.001). There was no significant difference between the overall diagnostic capability VAS for TN-OGD and C-OGD scores (8.9 vs 9.1, respectively, p=0.47). <h3>Conclusion</h3> The final analysis of SCENT supports the findings of previously reported studies and suggests that TN-OGD is feasible, more comfortable for patients than C-OGD, avoids the need for sedation and reduces recovery time. The results also suggest that it is the TN route and not just the endoscope diameter that makes the procedure more comfortable for patients.
253. Expanded Packaging Capacity of AAV by Lumenal Charge Alteration
Authors: Matthew Tiffany, Mark A. Kay
Journal: Molecular Therapy (2016)

Adeno-associated virus (AAV) is widely believed to be the safest viral vector for gene therapy. Moreover, the array of AAV serotypes available allows transduction of different tissues in vivo. However, one major limitation of AAV is the relatively small DNA packaging size (4,700 nt). Existing serotypes have been over-packaged with limited success and varying reproducibility. The consensus appears to be that AAV can be over packaged by ~10%, but with a concomitant reduction in both viral titers and in vivo transduction. We have taken a novel approach to increase the packaging limitations of AAV by focusing on the lumen of AAV where vector DNA interacts with the capsid. We have created a series of AAV capsid variants that alter the capsid lumenal charge using AAV-DJ as the scaffold. The variants add positively charged lysine and arginine residues at lumenally exposed sites within the capsid that, we believe, may allow for interaction and condensation of vector DNA increasing the packaging capacity and/or stabilizing the capsid in an over-packaged state. We present in vitro characterization of the library of capsid variants and demonstrate that variants with intermediate charge (+4 to +7 over wildtype) can be produced at high titer when over-packaged up to 6.2 kb. In addition, these variants can transduce HEK293 cells with a 5.6 kb length vector better than wildtype. Finally, these variants can completely encapsidate at least a 5.4 kb vector by alkaline Southern blot. To validate that these new vectors are functional, we establish that a subset of these vectors are still able to transduce mouse liver in vivo. We are currently establishing the relative transduction efficiencies using standard length and expanded genome sizes in order to establish the maximal DNA length that can be functionally packaged by these new vectors. We believe our capsid alteration strategy can be extrapolated to other serotypes with distinct tissue tropism and applied in vivo to treat hemophilia A and other monogenic disorders suitable to replacement therapy.
Abstract 757: Genetic Association of the Serotonin Transporter and the Bone Morphogenetic Protein Receptor-2 in Pulmonary Arterial Hypertension
Authors: Keiko Yamauchi-Takihara, Shoko Sugiyama, Hisao Hirota, Mitsuru Masaki, Tadashi Kuroda, Yoshimune Hiramoto, Masatsugu Hori
Journal: Circulation (2006)

Background: Mutations in the bone morphogenetic protein receptor-2 (BMPR-2) gene have been found in patients with pulmonary arterial hypertension (PAH). However, the low disease penetrance suggests that other factors are necessary to manifest the disease. Recently, the 5-HT transporter (5-HTT) polymorphism has been also reported to associate with PAH, although this association has recently been challenged. Compared with the short (S) allele, the long (L) 5-HTT promoter allele is known to associate with increased 5-HTT transcription and more prevalent in PAH compared with control subjects. To investigate whether 5-HTT gene polymorphism affect clinical condition in PAH patients, we examined 5-HTT polymorphism and BMPR-2 mutations in patients with idiopathic (IPAH) and connective tissue disease-associated PAH (CPAH).

Methods and Results: Mutations in the 13 exons from the BMPR-2 gene and L and S allelic variant of the 5-HTT gene promoter in 12 IPAH and 10 CPAH patients were determined. Clinical severity was evaluated by pulmonary arterial pressure (PAP) by Doppler echocardiography and plasma BNP level. Twenty-three subjects were served as control (LS genotype 4%, SS genotype 96%). Distribution of the LL, LS and SS genotypes were 0, 36 and 64% in PAH. There was no significant difference in the distribution of the genotypes between IPAH and CPAH. Moreover, there was no significant difference in systolic PAP and BNP with the LS and SS genotypes either in IPAH (PAP: 83.8 mmHg vs 81.3 mmHg, BNP: 176.6 pg/ml vs 324.2 pg/ml) or CPAH (PAP: 77.0 mmHg vs 67.5 mmHg, BNP: 245.2 pg/ml vs 308.5 pg/ml). Although BMPR-2 mutation was not detected in patients with CPAH, 50% patients presented BMPR-2 mutation in IPAH. The distribution of LS and SS genotypes in IPAH patients were 67% and 33% with BMPR-2 mutation and 17% and 83% without mutation.

Conclusion: These data suggests that 5-HTT regulatory region polymorphism does not associate with clinical severity of PAH. BMPR-2 mutation was found only in IPAH, and the patients with BMPR-2 mutation associate with the LS genotype with high frequency. There might be a possible relationship between the BMPR-2 mutation and the L allelic variant of the 5-HTT gene in the genetic determinant of disease susceptibility.
Final report of a phase I evaluation of TNFerade biologic plus chemoradiotherapy prior to esophagectomy for locally advanced resectable esophageal cancer.
Authors: H. Pinto, K. J. Chang, T. R. Reid, N. N. Senzer, S. Swisher, N. Hanna, A. Chak, R. Soetikno
Journal: Journal of Clinical Oncology (2011)

e13610 Background: Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human TNF-α gene, with chemoradiotherapy in locally advanced esophagus cancer. Methods: The primary endpoints were safety, feasibility, tolerability and the rate of complete pathologic response (pCR). The secondary endpoints were disease free (DFS), and overall survival (OS). The study enrolled adults with stage II and III esophagus cancer, and KPS ≥ 70. Five weekly intratumoral injections of TNFerade dose-escalated at 4 X 108, 4 X 109, 4 X 1010, or 4 X 1011 p.f.u. were given in combination with cisplatin 75 mg/m2 on day 1 and 29 and intravenous 5-FU 1,000 mg/m2/day for 96 hours day 1 and 29 and concurrent RT to 45Gy. Surgery was performed between weeks 9 and 15. Results: 24 patients were enrolled, the median age was 62; 88% were male, 21% stage II and 79% stage III. Dose-limiting toxicity was not observed. At the top dose of 4x1011pu, 4/8 patients developed thromboembolic events. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). Esophagectomy was performed in 20/24 patients (83%). Six (29%) demonstrated a pathological complete response (pCR). At a median follow-up of 42.9 months 3- and 5-year DFS were 57% and 52%, and OS was 54% and 41%. Conclusions: Preoperative TNFerade, in combination with chemoradiation is active and safe at doses up to 4x1010pu and is associated with long survival. This regimen warrants additional study.
MRI and 18F-FDG PET/CT of Laryngeal Cartilaginous Tumor
Authors: Junichi Nakagawa, Osamu Manabe, Takatsugu Mizumachi, Hiromi Kanno-Okada, Kanako C Hatanaka, Tomoko Mitsuhashi, Noriko Oyama-Manabe, Kenji Hirata, Nagara Tamaki
Journal: Clinical Nuclear Medicine (2016)

Cartilaginous tumors of the larynx are uncommon neoplasms that sometimes mimic laryngeal cancers. There has been no report of 18F-FDG PET/CT for the evaluation of laryngeal cartilaginous tumors. We reported 3 cases of laryngeal cartilaginous tumors with the image findings, including CT, FDG PET/CT, and MRI and reviewed literatures. We concluded that the combination of a very high-signal mass on T2-weighted magnetic resonance images and lower FDG uptake might be diagnostic image characteristics for distinguishing laryngeal cartilaginous tumor from laryngeal cancer.
91. Identification and Mutagenesis of the AAV5 Sialic Acid Binding Region
Authors: Sandra Afione, Michael A. DiMattia, Sujata Halder, Giovanni Di Pasquale, Mavis Agbandje-McKenna, John Chiorini
Journal: Molecular Therapy (2015)

As a genus, the dependoviruses use a diverse group of cell surface carbohydrates for attachment and entry. Despite the fact that a majority of AAVs utilize sialic acid (SIA) for binding and transduction, this virus:carbohydrate interaction is poorly understood. Utilizing X-ray crystallography, two SIA binding regions were mapped for AAV5. The first site mapped to the depression in the center of the threefold axis of symmetry, while the second site was located under the HI loop close to the fivefold axis. Mutagenesis of amino acids 569 and 585 or 587 within the threefold depression resulted in elimination or alteration in SIA dependent transduction, respectively. This change in SIA binding was confirmed using glycan microarrays. Mutagenesis of the second site identified a role in transduction that was SIA independent. Further studies of the mutants at the threefold site demonstrated a change in transduction activity and cell tropism in vivo as well as resistance to neutralization by a polycloncal antibody raised against the wild type virus.
Abstract 5389: Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation
Authors: Soon-Sun Hong, Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Zhenghuan Fang, Joo Han Lim, Jeong Seon Ryu
Journal: Cancer Research (2015)

Abstract Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathways in a dose dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing the expression of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients. Citation Format: Soon-Sun Hong, Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Zhenghuan Fang, Joo Han Lim, Jeong Seon Ryu. Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation. [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 5389. doi:10.1158/1538-7445.AM2015-5389
The Histone Deacetylase Inhibitor MGCD0103 Down Regulates CD30, Activates NF-Kb, and Synergizes with Proteasome Inhibitors by HDAC6 Independent Mechanism in Hodgkin Lymphoma.
Authors: Daniela Buglio, Vidya Mamidipudi, Noor M Khaskhely, Annunziata Gloghini, Antonino Carbone, Carla Heise, Jeffrey M. Besterman, Robert E Martell, Kyle J MacBeth, Anas Younes
Journal: Blood (2009)
Abstract 2324: The histone acetyltransferase inhibitor CPTH6 selectively targets lung cancer stem-like cells
Authors: Marta Di Martile, Mariannna Desideri, Teresa De Luca, Chiara Gabellini, Adriana Eramo, Michele Milella, Daniela Secci, Simone Carradori, Simona Buglioni, Donatella Del Bufalo, Daniela Trisciuoglio
Journal: Cancer Research (2015)

Abstract Targeting epigenetic regulators is emerging as a promising strategy for cancer therapy. In this context, we recently identified the thiazole derivative 3-methylcyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) as a novel pCAF and GCN5 histone acetyltransferase inhibitor. CPTH6 exerts in vitro anti-tumoral effect in a panel of human tumor cell lines derived from different histotypes. In this study, we evaluated the efficacy of CPTH6 as a novel drug that targets Lung Cancer Stem-like Cells (LCSC) derived from non-small cell lung cancer (NSCLC) patients. We found that CPTH6 has a stronger growth-inhibitory effect in patient-derived LCSC than in established NSCLC lines. Unlike LCSC models, in which CPTH6 treatment induces cell cycle perturbation and apoptosis even at low doses, in established NSCLC lines CPTH6 triggers a cell cycle perturbation associated to DNA damage only at higher concentrations. Of note, differentiated progeny of LCSC lines are more resistant to CPTH6 cytoxicity when compared to their undifferentiated counterparts. Interestingly, CPTH6 treatment is also associated with reduced expression of the CD133 stemness marker in LCSC lines. Analysis of the CD133+ subpopulation in LCSC lines indicates that CD133+ cells not only undergo apoptosis following CPTH6 treatment but also shift toward a more differentiated phenotype. Furthermore, the growth inhibitory effect seems to be tightly related to baseline expression of acetylated alpha-tubulin, which was particularly prominent in sensitive LCSC lines. In vivo experiments confirmes the antitumor efficacy of CPTH6, particularly in LCSC-derived models, where a pronounced apoptosis induction and growth inhibitory effect is observed after CPTH6 treatment. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC. Citation Format: Marta Di Martile, Mariannna Desideri, Teresa De Luca, Chiara Gabellini, Adriana Eramo, Michele Milella, Daniela Secci, Simone Carradori, Simona Buglioni, Donatella Del Bufalo, Daniela Trisciuoglio. The histone acetyltransferase inhibitor CPTH6 selectively targets lung cancer stem-like 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 2324. doi:10.1158/1538-7445.AM2015-2324
Stereotactic body radiotherapy for pulmonary oligometastases with emphasis on the difference in oligometastatic state
Authors: Yuzuru Niibe, Hideomi Yamashita, Takaya Yamamoto, Kuniaki Katsui, Keiichi Nakagawa, Susumu Kanazawa, Jiro Kawamori, Wataru Takahashi, Atsuro Terahara, Keiichi Jingu
Journal: Annals of Oncology (2015)
Improved Early Outcomes with T-Cell Replete (TCR) Compared with T-Cell Depleted (TCD) Haploidentical Stem Cell Transplantation (HaploSCT)
Authors: Stefan O Ciurea, Rima M. Saliba, Ulas D. Bayraktar, Susan Xie, Gabriela Rondon, Simrit Parmar, Partow Kebriaei, Nivia Montes, Manish Sharma, Marina Konopleva, Yago Nieto, Muzaffar H. Qazilbash, Amin M Alousi, Borje S Andersson, Chitra M Hosing, Elizabeth J Shpall, Issa F. Khouri, Marcos de Lima, Richard Champlin
Journal: Blood (2011)